Anxiety and depression in people with acquired brain

injury
Citation for published version (APA):

Rauwenhoff, J. C. C. (2022). Anxiety and depression in people with acquired brain injury: Acceptance and
Commitment Therapy as a possible intervention. [Doctoral Thesis, Maastricht University]. Maastricht
University. https://doi.org/10.26481/dis.20221130jr

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Anxiety and depression in people
with acquired brain injury
Acceptance and Commitment Therapy
as a possible intervention

Johanne Rauwenhoff
Anxiety and depression in people with acquired brain injury
Acceptance and Commitment Therapy as a possible intervention

Johanne Rauwenhoff
The research described in this thesis was performed at the Department of Psychiatry and Neuropsychology,
School for Mental Health and Neuroscience, Maastricht University, Limburg Brain Injury Centre, the
Netherlands, and was financially supported by ZonMw.

Printing of this thesis was kindly supported by Maastricht University.

Cover Design Schilderij van de Hoge Fronten gemaakt door Emmy Mevissen
Lay-out Publiss | www.publiss.nl
Printing Ridderprint | www.ridderprint.nl
ISBN 978-94-6458-697-8

© Copyright Johanne Rauwenhoff, Maastricht, the Netherlands (2022)

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, by photocopying, recording, or otherwise, without the
prior written permission of the author.
Anxiety and depression in people with acquired brain injury
Acceptance and Commitment Therapy as a possible intervention

PROEFSCHRIFT

Ter verkrijging van de graad van doctor aan de Universiteit Maastricht,

op gezag van de Rector Magnificus, Prof. dr. Pamela Habibović,
volgens het besluit van het College van Decanen,
in het openbaar te verdedigen
op 30 november 2022 om 13.00 uur

door

Johanne Catharina Charlotte Rauwenhoff

geboren op 28 november 1993 te Leicester

Promotores
Prof. dr. Caroline M. van Heugten
Prof. dr. Frenk Peeters

Copromotor
Dr. Yvonne Bol (Zuyderland Medisch Centrum)

Beoordelingscommissie
Prof. dr. Marleen M. Rijkeboer (voorzitter)
Prof. dr. Koen R.J. Schruers
Dr. Diane L. Whiting (Ingham Institute for Applied Medical Research)
Dr. Dirk Bertens (Radboud Universiteit)
CONTENTS

Chapter 1 General introduction 9

Chapter 2 Personalized predictions of treatment outcome in patients with post-stroke 23

depressive symptoms
Journal of Rehabilitation Medicine, 2020

Chapter 3 Measuring psychological flexibility and cognitive defusion in individuals with 43

acquired brain injury
Brain Injury, 2021

Chapter 4 Acceptance and Commitment Therapy for people with acquired brain injury: 57
rationale and description of the BrainACT treatment
Under revision

Chapter 5 Acceptance and Commitment Therapy for individuals with depressive and 73
anxiety symptoms following acquired brain injury: a non-concurrent multiple
baseline design across four cases
Neuropsychological rehabilitation, 2022

Chapter 6 The BrainACT study: Acceptance and Commitment Therapy for depressive 103
and anxiety symptoms following acquired brain injury: study protocol for a
randomized controlled trial
Trials, 2019

Chapter 7 Acceptance and Commitment Therapy is feasible for people with acquired 121
brain injury: a process evaluation of the BrainACT treatment
Submitted

Chapter 8 General discussion 141

Addendum 159
kom gaan we rijden, pijn doet het toch wel
waar je ook bent

Uit het lied Soms breekt er een hart, soms blaft er een hond van Spinvis
CHAPTER 1
General introduction
Chapter 1

Anxiety and depressive symptoms following acquired brain injury

An acquired brain injury (ABI) can be defined as damage to the brain that occurs after birth and is not related
to congenital disorders, developmental disabilities, or processes that progressively damage the brain (1).
The National Institute for Public Health and the Environment estimated that approximately 650.000 people
live with the consequences of an ABI in the Netherlands (2). An ABI can have different causes of which the
most common are a stroke (caused by blood leakage in the brain or when blood supply is blocked) and
trauma (caused by a fall or accident). Other causes can be hypoxia (due to for instance a heart attack) or a
brain tumour. When ABI is mentioned in this thesis, it refers to traumatic brain injury (TBI) or brain injury
caused by a stroke. An ABI can lead to a wide variety of consequences. People can experience physical
consequences, such as (one sided) paralysis, muscle weakness, or changed sensory sensations. However, ABI
can also lead to non-physical, ‘invisible’ consequences. These include fatigue, cognitive impairments such as
memory, attention, and executive difficulties, and behavioural changes such as impulsivity, aggression, and
irritability (5, 6).
People with ABI are at an increased risk of developing anxiety and depressive symptoms (7-9). The
prevalence rates for anxiety symptoms following TBI vary from 21 to 37% and for depressive symptoms from
30 to 43% (10-13). The prevalence rates for anxiety symptoms following stroke vary from 20 to 29% and for
depressive symptoms from 29 to 33% (8, 14-17). The varying prevalence rates are likely due to differences in
study populations, time since injury, and outcomes used. Besides, depressive and anxiety symptoms often
co-occur (8). The trajectories of these symptoms can vary. In the year following the ABI, symptoms can stay
constant, increase, or decrease (18).
The pathophysiology of anxiety and depressive symptoms post-ABI is not yet clearly understood.
However, it seems likely that there is a complex and multifactorial interplay between biological, psychological,
and social processes, possibly depending on the time since injury. Possible biological mechanisms are related
to oxidative stress, lipids, and inflammation (19-21). The results of studies on the potential association
between lesion location, TBI severity, and anxiety and depressive symptoms are inconclusive (16, 22-24).
Next to biological mechanisms, several psychological factors likely play a role in the development of ABI-
related anxiety and depressive symptoms. An ABI is a life-changing event; people have to cope with a new
way of life and are faced with many forms of loss. Feelings of grief often follow loss. People suffer from
alterations or losses in health, independence, occupation, social roles, and social contacts. Furthermore,
people with ABI can experience a loss regarding the subjective experience of who they are, their own
identity or self. Their present self is often viewed negatively in comparison with the pre-injury self (25,
26). Previous studies have found that changes in self-identity are related to higher levels of depression and
grief (26, 27). Additionally, various psychosocial risk factors for the development of ABI-related anxiety and
depressive complaints have been identified. These include psychiatric history, neurotic personality traits,
an avoidant coping style, impaired social functioning, and social isolation (28-31). Other general risk factors
are sleep difficulties, gender, age, time since injury, cognitive and functional impairments, and insufficient
rehabilitation (7, 22, 30). How these psychological and biological processes relate to each other is unclear.

10
 General introduction

However, Fang and Cheng (32) proposed that the biological mechanisms might be more prominent in the
acute period following the stroke, whereas psychological and environmental factors start playing a more 1
important role over time. This is likely comparable for other forms of ABI.
Anxiety and depressive symptoms can have a large impact on the well-being of patients with ABI and
are negatively associated with quality of life (33, 34). Moreover, anxiety and depressive symptoms can lead to
increased caregiver burden (35) and are associated with higher hospitalization costs and mortality (30, 36).

Treatment of anxiety and depressive symptoms

Given their high prevalence and large impact on the lives of people with ABI, it is important to develop
evidence-based prevention and treatment options for anxiety and depressive symptoms post-ABI.
Unfortunately, it remains unclear what optimal strategies are for prevention and treatment (37). A Cochrane
review concluded that the evidence-base for pharmacological interventions for post-stroke depressive
symptoms was weak and stroke-survivors receiving a pharmacological intervention experienced more
adverse events compared to placebo (38). Furthermore, pharmacological interventions do not offer people
approaches on how to cope with the consequences of an ABI. Given the fact that psychological interventions
have no neurological side effects, they might be preferred for people with ABI. However, several meta-
analyses have concluded that the effect of psychotherapies is uncertain for people with ABI, with some
reporting an effect that did not sustain at follow-up or rather small effect sizes (38-42). Most of these studies,
furthermore, mentioned that there is a need for more high-quality studies investigating psychotherapies for
ABI-related anxiety and depressive symptoms.
Next to deciding whether treatments are likely effective, it is important to know what the right
treatment is for a particular patient, as there is individual variability in the effectiveness of psychotherapy
(43). Currently, it is difficult for clinicians to decide what treatment option is most suitable or effective for a
certain patient (44). It is therefore not clear what works for whom and models to predict treatment outcomes
are lacking. New statistical analyses permit the development of prediction models utilizing machine learning
techniques (45). These techniques are increasingly being used in the depression research field (46, 47), while
applications to predict the outcome of psychotherapy for depressive symptoms following ABI are lacking.
In this thesis, it was investigated how to optimize the treatment of depressive symptoms by developing
a clinical prediction tool for post-stroke depressive symptoms. Furthermore, we investigated if Acceptance
and Commitment Therapy (ACT) would be a possible intervention for people with ABI-related anxiety and
depressive symptoms.

Acceptance and Commitment Therapy for people with acquired brain injury
An approach which may form an interesting perspective on how to treat patients with ABI-related anxiety
and depressive symptoms is ACT (48, 49). Below the philosophical and theoretical underpinnings of ACT are
explored, next to the applicability of ACT for people with ABI, and the evidence-base of ACT.

11
Chapter 1

Theoretical foundations of Acceptance and Commitment Therapy

The philosophical view behind ACT is functional contextualism. The goal of functional contextualism is to
predict and influence behaviour, accurately and effectively, using empirically supported principles. Events
are viewed as ongoing actions; an act is always placed within a situational and historical context (50).
From this point of view, thoughts, feelings, or memories are inherently not problematic, dysfunctional, or
pathological. Therefore, merely analysing the behavioural symptoms, outside of the context in which the
behaviour occurs, is thought to miss the essence of the problem and ways to reach a solution (51). The truth
criterion of functional contextualism is ‘successful working’. This means working towards an explicitly stated
behavioural goal, which has value or importance and is defined preceding the analysis (52).
The theoretical base of ACT is the relational frame theory (RFT), which is a behavioural model of
language and cognition and builds upon operant learning theory (3, 53). It explains the concept of relational
framing, which share three common properties; mutual entailment, combinatorial mutual entailment, and
transformation of stimulus functions. Box 1 below illustrates these properties with an example.

Box 1. Mutual entailment, combinatorial mutual entailment, transformation of stimulus functions, and Pom

In the first corona lockdown, my partner and I adopted Pom. Pom is a dog. I just trained you in the relation between ‘Pom’
→ ‘Dog’. If I now start to talk about my dog, you will assume this is Pom, while this association is not trained. This derived
relation is called mutual entailment. We train one relation (‘Pom’ → ‘Dog’) between stimuli, and another relation (‘Dog’
→ ‘Pom’) is entailed. You might feel this is obvious. It probably is obvious because this is something we (humans) are
constantly doing and feels natural to us. Previous studies, however, have not convincingly shown that other species have
this ability (3, 4). This summer we went to Italy and there a dog is called cane. When I now present you with the word
‘Pom’ and several Italian words such as ‘fiore’, ‘cane’, and ‘libro’, which word would you choose in relation to ‘Pom’? Most
likely you chose ‘cane’. Assuming you do not speak Italian, a relation was derived between ‘Pom’ and ‘cane’, although they
are not in a directly trained mutual relation. This derived relation is called combinatorial mutual entailment. The derived
relations through mutual entailment and combinatorial mutual entailment can be seen in figure 1.

Figure 1. Mutual entailment and derived mutual entailment

These derived relations can include much more than three stimuli and there are multiple types of relations; causal
relations (if/then), temporal relations (before/after), perspective (I/you/them), and so on. Moreover, most stimuli
have various functions, based on the characteristics of the stimulus, previously established relations, and earlier
history of relational framing of the individual. Now imagine that you had a very bad experience with a dog in the
past and developed a fear of dogs. Me talking about Pom might therefore elicit a fear reaction, despite that you have
never encountered a ‘Pom’ before. This is called transformation of stimulus function. The function of ‘Pom’ (formally
presumably a quite neutral stimulus) was altered by the derived relation with ‘dog’. The function of a stimulus can be
transferred to another stimulus in the same network.

12
 General introduction

Due to relational framing humans can relate any sort of stimulus to another related stimulus and develop
complex, uncontrollable, verbal networks of relations, called relational frames (3). Relational framing 1
improves our ability to learn and take perspectives, which leads to the experience of self, and it can lead to
rule-governed behaviour. Antecedents can lead to rule-governed behaviour, by functioning as an instruction
or rule, without an actual intervention or contingency (54). For instance, the rule ‘don’t put your hand in an
electrical socket or you will get electrocuted’ can shape your behaviour without directly experiencing the
contingency (actually being electrocuted by putting your hand in a socket). While rule-governed behaviour
gives us the ability to behave flexibly, it can also have highly negative consequences. Humans form rules on
how to behave and live meaningful and good lives. We are often fused with our own language and tend to
take our own thoughts very seriously. When private events obtain negative functions, we try to control or
avoid them, which is called experiential avoidance (3).
For example: a man, who survived a stroke, lost his job due to the consequences of the stroke. He
finds this very painful since he always had the belief ‘my job gives me purpose’. He starts to avoid things
that remind him of his former job, as these make him feel sad and frustrated. He no longer talks to his ex-
colleagues, avoids coming near his old office building, and eventually stops reading the newspaper afraid to
read something that reminds him of his old job.
The avoidance of emotions, thoughts, and bodily sensations can be rewarding in the short term,
however, in the long term, this will often be counterproductive. Given the nature of relational framing,
thoughts and self-rules are difficult to change. ACT tries to decrease the influence of the verbal content of
cognition that can cause avoidant behaviour and dismantle ineffective rule-governed behaviours (51).

The psychological flexibility model

ACT is a third-wave cognitive behavioural therapy and given its pragmatic nature, the outcome of an
intervention is always related to valued behaviour as opposed to symptom reduction. The main treatment
aim of ACT is an increase in psychological flexibility (48), which is described as “the ability to contact the
present moment more fully as a conscious human being and to change, or persist in, behaviour when doing
so serves valued ends” (51). Psychological flexibility is established through the six core components of ACT:
acceptance, cognitive defusion, self-as-context, mindfulness, values, and committed action. These core
processes both overlap and interact with each other (55) as illustrated in figure 2. Patients are familiarized
with these six core components using experiential therapeutic processes. Experiential exercises, behavioural
change processes, and metaphors are used. Metaphors let the patient view their situation from a different
perspective and facilitate a transfer of functions from one network to another (49). As a result, the abstract
becomes concrete and implicit memory resources are engaged to support learning (56). In the remainder of
this paragraph the core components of ACT will be further explained and discussed in the context of their
potential therapeutic applicability for people with ABI.

13
Chapter 1

Figure 2. The psychological flexibility model

Acceptance. ACT therapists will explore the different (ineffective) control strategies that their patients have
used so far to avoid and control negative thoughts, feelings, or sensations. ACT suggests acceptance as an
alternative approach to dealing with these phenomena. Acceptance is tolerating negative and positive
thoughts and feelings related to events or circumstances that cannot be changed or one has no control over
(51). For patients with ABI, this would imply accepting thoughts associated with the ABI and its consequences.
For instance, patients are encouraged to make contact with feelings of pain or loss instead of avoiding them.
In neuropsychological rehabilitation, acceptance is an important concept in the recovery of patients with ABI.
Ben-Yishay and Diller (57) wrote in their handbook on holistic neuropsychological rehabilitation: “Acceptance
of limitations is not so much an act of passive ‘surrender’ or defeat, but rather it is the result of an active
process of psychological transformation, leading to the recognition that, despite limitations, one can find
meaningful alternatives worth living for” (page 132). Furthermore, acceptance has been associated with better
psychological outcomes and positive experiences of self-identity following ABI (58, 59).
Cognitive Defusion. Instead of altering the content, form, or frequency of thoughts, as is done in
traditional cognitive therapies, ACT focuses on the function of thoughts. Patients are asked to perceive
their thoughts more mindfully and to detach from these thoughts (49). This likely decreases the influence
of relational frames and self-rules on behaviour. Therefore, implying that not the content of the brain injury-
related thoughts but the response to these thoughts is the problem. The thought “I am not going to that
party because I cannot follow the conversation” is not attacked in its validity or negativity but in its avoidant
content. Cognitive defusion is likely a more suitable process for patients with cognitive deficits as opposed
to cognitive restructuring techniques. For example, there is no need to detect thoughts and keep them in
mind while looking for positive alternatives, which can be quite a cognitively demanding process. Furthermore,
following a life-changing event, such as ABI, patients might have quite realistic worries and thoughts given the
situation. Challenging these thoughts might therefore work counterproductive for the adaptation process (60).
Self-as-context. According to RFT, there are three senses of self. Firstly, the conceptualized self (self-
as-content) entails the thoughts, social roles, and the image humans relate to and of themselves. We often

14
 General introduction

behave in accordance with our conceptualized self. Secondly, the experiential self (self-as-process) is the
verbal awareness of ongoing psychological experiences and the ability to describe thoughts, feelings, and 1
senses in light of the external context (49), for instance, “I feel energetic now”. Thirdly, the observing self
(self-as-context) is a sense of perspective and a point of view that is unique. Being in contact with the
observing self is seen as beneficial and associated with increased psychological flexibility. However, often
the conceptualized self overshadows the observing self. As described above people with ABI can experience
negative changes in self-identity. Myles (61) describes how an ABI can lead to a crisis in the conceptualized
self as people might not be able to keep up with the thoughts, social roles, and images they have of
themselves. This crisis in the conceptualized self often leads to emotional distress as patients might try to
protect or sustain the pre-injury conceptualized self. Denial of injury-related changes can be seen as a coping
mechanism to avoid emotional distress, though this is not sustainable in the long term (61). Moreover, it is
also imaginable that a person with ABI becomes very fused with the idea of being an ABI-patient and that a
large part of their identity is related to the ABI and its consequences.
During an ACT intervention, patients loosen their identification with the conceptualized self and increase
contact with the observing self (49). This can lead to flexible and value-driven behaviour, rather than acting to
keep up or protect the pre-injury conceptualized self. From the perspective of the observing self, patients can
accept the post-injury changes (61) and experience that the story of the ABI is one of their stories.
Mindfulness. Mindfulness means being present in the moment and having full, non-judgemental
attention to the here and now. Paying attention in this particular way will help to accept the reality of the
present moment (62). During an ACT intervention, having attention to the present moment is trained with
the help of mindfulness exercises. Mindfulness conforms with cognitive strategies such as doing activities
or tasks with attention and just one at a time (63). Mindfulness has become increasingly popular and
much research has been done on its effectiveness. Lawrence et al. (64) conducted a systematic review and
concluded that mindfulness-based interventions can have a positive effect on anxiety, depression, fatigue,
and quality of life in stroke survivors. Furthermore, mindfulness-based interventions have been found
beneficial for people with different psychiatric diagnoses and multiple sclerosis (65, 66).
Values. Value exploration and clarification are an important part of ACT. During this process, the patient
might be asked to identify values within different life domains such as family, health, and spirituality (51).
Values and goals are closely related but are not the same. Goals can be completed. Values, on the contrary,
can be used as an “inner compass”, guiding choice-making and goal-setting. Consequently, personal values
can guide goal setting during rehabilitation. Limitations as a consequence of the ABI might prevent returning
to the pre-injury lifestyle and activities. Whereas inquiry into values may help people to find new ways of
living. Furthermore, people with a chronic illness can be quite narrowly focused on their illness. Thinking about
values can help to take a step back and look at life from a broader perspective. Pais et al. (68) investigated the
role of valued living on psychological and functional outcomes in patients with a TBI. They found that valued
living was strongly related to functional outcome, positive outlook, and reduced depressive symptomatology.
Furthermore, valued living has been found to be related to enhanced well-being and post-traumatic growth
and negatively related to distress and post-traumatic stress symptoms in people with ABI (69).

15
Chapter 1

Committed action. Once the patient has set their values, the next step is to commit to these values.
To achieve behavioural change, ACT uses various techniques which stem from traditional behavioural
therapies (51). These can include exposure and setting small, achievable goals. Traditionally goal setting
is an essential component of neuropsychological rehabilitation (5). For instance, a patient can be narrowly
focused on returning to work and as difficulties arise, the patient might struggle with coming to terms with
the realization that returning to work might not be possible. Following the value exploration, the patient
realizes that one of the core values behind their focus on going back to work is to contribute to society. The
first step to living by this value could be to search for charity organizations that are looking for volunteers.
Therapists can aid in formulating goals and help with finding creative ways for to engage in valued driven
behaviour while keeping in mind cognitive and physical impairments.

Evidence for ACT

Several meta-analyses have been conducted showing that ACT can be an effective treatment for anxiety and
depressive symptoms, addiction, obsessive-compulsive disorder, and schizophrenia (70-72). Moreover, ACT
is effective for people with various chronic health conditions and related mood complaints such as chronic
pain and multiple sclerosis (66, 73).
At the start of this PhD trajectory, there was little evidence for the effectiveness of ACT for people with
ABI-related mood symptoms. Kangas and McDonald (74) had published an article describing that ACT could be
an interesting treatment option for people with ABI-related depression symptoms and Soo et al. (75) did this for
ABI-related anxiety symptoms. Furthermore, Graham et al. (76) performed a case study in which a man with post-
stroke depressive symptoms and medically unexplained symptoms benefited from an ACT intervention. Besides,
Whiting (77) described the results of a pilot RCT in which they compared ACT (n = 10) to befriending therapy
(n = 9) for people with severe TBI and psychological distress. The study had a follow-up period of one month.
Despite the small sample size, a significant greater reduction in depressive and stress symptoms was found in
the ACT group compared to the control group. However, no significant differences were found regarding ACT
related processes such as psychological flexibility. Additionally, they described two cases who received ACT in
a dyad. A therapeutic effect was found for one participant and the ACT intervention was acceptable to both
participants (78, 79). Since then, the evidence-base of ACT for people with ABI has grown rapidly. Sander et
al. (80) conducted a RCT comparing ACT (n = 49) to devised usual care (n = 49; this consisted of a referral to a
psychological service, however, it is unclear whether participants received care) in a sample of people with a TBI.
The study had a follow-up period of three months. They found a significantly greater reduction in depressive
symptoms and a significant increase in psychological flexibility in the ACT group compared to the control group.
Majumdar and Morris (81) conducted an RCT investigating the effectiveness of a didactic ACT group intervention
(n = 26) for stroke survivors compared to treatment as usual (n = 27). The study had a follow-up period of two
months. Significant improvements were found in depression, self-rated health status, and hopefulness. These
studies have shown promising results. Nevertheless, they also concluded that more and larger scale studies with
longer follow-up time and active control interventions are needed to confirm these findings.

16
 General introduction

This thesis
Currently, it is not known how to best treat anxiety and depressive symptoms following ABI. There is a
1
clear need to improve the care of people with ABI-related anxiety and depressive symptoms. To optimize
treatment selection, we investigated if it was possible to develop a clinical prediction tool for post-stroke
depressive symptoms. Additionally, we investigated a novel treatment option for people experiencing ABI-
related anxiety and depressive symptoms. Philosophically and theoretically, ACT seems a fitting treatment
option for people with ABI who experience anxiety and depressive symptoms. We started by investigating
how to measure psychological flexibility and cognitive defusion in people with ABI. Hereafter, we developed
the BrainACT treatment, an ACT treatment adapted for the needs and possible cognitive deficits of people
with ABI. We consequently tested the effectiveness of the BrainACT intervention and examined its feasibility.
The outline of the thesis is as follows:

Can we predict the outcome of an intervention for post-stroke depressive symptoms?

In chapter 2 we developed a prognostic index model for treatment outcome in patients with post-stroke
depressive symptoms who received cognitive behavioural therapy or computerized cognitive training.

How to measure cognitive defusion and psychological flexibility in people with ABI?

In order to measure the effect of the BrainACT treatment, we investigated the validity of the Dutch versions
of the Acceptance and Action Questionnaire for Acquired Brain Injury (AAQ-ABI; measuring psychological
flexibility related to thoughts and feelings about ABI) and the Cognitive Fusion Questionnaire (CFQ-7;
measuring cognitive defusion) in a population of people with ABI in Chapter 3.

How to adapt ACT for people with ABI?

In chapter 4, the rationale and description of the BrainACT treatment protocol are presented. This is an ACT
treatment adjusted to possible cognitive deficits and needs of people with ABI.

Is ACT effective and feasible for people with ABI?

In chapter 5 we investigated the effectiveness of the BrainACT treatment in four people with ABI-related
anxiety and/or depressive complaints using a single case experimental design. We described the protocol of
the BrainACT randomized controlled trial in chapter 6, and in chapter 7 we performed a process evaluation
of the BrainACT treatment in order to investigate the feasibility of ACT for people with ABI.
In the final chapter, all results are integrated and discussed, clinical implications are provided, and
recommendations are made for future directions.

17
Chapter 1

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Clinical Psychology. 2019;58(1):70-90.

21
CHAPTER 2
Personalized predictions of treatment outcome in
patients with post-stroke depressive symptoms

Johanne C.C. Rauwenhoff

Suzanne C. van Bronswijk
Frenk Peeters
Yvonne Bol
Alexander C.H. Geurts
Caroline M. van Heugten

Journal of Rehabilitation Medicine, 2020

Chapter 2

Abstract
Objective. Post-stroke depressive symptoms (PSDS) have a vast individual and societal impact. Studies on
interventions for PSDS show contradictory results. It is unclear what works for whom and clinical prediction
tools are lacking. This study aimed to develop a prognostic index (PI) model for treatment outcome in
patients with PSDS.

Methods. Data from a randomized controlled trial (n = 61) evaluating two interventions for PSDS were used to
predict post-treatment PSDS and participation. From 18 pre-treatment variables of patients and caregivers,
predictors were selected using elastic net regression. Based on this selection PI scores (i.e. predictions) for
both outcomes were computed for each individual patient.

Results. The depression model included all pre-treatment variables, explaining 44% of the variance. The
strongest predictors were: lesion location, employment, participation, comorbidities, mobility, sex, and
pre-treatment depression. Six predictors of post-treatment participation were identified, explaining 51% of
the variance: mobility, pre-treatment participation, age, satisfaction with participation, caregiver strain and
psychological distress of the spouse. The cross-validated PI scores correlated highly with the actual outcome
scores (depression: corr.=0.672; participation: corr.=0.718).

Conclusions. PSDS forms a complex and multifactorial problem. Treatment outcome is influenced by
characteristics of the stroke, patient, and spouse. Results indicate that psychological distress is likely no obstacle
when attempting to improve participation. The personalized predictions (PI scores) of treatment outcome
show promising results which can, after replication and validation, aid clinicians with treatment selection.

24
 A prognostic index for post-stroke depressive symptoms

Introduction
Depressive symptoms are common following stroke and have a vast impact on functional and neurological
outcome (1, 2), the rehabilitation process (3), and overall quality of life (4) of patients. Moreover, it places a
high burden on society and the health care system (5). The treatment of post-stroke depressive symptoms 2
(PSDS) has been proven challenging. In clinical practice, treatment selection is often based on trial and
error with modest treatment efficacy. Furthermore, randomized controlled trials (RCTs) evaluating possible
effective treatments, such as psychotherapy and pharmacological treatment, show contradictory results (6-
8). A potential explanation is the heterogeneity and the multifactorial nature of the disorder (9). As a result,
it is not clear what works for whom and clinical prediction tools for treatment outcome are currently lacking.
There is a growing interest in the development of clinical prediction tools utilizing machine learning
techniques (10). One such approach is the use of a large pool of variables to develop predictive algorithms,
which produce estimates of an individual’s prognosis, otherwise known as prognostic index (PI) scores
(11, 12). These predictive algorithms, or PI models, can predict the future symptom status of an individual
patient, for instance following a certain therapy, to determine the level of care that is needed in the future
and therefore aid treatment selection. This technique is used within medical decision making, for instance, to
predict the effectiveness of different treatment options for breast cancer (13). Furthermore, the application
is rapidly growing within the depression literature (11, 12). The current study aimed to develop a PI model to
predict the post-treatment outcome scores for patients with PSDS. Pre-treatment variables (such as clinical
and injury-related variables) of a RCT, investigating two treatments for PSDS, were used to develop the PI
model. This PI model predicted post-treatment outcome scores of depression and experienced participation
restrictions for each participant. These predicted values are referred to as “PI scores”.

Method
The study
Data used in this study came from a multicentre RCT investigating the effectiveness of cognitive behavioural
therapy (CBT) and computerized cognitive training for PSDS (6). CBT was adapted for people with a stroke;
for instance, three sessions of occupational- or movement therapy were added to the treatment to enable
the application of pleasurable activities. A detailed description of the intervention is published elsewhere
(14). During computerized cognitive training, patients could select a combination of four cognitive
domains, such as memory, for training. The program difficulty level was adjusted accordingly (6). Both
interventions consisted of 13 to 16 sessions in a 4-month time period. Both interventions were effective
in significantly improving depressive symptoms and quality of life. However, no significant differences
between the interventions were found for any of the outcome measures. Further procedures of the study
and efficacy results can be found elsewhere (6). The trial was approved by the Medical Ethical Committee
of Nijmegen (the Netherlands).

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Chapter 2

Participants
Participants met the following inclusion criteria: having sustained any type of clinically confirmed stroke at
least 3 months earlier, scoring >7 on the depression subscale of the Hospital Anxiety and Depression Scale
(HADS-D), being 18 years or older, having only mild cognitive impairments (Mini-Mental State Examination
score (MMSE) >27 out of 30), scoring positively on the communication-related items of the National
Institutes of Health Stroke Scale, and mastering the Dutch language. Exclusion criteria were pre-stroke major
depression requiring psychiatric care, premorbid disability as reflected in a Barthel Index (BI) score <19 (out
of 20), stay in an inpatient setting, severe comorbidity that might affect mood (eg, malignancies), and post-
stroke major depression requiring treatment with antidepressants.

Outcomes
Both depression and participation restriction scores, assessed immediately post-treatment, were used as
primary outcome measures for the current analysis. Post-treatment depression scores were measured using
the HADS-D. Scores on the depression subscale range from zero to 21, with higher scores indicating more
depressive symptoms. Good internal consistency for the HADS-D (Cronbach’s α=0.81) was found in a stroke
population (15). In the current sample, patients showed a significant decrease in the HADS-D pre-treatment
compared to post-treatment (mean difference, -4.6; 95% CI, -5.7 to -3.6) (6).
Participation restrictions were measured using the restrictions subscale of the Utrecht Scale for
Evaluation of Rehabilitation-Participation (USER-P). This scale measures the experienced restrictions
regarding vocational, leisure, and social participation. The ten items are rated on a scale from zero to three
or a “not applicable option”. The sum score is converted to a 0-100 scale based on the items deemed
applicable, with a higher score indicating fewer participation restrictions. It is a valid and reliable measure
for former rehabilitation outpatients; the internal consistency of the restriction subscale was found to be
good (Cronbach’s α=0.91) (16). In the current sample, patients did not show a significant difference pre-
treatment compared to post-treatment on the USER-P restriction scale (mean difference, 2.9; 95% CI, -0.4
to 6.2). Despite this overall non-significant difference, inspection of raw data showed vast differences in pre-
post change scores between participants. Because of this high variability, it is interesting to predict individual
post-treatment scores in order to identify who might benefit from the treatments.

Pre-treatment variables
A correlation matrix was computed for all variables measured pre-treatment in the original study. Variables
that were highly correlated (r ≥ 0.60) were discussed between co-authors (JR, SB, FP, and CvH) and based
on previous research and consensus, the variable that was considered redundant was removed from the
dataset (see supplemental material). As a result, the following 18 variables were selected as potential
predictors in order to develop the PI model.
Demographic variables included sex, age, and employment status. Variables related to the stroke
were: time since stroke, type of stroke (ischemic stroke, hemorrhagic stroke, subarachnoidal haemorrhage,

26
 A prognostic index for post-stroke depressive symptoms

or combination), location (left hemisphere, right hemisphere, brainstem, subarachnoidal haemorrhage, or

combination), cognitive impairments measured with the MMSE (17), activities of daily living measured with
the BI (18), and stroke impact measured with the mobility subscale of the Stroke Impact Scale (SIS) (19).
Variables related to the psychological characteristics of the patients were: symptoms of anxiety measured 2
with the anxiety subscale of the HADS (HADS-A), depressive symptoms measured with the HADS-D, coping
style measured with the Utrecht Proactive Coping Competency List (UPCC) (20), frequency of behaviour
regarding social participation measured with the frequency subscale of the USER-P, participation restrictions
measured with the restriction subscale of the USER-P, satisfactions regarding social participation measured
with the satisfaction subscale of the USER-P, and comorbidities measured with the Cumulative Illness Rating
Scale (CIRS) (21). Finally, since stroke places a high burden on the spouse, variables related to the psychological
characteristics of the spouses were considered as possible predictors. These included symptoms of anxiety and
depression measured with the HADS and caregiver strain measured with the Caregiver Strain Index (CSI) (22).

Statistical analyses

Data pre-processing
Missing data. Missing data (outcome variables and pre-treatment variables) were imputed using a non-
parametric random forest approach (R-package “MissForest”, (23)). This imputation method has been
proven to be accurate with lower imputation errors compared to other methods (23, 24). The following
data was used to inform the imputation procedure: 1) non-missing outcome variables; 2) non-missing pre-
treatment variables; 3) post-treatment measures of the pre-treatment variables (available for HADS-A, UPCC,
the USER-P subscales, and the spouses’ HADS and CSI); and 4) treatment condition (CBT or computerized
cognitive training). The imputation method was tested by producing missing data in the complete (non-
missing) dataset and then comparing the imputed data values with the actual data values. This comparison
was done using the normalized root mean squared error (NRMSE) for continuous data and the proportion of
falsely classified entries (PFC) for categorical data (23).
Variable transformation. All continuous variables were standardized and categorical variables were
mean-centred to prevent potential errors in statistical inference (25). Variables with skewed distributions
were transformed using a log transformation or a square root transformation based on visual inspection and
normality tests. For variables that contained categories with limited observations, these categories were
merged, since previous research recommends at least 10% of the sample in each category (26).

Prognostic index
Building the PI model. Two PI models were built to predict the study outcomes; one to predict post-
treatment PSDS severity (HADS-D) and one to predict post-treatment participation restrictions (USER-P
participation subscale). These PI models were constructed using elastic net regression (with R-package
glmnet (27)). Elastic net regression is a combination of Lasso and Ridge regression. These are both linear
regression models, which incorporate two penalty terms into the regression to prevent overfitting when

27
Chapter 2

many variables are included (28). Both penalty terms work by shrinking the regression coefficients of these
variables. The Lasso (L1) penalty term can exclude variables by shrinking coefficients to 0, however, has
difficulties with handling highly correlated variables. The Ridge regression penalty (L2) is less affected by
highly correlated variables, but shrinking coefficients to 0, and therefore selecting variables, is not allowed.
Two tuning parameters are of importance in elastic net regression: 1) Alpha that regulates the ratio between
the L1 and L2 penalty terms (range between 0-1; 0=Ridge/L2 penalty; 1=LASSO/L1 penalty). 2) Lambda that
regulates the overall degree of penalization. To determine the optimal alpha parameter, 25 iterations of 10-
fold cross-validation were run with alpha values between 0 and 1 with 0.05 intervals. The optimal alpha was
defined as the alpha that had the lowest cross-validation prediction error. With the resulting optimal alpha
parameter, we determined the optimal lambda parameter, using 1000 iterations of 10-fold cross-validation.
The optimal lambda was defined as the lambda with the lowest cross-validation prediction error.
Estimating the PI scores (i.e. predictions). Post-treatment depression severity and post-treatment
participation restrictions were estimated for each individual using the final PI models. These individual
estimates are also referred to as scores on the PI (“PI scores”) since these predictions can be used to
determine the level of future care that is needed (11, 12). To evaluate the predictive accuracy of the PI scores,
the average difference between the actual outcomes and the PI scores was calculated, and the association
between these scores was examined using a correlation analysis. Finally, we determined whether outcomes
varied between the two treatments for different levels on the PI: i.e. did individuals with certain prognoses
benefit more from one of the two therapies? To test this, we examined the interactions between the PI
scores and treatment condition in the following multiple regression analyses:

Evaluating the PI models. Predictors that were included in the PI models were categorized important to less
important depending on their parameters. The prediction accuracy of the PI models was evaluated using the
adjusted R-square, i.e. the explained variance corrected for the number of included pre-treatment variables and
the root mean squared error (RMSE), i.e. the root of the sum of the squared residuals, which are the observed
values minus the model predictions. Furthermore, the model performance was assessed using a resampling
technique, namely 5-fold cross-validation (26). Therefore, the sample was (randomly) split into five equal groups.
Then, for each of these groups, the PI scores of the individuals were predicted using the regression model based
on information from the other four groups (the “training dataset,” (29)). Model performance was then determined
by evaluating the adjusted R-square, the RMSE, and the correlations between actual outcomes and PI scores.

Results
Sample description, imputation of missing variables, and variable transformation
In the original study, 62 patients were included. For the current analyses, one participant was excluded, due
to drop-out before randomization. In total 52 patients completed the post-treatment assessment. Table I

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 A prognostic index for post-stroke depressive symptoms

shows the 18 pre-treatment variables grouped into four domains. No values were missing in the demographic
variables. Of the injury-related variables, 18 values were missing (4.2%). Of the psychological variables of the
patient, no values were missing. For the psychological variables of the spouse 24 values were missing (19.4%),
this is due to the fact that not all spouses participated in the study (38 spouses did participate). The data 2
imputation was tested to be successful with an estimated NRMSE of 0.27 and an estimated PFC of 0.26.
After standardization of the variables, two pre-treatment variables were not normally distributed
(time since stroke and CIRS score). These variables were both log-transformed.

Table 1. Sample Description (n=62)

Demographic variables Mean (SD) or n (%)

Sex, n women (%) 23 (37.1)
Age, median (range) 61 (25-79)
Active employment, n (%) 10 (16.1)
Injury-related variables
Time (months) since stroke, mean (SD) 41.9 (46.5)
Type of stroke
Ischemic stroke, n (%) 45 (72.6)
Hemorrhagic stroke, SAB, Combination, n (%) 11 (17.7)
Unknown, n (%) 6 (9.7)
Location of stroke
Left, n (%) 24 (38.7)
Right, n (%) 19 (30.6)
Brainstem, cerebellum, combination, n (%) 11 (17.7)
Unknown, n (%) 8 (12.9)
MMSE score, mean (SD) 29.1 (1.4)
BI, mean (SD) 19.5 (1.32)
SIS score, mean (SD) 65.2 (20.6)
Psychological variables Pre-treatment Post-treatment
HADS-D, mean (SD) 12.4 (3.3) 7.8 (3.6)
HADS-A, mean (SD) 9.9 (4.2) 7.4 (3.9)
UPCC, mean (SD) 2.5 (0.5) 2.5 (0.6)
USER-P frequency, mean (SD) 28.7 (9.9) 28.9 (9.2)
USER-P restriction, mean (SD) 72.2 (12.1) 75.3 (13.3)
USER-P satisfaction, mean (SD) 52.6 (16.9) 62.7 (16.8)
CIRS, mean (SD) 5 (3.9) -
Psychological variables spouse
HADS total score, mean (SD) 11.4 (6.6)
CSI, mean (SD) 6.4 (3.1)
SD, standard deviation; MMSE, Mini-Mental State Examination; BI, Barthel Index; SIS, Stroke Impact Scale; HADS, Hospital
Anxiety and Depression Scale; UPCC, Utrecht Proactive Coping Competence Scale; USER-P, Utrecht Scale for Evaluation of
Rehabilitation-Participation; CIRS, Cumulative Illness Rating Scale; CSI, Caregiver Strain Index

Predictor selection
For the depression PI model the alpha was estimated to be zero, indicating that it is based on a pure Ridge
regression (including all pre-treatment variables). Therefore, all 18 variables were included as predictors in the
depression model (see Table II). The seven variables with the highest parameters (higher than 0.3) were a lesion
in the left hemisphere, being employed, more social participation, fewer comorbidities, better mobility, male

29
Chapter 2

sex, and less severe depressive symptomatology pre-treatment. These variables were all associated with a lower
HADS-D score post-treatment. For the participation restrictions PI model, the alpha was estimated to be 0.95,
indicating that it is a combination of Lasso and Ridge regression. In this model, a total of six predictors were
selected (see Table III). These were better mobility, fewer pre-treatment participation restrictions, older age, less
caregiver strain, less anxiety, and less depression of the spouse, and more satisfaction regarding participation pre-
treatment. These variables were all associated with fewer participation restrictions post-treatment.

Table 2. Predictors Selected with Elastic Net Regression for the Depression Model

Predictor Coefficient
Location of stroke (right vs left) 0.530
Active employment -0.445
USER-P frequency -0.442
CIRS 0.405
SIS score -0.382
Sex 0.338
HADS-D 0.330
USER-P satisfaction -0.296
MMSE score 0.203
UPCC -0.198
CSI 0.171
HADS-A -0.159
USER-P restriction -0.153
Time since stroke -0.121
Location of stroke (left vs brainstem, cerebellum, combination) 0.093
BI -0.087
Type of stroke -0.642
HADS spouse -0.0004
Age 0.00002

USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation; CIRS, Cumulative Illness Rating Scale; SIS, Stroke Impact
Scale; HADS, Hospital Anxiety and Depression Scale; MMSE, Mini-Mental State Examination; UPCC, Utrecht Proactive
Coping Competence Scale; CSI, Caregiver Strain Index; BI, Barthel Index

Table 3. Predictors Selected with Elastic Net Regression for the Participation Restrictions Model

Predictor Coefficient
SIS score 4.105
USER-P restriction 1.966
Age 1.946
CSI 1.491
HADS spouse -0.430
USER-P satisfaction 0.049
SIS, Stroke Impact Scale; USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation; CSI, Caregiver Strain Index;
HADS, Hospital Anxiety and Depression Scale

30
 A prognostic index for post-stroke depressive symptoms

Estimating and evaluating the PI models

Table IV shows the model performance of the PI models of Depression and Participation Restrictions based
on the complete dataset and based on a hold-out dataset. The R² of the depression model was 0.442,
meaning that the model explains 44.2% of the variance. The mean difference between the actual post- 2
treatment HADS-D scores and the PI scores was 2.162 (SD=1.562). The RMSE was 2.66, indicating that the
average of the model residuals (actual scores minus the model predictions) was 2.66 points on the HADS
depression scale. Furthermore, the correlation between the actual and predicted values was significant and
strong (corr.=0.672, p < 0.001, see figure 1).

Table 4. Model performance of PI models of Depression and Participation Restrictions

Depression PI Model Participation Restrictions PI Model

Model performance based on models fitted on the complete dataset
R² 0.451 0.516
RMSE 2.660 8.927
Model performance based on models fitted on a hold-out dataset (5-fold cross-validation)
R² 0.134 0.316
RMSE 3.169 10.321
RMSE, root mean squared error

The R² of the depression PI model that was developed and fitted on a hold-out dataset (5-fold cross-validation)
was 0.134 and the RMSE was 3.17. When examining the association between actual post-treatment HADS-D
scores and the PI scores based on this cross-validation model, a moderate and significant correlation was
found (corr.=0.366, p = 0.004, see figure 1).
The R² of the participation PI model was 0.507, meaning that the model explains 50.7% of the variance.
The mean difference between the actual post-treatment USER-P restriction scores and the PI scores was
6.563 (SD=6.102). The RMSE was 8.93 indicating that the average of the model residuals (observed values
minus the model predictions) was 8.93 points on the USER-P restriction scale. The correlation between the
observed and predicted values was again strong and significant (corr.=0.718, p < 0.001, see figure 1).
For the participation PI model that was developed and fitted on a hold-out dataset (5-fold cross-
validation), the R² was 0.335 and the RMSE was 10.15. When examining the association between actual
post-treatment USER-P restriction scores and the PI scores based on this cross-validation model, a moderate
and significant correlation was found (corr.=0.562, p < 0.001, see figure 1).
Multiple regression analyses were carried out to test whether depression and restriction outcomes
varied between the two treatments for different levels on the PI. The models indicated no distinct treatment
effects on different PI levels.

31
Chapter 2

Figure 1. Scatterplot of A. the actual and the predicted HADS-D scores; B. the actual and the predicted USER-P restriction
scores; C. the actual HADS-D scores and the HADS-D scores predicted with cross-validation; and D. the actual USER-P
restriction scores and the USER-P restriction scores predicted with cross-validation

HADS, Hospital Anxiety and Depression Scale; USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation

Discussion
The goal of this study was to develop a PI model for treatment outcome in patients with PSDS. The post-
treatment outcome scores for depression and experienced participation restrictions were predicted based
on pre-treatment variables of both the patient and the spouse. The depression model explained 44.2% of
the variance and the actual depression scores correlated highly with the predicted scores. The participation
model explained 50.7% of the variance and predicted scores again correlated highly with actual scores.
The range of the HADS-D is 0-21. The RMSE, the squared root of the average of squared differences
between predictions and actual outcomes, was 2.66 for the HADS-D, which is likely not a clinically significant
difference (the minimum difference on the HADS-D to be a clinically significant difference ranges from 0.5
to 6 dependent on the population (30-32)). The range of the USER-P participation is 0-100. The RMSE was
8.927 for the USER-P, which is likely not a clinically significant difference either (although this has not been
studied yet, in this situation Ringash et al. (33) advice that 10% of the instrument range can be considered
the minimum important difference, which would be at least 10 points in this case).
Furthermore, the performance of both models was promising when assessed using a resampling
technique. No interaction effect was found between predicted scores and the received intervention,
meaning that there was not a group of patients with a certain (predicted) prognosis who benefited more
from one of the two therapies.

32
 A prognostic index for post-stroke depressive symptoms

A more favourable outcome of PSDS was predicted by a left-hemispheric lesion, sex, better mobility,
less depressive symptoms pre-treatment, more social participation, fewer comorbidities, and being
employed. These variables showed to be most predictive of PSDS post-treatment of the 18 variables
included in the depression model. 2
A left hemispheric lesion was identified as an important predictor for less depressive symptoms post-
treatment, which is somewhat surprising. To our knowledge, there is no earlier research on the association
between lesion location and treatment outcome and studies identifying lesion laterality as a possible predictor
related to post-stroke depression show inconsistent results (34, 35). Nevertheless, the meta-analyses of Wei
et al. (36) did find an association between right-hemispheric lesion and risk of depression. However, this
association was only apparent one to six months’ post-stroke. The results are therefore likely not applicable
to our sample, since there were only three patients who were less than six months post-stroke. Currently, the
focus is shifting to damaged neuronal networks instead of brain regions as an underlying mechanism for PSDS
(35), which, in future research, should also be considered in relation to treatment outcome for PSDS. The
finding that pre-treatment depression severity is predictive of PSDS outcome, is in line with previous studies,
which show that pre-treatment depression levels play an important role in treatment outcome in patients
irrespective of the presence of acquired brain injury (11, 37, 38). Likewise, the finding that being employed is
a predictive factor of a more favourable outcome is in line with earlier research in depressed patients without
brain injury (11). The other predictors of post-treatment depression severity in our study (including male sex,
better mobility, more social participation, and fewer comorbidities) are all known protective factors against the
development of PSDS (39-41). It is feasible that most of these resilience factors can also provide opportunities
to better use and apply the competencies obtained during therapy.
In this study, the potential predictors for fewer restrictions regarding participation scores post-
treatment in patients with PSDS were better mobility, fewer pre-treatment participation restrictions, older age,
less caregiver strain and psychological distress of the spouse, and more satisfaction regarding participation.
The finding that mobility is the strongest predictive factor is not surprising. Social participation is associated
with functional disability in the recovery process following a stroke (42). However, whereas one would hope
that a treatment for stroke patients would decrease participation restrictions despite physical disabilities, the
interventions in this study might not have achieved this. The finding that older age is predictive of a more
favourable outcome is not in line with earlier research. Previous studies found that older age is often related
to more experienced participation restrictions (43). However, in previous studies patients were relatively older
and might experience, next to stroke-related restrictions, more restrictions due to older age. It seems probable
that patients who are younger experience more participation restrictions because society expects a higher
level of participation (i.e. going back to work, taking care of children). Furthermore, participation satisfaction
and restrictions, but not participation frequency, were predictive factors. Earlier research found that change in
frequency of vocational activities but not social and leisure activities are predictive of participation restrictions
at six months post-stroke (44). Merely increasing participation frequency will, therefore, likely not lead to an
improvement of participation restrictions and satisfaction.

33
Chapter 2

Both the level of caregiver burden and psychological distress of the spouse were predictive of
participation restrictions following the interventions. It seems plausible that spouses who are psychologically
more resilient and experience less psychological distress and less caregiver strain can support and encourage
their spouses better during treatment and help to change therapeutical intentions into practical therapeutic
actions. Furthermore, earlier research found that spouses experience more participation restrictions
themselves, when they have more depressive symptoms, are employed, have a younger age, and support
a stroke patient with more disabilities and a lower participation levels (45). It seems that experienced
participation restrictions reflect a close interplay between spouse and patient.
When comparing the two models in this study, it becomes apparent that improving PSDS and decreasing
experienced participation restrictions might involve different processes. The treatment of depression seems
complicated, with many factors influencing the outcome, while less factors are influencing the outcome
when decreasing participation restrictions. The results highlight the complexity and multifactorial nature
of treating depressive symptoms following a stroke. The outcome of treatment for PSDS is influenced by
characteristics of the patient, stroke, and well-being of the spouse, which should all be considered when
treating a patient with PSDS. The process of decreasing experienced participation restrictions is for a
large part influenced by the physical characteristics of the patient and psychological characteristics of the
spouse. Interestingly, the levels of anxiety and depression of the patient him/herself were not predictive
of restriction, implying that the experienced participation restrictions can be decreased regardless of
experienced psychological distress. This is in line with third-generation cognitive behavioural therapies,
including Acceptance and Commitment Therapy (ACT). The goal of ACT is not to decrease symptomatology,
but to increase psychological flexibility and behaviours based on values despite the presence of for instance
depressive thoughts and feeling (46).
This study has several strengths. First, the state-of-the-art variable selection approach used (i.e. elastic
net regression) combines multiple predictors instead of examining individual predictors separately. To our
knowledge, this is the first study to incorporate multiple predictors to develop personalized predictions for the
outcome of treatment for PSDS. Second, elastic net regression is able to minimize the number of predictors
and to categorize predictors from important to less important. Third, we evaluated the performance of both PI
models using a resampling technique (cross-validation). Fourth, this study included a broad range of possible
predictors. For instance, characteristics of the spouse were considered as predictors of outcome which have
not been included in earlier research. Fifth, this study predicted both depression and experienced participation
restrictions and therefore was able to show the different nature of these two outcomes.
The results of the study should be considered in light of some limitations. The patients in this study
were quite young compared to the average stroke population (median age 61 yrs). Furthermore, patients with
severe cognitive impairments, communication problems, major depression, or who were in need of inpatient
care were excluded. This resulted in a sample of patients with less severe complaints. Both considerations
should be taken into account when interpreting the results. Furthermore, the small sample size can be seen
as a limitation, which is a common problem in studies using data from RCT’s to develop prediction models

34
 A prognostic index for post-stroke depressive symptoms

(47). Due to the relatively small sample size, no separate training and testing datasets were used. This could
have led to overfitting of the models to the current dataset, which decreases the external validity of the
PI models (48). However, machine learning methods have many advantages compared to more traditional
models (such as linear models), because they have an increased model prediction accuracy by reducing 2
overfitting (49). The external validity of both PI models was assessed with a resampling technique on a hold-
out dataset, which showed promising results. In addition, elastic net regression includes two penalty terms
to the regression function to prevent overfitting (28). Furthermore, although we tested whether depression
and participation outcomes varied between the two treatments for different levels on the PI, we were not
able to investigate predictors of differential treatment effects (i.e. moderators) specifically. This was due
to the small sample size. The results apply to both interventions which are very different in nature (i.e.
behavioural therapy and cognitive training), although equally effective in the original RCT from which the
data were drawn. It is clear that replication and external validation of the current results is needed.
In conclusion, this proof of concept study shows that machine learning techniques, such as elastic net
regression, can be used to compute personalized predictions of outcome following treatment for PSDS. The
models developed in this study are not yet ready for implementation in clinical practice. However, the results
do demonstrate the complex and multifactorial nature of PSDS, which should be considered in treatment
approaches. Furthermore, it was shown that psychological factors are likely no obstacles when improving
restrictions regarding social participation. In order to realize the use of these models in clinical practice,
future research should focus on their replication and external validation. PI models have a great potential
to aid clinicians and their patients with treatment selection and therefore increase the effectiveness of
treatments for PSDS.

35
Chapter 2

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38
 A prognostic index for post-stroke depressive symptoms

Supplementary material

Supplemental table 1. All pre-treatment variables measured in the original trial (1)

Demographic variables
Sex 2
Age
Active employment
Injury-related variables
Time since stroke
Type of stroke
Location of stroke
Mini-Mental State Examination
Barthel Index
Stroke impact scale
Psychological variables
Hospital Anxiety and Depression Scale – Depression Subscale
Hospital Anxiety and Depression Scale – Anxiety Scale
Post-stroke Depression Rating Scale
Short stroke specific Quality of Life scale
Utrecht Proactive Coping Competency List
Utrecht Scale for Evaluation of Rehabilitation Participation – Frequency subscale
Utrecht Scale for Evaluation of Rehabilitation Participation – Restriction subscale
Utrecht Scale for Evaluation of Rehabilitation-Participation – Satisfaction subscale
EQ5D
Life Satisfaction questions
Cumulative Illness Rating Scale
Psychological variables spouse
Hospital Anxiety and Depression Scale
Caregiver Strain Index
Involvement and Evaluation Questionnaire-Brain Injury

39
 Supplemental table 2. Spearman Correlation Matrix of all variables included in the original trial (6)

40
Barthel SIS UPCC USERP USERP USERP HADS CSI IEQ
Chapter 2

Measure MMSE CIRS HADS-D HADS-A PSDRS SSQ EQ5D LS2

Index score frequency restriction satisfaction spouce spouce spouce
MMSE - .058 .087 .013 -.031 -.013 .204 -.004 .090 .090 .130 -.076 .059 -.053 .045 -.125 -.161
**
Barthel Index .058 - .127 .048 .043 -.098 -.055 .045 .020 .347 -.013 .001 .126 -.008 -.054 -.205 .180
CIRS .087 .127 - -.408** .160 .355** .138 -.254* -.018 -.025 -.180 -.183 -.280* -.098 .040 .202 .406**
SIS score .013 .048 -.408** - -.198 -.129 -.150 .419** .261* .198 .526** .298* .418** .209 -.147 -.322* -.314*
HADS-D -.031 .043 .160 -.198 - .430** .431** -.402** -.152 -.253* -.295* -.451** -.421** -.359** -.032 .044 .154
** ** ** ** * ** **
HADS-A -.013 -.098 .355 -.129 .430 - .504 -.397 .030 -.038 -.317 -.363 -.409 -.241 .072 .260 .266
PSDRS .204 -.055 .138 -.150 .431** .504** - -.414** -.113 -.160 -.245 -.371** -.458** -.517** -.010 .025 .290
SSQ -.004 .045 -.254* .419** -.402** -.397** -.414** - .330** .154 .417** .611** .680** .501** -.168 -.285* -.341*
* ** * * * **
UPCC .090 .020 -.018 .261 -.152 .030 -.113 .330 - .161 .299 .274 .322 .353 -.189 -.248 -.390**
USER-P frequency .090 .347** -.025 .198 -.253* -.038 -.160 .154 .161 - .130 .273* .186 .236 -.208 -.167 -.314*
** * * ** * ** ** * **
USER-P restriction .130 -.013 -.180 .526 -.295 -.317 -.245 .417 .299 .130 - .524 .509 .313 -.241 -.460 -.434**
USER-P satisfaction -.076 .001 -.183 .298* -.451** -.363** -.371** .611** .274* .273* .524** - .697** .532** -.219 -.319* -.391**
EQ5D .059 .126 -.280* .418** -.421** -.409** -.458** .680** .322* .186 .509** .697** - .659** -.083 -.273 -.424**
** ** ** ** * ** **
LS2 -.053 -.008 -.098 .209 -.359 -.241 -.517 .501 .353 .236 .313 .532 .659 - -.209 -.268 -.488**
**
HADS spouce .045 -.054 .040 -.147 -.032 .072 -.010 -.168 -.189 -.208 -.241 -.219 -.083 -.209 - .462 .453**
* * ** * **
CSI spouce -.125 -.205 .202 -.322 .044 .260 .025 -.285 -.248 -.167 -.460 -.319 -.273 -.268 .462 - .637**
IEQ – BI spouce -.161 .180 .406** -.314* .154 .266 .290 -.341* -.390** -.314* -.434** -.391** -.424** -.488** .453** .637** -
MMSE, Mini-Mental State Examination; CIRS, Cumulative Illness Rating Scale; SIS, Stroke Impact Scale; HADS, Hospital Anxiety and Depression Scale; PSDRS, Post-stroke Depression
Rating Scale; SSQ, Short stroke specific Quality of Life scale; UPCC, Utrecht Proactive Coping Competence Scale; USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation;
LS2, Life Satisfaction questions; CSI, Caregiver Strain Index; IEQ–BI, Involvement and Evaluation Questionnaire-Brain Injury; *p < .05; **p < .01
A prognostic index for post-stroke depressive symptoms

41
CHAPTER 3
Measuring psychological flexibility and cognitive
defusion in individuals with acquired brain injury

Johanne C.C. Rauwenhoff

Frenk Peeters
Yvonne Bol
Caroline M. van Heugten

Brain Injury, 2021

Chapter 3

Abstract
Purpose. Acceptance and Commitment Therapy (ACT) is used increasingly for individuals with psychological
distress following acquired brain injury (ABI) in different countries. However, questionnaires measuring
ACT-processes are often not validated for this patient group and need cross-cultural validation. This study
investigated the psychometric properties of the Acceptance and Action Questionnaire for Acquired Brain
Injury (AAQ-ABI; measuring psychological flexibility related to thoughts and feelings about ABI) and the
Cognitive Fusion Questionnaire (CFQ-7; measuring cognitive defusion).

Materials and methods. Score distribution, reliability, and convergent validity of the AAQ-ABI and the CFQ-7
were examined in Dutch individuals with ABI.

Results. Seventy-three patients with ABI were included. The AAQ-ABI showed good reliability (Cronbach’s
α=0.87) and the CFQ-7 excellent reliability (Cronbach’s α=0.97). Both did not show a floor or ceiling effect,
nor a skewed distribution. There were strong to moderate correlations between the questionnaires and
measures of psychological flexibility, mood, quality of life, and value-driven behavior (AAQ-ABI: r =-0.70–
0.81; CFQ-7=-0.67–0.84). Inter-item total correlations indicate that the questions within each questionnaire
measured the same construct (AAQ-ABI: r=0.40–0.78; CFQ-7: r=0.84–0.93).

Conclusions. The current study shows that the Dutch AAQ-ABI and CFQ-7 have acceptable to good psychometric
properties when measuring psychological flexibility and cognitive defusion in patients with ABI.

44
 Measuring psychological flexibility and cognitive defusion in individuals with ABI

Introduction

Acquired brain injury (ABI) is associated with an increased risk for the development of psychological
distress (1, 2). The psychological flexibility model provides an interesting perspective on how to deal with
psychological distress related to medical conditions (3). This model forms the basis of Acceptance and
Commitment Therapy (ACT), a third-generation Cognitive Behavioral Therapy. Psychological flexibility is the
ability to adjust or persist in behaviors based on chosen values while staying in contact with the present 3
moment, regardless of unpleasant thoughts, feelings, and bodily sensations (4). The treatment goal of ACT
is the improvement of psychological flexibility. This is achieved through several interacting processes such as
acceptance, cognitive defusion, mindfulness, and value based living.
Psychological flexibility is associated with wellbeing and is suggested to be a fundamental aspect of
mental health. Previous studies have found relationships between psychological flexibility and physical and
mental health, life satisfaction, quality of life, and rehabilitation adherence (5-7). Psychological inflexibility
(which is characterized by the avoidance of thoughts and feelings, also called experience avoidance)
is associated with psychopathology. This is especially apparent in individuals suffering from anxiety and
depressive disorders (8-10), which are also common following an ABI (11).
Patients with ABI often experience negative thoughts (for instance: “life will never be the same again”
or “I cannot do what I used to do”). These thoughts can be upsetting and therefore patients will try to
avoid these thoughts. Cognitive defusion is the disentanglement and the process of creating a distance from
thoughts (4) which can be helpful in the adaptation process following ABI, since people often experience
thoughts that hold some truth (12). For instance, if the patient learns to let a reoccurring thought (such as “I
cannot do what I used to do”) come and go (defusion) instead of focusing on or trying to avoid this thought
(fusion), the impact of these thoughts on the patient’s behavior will decrease and there is more room for
valued driven behavior.
When applying and evaluating ACT, both psychological flexibility and cognitive defusion as core
elements must be measured validly for treatment selection, monitoring of patients during rehabilitation
and treatment, and the evaluation of interventions. Several questionnaires have been developed to
measure psychological flexibility and cognitive defusion. The Acceptance and Action Questionnaire (AAQ-II)
is a widely used questionnaire measuring experiential avoidance and psychological inflexibility (13). Since
ACT is used for various disorders, the AAQ-II has been adapted for different patient populations, including
patients with chronic pain (14), diabetes (15), and substance abuse (16). These population-specific measures
are valuable since they measure experiential avoidance and psychological flexibility related to the problem
area of interest. Consequently, they are thought to be more treatment-sensitive and measure psychological
flexibility in a more content-valid manner compared to a generic measure (17). Sylvester (18) adapted
the AAQ-II to measure both psychological inflexibility and avoidance of issues relating to ABI, namely the
Acceptance and Action Questionnaire for Acquired Brain Injury (AAQ-ABI). The AAQ-ABI has only been
validated within an Australian ABI population (19). Cross-cultural validation is needed, especially, since ACT
is used frequently for patients with psychological distress following ABI in other countries as well (12).

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Chapter 3

To measure cognitive defusion, Gillanders et al. (20) developed the Cognitive Fusion Questionnaire
(CFQ-7) which can be used for various patient populations. In patients with chronic pain (20), mental health
problems, multiple sclerosis, and caregivers of people with dementia (21) it shows good psychometric
properties. However, the psychometric properties have not yet been examined for patients with ABI.
Therefore, this study aimed to perform a cross-cultural validation of the Dutch AAQ-ABI and to
validate the CFQ-7 for patients with ABI. The score distribution and reliability of the two questionnaires
were examined. Convergent validity was established by comparing the questionnaires to measures of
psychological flexibility, mood, quality of life, and value based living. We hypothesized that the correlations
between the AAQ-ABI and CFQ-7 would correlate positively with the AAQ-II. We furthermore expected
stronger correlations between the AAQ-II and AAQ-ABI (since they are both measures of psychological
flexibility) than between the AAQ-II and the CFQ-7. Lastly, positive correlations were expected between
measures of mood and negative correlations between measures of quality of life and value based living.

Methods
Participants
The inclusion criteria were: having sustained any type of acquired brain injury (such as a stroke, traumatic
brain injury, or hypoxia), which is diagnostically confirmed by a neurologist; being 18 years or older;
mastering the Dutch language sufficiently to fill in the questionnaires; and giving informed consent. The
exclusion criteria were: the inability to complete the questionnaire because of cognitive impairment
or communicative impairment based on the clinical judgment of a psychologist or inability to complete
questionnaires in previous research.

Measures
Acceptance and Action Questionnaire Acquired Brain Injury (AAQ-ABI). The AAQ-ABI measures psychological
inflexibility regarding thoughts, feelings, and behaviors related to an ABI (19). The scale specifically focusses
on identifying thoughts, feelings, and behaviors that may arise around functional disability occurring after
an ABI. The AAQ-ABI relies on a 5-point Likert scale to reduce cognitive demand. Sylvester (18) initially
developed a questionnaire consisting of 15 items. Whiting et al. (19) evaluated the psychological properties
of the AAQ-ABI and concluded that, based on a factor analysis, a shorter (one-factor) version with nine items
has good reliability across time, satisfactory internal consistency (Cronbach’s α = .89), and associations with
theoretically-relevant constructs. The scale includes items such as “I stop doing things when I feel scared
about my brain injury” and “I need to get rid of my anxiety about my brain injury”. The score ranges from
0 to 36 with higher scores indicating greater psychological inflexibility. The questionnaire was translated
into Dutch using a forward and backwards-translation method. It was first translated into Dutch by the first
author (JR); afterwards, it was translated back into English by a native English speaker who was blinded for
the original version. Differences were discussed and a final version was agreed upon.

46
 Measuring psychological flexibility and cognitive defusion in individuals with ABI

Cognitive fusion Questionnaire (CFQ-7). The CFQ-7 (20) consists of seven items and measures cognitive
fusion on a 7-point Likert scale. Scores range from 7 to 49. The higher the score, the more fused one is with
one’s thoughts or identifies with one’s thoughts. The English version of the CFQ-7 demonstrated excellent
internal consistency (Cronbach’s α = .90) and good test-retest reliability (20). The questionnaire was translated
into Dutch by Batink and De Mey (22) and this version showed good psychometric properties. The English
version had good psychometric properties in patients with chronic pain and multiple sclerosis (20, 21).
Acceptance and Action Questionnaire II (AAQ-II). The AAQ-II (23) is a seven-item questionnaire
3
measuring experiential avoidance and psychological inflexibility. The items measure the negative evaluation
of feelings, forms of cognitive entanglement, and the influence of thoughts and feelings (13, 24). The items
are scored on a 7-point Likert scale and the total score ranges from 7 to 49 with a higher score indicating
greater experiential avoidance and psychological inflexibility. The internal consistency of the AAQ-II is good
(Cronbach’s α = .84) (13). The questionnaire was translated into Dutch by Jacobs et al. (25) and showed
good psychometric properties. In an Australian ABI sample, the questionnaire showed excellent internal
consistency (Cronbach’s α = .90) and good test-retest reliability (19).
Hospital Anxiety and Depressive Scale (HADS). The HADS was used to measure anxiety and depressive
symptoms. The score ranges from 0 to 42 with higher scores indicating higher levels of depression or anxiety.
The HADS was found to have good psychometric properties in patients with TBI and stroke (Cronbach’s α =
0.94) (26, 27).
Depression Anxiety Stress Scales-21 (DASS-21). The DASS-21 was used to measure the levels of anxiety,
depression, and stress of the participants. It consists of 21 items which are rated on a 4-point Likert-scale.
The score ranges from 0 to 63 with higher scores indicating greater levels of depression, anxiety, or stress.
The questionnaire has been validated and found to have good psychometric properties in a TBI sample
(Cronbach’s α = 0.95) (28). The DASS-21 was included next to the HADS because it includes a stress scale and
includes items on devaluation of life, self-deprecation, and hopelessness which the HADS lacks (29).
Short Form Survey (SF-12). Quality of life was measured with the Short Form Survey (SF-12). The
SF-12 was used to measure the health status of the participants, but it can also be described as a broad
assessment of quality of life (30). The SF-12 has two subscales: the Physical Component Summary (PCS) and
the Mental Component Summary (MCS). The total score of both scales ranges from 0 to 100, with a higher
score indicating a better health status. The SF-12 demonstrates good psychometric properties in patients
with stroke (Cronbach’s α PCS = 0.85 and MCS = 0.81) (31).
Valued Living Questionnaire (VLQ). The Valued Living Questionnaire (VLQ) is a two-part instrument
that measures value based living (32). The participants rate the importance of ten value domains on a
10-point Likert scale. Subsequently, participants rate how consistently they have lived by their values within
these domains. Scores from both parts are used to calculate a value based living component. The internal
consistency of the valued living component is adequate (Cronbach’s α = 0.74) (32). The VLQ has been used
in earlier research to measure valued living in patients with TBI (33).
Demographic questionnaire. Participants filled in details on demographic characteristics, including age,
sex, educational level, marital status, employment status, type of brain injury, and time since brain injury.

47
Chapter 3

Procedure
Individuals with ABI were recruited between October 2018 and May 2020 via databases of participants
from previous studies investigating the consequences of an ABI (which matched the inclusion criteria of this
study) for which medical ethics approval had been acquired. The participants had given written permission
to be contacted for participation in future studies. If the participant agreed to participate and had given
informed consent, they received a secure link to the questionnaires, which they could fill out at home. The
participants filled in the questionnaires at one time point. A forced-choice response format was employed
and thus there was no missing data. Additionally, part of the data was collected retrospectively. The data was
drawn from an RCT examining the effect of ACT for patients with ABI for which the baseline measurement
was used. The procedures for this study can be found elsewhere (34). Only these patients (N=33) filled in
the HADS, DASS-21, SF-12, and VLQ. The current study was approved by the medical ethics committee of
Maastricht University Medical Centre and Maastricht University (reference number 2018-0543).

Statistical analyses
The score distribution of the AAQ-ABI and CFQ-7 was reported in terms of mean, SD, median, range,
skewness, and floor and ceiling effects. Skewness values lower than -1.0 or higher than 1.0 were considered
strong. Those between 0.5 and 1.0 and -0.5 and -1.0 were regarded as moderate (46). Floor and ceiling
effects were interpreted as present if at least 15% of the participants obtained the highest or lowest score
(35). Furthermore, to test the homogeneity of the scales the item-total correlations were computed (the
correlation between one item and the rest of the items). Each item was required to have a correlation
coefficient higher than 0.3 (36). Furthermore, internal consistency was assessed in terms of Cronbach’s α
(>0.9 = excellent; 0.9 - 0.8 = good; 0.8 - 0.7 = acceptable; 0.7 - 0.6 = questionable; 0.6 - 0.5 = poor) (36).
Convergent validity was examined by calculating Spearman’s rank correlation coefficients between the AAQ-
ABI, CFQ-7, AAQ-II, HADS, DASS-21, SF-12, and VLQ. Correlations were interpreted as strong if higher than
0.6, moderate if between 0.3 and 0.6, and weak if smaller than 0.3. Data were analyzed using SPSS version
26.0 (37).

Results
Participants’ characteristics
A total of 73 participants filled in the questionnaires. Participants’ characteristics are shown in Table 1.

48
 Measuring psychological flexibility and cognitive defusion in individuals with ABI

Table 1. Demographic characteristics

Demographic variables Mean (SD) or n (%)

Sex, n women (%) 34 (46.6)
Age, mean (SD) 56.5 (11.47)
Marital Status, n (%)
Unmarried 5 (6.8)
Married 48 (65.8)
Living together with partner 12 (16.4)
Divorced
Widowed
5 (6.8)
3 (4.1)
3
Education, n (%)
Low (primary education and lower vocational education) 12 (16.4)
Medium (general secondary education and secondary 24 (32.9)
vocational education)
High (pre-university education, higher professional 37 (50.7)
education, and university education)
Employment, n (%)
Employed 26 (35.6)
Incapacitated for work 24 (32.9)
Unemployed 4 (5.5)
Retired 11 (15.1)
Other 8 (10.9)
ABI-related variables Mean (SD) or n(%)
Time (years) since ABI, mean (SD) 3.68 (5.39)
Type of ABI, n (%)
Ischemic stroke 34 (46.6)
Hemorrhagic stroke 8 (10.9)
Traumatic brain injury 31 (42.5)
ABI, acquired brain injury

Score distribution and reliability

Table 2 shows the score distributions of the AAQ-ABI and the CFQ-7. The mean score of the AAQ-ABI was
11.18 (SD = 8.40). 2.7% of the participants obtained the lowest score and no participants obtained the
highest score. The skewness value was 0.28 and the Cronbach’s α was 0.87.
The mean score of the CFQ-7 was 22.73 (SD = 12.24). On the CFQ-7, 13.7% of the participants
obtained the lowest score while no participants obtained the highest score. The skewness value was 0.18
and the Cronbach’s α was 0.97.

Table 2. Score distribution and reliability

M SD Median Range % lowest score % highest score Skewness α

AAQ-ABI 11.18 8.40 8 0-31 2.7 % 0% 0.28 0.87
CFQ-7 22.73 12.24 24 7-45 13.7% 0% 0.18 0.97
AAQ-ABI, Acceptance and Action Questionnaire Acquired Brain Injury; CFQ-7, Cognitive Fusion Questionnaire

Item-total correlations
All item-total correlations were above 0.3 for the AAQ-ABI (r = 0.40 – 0.78) and CFQ-7 (r = 0.84 - 0.93) as can
be seen in Tables 3 and 4.

49
Chapter 3

Table 3. The corrected item-total correlations of the Acceptance and Action Questionnaire Acquired Brain Injury

Item No. Corrected Item-Total

Correlation
1 I hate how my brain injury makes me feel about myself 0.69
2 I need to get rid of my anxiety about my brain injury 0.76
3 I stop doing things when I feel scared about my brain injury 0.64
4 My brain injury defines me as a person 0.54
5 I am moving forward with my life 0.44
6 I would give up important things in my life if I could make the brain injury go away 0.40
7 My worries and fears about my brain injury are true 0.78
8 Other people make it hard for me to accept myself 0.60
9 Most people are doing better than me 0.74

Table 4. The corrected item-total correlations of the Cognitive Fusion Questionnaire

Item No. Corrected Item-

Total Correlation
1 My thoughts cause me distress or emotional pain 0.91
2 I get so caught up in my thoughts that I am unable to do the things that I most want to do 0.84
3 I over-analyse situations to the point where it’s unhelpful to me 0.88
4 I struggle with my thoughts 0.93
5 I get upset with myself for having certain thoughts 0.87
6 I tend to get very entangled in my thoughts 0.87
7 It’s such a struggle to let go of upsetting thoughts even when I know that letting go would 0.90
be helpful

Convergent validity
Table 5 shows the correlations between the AAQ-ABI, CFQ-7 and the AAQ-II, HADS, DASS-21, SF-12, and
VLQ. The AAQ-ABI and the CFQ-7 correlated strongly with each other and with the AAQ-II. Correlations
between the AAQ-ABI and the HADS were moderate and between the AAQ-ABI and the DASS-21 strong,
while the CFQ-7 correlated strongly with the HADS and moderately with the DASS-21. Both measures had
weak correlations with the PCS and stronger correlations with the MCS. Lastly, the AAQ-ABI showed strong
correlations with the VLQ and the CFQ-7 showed moderate correlations.

Table 5. Spearman’s rank correlation matrix

AAQ-ABI CFQ-7 AAQ-II HADS¹ DASS-21¹ PCS¹ MCS¹ VLQ¹

AAQ-ABI - 0.72** 0.81** 0.47* 0.65** -0.22 -0.57* -0.70**
CFQ-7 0.72** - 0.84** 0.65** 0.57** -0.06 -0.67** -0.50**
AAQ-ABI, Acceptance and Action Questionnaire Acquired Brain Injury; CFQ-7, Cognitive Fusion Questionnaire; AAQ-
II, Acceptance and Action Questionnaire II; HADS, Hospital Anxiety and Depression Scale; DASS-21, Depression, anxiety
and stress scale-21; PSC, Physical Component Summary; MCS, Mental Component Summary; and VLQ, Valued Living
Questionnaire; * p < .05; ** p < 0.01
¹ Based on a smaller sample (N=33)

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 Measuring psychological flexibility and cognitive defusion in individuals with ABI

Discussion
The aims of this study were to perform a cross-cultural validation of the AAQ-ABI and to validate the CFQ-
7 in a Dutch ABI population. The internal consistency of the AAQ-ABI was good (Cronbach’s α = 0.87) and
of the CFQ-7 excellent (Cronbach’s α = 0.97). Neither of the questionnaires showed floor or ceiling effects
and skewness levels were acceptable. The strong positive correlation between both the AAQ-ABI and the
CFQ-7 and the AAQ-II indicated a good convergent validity. The AAQ-ABI showed a stronger correlation with
3
the AAQ-II than with the CFQ-7. This was expected since the AAQ-II and AAQ-ABI both measure constructs
related to psychological flexibility. Whiting et al. (19) found similar correlations between the English versions
of the AAQ-II and the AAQ-ABI. However, in the current study, the AAQ-II correlated stronger with the CFQ-
7 than with the AAQ-ABI, which was not expected. A possible explanation for this finding could be that
the constructs measured by the AAQ-II and the CFQ-7 are closely related (20). Where the CFQ-7 measures
psychological flexibility regarding cognition, the AAQ-II does this in a broader way regarding emotions and
thoughts. Therefore, the AAQ-II contains items that may estimate levels of cognitive fusion (such as; I worry
about not being able to control my worries and feelings). In addition, both questionnaires had positive
correlations with measures of mood and negative correlations with measures of value-driven behavior,
which was expected. Both questionnaires correlated significantly with quality of life, but only when related
to mental health and less when related to physical health. The AAQ-ABI had a weak association with physical
health-related quality of life. Lower associations between measures of psychological functioning and physical
functioning are not uncommon (38). There was no association between the CFQ-7 and physical health-
related quality of life. It could be that cognitive defusion is simply not as related to physical health-related
quality of life as the other components of psychological flexibility or has a more indirect effect that the
measures used did not capture. Finally, all separate items of the AAQ-ABI and CFQ-7 correlated adequately
with the total score of the respective questionnaire, indicating that the items within each questionnaire
measure the same construct.
The results suggest that the AAQ-ABI and the CFQ-7 measure psychological flexibility and cognitive
defusion in patients with ABI. The questionnaires can therefore further help to improve the care for patients
with ABI related anxiety and depressive complaints. Clinicians can use these scales to monitor their patients
with ABI during an ACT intervention, to evaluate the treatment, and to give the patient insight into the
treatment process. Furthermore, the questionnaires can be used in studies to further investigate the
effectiveness of ACT for patients with ABI. This is important since psychological distress is common following
ABI and more research into the effectiveness of different treatment options is needed (11, 39).

Limitations and future research

The discriminant validity of the questionnaires was not investigated in this study, which should be further
examined in future research, especially given the growing concern regarding the discriminant validity of
the AAQ-II (40). Several studies have found that it measures psychological distress or neuroticism rather

51
Chapter 3

than psychological flexibility (41, 42), which is a matter of concern and has to be taken into account when
using the AAQ-II. The AAQ-ABI is based on the AAQ-II and therefore there might be doubts regarding the
discriminant validity of the AAQ-ABI as well. Therefore, more research into the discriminant validity of the
AAQ-ABI is needed.
Population-specific versions of the AAQ-II, such as the AAQ-ABI, are thought to be more treatment
sensitive (17). However, their responsiveness to measuring change in treatment contexts has not well been
examined yet. For these reasons, it is recommended to use an AAQ specific questionnaire in addition to the
AAQ-II as the treatment sensitivity of the AAQ-II has been better studied (17, 43). Furthermore, this will aid
the comparability between trials. Regarding the treatment sensitivity of the AAQ-ABI, the English version
of the questionnaire was used in a pilot RCT investigating the effectiveness of ACT for people with severe
traumatic brain injury (44). No significant change was measured on the AAQ-ABI, however, no significant
difference was also found on the AAQ-II. This could be due to the small sample size of the study (N=19).
More research is needed to investigate the treatment sensitivity of the AAQ-ABI.
The test-retest reliability of both scales was not examined in this study. However, the test-retest
reliability of the English AAQ-ABI was good in an Australian ABI sample (19). Furthermore, the test-retest
reliability of the CFQ-7 was good in student and community samples (20, 45). However, the test-retest
reliability should still be examined in Dutch individuals with ABI.
The largest part of the data was collected online, which has several advantages. Patients are easy to
reach and it takes them a minimal amount of time to participate in the study. However, the questionnaires
are not filled in in a controlled environment. Furthermore, the sample may have limited representativeness
since these are all participants who have access to and know how to use a computer.

Conclusion
The current study shows that the Dutch AAQ-ABI and CFQ-7 have acceptable to good psychometric properties
when measuring psychological flexibility and cognitive defusion in Dutch patients with ABI. The AAQ-ABI and
CFQ-7 can help clinicians to monitor their patients with ABI during an ACT intervention and can help evaluate
the treatment. Furthermore, the questionnaires can be used in studies further investigating the effectiveness
of ACT for patients with ABI. When using the AAQ-ABI in intervention studies it is recommended to use it in
combination with the AAQ-II, since the treatment sensitivity of the AAQ-II is better studied.

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 Measuring psychological flexibility and cognitive defusion in individuals with ABI

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multimethod exploration of pursuing valued goals despite the presence of distress. Psychol Assess. 2020;32(9):829-
50.
42. Rochefort C, Baldwin AS, Chmielewski M. Experiential Avoidance: An Examination of the Construct Validity of the
AAQ-II and MEAQ. Behav Ther. 2018;49(3):435-49.
43. Gloster AT, Klotsche J, Chaker S, Hummel KV, Hoyer J. Assessing psychological flexibility: What does it add above and
beyond existing constructs? Psychological assessment. 2011;23(4):970.
44. Whiting D, Deane F, McLeod H, Ciarrochi J, Simpson G. Can acceptance and commitment therapy facilitate
psychological adjustment after a severe traumatic brain injury? A pilot randomized controlled trial. Neuropsychological
rehabilitation. 2019:1-24.

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45. Campbell L. Test-retest reliability and further validity of the cognitive fusion questionnaire. Edinburgh The University
of Edinburgh; 2010.
46. Bulmer MG. Principles of statistics. Dover Books on Mathematics, Courier Corporation; 1979.

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 ED
CHAPTER 4
O
Acceptance and Commitment Therapy for
people with acquired brain injury: rationale
G
and description of the BrainACT treatment
R
BA
EM

Johanne C.C. Rauwenhoff*

Yvonne Bol*
Caroline M. van Heugten
Tim Batink
Chantal A.V. Geusgens
Anja J.H.C. van den Hout
Peter Smits
Christianne R.T. Verwegen
Annemarie Visser
Frenk Peeters

*Co-first authorship

Under revision
CHAPTER 5
Acceptance and Commitment Therapy for
individuals with depressive and anxiety symptoms
following acquired brain injury: a non-concurrent
multiple baseline design across four cases

Johanne C.C. Rauwenhoff

Yvonne Bol
Frenk Peeters
Anja J.H.C. van den Hout
Chantal A.V. Geusgens
Caroline M. van Heugten

Neuropsychological rehabilitation, 2022

Chapter 5

Abstract
Background. Patients with acquired brain injury (ABI; such as stroke or traumatic brain injury) often
experience symptoms of anxiety and depression. Until now, evidence-based treatment is scarce. This study
aimed to investigate the effectiveness of Acceptance and Commitment Therapy (ACT) for patients with ABI.

Methods. To evaluate the effect of ACT for people with ABI, a non-concurrent multiple baseline design
across four cases was used. Participants were randomly assigned to a baseline period, followed by treatment
and then follow-up phases. Anxiety and depressive symptoms were repeatedly measured. During six
measurement moments over a year, participants filled in questionnaires measuring anxiety, depression,
stress, participation, quality of life, and ACT-related processes. Randomization tests and NAP scores were
used to calculate the level of changes across phases. Clinically significant change was defined with the
Reliable Change Index.

Results. Three out of four participants showed medium to large decreases in anxiety and depressive
symptoms (NAP=0.848 till 0.99). Furthermore, participants showed improvements regarding stress,
cognitive fusion, and quality of life. There were no improvements regarding psychological flexibility, value-
driven behaviour, or social participation.

Conclusion. This study shows that ACT is possibly an effective treatment option for people experiencing ABI
related anxiety and depression symptoms. Replication with single case or large scale group studies is needed
to confirm these findings.

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 A SCED study on the effectiveness of ACT for people with ABI

Introduction
Individuals suffering from acquired brain injury (ABI), such as a traumatic brain injury (TBI) or a stroke are at
increased risk of developing anxiety or depressive symptoms (1, 2). These can have a significant impact on
patients’ quality of life. Post-ABI depressive and anxiety symptoms are related to higher re-hospitalization
rates, less social participation (dependency in daily living and lower return to work rates), and more cognitive
and physical impairments (3).
Studies investigating interventions for ABI related anxiety and depressive complaints are scarce (4,
5) and there are therefore limited evidence-based treatment options (6, 7). For instance, second wave
behavioural therapies such as cognitive behavioural therapy (CBT) have shown to be effective in treating
depression and anxiety, but seem less effective for patients with ABI compared to non-ABI samples (8).
Second-wave therapies aim to influence how situations are experienced and dealt with by changing
5
unhelpful or irrational thoughts and cognitive schemas (9). Third-wave therapies such as Acceptance
and Commitment Therapy (ACT) utilize a different approach, thoughts and feelings are not changed, but
the functions of and one’s relationship to these psychological events are changed. This might be a fitting
approach for people with ABI since they often have realistic thoughts which might be hard to challenge.
The aim of ACT is to accept one’s thoughts and feelings, without judgment, and to commit to pursuing
value-driven behaviour, which is named psychological flexibility (10). ACT might help people to live in a
meaningful way with the lasting and impairing consequences of an ABI (11, 12). Psychological flexibility
is increased using the six core-components of ACT (acceptance, cognitive defusion, mindfulness, self-as-
context, values, and committed action). For patients to become accustomed to these processes, behavioural
change strategies, metaphors, and experiential exercises are used. Although the main treatment aim of
ACT is not to reduce symptomatology, a reduction of anxiety and depressive complaints is often observed
following ACT interventions (13). Furthermore, an increase in psychological flexibility is thought to be related
to improved mental health (14).
There is some preliminary evidence that ACT is effective in treating psychological distress following
TBI. Whiting et al. (15) found that patients with severe TBI experienced greater reductions in depression and
stress following an ACT treatment (N=10) compared to a befriending treatment (N=9) in a pilot randomized
controlled trial. However, these results were not maintained in the one-month follow-up. Sander et al. (16)
compared ACT to devised usual care (which consisted of an intake and referral to a psychological service
without a follow-up). The study concluded that patients receiving the ACT intervention showed greater
improvements regarding psychological distress and psychological flexibility compared to the patients in the
usual care group. Moreover, Majumdar and Morris (17) found that ACT reduced depression and increased
self-rated health status and hopefulness in people with a stroke. These studies indicate that ACT can be a
suitable treatment for patients with ABI related anxiety or depressive complaints, however more research
is needed to confirm these findings. Moreover, the long-term effects of ACT in people with ABI remain
unknown. Therefore, this study aimed to evaluate the BrainACT intervention, an ACT intervention specifically
developed for people with ABI. This was done using single-case experimental design (SCED) methodology.

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A non-concurrent multiple baseline design across four cases was performed with a follow-up period of one
year. It was hypothesized that the BrainACT intervention would reduce anxiety and depressive symptoms.
Since the trajectories of change during psychotherapy are diverse and vary per patient (18), both immediate
and delayed effects of the interventions were tested. Furthermore, it was expected that the intervention
would improve psychological flexibility, cognitive defusion, and value-driven behaviour. Lastly, the study
investigated if these outcomes generalized to improvements in levels of stress, social participation, and
quality of life.

Methods
Design
In the current study, a non-current multiple baseline design was used, meaning that the study contained
four AB designs with a varying baseline length (19). Randomization was achieved by randomly assigning
patients to a baseline (waiting) period. This was done separately for every patient as you would do in an AB
design. The minimum baseline period was 20 days and the maximum baseline period was 42 days. The study
was approved by the Ethical Review Committee of Psychology and Neuroscience of Maastricht University
(reference number: ERCPN-192_21_04_2018) and the medical ethics committee of Zuyderland Medical
Centre (METCZ20180074). All participants gave informed consent.

Participants
Patients were recruited at Zuyderland Medical Centre between August 2018 and January 2019. Patients
with ACT treatment indicated as part of their regular care were screened for eligibility in the study. To
participate in this study, participants had to meet all of the following criteria: having sustained any type
of stroke or traumatic brain injury diagnosed by a neurologist; having a score of seven or higher on the
anxiety and/or the depression subscale of the Hospital Anxiety and Depression Scale (HADS); being more
than three months post-injury to prevent confounding by spontaneous recovery; being 18 years or older;
when using psychopharmacological medication, the dose should be stable four weeks prior to the study and
for the duration of the study; having access to the internet and a computer; mastering the Dutch language
sufficiently to benefit from treatment; and giving informed consent. Exclusion criteria were: history of brain
injury or disease (diagnosed by a neurologist and classified as moderate or severe) or a neurological disorder
other than a stroke or traumatic brain injury; pre-morbid disability as assessed with the Barthel Index
(score<19/20); severe co-morbidity that might affect outcome (e.g. cancer or major psychiatric illnesses)
for which treatment is given at the moment of inclusion; ongoing mood and/or anxiety disorder based on
the DSM 5 (20) for which pharmacological and/or psychological treatment was necessary at the onset of the
brain injury; and ACT for comparable problems in the year preceding study entry.

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Measures
Repeated measures. During the baseline period, participants were asked daily to rate the following
statements “I feel depressed” and “I feel anxious” on a 7-point Likert scale (with 1 being not depressed/
anxious and 7 being very depressed/anxious). These questions were based on questions from a study using
the experience sampling method, which have shown to be feasible for people with ABI (21). During the
treatment and follow-up phase, patients answered these questions weekly. Participants received a link via
email in the morning, which they had the whole day to complete. Since they always received the same link,
they occasionally filled in questions more than once per day. If this happened, the first answer was chosen.
Demographic information. Participants completed a demographic questionnaire at the start of the
study. Participants filled in information on gender, age, education, employment, and marital status. The
patients’ medical files provided clinical information on injury-related factors; type of brain injury, time since
brain injury, severity of injury, and lesion location.
5

Psychological distress
Hospital Anxiety and Depression Scale. The anxiety and depression subscales of the HADS were used to
measure anxiety and depressive symptoms (22). The scores range from 0 to 21 with higher scores indicating
higher levels of depression or anxiety. The HADS was found to have good psychometric properties in a
TBI sample (Cronbach’s α depression scale = .88; anxiety scale = .92) (23). Furthermore, a good internal
consistency for both subscales (Cronbach’s α depression scale = .81; anxiety scale = .84) was found in a
stroke population (24).
Depression Anxiety Stress Scales-21. The Depression Anxiety Stress Scales-21 (DASS-21) was used to
measure the levels of anxiety, depression, and stress of the participants (25). It consists of 21 items which
are rated on a 4-point Likert-scale. The scores range from 0 to 63 with higher scores indicating greater
levels of depression, anxiety, or stress. The questionnaire has been validated in a TBI sample. The internal
consistency was good for all three scales (Cronbach’s α depression scale = .90; stress scale = .89; and anxiety
scale = .82) (26). The DASS-21 was included next to the HADS because it includes a stress scale and includes
items on devaluation of life, self-deprecation, and hopelessness which the HADS lacks (27).

Psychological flexibility
Acceptance and Action Questionnaire-Acquired Brain Injury. The Acceptance and Action Questionnaire-
Acquired Brain Injury (AAQ-ABI) was used to measure psychological flexibility about the thoughts, feelings,
and behaviours that occur as a result of the brain injury (28). The AAQ-ABI is a nine-item self-report
measure that is scored on a 5-point Likert scale from 0 (not at all true) to 4 (very true). The total scores
range from 0 to 36, with a higher score indicating greater psychological inflexibility. This scale has a good
internal consistency in a Dutch sample of patients with ABI (Cronbach’s α=.87) (29) and in an Australian TBI
population (Cronbach’s α = .90) (28).

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Acceptance and Action Questionnaire II. The Acceptance and Action Questionnaire II (AAQ-II) was
administered to measure psychological inflexibility and experiential avoidance (30). The answers are scored
on a seven-point Likert scale with a range of 0 to 49. Higher scores indicate less acceptance and psychological
flexibility. Whiting et al. (28) validated the AAQ-II in a sample of patients with ABI (Cronbach’s α = .90). The
AAQ-II was included next to the AAQ-ABI for its added value as a measure with better studied treatment
sensitivity (29, 31).
Cognitive fusion. The Cognitive Fusion Questionnaire (CFQ-7) measures cognitive fusion on a 7-point
Likert scale (32). Scores range from 0 to 49. The higher the score, the more fused one is with one’s thoughts.
Gillanders et al. (32) showed that the CFQ has an excellent internal consistency (Cronbach’s α = .93) in a
sample of patients with multiple sclerosis. Furthermore, the CFQ-7 showed excellent internal consistency in
a Dutch sample of people with ABI (Cronbach’s α = .97) (29).
Valued living. The Valued Living Questionnaire (VLQ) is a two-part instrument that measures valued
living (33). First, the participant rates the importance of ten value domains on a ten point Likert scale.
Second, participants rate how consistently they have lived in accordance with their values within these
domains. Scores from both parts are used to calculate a valued living component. The internal consistency
of the valued living component has been demonstrated as adequate (Cronbach’s α = .74) (33). The VLQ has
been used in earlier research to measure valued living in patients with TBI (34).
Quality of life. Quality of life (QoL) was measured with the Short Form Survey (SF-12). The SF-12 was
used to measure the health status of the participants, but it can also be described as a broad assessment
of quality of life (35). The SF-12 has two subscales, the Physical Component Summary (PCS) and the Mental
Component Summary (MCS). The total score of both scales ranges from 0 to 100, with a higher score
indicating a better health status. The SF-12 demonstrates good psychometric properties (Cronbach’s α PCS
= .85 and MCS = .81) (36).
Participation. The Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) was used to
measure three aspects of participation: frequency of behaviours, participation restrictions experienced due
to health condition, and satisfaction with participation (37). The frequency scale measures the objective
level of participation, while the restrictions and satisfaction scales offer an insight into the subjective rating
of participation. The questionnaire consists of 31 items. A score ranging from 0 to 100 is calculated for
each scale. Higher scores indicate more participation, less restriction, and more satisfaction. It is a valid and
reliable measure for patients with ABI with a good internal consistency (Cronbach’s α = .70–.91) (37).

Blinding
Blinding of the participants and therapists was not feasible, due to the nature of the intervention. However,
research assistants who collected the data were blinded for the phase (baseline, intervention, or follow-up)
the participant was in at the moment of assessment.

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 A SCED study on the effectiveness of ACT for people with ABI

Intervention
The BrainACT intervention is an ACT treatment adapted for the needs and possible cognitive deficits of
people with ABI. The ACT intervention consisted of eight individual sessions of 90 minutes during a period of
3.5 months. The first four sessions were weekly, thereafter the sessions were biweekly, with a 3-week break
between the seventh session and last session. Participants did homework exercises lasting approximately
30 minutes for 6 days per week. Homework consisted of reading or listening to summaries of the sessions,
practising skills, and doing mindfulness exercises. At the start of the intervention, participants received a
workbook with instructions to read at home after each session. We used an eight-session protocol (see
Table 1) based on Jansen and Batink (38), Luoma et al. (39), and Whiting et al. (15) in which all six ACT
core processes were addressed. The protocol was altered based on the recommendations by Kangas and
McDonald (11) and Broomfield et al. (40). An expert group of six psychologists experienced in ACT and/or
in working with people with ABI gave further advice on the alterations. Alterations consisted of adaptions
5
taking into account the possible cognitive deficits of the participants, and brain-injury-related topics
discussed during the treatment. The intervention was provided individually by three certified psychologists
who completed an ACT training course of at least five days and are experienced in working with patients
with ACT (from four to seven years of experience) and TBI (three to 20 years of experience). Furthermore,
the therapists were trained by a researcher (JR) in delivering the protocol.

Table 1. Overview of the BrainACT intervention

Session Content Experiential exercises and Homework exercises

number metaphors
1 Value exploration and defining - Bus of life metaphor - Reading or listening to the summary
core values. - Values sorting exercise of this session
- Describing your gravestone or 80th - Explore which values deserve more or
birthday exercise less attention
- Writing down core values - Making pictures of valuable moments
2 Committed action on the long - What’s the next stop of your bus of - Reading or listening to the summary
and short term in relation life? (defining short-term goals) of this session
to values. Education about - Keep driving (defining long-term - Perform a daily activity with full
mindfulness and practising goals) attention
contact with the present - Introduction mindfulness: raisin - Valuable activity of the week:
moment. exercise performing one concrete action that
fits within one of the patient’s values
- Defining obstacles while making these
homework exercises
3 Creative hopelessness; the - Mindfulness exercise: mindful - Reading or listening to the summary
undeniability of human breathing of this session
suffering and the consequences - Identifying how the patient copes - Keeping track of unpleasant thoughts
on the long term of trying to with unpleasant experiences. or feelings and how the patient coped
control it. Identifying strategies - Tug-of war with a monster or with them
used to cope with negative bouncing ball metaphor - Reread the metaphor of the monster
thoughts and emotions. - Mindfulness exercise: body scan or bouncing ball
- Valuable activity of the week

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Session Content Experiential exercises and Homework exercises

number metaphors
4 Introducing acceptance as an - Tug-of war with a monster, - Reading or listening to the summary
alternative to control. unwanted guest in your bus of life, or of this session
the finger trap metaphor - Willingness exercise
- Explanation of the difference - Valuable activity of the week
between pain and suffering with the
glass of water exercise
- Mindfulness exercise: making space,
and allowing what is there
5 Changing the relationship with - Mindfulness exercise: attention for - Reading or listening to the summary
thoughts, naming the mind. thoughts of this session.
- The passengers in your bus of life - Watch the YouTube video of the bus
(in combination with post-its) of life
- Defusion exercise: naming the mind - Practice defusion exercises
- Defusion exercise: singing difficult -Valuable activity of the week
thoughts -Observing the mind during valuable
- Mindfulness exercise: floating activity
leaves on a river
6 Changing the relationship with - Metaphor: the sky and the weather - Reading or listening to the summary
thoughts about oneself and - Exercise: lifeline of this session
introducing the constant self. - Metaphor: Suits (thoughts about - Take off a suit that doesn’t fit
oneself) that don’t fit (anymore)
- Exercise: backpack - Practice a mindfulness exercise
-Valuable activity of the week
7 Repetition on defusion and - Mindfulness exercise: the body scan - Reading or listening to the summary
mindfulness. -Defusion exercises: physicalizing the of this session
thought - Practice a mindfulness exercise daily
- Mindfulness exercise: mindful -Valuable activity of the week
breathing
8 Review of the different core - Mindfulness exercise: attention for - Reading or listening to the summary
components, explanation on noise of this session
how these skills together lead - Car metaphor - Try to keep practising with the
to psychological flexibility, and - Bus of life metaphor and exercise different ACT skills
preparation on relapse and - Strategies on how to keep using - Start integrating ACT into your daily life
setbacks. acquired ACT skills in daily life - Live your life as is valuable to you!
Stop fighting, start living!

Setting
The sessions were performed at Zuyderland Medical Centre, a general hospital in the Netherlands, at the
rehabilitation and medical psychology department. The sessions took place in a therapy room where the
psychologist and participant sat across from each other at a table.

Treatment adherence
Treatment adherence was checked using a checklist which the therapists filled out following each session. In
this checklist, they indicated which exercises and metaphors they had covered and which ones were skipped
or altered. Based on this information, a percentage was calculated from the total number of exercises and
metaphors (see table 1) in the protocol. Likewise, therapists indicated which homework assignments were

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completed and a percentage was calculated. The treatment adherence rate was 60%, 80%, 82%, and 97%
for participant one, two, three, and four respectively. Furthermore, participant one completed 83% of the
homework exercises, participant two 86%, participant three 90%, and participant four 97%.

Procedure
Participants with ABI for whom an ACT treatment was indicated were eligible for this study. Psychologists
screened patients on the in- and exclusion criteria and when patients met the criteria they were informed
about the study. After signing the informed consent, the pre-baseline measurements and baseline
randomization took place. Participants were allocated to a baseline varying from 20 to 42 days, after which
they started with the ACT intervention (treatment phase) and follow-up phase. During the baseline phase,
repeated measures were filled in daily, and during the treatment and follow-up phase this was filled in 5
weekly. There were five more measuring moments (pre-treatment, during treatment, post-treatment, and
at seven and 12 months) during which participants filled in the questionnaires on paper. Research assistants
performed these measurements after instructions of a researcher (JR) and following a protocol.

Data analyses
For each participant, levels of anxiety and depressive symptoms were plotted graphically for visual analyses.
Visual analyses were conducted following the recommendations of Ledford and Gast (41). Horizontal lines
are depicted to observe changes in the average between phases. The trend was determined by the slope
and direction of the best fitting straight line for each phase. This was done using the Split Middle Method as
proposed by Ledford and Gast (41). Trend stability was defined by a stability window +/−25% of the trend
line. Autocorrelation often occurs in SCED data and is associated with an increase in the occurrence of Type
I or II errors (42) and therefore, it is important to assess and report it (43). Autocorrelation was calculated
using the formula proposed by Box and Jenkins (44). A lag-1 autocorrelation coefficient of 0.5 or higher was
considered high (45). Autocorrelation was not calculated for four phases (both treatment+follow-up phases
of participant 1 and 4) because they were constant at floor level. Autocorrelation coefficients were higher
than 0.5 for six phases (both baseline phases of participant 1, both treatment+follow-up phases phases of
participant 2, and both baseline phases of participant 3).
Randomization tests were used to determine if the levels of anxiety and depression significantly
differed between phases (baseline versus treatment+follow-up phase). This was done as described by Bulte
and Onghena (46). These tests are permutation tests relying on random assignment (baseline length in
our case) to test a null hypothesis (47, 48), the null hypothesis for the current study being no difference
between phases (no treatment effect). In order to compare the phases, a t-statistic was calculated for each
possible permutation. This t-statistic is the absolute difference between the mean of the baseline phase
and the mean of the treatment+follow-up phase (mean of baseline phase - mean of treatment+follow-up
phase). The t-statistic is calculated for every possible starting point of the intervention. The t-statistics that

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are as large as or larger than the observed data point (starting point of treatment) are divided by the total
number of possible permutations, which is the probability association (48). Therefore, there is a minimum
number of possible starting points in order to obtain a p-value of <0.05. In the current study 23 possible
randomization assignments permit a p-value of <0.05 (1/23 = 0.043). Since it was unclear beforehand when
participants would start to respond to the intervention (i.e. decrease in anxiety or depressive symptoms),
randomization tests were performed assuming a delayed effect. After the main randomization test, to test
for immediate effect, the randomization tests were repeated until the smallest p-value was reached (49,
50). The smallest p-value is equivalent to the moment in which the difference between means (and thus
the t-statistic) of both phases is the largest. We hypothesized that the delayed effect should take place
during the first thirteen measurements of the treatment+follow-up phase since we did expect the effect
to take place during the treatment. Additionally, the p-values of the immediate and delayed effects were
combined following Edgington’s (51) additive method. Randomization tests and combining of the p-values
were performed using the SCDA plug-in package in R (52).
Non-overlap of all pairs (NAP) was used as a measure of effect (53). Since the participants were all
more than three months post-ABI, we did not expect spontaneous improvements in the baseline phase.
Therefore, NAP is a more appropriate measure than baseline corrected TAU (54). NAP is a non-overlap index
that can be derived from Mann-Whitney U (55). NAP summarizes the data overlap between each baseline
data point and each treatment+follow-up phase data point in turn. NAP is calculated by dividing the number
of comparisons with no overlap by the total number of comparisons (53). Parker and Vannest (53) proposed
the following ranges in order to interpret NAP; scores ranging from 0 to 0.65 are weak effects, from 0.66
to 0.92 are medium effects, and from 0.93 to 1.0 are large or strong effects. An online calculator was used
to calculate NAP (56). High levels of autocorrelation can lead to overestimation of the effect measure and
therefore NAP scores should be interpreted with some caution (57), however confidence intervals computed
for NAP do assume independence, as I mentioned in the previous review.
In order to define clinical significant change, the Reliable Change Index (RCI) was calculated between
the pre-treatment measurements and the other measurements. This was done using the formula of
Jacobson and Truax (58). Since the outcomes are z-scores they are significant if z < -1.96 or z > 1.96.

Results
Four participants were included in the study. The demographic and injury-related characteristics can be
found in table 2. There were some deviations from protocol. First, during the follow-up phase of participant
1, he did not want to continue to answer the weekly questions. He had been filling out the same answers
for weeks and expected to continue to do so. It was therefore agreed that the researcher (JR) would fill in
the answers for him and if the answer was different, he would let the researcher know. Participant 1 did
fill in the questionnaires during the follow-up measurements, the scores of which corresponded with the
answers that he had filled in. Second, participant 2 filled in 1 (the lowest score) for the anxiety score for the
first 16 days. However, during the pre-treatment measuring moment, he explained that he misunderstood

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the question and that the score should be higher in these first 16 days. It was agreed upon to impute these
16 days with the average score of the remaining 11 days (score of 3.18).

Table 2. Participant characteristics

Participant 1 2 3 4
Sex Male Male Male Female
Age 59 63 35 47
Educational level Higher professional Secondary vocational Primary vocational Higher professional
education education education education
Occupation Incapacitated Employed Incapacitated Employed
Marital status Married Married Married Married
Time since injury (months) 22 64 10 36
Type of injury Traumatic brain
injury
Brainstem stroke Traumatic brain injury Right hemispheric
stroke 5

Case formulation

Participant 1
Participant 1 is a 59-year old man, who sustained a TBI after falling down a set of stairs in 2016. After the
accident he lost consciousness (unknown for how long) and experienced post-traumatic amnesia for one hour.
He had no psychiatric history. After the accident, he completed an outpatient rehabilitation programme, during
which he started an e-health module for panic disorder, which he did not finish. Several months after the
rehabilitation programme he experienced a severe increase in fatigue, cognitive, and emotional complaints. His
physiatrist (rehabilitation physician) then referred him to the department of medical psychology. He worried
a lot about his future. He avoided busy or stressful situations. He for instance stopped seeing his friends from
a cycling group. He did this to control his complaints, however, he felt frustrated that this did not reduce his
complaints. The participant is married and has two adult children. He works in finance and was on sick leave.
During the intervention, he started to share his complaints and negative feelings with his wife and
his friends. Instead of hiding his feelings, pretending he was okay, or avoiding others. This helped him
to reconnect to others and to restart undertaking activities together. When introduced to the theme of
fusion, he initially found it hard to recognize that this could apply to him. However, looking back at the
intervention he felt that fusion, defusion, and self as context had been the most helpful and valuable parts
of the intervention. Moreover, it is good to mention that during the treatment a financial dispute, which had
caused a lot of stress, was resolved.

Participant 2
Participant 2 is a 63-year-old man, who suffered from an ischemic brainstem stroke in 2013. He had no
psychiatric history. He was referred by his general practitioner to the mental health care department because

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of a depressive disorder based on the DSM criteria. He reported mood problems, excessive worrying,
fatigue, and poor concentration. He was regarded as a very active and sporty man, who sets high standards
for himself. In his free time, he was active as a swimming trainer, four evenings a week, for more than 30
years. In the year before the intervention, the emotional problems and fatigue slowly increased. He stopped
running and slept a lot, also during the day. He was working as a lawyer, 32 hours a week. The patient is
married and has two children and three grandchildren.
During the intervention, he decided to stop with his activities as a swimming coach, because he
realized that this role cost him a lot of energy and was no longer satisfactory. He told the therapist: “my
mind told me that I have to do this, but I realized that it was no longer satisfactory for me”. He also restarted
running and going to the cinema with his wife. After the intervention, he needed less sleep during the day
and the depressive disorder was in remission (based on the DSM criteria). His partner joined the treatment
sessions and was actively involved in the homework assignments.

Participant 3
Participant 3 is a 35-year-old man, who sustained a TBI after a bike accident in 2018. Symptoms he experienced
following the accident were nausea, emesis, headache, tinnitus, and diplopia. He had no psychiatric history.
He was referred by the neurologist to the mental health care department. He reported mood problems,
including apathy, irritability, and restlessness. In addition, he suffered from fatigue, memory and attention
problems, and tinnitus. Because of his symptoms, he often cancelled social appointments and was worrying
about the future. He experienced pain in his shoulder for years. As a result of these, he could not carry out
his work as a house painter and was receiving a disability payment. He could not carry out his work as a
house painter because of severe shoulder dysfunction and was receiving a disability payment. The patient
is married.
During the intervention, he discovered he did many activities because it was expected by others.
He has become more assertive and makes more value-oriented choices regarding activities. After the
intervention, he indicated that he mainly lived more in the here and now and he experienced fewer worries,
also regarding his tinnitus. His wife was actively involved in the process at home, partly because of his severe
dyslexia. The patient was satisfied with the treatment and experienced fewer emotional complaints.

Participant 4
Participant 4 is a 47-year old woman who had a lacunar stroke in 2016. She had no psychiatric history.
Following the stroke, the patient followed a rehabilitation programme, which included psychological
treatment consisting of 10 sessions CBT. After this first rehabilitation period, she had a 100% return to work.
The patient tried to bring everything back to normal, leaving this difficult period in her life behind her and
putting a lot of effort into her return to work. Soon, however, she noticed that things were everything but
normal. She suffered from fatigue and could not return to her normal activities like leisure time with her

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family and sports. The patient reported an agitated mood, fatigue, and a general loss of pleasure. Moreover,
she reported feelings of guilt because of her lack of energy to spend time with her children. Next to that,
she feared recurrence of a stroke when experiencing sudden dizziness or nausea. Finally, she experienced
her relapse of these symptoms as a failure. She worked as a logistic manager in a peripheral hospital for 20
hours a week. She is married and has 2 children of which the eldest has an intellectual disability.
During the intervention, the patient was confronted with her experiential avoidance. Strategies she
used to avoid difficult emotions were to endure in work and to trivialise or rationalize problems. Once
confronted with her behaviour she started to open up, especially to her husband. Particularly, she discussed
with him her negative feelings when her oldest child showed difficult behaviour. She learned to allow her
negative feelings instead of suppressing them. The theme of cognitive defusion was difficult for her at
first. In the end, however, it gave her new insights on how to accept her thoughts and feelings as they
were. Additionally, she recognized her tendency to take control of everything herself. She began to share
5
and delegate, both at home and at work. This resulted in more time to spend with her family. The patient
reported feeling happier at the end of the intervention.

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Figure 1. Repeated measures of depressive symptoms per participants 1, 2, 3, and 4 over time. The vertical lines are the
start of the intervention. The horizontal line is the average score per phase. The participants started with the baseline
phase at different dates (participant one started on 6-8-2018, participants two on 9-8-2018, participant 3 on 31-10-2018,
and participant 4 on 22-1-2019).

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Figure 2. Repeated measures of anxiety symptoms per participants 1, 2, 3, and 4 over time. The vertical line is the start
of the intervention. The horizontal line is the average score per phase. The participants started with the baseline phase
at different dates (participant one started on 6-8-2018, participants two on 9-8-2018, participant 3 on 31-10-2018, and
participant 4 on 22-1-2019).

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Table 3. Phase characteristics of the repeated depression scores

Participant Number of measurements Baseline Mean (SD) Number of measurements Intervention + FU

baseline phase intervention + FU phase Mean (SD)
1 36 4.86 (1.17) 48 1.29 (0.74)
2 27 3.93 (0.87) 51 2.63 (1.00)
3 30 2.52 (0.95) 46 2.04 (0.51)
4 39 2.66 (0.63) 55 1.16 (0.46)

Table 4. Phase characteristics of the repeated anxiety scores

Participant Number of measurements Baseline Mean (SD) Number of measurements Intervention + FU

baseline phase intervention + FU phase Mean (SD)
1 36 5.97 (0.88) 48 1.58 (1.38)
2 27 3.18 (2.37) 51 2.37 (1.06)
3 30 1.76 (0.74) 46 1.64 (0.53)
4 39 1.92 (0.27) 55 1.07 (0.26)

Visual analyses, randomization tests, and NAP

The repeated anxiety and depression scores are represented visually in figure one and two. Characteristics
of phase lengths and measurements are represented in table three and four.

Participant 1
Participant one was assigned to a baseline length of 37 days.

Depression scores
Visual analyses. There was a decrease in the average depression scores in the baseline compared to the
treatment+follow-up phases. The trend in the baseline phase was accelerating, this levelled to zero-
celerating in the treatment phase. Both phases had high trend stability, which was 88.89% for the baseline
phase and 85.42% for the treatment+follow-up phase.
Response to the intervention. Randomization tests (Table 5) showed a statistically significant delayed
effect (t = 3.63, p = 0.043), which reached significance after two weeks. Furthermore, there was a large
difference between the baseline and treatment+follow-up phase (NAP = 0.99, 90%CI = 0.95 to 1).

Anxiety scores
Visual analyses. There was a decrease in the average anxiety scores in the baseline compared to the
treatment+follow-up phases. The trend in the baseline phase was accelerating, this levelled to zero-
celerating in the treatment+follow-up phase. Both phases had high trend stability, which was 100% for the
baseline phase and 81.25% for the treatment+follow-up phase.
Response to the intervention. Randomization tests (Table 6) showed a statistically significant delayed
effect (t = 4.72, p = 0.043), which reached significance after six weeks. Furthermore, there was a large
difference between the baseline and treatment+follow-up phase (NAP = 0.97, 90%CI = 0.92 to 0.99).

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Participant 2
Participant two was assigned to a baseline length of 27 days.

Depression scores
Visual analyses. There was a decrease in the average depression scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was decelerating and zero-celerating in the
treatment+follow-up phase. Both phases had high trend stability, which was 96.3% for the baseline phase
and 50.98% for the treatment phase.
Response to the intervention. Randomization tests showed a statistically significant delayed effect (t
= 1.56, p = 0.043), which reached significance after six weeks. Furthermore, there was a medium difference
between the baseline and treatment+follow-up phase (NAP = 0.85, 90%CI = 0.75 to 0.91).
5
Anxiety scores
Visual analyses. There was a decrease in the average anxiety scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was zero-celerating, which stayed zero-
celerating in the treatment+follow-up phase. Both phases had high trend stability, which was 85.19% for the
baseline phase and 49.02% for the treatment phase.
Response to the intervention. Randomization tests showed a statistically significant delayed effect (t =
1.21, p = 0.043), which reached significance after five weeks. Furthermore, there was a medium difference
between the baseline and treatment+follow-up phase (NAP = 0.85, 90%CI = 0.77 to 0.91).

Participant 3
Participant three was assigned to a baseline length of 38 days.

Depression scores
Visual analyses. There was a decrease in the average depression scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was decelerating and zero-celerating in the
treatment+follow-up phase. Both phases had high trend stability, which was 62.07% for the baseline phase
and 74.47% for the treatment+follow-up phase.
Response to the intervention. Randomization tests showed no statistically significant immediate or
delayed effect (t = 3,63, p = 0.27). Furthermore, there was a weak difference between the baseline and
treatment+follow-up phase (NAP = 0.63, 90%CI = 0.52 to 0.73).

Anxiety scores
Visual analyses. There was a small decrease in the average anxiety scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was zero-celerating and accelerating in the
treatment+follow-up phase. Both phases had high trend stability, which was 51.72% for the baseline phase
and 74.47% for the treatment+follow-up phase.

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Response to the intervention. Randomization tests showed a statistically significant immediate effect
(t = 0.120, p = 0.043. However, there was a small difference between the baseline and treatment+follow-up
phase (NAP = 0.53, 90%CI = 0.42 to 0.64).

Participant 4
Participant four was assigned to a baseline length of 39 days.

Depression scores
Visual analyses. There was a decrease in the average depression scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was zero-celerating, which stayed zero-
celerating in the treatment+follow-up phase. Both phases had high trend stability, which was 50% for the
baseline phase and 87.27% for the treatment+follow-up phase.
Response to the intervention. Randomization tests showed a statistically significant delayed effect (t
= 1.58, p = 0.043), which reached significance after five weeks. Furthermore, there was a large difference
between the baseline and treatment+follow-up phase (NAP = 0.96, 0.90 to 0.98).

Anxiety scores
Visual analyses. There was a decrease in the average anxiety scores in the baseline compared to
treatment+follow-up phase. The trend in the baseline phase was zero-celerating, which stayed zero-
celerating in the treatment+follow-up phase. Both phases had high trend stability, which was 92.11% for the
baseline phase and 92.73% for the treatment phase.
Response to the intervention. Randomization tests showed a statistically significant delayed effect (t
= 0,91, p = 0.043), which reached significance after five weeks. Furthermore, there was a large difference
between the baseline and treatment phase (NAP = 0.93, 90%CI = 0.86 to 0.96).

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Table 5. Immediate and delayed randomization tests of the depression scores with combined p-values

Participant Immediate Delayed effect Delayed Delayed Delayed Delayed effect Effect was
effect p-values after two week effect after effect after effect after after six weeks significant at
three weeks four weeks five weeks week
1 .261 .043* .087 .174 .217 .130 2
2 .522 .478 .435 .087 .217 .043* 6
3 .217 .391 .478 .956 .607 .652 -
4 .217 .174 .130 .087 .043* (not within 5
randomization
possibilities)
Combined .091 .058 .072 .119 .057 .935
p-values
*significant immediate or delayed effect

Table 6. Immediate and delayed randomization tests of the anxiety scores with combined p-values
5
Participant Immediate Delayed effect Delayed Delayed Delayed Delayed effect Effect was
effect p-values after two week effect after effect after effect after after six weeks significant at
three weeks four weeks five weeks week
1 .261 .217 .174 .130 .087 .043* 6
2 .565 .478 .348 .087 .043* .174 5
3 .043* .217 .130 .083 .261 .565 1
4 .217 .174 .130 .087 .043 (not within 5
randomization
possibilities)
Combined .058 .058 .016* .016* <.01* .079
p-values
*significant immediate or delayed effect

Reliable Change Index

In table 7 the Reliable Change Index can be found between the different measurement moments of the
HADS, DASS-21 stress scale, AAQ-II, AAQ-ABI, CFQ-7, and VLQ. The complete table including the DASS-21
anxiety and depression scale, Sf-12, and USER-P can be found in the supplemental materials.

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Table 7. Reliable Change Index

PP1 PP2 PP3 PP4

HADS-D
Pre-baseline 7 9 9 5
Pre-treatment (RCI pre-baseline/pre-treatment 6 (0.40) 11 (-0.80) 9 (0) 9 (-1.61)
During-treatment (RCI pre-treatment/During-treatment) 5 (0.40) 3 (3.21*) 8 (0.40) 6 (1.21)
Post-treatment (RCI pre-treatment/post-treatment) 2 (1.61) 7 (1.61) 5 (1.61) 3 (2.41*)
7 month FU (RCI pre-treatment/7FU) 1 (2.01*) 3 (3.22*) 11 (-0.80) 3 (2.41*)
12 months FU (RCI pre-treatment/12FU) 0 (2.41*) 3 (3.22*) 10 (-0.40) 0 (3.62*)
HADS-A
Pre-baseline 10 3 6 7
Pre-treatment (RCI pre-baseline/pre-treatment 10 (0) 16 (-5.66) 8 (-0.87) 8 (-0.43)
During-treatment (RCI pre-treatment/During-treatment) 10 (0) 6 (4.35*) 7 (0.44) 6 (0.87)
Post-treatment (RCI pre-treatment/post-treatment) 4 (2.61*) 8 (3.48*) 3 (2.17*) 5 (1.31)
7 month FU (RCI pre-treatment/7FU) 2 (3.48*) 4 (5.22*) 7 (0.43) 5 (1.31)
12 months FU (RCI pre-treatment/12FU) 0 (4.35*) 6 (4.35*) 10 (-0.87) 5 (1.31)
DASS-21 stress
Pre-baseline 15 9 12 5
Pre-treatment (RCI pre-baseline/pre-treatment 11 (1.65) 18 (-3.72) 11 (0.41) 6 (-0.41)
During-treatment (RCI pre-treatment/During-treatment) 12 (-0.41) 5 (5.37*) 9 (0.83) 6 (0)
Post-treatment (RCI pre-treatment/post-treatment) 5 (2.48*) 6 (4.96*) 6 (2.07*) 5 (0.41)
7 month FU (RCI pre-treatment/7FU) 3 (3.31*) 5 (5.37*) 8 (1.24) 4 (0.83)
12 months FU (RCI pre-treatment/12FU) 0 (4.54*) 4 (5.78*) 10 (0.41) 4 (0.83)
AAQ-II
Pre-baseline 15 15 14 9
Pre-treatment (RCI pre-baseline/pre-treatment 12 (0.66) 34 (-4.17) 11 (0.66) 11 (-0.44)
During-treatment (RCI pre-treatment/During-treatment) 15 (-0.66) 17 (3.73*) 12 (-0.22) 10 (0.22)
Post-treatment (RCI pre-treatment/post-treatment) 9 (0.66) 7 (5.93*) 9 (0.44) 9 (0.44)
7 month FU (RCI pre-treatment/7FU) 8 (0.88) 14 (4.39*) 16 (-1.09) 8 (0.66)
12 months FU (RCI pre-treatment/12FU) 8 (0.88) 11 (5.05*) 13 (-0.44) 7 (0.88)
AAQ-ABI
Pre-baseline 12 7 8 9
Pre-treatment (RCI pre-baseline/pre-treatment 7 (1.20) 27 (-4.80) 10 (-0.48) 9 (0)
During-treatment (RCI pre-treatment/During-treatment) 12 (-1.20) 10 (4.08*) 9 (0.24) 7 (0.48)
Post-treatment (RCI pre-treatment/post-treatment) 1 (1.44) 11 (3.84*) 7 (0.72) 5 (0.96)
7 month FU (RCI pre-treatment/7FU) 2 (1.20) 6 (5,04*) - 3 (1.44)
12 months FU (RCI pre-treatment/12FU) 1 (1.44) 8 (4,56*) 12 (-0.48) 1 (1.92)
CFQ-7
Pre-baseline 33 35 24 17
Pre-treatment (RCI pre-baseline/pre-treatment 19 (3.61*) 44 (-2.32) 36 (-3.10) 12 (1.28)
During-treatment (RCI pre-treatment/During-treatment) 23 (-1.03) 32 (3.10*) 33 (0.77) 11 (0.26)
Post-treatment (RCI pre-treatment/post-treatment) 10 (2.32*) 17 (6.97*) 14 (5.68*) 12 (0)
7 month FU (RCI pre-treatment/7FU) 7 (3.10*) 11 (8.51*) 26 (2.58*) 10 (0.52)
12 months FU (RCI pre-treatment/12FU) 10 (2.32*) 20 (6.19*) 24 (3.10*) 9 (0.77)
VLQ composite score
Pre-baseline - 53.50 - 56.80
Pre-treatment (RCI pre-baseline/pre-treatment 45.20 52.00 (0.14) 47.40 61.90 (-0.49)
During-treatment (RCI pre-treatment/During-treatment) 55.90 (-1.02) 48.20 (0.36) 33.90 (1.29) 53.20 (0.83)
Post-treatment (RCI pre-treatment/post-treatment) - 57.60 (-0.54) 35.80 (1.11) 58.90 (0.29)
7 month FU (RCI pre-treatment/7FU) 53.60 (-0.80) 59.20 (-0.69) 34.40 (1.25) 66.70 (-0.46)
12 months FU (RCI pre-treatment/12FU) - 48.40 (0.38) 49.30 (-0.20) 56.20 (0.60)
HADS, Hospital Anxiety and Depression Scale; DASS-21, Depression, Anxiety and Stress Scale-21; AAQ-II, Acceptance
and Action Questionnaire II; AAQ-ABI, Acceptance and Action Questionnaire Acquired Brain Injury; VLQ, Valued Living
Questionnaire; CFQ-7, Cognitive Fusion Questionnaire.
Table includes raw scores with the RCI, Reliable Change Index between brackets
* clinical significant change

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Discussion
The main goal of this study was to examine the effectiveness of the BrainACT intervention for people
experiencing ABI related anxiety and depressive symptoms. This was done using a non-concurrent multiple
baseline design across four cases.

Main outcome measures

Participants 1, 2, and 4 showed medium to large improvements in anxiety and depressive complaints.
Furthermore, these three participants responded to the treatment within two to six weeks after starting the
BrainACT intervention. The delayed effect of participant 1 reached significance after two weeks. A study by
Keinonen et al. (59) found that 25% of patients can experience a sudden gain (an abrupt reduction in symptom
severity after which they stabilize) after the first two sessions of an ACT intervention. It seems likely, also looking 5
at his graph, that participant 1 experienced a sudden gain in depression scores after session two. Interestingly,
all other delayed effects reached significance at week five or six. Furthermore, these three participants
(except for the anxiety and stress symptoms of participant four, which however were low at the start of the
intervention) showed clinically significant improvements in anxiety, depressive, and stress symptoms. These
lasted up to a year after the start of the intervention. Based on these results it can be concluded that the
BrainACT intervention was successful in decreasing anxiety and depressive complaints.
For participant 3 the results were less evident. NAP scores indicated that he experienced a weak
decrease in depression and anxiety scores, while the randomization tests showed a significant immediate
effect for anxiety and no significant effects for depression. There was a clinically significant change on the
HADS-anxiety post-treatment of participant 3. However, this did not last and the HADS scores on the follow-
up moments are even higher than before the treatment. The scores of the repeated measures on both
graphs show a similar pattern. This could be an indication that the treatment was not long enough or that
extra booster sessions after a few months would have been beneficial. While the patient did state that he
was satisfied with the treatment and experienced fewer emotional complaints, these results do not indicate
that the BrainACT intervention decreased his anxiety and depressive complaints.
For all four participants, the clinically significant changes in anxiety and depression are mostly seen on the
subscales of the HADS and not on DASS-21. Although the DASS-21 was primarily included to measure stress and
not anxiety or depression, it would have been more convincing if anxiety and depression had reached clinically
significant change on the DASS-21 as well. Patients scored lower pre-treatment anxiety and depression scores on
the DASS-21 compared to the HADS scores. As a result, there was less room for improvement on the DASS-21.

ACT-process measures
Participants 1, 2, and 4 showed no clinically significant improvement regarding psychological flexibility,
experiential avoidance, or psychological flexibility related to thoughts and feelings about ABI, although the
scores did improve for these patients. Participant 3 did show clinically significant improvements in these

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domains. However, this seems to be a result of a very high score for both measures on the pre-treatment
measurement moment, making these results quite unreliable. The non-clinical significant improvement in
psychological flexibility corresponds with the results of Whiting et al. (15), where an improvement in stress
and depression was also found, but no improvement in psychological flexibility in severe TBI participants,
who had received an ACT intervention. However, Sander et al. (16) did find a significant improvement
regarding psychological flexibility in TBI participants who had received an ACT intervention. Clearly, more
research is needed into the role of psychological flexibility during an ACT intervention for ABI related
anxiety and depression symptoms. Although the psychometric properties of the AAQ-II and AAQ-ABI have
been studied in patients with ABI (28, 29), there has been critique on the validity of the AAQ-II. Studies
found that rather than measuring psychological flexibility it measures psychological distress or neuroticism
(60, 61). This should be taken into account when using the AAQ-II. However, if the AAQ-II is a measure
of psychological distress, one would expect greater reductions in scores, similar to the other measures of
psychological distress in this study.
Furthermore, no improvements were found in value-driven behaviour for all four participants. This is
somewhat surprising since the treatment protocol places a strong emphasis on the identification of values
and afterwards, valued behaviours were followed up and encouraged each session (valuable activity of
the week). Nonetheless, it might be possible that this was still not sufficient to elicit behavioural change,
which has proven to be complex (62). Another explanation could be found in the instrument used for the
measurement of valued behaviour, the VLQ. This questionnaire uses ten broad value domains, which leaves
no room for personal values (that might have been targeted during treatment) outside these domains
and the second part of the questionnaire is quite difficult to fill in. Moreover, changes in only one or two
domains, may not be noticed in the total score of the VLQ. On the other hand, in other studies, the VLQ has
shown improvements following ACT interventions (63). Currently, an adapted version for patients with ABI
of the VLQ is being developed specifically to tackle these problems (64). It would be interesting to know if
this adapted scale would be able to measure change regarding valued behaviour.
There was a reduction in cognitive fusion for all four participants, which was clinically significant for
participants 1, 2, and 3. This could be the result of the emphasis placed on cognitive defusion in the treatment
protocol. For instance, in session seven, information on cognitive defusion was rehearsed and practised to
improve this skill. In other medical populations, cognitive fusion (and not illness-related symptoms) was
related to levels of depression (65, 66). Furthermore, previous research has found that cognitive defusion
significantly mediates changes in quality of life, behavioural avoidance, and depression in both ACT and CBT
interventions (67, 68).

Secondary outcome measures

There were no clear improvements in social participation or physical health-related quality of life. However,
mental health-related quality of life did improve for all participants, which was a clinically significant
improvement for two participants and very close to significance for the other two participants. These findings

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are in line with results from previous studies which also found improvements in mental health-related quality
of life but not in physical health-related quality of life following ACT interventions (69, 70). It can be concluded
that all four participants, to some extent, benefited from the treatment regarding this outcome.

Strengths and limitations

This study has several strengths. The follow-up time of a year is long compared to other single case
studies. Therefore, there were a considerable number of data points in each phase (ranging from 27 to
54), especially considering the minimum of five data points per phase (71) and Michiels and Onghena (72)
advise at least 30 measurements in total to achieve adequate power for randomization tests. Furthermore,
the study succeeded in replicating the treatment effect in three different participants, thus strengthening
the hypotheses that ACT is an effective treatment for psychological distress following ABI. Lastly, no adverse 5
events occurred for any of the participants.
However, this study is not without its limitations. First, increased levels of autocorrelation were found
for six phases. As mentioned earlier, NAP does not control for autocorrelation. High levels of autocorrelation
can lead to overestimation of the effect measure and therefore NAP scores should be interpreted with some
caution (57). This should be taken into account when the results in the phases with high autocorrelation.
Second, the two participants with a stroke were relatively young and three participants had high education
levels. As a result, these findings might not translate to older stroke patients or patients with a lower education
level. Third, the treatment adherence rating was not done completely independently, which is recommended
(71). Although the treatment adherence rate was calculated by the researcher, the checklists were filled in
by the psychologists. Furthermore, the treatment adherence rate of the treatment delivered to participant
1, is quite low with 60%, while the minimum is an 80% compliance with the rating protocol (71). The patient
experienced the treatment as cognitively challenging and in agreement with the researcher it was decided
to decrease the number of exercises and metaphors discussed in the sessions. Fourth, from these results, no
conclusions can be made as to whether ACT is more effective for patients with stroke or TBI, which was also not
within the scope of this study. However, it seems that levels and aetiology of depression generally do not differ
between stroke or TBI patients (73), nor does their coping style (74). Levels of anxiety can be higher for patients
with a stroke, since they can experience fear of stroke recurrence (75, 76). Further research should focus on
possible differences in the effectiveness of ACT for patients with different types of ABI.

Conclusion
In conclusion, this study adds to the existing knowledge that ACT is likely helpful in treating psychological
distress following ABI and that the BrainACT intervention can decrease anxiety and depressive complaints in
individuals with ABI. Larger randomized controlled trials or replication with single case studies are needed
to obtain additional evidence on the efficacy of ACT for individuals with ABI.

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Supplementary material

Table 1. Reliable Change Index

PP1 PP2 PP3 PP4

HADS-D
Pre-baseline 7 9 9 5
Pre-treatment (RCI pre-baseline/pre-treatment 6 (0.40) 11 (-0.80) 9 (0) 9 (-1.61)
During-treatment (RCI pre-treatment/During-treatment) 5 (0.40) 3 (3.21*) 8 (0.40) 6 (1.21)
Post-treatment (RCI pre-treatment/post-treatment) 2 (1.61) 7 (1.61) 5 (1.61) 3 (2.41*)
7 month FU (RCI pre-treatment/7FU) 1 (2.01*) 3 (3.22*) 11 (-0.80) 3 (2.41*)
12 months FU (RCI pre-treatment/12FU) 0 (2.41*) 3 (3.22*) 10 (-0.40) 0 (3.62*)
HADS-A
Pre-baseline 10 3 6 7
Pre-treatment (RCI pre-baseline/pre-treatment 10 (0) 16 (-5.66) 8 (-0.87) 8 (-0.43)
During-treatment (RCI pre-treatment/During-treatment) 10 (0) 6 (4.35*) 7 (0.44) 6 (0.87)
Post-treatment (RCI pre-treatment/post-treatment) 4 (2.61*) 8 (3.48*) 3 (2.17*) 5 (1.31)
7 month FU (RCI pre-treatment/7FU) 2 (3.48*) 4 (5.22*) 7 (0.43) 5 (1.31)
12 months FU (RCI pre-treatment/12FU) 0 (4.35*) 6 (4.35*) 10 (-0.87) 5 (1.31)
DASS-21 depression
Pre-baseline 3 7 4 2
Pre-treatment (RCI pre-baseline/pre-treatment 4 (-0.44) 7 (0) 7 (-1.33) 2 (0)
During-treatment (RCI pre-treatment/During-treatment) 1 (1.33) 7 (0) 3 (1.77) 2 (0)
Post-treatment (RCI pre-treatment/post-treatment) 1 (1.33) 3 (1.77) 0 (3.10*) 0 (0.89)
7 month FU (RCI pre-treatment/7FU) 1 (1.33) 2 (2.22*) 8 (-0.44) 1 (0.44)
12 months FU (RCI pre-treatment/12FU) 0 (1.77) 4 (1.33) 6 (0.44) 1 (0.44)
DASS-21 anxiety
Pre-baseline 5 4 6 0
Pre-treatment (RCI pre-baseline/pre-treatment 3 (0.83) 8 (-1.66) 6 (0) 0 (0)
During-treatment (RCI pre-treatment/During-treatment) 5 (-0.83) 1 (2.90*) 1 (2.07*) 1 (-0.41)
Post-treatment (RCI pre-treatment/post-treatment) 1 (0.83) 0 (3.32*) 3 (1.23) 0 (0)
7 month FU (RCI pre-treatment/7FU) 0 (1.24) 3 (2.07*) 4 (0.83) 1 (-0.41)
12 months FU (RCI pre-treatment/12FU) 0 (1.24) 6 (0.83) 4 (0.83) 0 (0)
DASS-21 stress
Pre-baseline 15 9 12 5
Pre-treatment (RCI pre-baseline/pre-treatment 11 (1.65) 18 (-3.72) 11 (0.41) 6 (-0.41)
During-treatment (RCI pre-treatment/During-treatment) 12 (-0.41) 5 (5.37*) 9 (0.83) 6 (0)
Post-treatment (RCI pre-treatment/post-treatment) 5 (2.48*) 6 (4.96*) 6 (2.07*) 5 (0.41)
7 month FU (RCI pre-treatment/7FU) 3 (3.31*) 5 (5.37*) 8 (1.24) 4 (0.83)
12 months FU (RCI pre-treatment/12FU) 0 (4.54*) 4 (5.78*) 10 (0.41) 4 (0.83)
AAQ-II
Pre-baseline 15 15 14 9
Pre-treatment (RCI pre-baseline/pre-treatment 12 (0.66) 34 (-4.17) 11 (0.66) 11 (-0.44)
During-treatment (RCI pre-treatment/During-treatment) 15 (-0.66) 17 (3.73*) 12 (-0.22) 10 (0.22)
Post-treatment (RCI pre-treatment/post-treatment) 9 (0.66) 7 (5.93*) 9 (0.44) 9 (0.44)
7 month FU (RCI pre-treatment/7FU) 8 (0.88) 14 (4.39*) 16 (-1.09) 8 (0.66)
12 months FU (RCI pre-treatment/12FU) 8 (0.88) 11 (5.05*) 13 (-0.44) 7 (0.88)
AAQ-ABI
Pre-baseline 12 7 8 9
Pre-treatment (RCI pre-baseline/pre-treatment 7 (1.20) 27 (-4.80) 10 (-0.48) 9 (0)
During-treatment (RCI pre-treatment/During-treatment) 12 (-1.20) 10 (4.08*) 9 (0.24) 7 (0.48)
Post-treatment (RCI pre-treatment/post-treatment) 1 (1.44) 11 (3.84*) 7 (0.72) 5 (0.96)
7 month FU (RCI pre-treatment/7FU) 2 (1.20) 6 (5,04*) - 3 (1.44)
12 months FU (RCI pre-treatment/12FU) 1 (1.44) 8 (4,56*) 12 (-0.48) 1 (1.92)

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PP1 PP2 PP3 PP4

CFQ-7
Pre-baseline 33 35 24 17
Pre-treatment (RCI pre-baseline/pre-treatment 19 (3.61*) 44 (-2.32) 36 (-3.10) 12 (1.28)
During-treatment (RCI pre-treatment/During-treatment) 23 (-1.03) 32 (3.10*) 33 (0.77) 11 (0.26)
Post-treatment (RCI pre-treatment/post-treatment) 10 (2.32*) 17 (6.97*) 14 (5.68*) 12 (0)
7 month FU (RCI pre-treatment/7FU) 7 (3.10*) 11 (8.51*) 26 (2.58*) 10 (0.52)
12 months FU (RCI pre-treatment/12FU) 10 (2.32*) 20 (6.19*) 24 (3.10*) 9 (0.77)
VLQ composite score
Pre-baseline - 53.50 - 56.80
Pre-treatment (RCI pre-baseline/pre-treatment 45.20 52.00 (0.14) 47.40 61.90 (-0.49)
During-treatment (RCI pre-treatment/During-treatment) 55.90 (-1.02) 48.20 (0.36) 33.90 (1.29) 53.20 (0.83)
Post-treatment (RCI pre-treatment/post-treatment) - 57.60 (-0.54) 35.80 (1.11) 58.90 (0.29)
7 month FU (RCI pre-treatment/7FU) 53.60 (-0.80) 59.20 (-0.69) 34.40 (1.25) 66.70 (-0.46)
12 months FU (RCI pre-treatment/12FU) - 48.40 (0.38) 49.30 (-0.20) 56.20 (0.60)
SF-12 Physical health summary scale
Pre-baseline 31.60 40.22 28.00 44.02
5
Pre-treatment (RCI pre-baseline/pre-treatment) 34.51 (-0.49) 43.50 (-0.56) 28.65 (-0.11) 49.10 (-0.86)
Post-treatment (RCI pre-treatment/post-treatment) 34.62 (-0.02) 53.16 (-1.64) 29.71 (-0.18) 44.20 (0.83)
7 month FU (RCI pre-treatment/7FU) 37.71 (-0.54) 48.16 (-0.79) 28.30 (0.06) 45.08 (0.68)
12 months FU (RCI pre-treatment/12FU) 45.51 (-1.87) 44.32 (-0.14) 25.22 (0.58) 48.89 (0.04)
SF-12 Mental health summary scale
Pre-baseline 36.40 40.80 40.35 41.03
Pre-treatment (RCI pre-baseline/pre-treatment) 36.30 (0.02) 31.73 (1.38) 37.83 (0.38) 45.16 (-0.63)
Post-treatment (RCI pre-treatment/post-treatment) 62.72 (-4.03*) 38.59 (-1.05) 47.84 (-1.53) 57.29 (-1.85)
7 month FU (RCI pre-treatment/7FU) 65.21 (-4.41*) 55.90 (-3.68*) 45.08 (-1.10) 57.54 (-1.89)
12 months FU (RCI pre-treatment/12FU) 62.03 (-3.92*) 44.76 (-1.99*) 50.27 (-1.90) 56.63 (-1.75)
USER-P frequency
Pre-baseline 38.93 39.29 18.93 42.50
Pre-treatment (RCI pre-baseline/pre-treatment) 29.64 (1.07) 50.36 (-1.27) 27.14 (-0.95) 40.36 (0.25)
Post-treatment (RCI pre-treatment/post-treatment) 33.57 (-1.62) 35.36 (6.20) 27.50 (-0.15) 31.79 (3.54)
7 month FU (RCI pre-treatment/7FU) 37.86 (-3.40*) 29.29 (8.71) 16.43 (4.43) 41.43 (-0.44)
12 months FU (RCI pre-treatment/12FU) 36.43 (-2.81*) 39.29 (4.57) 24.64 (1.03) 40.71 (-0.14)
USER-P restriction
Pre-baseline 63.64 90.00 73.33 90.91
Pre-treatment (RCI pre-baseline/pre-treatment) 63.64 (0) 90.91 (-0.11) 70.00 (0.38) 87.88 (0.35)
Post-treatment (RCI pre-treatment/post-treatment) 66.67 (-0.35) 84.85 (0.70) 70.00 (0) 84.85 (0.35)
7 month FU (RCI pre-treatment/7FU) 63.64 (0) 86.67 (0.49) 60.00 (1.15) 87.88 (0)
12 months FU (RCI pre-treatment/12FU) 84.85 (-2.45*) 72.73 (2.10) 66.67 (0.38) 100.00 (-1.40)
USER-P satisfaction
Pre-baseline 65.00 97.50 72.22 67.50
Pre-treatment (RCI pre-baseline/pre-treatment) 69.44 (-0.48) 82.50 (1.64) 58.33 (1.51) 67.50 (0)
Post-treatment (RCI pre-treatment/post-treatment) 78.13 (-0.95) 77.50 (0.55) 72.22 (-1.52) 72.50 (-0.55)
7 month FU (RCI pre-treatment/7FU) 80.56 (-1.21) 75.00 (0.82) 50.00 (0.91) 85.00 (-1.91)
12 months FU (RCI pre-treatment/12FU) 86.11 (-1.82) 80.00 (0.27) 63.89 (-0.61) 92.50 (-2.73*)
HADS, Hospital Anxiety and Depression Scale; DASS-21, Depression, Anxiety and Stress Scale-21; AAQ-II, Acceptance
and Action Questionnaire II; AAQ-ABI, Acceptance and Action Questionnaire Acquired Brain Injury; VLQ, Valued Living
Questionnaire; CFQ-7, Cognitive Fusion Questionnaire; USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation;
SF-12, Short Form Survey.
Table includes raw scores with the RCI, Reliable Change Index between brackets
* clinical significant change

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CHAPTER 6
The BrainACT study: Acceptance and Commitment
Therapy for depressive and anxiety symptoms
following acquired brain injury: study protocol for
a randomized controlled trial

Johanne C.C. Rauwenhoff

Frenk Peeters
Yvonne Bol
Caroline M. van Heugten

Trials, 2019
Chapter 6

Abstract
Background. Following an acquired brain injury, individuals frequently experience anxiety and/or depressive
symptoms. However, current treatments for these symptoms are not very effective. A promising treatment
is acceptance and commitment therapy (ACT), which is a third wave behavioural therapy. The primary goal
of this therapy is not to reduce symptoms, but to improve psychological flexibility and general well-being
which may be accompanied by a reduction of symptom severity. The aim of this study is to investigate
the effectiveness of an adapted ACT intervention (BrainACT) for people with acquired brain injury who
experience anxiety and/or depressive symptoms.

Methods. The study is a multicentre randomized controlled two-armed parallel trial. In total, 94 patients who
survived a stroke or traumatic brain injury will be randomized into an ACT- or control (i.e. psycho-education
and relaxation) intervention. The primary outcome measures are the Hospital Anxiety and Depression
Scale and the Depression Anxiety Stress Scale. Outcomes will be assessed, by trained assessors blinded to
treatment condition, pre-treatment, during treatment, post-treatment, and at seven and twelve months.

Discussion. This study will contribute to the existing knowledge on how to treat psychological distress
following acquired brain injury. If effective, BrainACT could be implemented in clinical practice and potentially
help a large number of patients with acquired brain injury.

Trial registration. The study is registered in the Dutch Trial Register (Trial NL691, NTR 7111) on 26-03-2018,
https://www.trialregister.nl/trial/6916.

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 The study protocol of the BrainACT RCT

Introduction
Patients with acquired brain injury (ABI) have an increased risk of developing emotional disturbances (1).
After surviving a stroke, a quarter of the patients experience depressive symptoms at six months post-
stroke (2); almost half of the patients who experienced a traumatic brain injury (TBI) suffer from a major
depressive disorder and 38% suffer from anxiety symptoms (3). Depression has significant effects on the
health of patients with ABI. It leads to more hospitalizations, less societal participation, reduces the return-
to-work rates, places a greater burden on caregivers, affects social relationships, and has a vast impact on
general quality of life (4). Moreover, anxiety and depressive symptoms have a negative influence on patient
rehabilitation (5) and they increase the severity and number of reported health problems such as fatigue,
memory, headaches, and concentration problems (6, 7).
Despite their high prevalence and negative consequences with a significant burden of disease,
it is still not clear how to best treat post-ABI depressive and anxiety symptoms. Psychopharmacological
interventions show mixed results when treating depression in stroke survivors. Additionally, stroke patients
seem sensitive to the side effects of psychopharmacological medication (8). Furthermore, antidepressants 6
have not shown to be more beneficial than placebo when treating depression following TBI (9). Cognitive
behavioural therapy is widely used for treating depression and anxiety, but there is no strong evidence for
its post-stroke effectiveness (10, 11), research into its effectiveness following TBI is inconclusive (12-15).
A recent therapy which has been proven to be effective over a wide range of clinical populations is
Acceptance and Commitment Therapy (ACT) (16-19). ACT is a third wave cognitive behavioural therapy which
uses commitment and behaviour change strategies to increase psychological flexibility (20). Psychological
flexibility is described as “the ability to contact the present moment more fully as a conscious human being,
and to change or persist in behaviour when doing so serves valued ends” (21, p. 7). This results from a
combination of the six core processes of ACT: acceptance (accepting positive and negative thoughts to
situations one cannot change), defusion (disentanglement of thoughts), sense of self (separating the self
from the process of thinking), mindfulness (contact with the present moment), valued living (being aware of
what really matters), and committed action (taking action guided by one’s values) (21). Although symptom
reduction is not the primary treatment goal, an increase in psychological flexibility is often accompanied
by a decrease in symptomatology (22, 23). ACT is an interesting approach for people with ABI who suffer
from psychological distress (24). Instead of applying cognitive restructuring techniques as used in traditional
cognitive therapy, ACT focusses on learning to accept both the negative and positive thoughts and feelings
related to those circumstances which cannot be changed or controlled (25). It enables the individual to carry
out value-based behaviour while feeling distressed (25). Higher levels of acceptance and valued living have
been associated with better psychological outcomes in patients with ABI (26-28).
Currently, there is some evidence that people who developed depressive or anxiety symptoms after
ABI can benefit from ACT. Majumdar and Morris (29) performed a RCT in which an ACT group-intervention
of four weekly didactic PowerPoint sessions was compared to treatment as usual in stroke survivors. They
found that people in the ACT intervention showed a significant reduction in depression and increased

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hopefulness and self-rated health. However, no differences were found related to anxiety or quality of
life. Graham et al. (30) described a case study in which a stroke patient no longer experienced chest pain,
showed a decrease in anxiety and depressive symptoms, and improved illness perception and psychological
flexibility following an ACT intervention. Whiting et al. (31) performed a pilot RCT comparing an ACT group
intervention with befriending therapy in patients with severe TBI. Their results show that ACT decreased
the levels of anxiety and depression significantly compared to the befriending treatment. However, it could
not be confirmed that the mechanism through which this decrease was elicited was psychological flexibility
(31). These findings should, however, be considered in light of the small sample size of the study and the
restricted sample characteristics.
These studies provide preliminary support for the hypothesis that ACT can be effective in treating
psychological distress following ABI. With the current BrainACT study, we aim to investigate whether an ACT
intervention, adapted for the needs and possible cognitive deficits of people with ABI, results in decreased
anxiety and depressive symptoms compared to a control intervention. Furthermore, we will examine ACT
related processes, quality of life, social participation, and the cost-effectiveness of both interventions.

Research questions addressed in the study:

1) Does ACT lead to a greater reduction of depressive and anxiety symptoms in patients with ABI compared
to an active control intervention (i.e. psycho-education and relaxation training)?

2) Is ACT more cost-effective in comparison to an active control intervention?

3) Is the (potential) reduction of anxiety and depressive symptoms mediated by an increase in psychological
flexibility, acceptance, valued living, and/or cognitive defusion in the ACT group?

4) Does ACT lead to higher levels of participation and quality of life, compared to an active control condition?

Methods
Study Design
The design of the study is a multicentre randomized controlled two-armed parallel trial in which an 8-week
ACT intervention will be compared to an active control intervention, namely psycho-education combined
with relaxation training. Outcome measures will be collected at baseline (T0), after one month (T1; during
treatment), and after three months (T2; post-treatment). At seven (T3) and twelve months (T4) there will be
follow-up measurements. See figure 1 for the flow chart of the study. Ethics approval for the study has been
given by the medical research ethics committee of Maastricht University Medical Centre and Maastricht
University and the local committees of participating clinical centres. The study is registered in the Dutch Trial
Register (TC: 7111).

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 The study protocol of the BrainACT RCT

Figure 1. Design of the study: multicentre randomized controlled two-armed parallel trial

Participants
A total of 94 survivors of TBI or stroke will be recruited from rehabilitation or medical psychology departments
at hospitals in the Netherlands. Patients who have been referred to a psychologist will be considered for
participation. Possible participants will be screened and informed about the study by their psychologists
for eligibility. Inclusion criteria are: (1) having sustained any type of stroke or TBI which is objectified by a
neurologist; (2) scoring higher than seven on the depression and/or anxiety subscale of the Hospital Anxiety
and Depression Scale (HADS); (3) being 18 years or older; (4) having a stable use of psychotropic medication
(such as antidepressants) for the duration of the study and stable use of antidepressants during four weeks
prior to the start of the study; (5) being able to access the internet and a computer because treatment
materials such as patient videos are shown via the internet, (6) mastering the Dutch language sufficiently to
benefit from treatment; and (7) giving informed consent. Exclusion criteria are: (1) history of brain injury or any
neurological disorder other than a stroke and TBI; (2) pre-morbid disability as assessed with the Barthel Index
(score<19/20); (3) severe co-morbidity, for which treatment is given at the moment of inclusion, that might
affect the outcome; (4) presence of a DSM 5-based mood and/or anxiety disorder for which pharmacological

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and/or psychological treatment was necessary during the onset of the brain injury; and (5) attendance in a
previous ACT intervention for comparable problems in the year proceeding entry to the current study.

Randomization and blinding

Participants who are eligible and agree to participate in the study are randomly assigned to either the
intervention group or the control group with an allocation ratio of 1:1. The randomization will be performed
centrally by an independent third person using computerized block randomization. The block size is six and
the randomization scheme includes pre-stratification on location (hospital) and type of brain injury (TBI versus
stroke). The randomization scheme has been developed with the use of a random generator (www.random.
org). After randomization, an opaque, sealed envelope will be prepared containing information about the
group allocation of the participant by the independent third person. After the first measuring moment (T0)
the researcher will open the sealed envelope and reveal treatment allocation to the patient and psychologist.
The trained research assistants that administer the questionnaires will be blinded to treatment
allocation (i.e. intervention or control) and should never be unblinded. Participants will be asked not to tell
research assistants about the treatment they received. In order to check the success of blinding, at T4 the
research assistants will be asked to indicate group allocation for all participants who completed the trial. The
research assistants will choose one of the following options: ‘Intervention group’, ‘Control group’, or ‘I don’t
know’. Participants will not be blinded. Data analyses will be done by the principal investigator (JR) who will
be blinded while performing the analyses.

Primary outcome measures

Psychological distress. The subscales of the HADS will be used to measure anxiety and depressive symptoms
over the past seven days. The scores for the scales, 7-items each, range from 0 to 21 with higher scores
indicating higher levels of depression or anxiety. This questionnaire has been validated in a TBI sample (32).
Furthermore, a good internal consistency for both subscales (Cronbach’s α depression scale: 0.81; anxiety
scale: 0.84) was found in a stroke population (33). The Depression Anxiety Stress Scales-21 (DASS-21) will
be used to measure the levels of anxiety, depression, and stress of the participants. It consists of 21 items
which are rated on a 4-point Likert-scale. The score ranges from 0 to 63 with higher scores indicating greater
levels of depression, anxiety, or stress. The questionnaire has been validated in a TBI sample. The internal
consistency was good for the three scales (Cronbach’s α depression scale = 0.90; stress scale 0.89; and
anxiety scale 0.82) (34). The primary outcome is the change in mood and anxiety symptoms between groups
over all time points, as measured by the total scores of the respective subscales of the HADS and DASS-21.
Cost-effectiveness. Two questionnaires will be used to measure cost-effectiveness: the 5 level EQ-
5D (EQ-5D-5L) and a 16-item cost-questionnaire. The EQ-5D-5L consists of five questions measuring health
status. The dimensions covered are mobility, self-care, daily activities (such as work, housework, study, and
leisure activities), pain or discomfort, and anxiety or depression. These domains are rated as ‘no problem’,

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‘slight problem’, ‘moderate problem’, ‘severe problem’, or ‘unable to do’. Consequently, the EQ-5D-5L can
distinguish between different health states. For each of the different states a weight is contributed based
on the valuation given by the general population (35). The healthcare costs of participants will be measured
with a self-report cost-questionnaire which is constructed to collect cost data from a societal perspective,
based on the steps described by Thorn et al. (36). The cost-questionnaire used in this study is based on
a questionnaire used in the study of Kootker et al. (11). Several questions are altered based on response
patterns and analyses in this prior study. The primary cost-effectiveness outcome is the change in the
amount of care used between groups over all time points, as measured by the total scores of the cost-
questionnaire and the EQ-5D-5L.

Secondary outcome measures

Participation. The Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) will be used to
measure three aspects of participation: frequency of behaviours, experienced participation restrictions
due to health condition, and satisfaction with participation. The frequency scale measures the objective
6
level of participation, while the restrictions and satisfaction scales offer an insight into the subjective rating
of participation. The questionnaire consists of 31 items. For each scale a score ranging from 0 till 100 is
calculated. Higher scores indicate more participation, less restriction, and more satisfaction. It is a valid and
reliable measure for patients with ABI; the internal consistency was good (Cronbach’s α = 0.70-0.91) (37).
Health status. The Short Form Survey (SF-12) will be used to measure the health status of the
participants. The total score ranges from 0 till 100 and a higher score indicates a better health status. The
SF-12 has been validated for use in TBI research (38). Secondary outcome is the change in participation and
health status between groups over all time point, as measured by the total scores of the respective subscales
of the USER-P and SF-12.

Secondary process measures

Psychological flexibility. The Acceptance and Action Questionnaire II (AAQ-II) is a seven-item questionnaire
measuring psychological flexibility. The items are scored on a 7-point Likert scale and the total score ranges
from 0 to 49 with a higher score indicating more psychological flexibility. The internal consistency of the AAQ-
II is good (Cronbach’s α = 0.84) (39). Furthermore, the questionnaire has been validated in an ABI sample
(40). The Acceptance and Action Questionnaire Acquired Brain Injury (AAQ-ABI) measures psychological
flexibility about the thoughts and feelings related to the brain injury, while the AAQ-II measures psychological
flexibility around general psychological distress. The AAQ-ABI consists of seven items which are scored on
a 5-point Likert scale. The score ranges from 0 to 36 with higher scores in indicating greater psychological
flexibility. The questionnaire has a good internal consistency (Cronbach’s α = 0.89) (40).
Valued living. The Valued Living Questionnaire (VLQ) is a two-part instrument which measures valued
living. First, the participant rates the importance of ten value domains on a 10-point Likert scale. Second,

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participants rate how consistently he or she has lived in accordance with their values within these domains.
Scores from both parts are used to calculate a valued living component. The internal consistency of the
valued living component was adequate (Cronbach’s α = 0.74) (41). The VLQ has been used in earlier research
to measure valued living in TBI patients (27).
Cognitive fusion. The Cognitive Fusion Questionnaire (CFQ-7) measures cognitive fusion on a 7-point
Likert scale. Scores range from 0 to 49. The higher the score, the more fused one is with one’s thoughts. Earlier
research has shown that the CFQ has good factor structure, validity, reliability, and stability over time (42). The
questionnaire has been validated in healthy and medical populations (42, 43). Secondary process outcome is
the change in psychological flexibility, valued living, and cognitive fusion between groups over all time point, as
measured by the total scores of the respective subscales of the AAQ-II, AAQ-ABI, VLQ, and CFQ-7.

Personal and brain-injury related characteristics and feasibility

When the study commences participants will fill out a demographic questionnaire. This questionnaire will
register age, gender, employment, and education. Injury related factors will be obtained from the medical
files of the participants. These include type of brain injury, time since brain injury, severity of injury, and
affected hemisphere. After ending the treatment, the participant’s opinion and satisfaction on the ACT
therapy (treatment feasibility) will be questioned by means of a short semi-structured interview.

Procedure
Participants will be recruited at participating hospitals and rehabilitation centers in the Netherlands. To
prevent unnecessary burden, the psychologists will check the in- and exclusion criteria. If the patient is
willing to participate the investigator will meet (at the home of the patient, the hospital, or the university as
is preferred by the patient) with the patient to discuss the participation in the study and answer questions.
If all is clear the informed consent will be signed by the patient and the researcher (see additional file 2).
Subsequently, the first measuring moment will take place (T0) and the participant will be randomly allocated
to the experimental group receiving ACT or to the active control group receiving psycho-education. The
therapy session will be scheduled with the psychologist or healthcare professional. One month after the
start of the intervention both groups will fill in the questionnaires for T1 (see table 1). Questionnaires will
be filled in on paper and measuring moment will be done by a research assistant blinded to allocation. After
three, when the treatment program is completed, the participants will fill in the questionnaires for T2. At
seven (T3) and twelve months (T4) there will be follow-up measurements. Again these measurements will
be conducted by a research assistant blinded to allocation. Data entry will be done by research assistants
and will be periodically checked during the monitoring visits. Follow-up appointments will be planned at the
end of each visit. One week before the appointment the participant will be reminded of the appointment
by the research assistant through telephone or e-mail. During the assessments, the researcher and research
assistants will be alert for any adverse events such as suicidality. All adverse events related to mood

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complaints reported spontaneously by the subject or observed will be systematically collected and reported
to the medical research ethics committee. Based upon these events it can be decided to discontinue
participation in the study. Furthermore, participants can leave the study without any consequences at any
time for any reason if they wish to do so. The investigator can decide to withdraw a subject from the study
for urgent medical reasons.

Table 1. SPIRIT diagram

Study Period
Enrolment Assessments
Time Point -1 week T0 T1 T2 T3 T4
Enrolment
Eligibility screening X
Informed consent X
Allocation X
Interventions
ACT intervention
Control intervention 6
Assessments
Demographic and Injury characteristics X
Treatment feasibility* X
Primary Outcome measures X X X X X
HADS, DASS-21
Primary cost-effectiveness measures X X X X
EQ-5D-5L, Cost-questionnaire
Secondary outcome measures X X X X
USER-P, SF-12
Secondary process measures X X X X X
AAQ-II, AAQ-ABI, VLQ, CFQ-7

ACT, Acceptance and Commitment Therapy; HADS, Hospital Anxiety and Depression Scale; DASS-21, Depression, Anxiety
and Stress Scale-21; EQ-5D-5L, 5 level EQ-5D; USER-P, Utrecht Scale for Evaluation of Rehabilitation-Participation; SF-
12, Short Form Survey; AAQ-II, Acceptance and Action Questionnaire II; AAQ-ABI, Acceptance and Action Questionnaire
Acquired Brain Injury; VLQ, Valued Living Questionnaire; CFQ-7, Cognitive Fusion Questionnaire.
* Only administered in the ACT group

Interventions
The BrainACT intervention. The ACT intervention involves eight weekly individual sessions of 60 minutes during
a period of three and a half months. The first four sessions are weekly, thereafter the sessions will be biweekly,
with a three-week break between the seventh session and last session. Participants will do homework exercises
of around 30 minutes for six days a week. Homework consists of reading or listening to summaries of the
sessions, practising skills, and doing mindfulness exercises. At the start of the intervention, participants will
receive a workbook with instructions that they can read at home after each session. We use an eight-session
protocol (see Table 2) based on Jansen and Batink (44), Luoma et al. (45), and Whiting et al. (31) in which all six
ACT core processes are addressed. Psychologists are free to decide on the order of the sessions. We altered the
treatment for people with ABI as suggested by Kangas and McDonald (24) and Broomfield et al. (46). An expert

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group of psychologists experienced with ACT and/or in working with people with ABI gave further advice on the
alterations. The possible cognitive deficits of the participants are taken into account and brain injury related
topics are discussed during the treatment. A treatment protocol is specified to ensure comparability of the
ACT intervention across settings. The intervention will be provided individually by certified psychologists who
completed an ACT training course of at least five days and are experienced in working with patients with ABI.
The therapy will take place at the outpatient facilities of hospitals.

Table 2. Overview of the BrainACT treatment program

Topic Content
Values Value exploration and difference between goals and actions.
Committed action and Committed action on the long and short term in relation to values, education about
Mindfulness mindfulness, and practising contact with the present moment.
Effect of control Creative hopelessness; the undeniability of human suffering and the consequences on the
long term of trying to control it.
Acceptance Introducing acceptance as an alternative to control.
Defusion Changing the relationship with thoughts, naming the mind.
Self-as-context Changing the relationship with thoughts about oneself and introducing the constant self.
Defusion and Mindfulness Review and exercises on defusion and mindfulness.
Psychological flexibility Review of the different core components, explanation on how these skills together lead to
psychological flexibility, and preparation on relapse and setbacks.

Active control intervention. The control condition (see Table 3 for an overview) consists of an eight-session
psycho-education intervention combined with relaxation training with a duration of one hour. A Cochrane
review concluded that active information provision is able to reduce depression and anxiety after brain injury
(47). Furthermore, earlier research has shown that relaxation exercises reduce post-stroke anxiety (48). The
psycho-education is based on the existing module ‘Niet rennen maar plannen’ (don’t run, plan) (49), which
is a training and education program focusing on cognitive rehabilitation for patients with brain damage and
mild cognitive problems. The intervention aims to offer information and education about brain injury and
its consequences. Relaxation exercises consist of progressive muscle relaxation (50) and autogenic training
(51). Participants will do homework exercises of around 30 minutes for six days a week. A treatment protocol
is specified to ensure comparability of the education intervention across settings. This intervention will be
provided individually by a health care professional with experience in working with brain injury patients
(e.g. psychologist, social worker, occupational therapist, psychological assistant, but not the psychologist
providing the ACT intervention) at outpatient facilities of hospitals.

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Table 3. Overview of the psycho-education and relaxation treatment program

Session Content
number
1 Psycho-education on the basic functions of the brain and causes of brain injury.
2 Psycho-education on relaxation training and a progressive muscle relaxation exercise.
3 Psycho-education on the consequences of brain injury and a progressive muscle relaxation exercise.
4 Psycho-education on changes in behaviour and mood following brain injury and an autogenic training exercise.
5 Psycho-education on fatigue following brain injury and an autogenic training exercise.
6 Psycho-education on memory problems following brain injury. Participants can choose between autogenic
training or a progressive muscle relaxation exercise. This technique will also be used in the following sessions.
7 Psycho-education on information processing and planning and an autogenic training exercise or a progressive
muscle relaxation exercise.
8 Review of the different sessions, wrap up and an autogenic training exercise or a progressive muscle relaxation
exercise.

Adherence. To ensure adherence to the intervention protocol, all therapists (of the intervention and control
condition) will be trained by the principal investigator (JR). Furthermore, to examine the adherence during 6
the different sessions, therapists have to fill in a checklist after every session. They tick off which exercises
were done according to the treatment protocol and which exercises were added or left out.

Sample size calculation

The sample size calculation was performed with G*Power based on a repeated measures design. With a
large effect size of 0.4, alpha value of 0.05, power value of 0.80, two groups (intervention and control),
and five measurements, at least 80 participants are required. With an expected drop-out rate of 15%, 94
participants need to be recruited.

Statistical analysis
The statistical analysis can be divided into four parts. First, the baseline characteristics will be described.
Second, between-group differences at baseline will be analysed using chi-square tests and independent-
sample t-tests to verify the success of randomization. Furthermore, groups will be compared on primary
outcome measures at T2 using chi-square tests and independent-sample t-tests. Linear mixed models for
repeated measures will be used to study the differences between groups with the primary and secondary
outcome measures as dependent variables. Models will include main effects of the intervention (ACT or
psycho-education) and time (T0, T1, T2, T3, and T4) as categorical variables and the interaction effect of
intervention and time. Baseline-adjusted mean differences between groups at each time point with 95%
confidence intervals will be presented. The effects of the intervention will be analysed according to the
intention-to-treat principle. Alpha will be set at 0.05. All quantitative analyses will be conducted using SPSS
software version 25 (52). Third, the clinically significant change will be determined on the primary outcome
measures (53) to gain insight into a clinical improvement on an individual level. The first step is to identify

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patients who ‘recovered’ by using the cut-off scores of the primary outcome measures (HADS and DASS-21).
The second step is to calculate the Reliable Change Index which identifies the patients with a significant
improvement. Patients who both recovered and showed a significant improvement will be considered
clinically significantly improved. The amount of clinically significantly improved patients will be compared
between interventions. Fourth, the trial-based economic evaluation will involve a combination of a cost-
effectiveness analysis and a cost-utility analysis.

Ethical considerations and dissemination

Data will be handled confidentially and reporting will be coded. Each participant is given a personal code
which is only convertible to a person when the coding key is known. Collected data and personal information
will be stored separately. The coded dataset will be available to the research team, health care inspectorate,
study monitors, and members of the medical research ethics committee. The handling of personal data
will comply with the General Data Protection Rule and the Research Data Management Code of Conduct of
Maastricht University. Data will be used for future studies if the patient agreed upon this in the informed
consent form. Data and material will be stored for 15 years on a repository of Maastricht University and can
be made available to researchers upon request.
Participants will be compensated for any harm or injury due to participation in the study. The sponsor/
investigator has a liability insurance which is in accordance with article 7 of the Medical Research involving
Human Subjects Act. All adverse events will be followed until they have abated, or until a stable situation
has been reached. Depending on the event, follow up may require additional tests or medical procedures
as indicated, and/or referral to the general physician or a medical specialist. If further treatment for mood
complaints is indicated after termination of the intervention this will be arranged within the healthcare
system. Adverse events will not be reported in the publication unless an adverse event occurs often and will,
therefore, lead to a bias.
Ethics approval for the study has been given by the medical research ethics committee of Maastricht
University Medical Centre and Maastricht University (committee’s reference number: NL65349.068.18). Any
protocol modifications will be communicated to the ethics committee. The study will be monitored by the
Clinical Trial Centre Maastricht. In every site, there will be a site initiation visit, two monitoring visits, and a
close-out visit. The monitoring will be independently performed from investigators and the sponsor.
In accordance with the Central Committee on Research Involving Human Subjects statement
on publication policy, the researchers aim to publish the results of the study (positive or negative) in
international, peer-reviewed journals. Furthermore, results will be presented at professional conferences
and provided to study participants upon request.
SPIRIT checklist for this trial can be found here: https://trialsjournal.biomedcentral.com/articles/10.1186/
s13063-019-3952-9#Sec27.

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Discussion
Currently, there are no evidence-based treatment options for people with ABI who experience psychological
distress. To our knowledge, no large RCTs have been conducted investigating the effectiveness of ACT for
anxiety and depressive symptoms following TBI or stroke. However, earlier studies have shown promising
results (29-31). The aim of the proposed study is to investigate the clinical and cost-effectiveness of an
upcoming cognitive-behavioural therapy, ACT, for anxiety and depressive symptoms following ABI.
We have taken into account recommendations made by Ost (18), to enhance the quality of studies
in the field of ACT, such as having an active control intervention, timing of follow-up measurements, and
choice of outcome measures. As described earlier, the aim of ACT is to change the functions and context of
behaviour and thoughts; symptom reduction is not a treatment outcome (21). However, the primary outcome
measures in this study are the HADS and DASS-21 (measures of anxiety and depression). We have chosen
these outcome measures for several reasons. First, a reduction in symptomatology (such as a decrease
in psychological distress) is still regarded as a beneficial treatment outcome in ACT next to an increase in
psychological flexibility. Second, when psychological flexibility increases, a decrease is often observed in 6
psychological distress (22, 23). We expect that a decrease in anxiety and depression is elicited through
an increase in psychological flexibility. Psychological flexibility is measured with the secondary process
outcomes. Lastly, choosing the HADS and DASS-21 as primary outcome measures will aid comparability with
studies outside the field of ACT.
This study has several strengths. First, it has a relatively large sample size. Second, the study has a
long follow-up period. Third, the ACT intervention will be compared to an active control intervention which
was revealed to have positive effects on anxiety and depressive symptoms following brain injury. Fourth,
the ACT treatment protocol was adapted to the needs and possible cognitive deficits of patients with brain
injury. These adaptations were based on suggestions made in previous literature and knowledge gained in
clinical practice. Fifth, the effectiveness of the ACT intervention will be investigated in a quantitative as well
as qualitative manner.
This study also has certain limitations. First, its clinical nature prevents blinding of the participants
and the therapists. However, the assessments will be performed by research assistants unaware of group
allocation. Second, participant recruitment and loss to follow-up are known to be problematic in studies with
patients with ABI. To aid study adherence research assistants will be trained and the outcome assessments
will take place at the participants’ home, the University, or the hospital, as preferred by the participant.
The results of this study, notwithstanding, should contribute to the limited knowledge on how to treat
psychological distress following ABI. If effective, the BrainACT intervention can be implemented in clinical
practice. Given the high prevalence of anxiety and depressive symptoms, it has the potential to help a large
number of patients with ABI.

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42. Gillanders DT, Bolderston H, Bond FW, Dempster M, Flaxman PE, Campbell L, et al. The development and initial
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The study protocol of the BrainACT RCT

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CHAPTER 7
O
Acceptance and Commitment Therapy is feasible
for people with acquired brain injury: a process
G
evaluation of the BrainACT treatment
R
BA
EM

Johanne C.C. Rauwenhoff

Frenk Peeters
Yvonne Bol
Caroline M. van Heugten

Submitted
CHAPTER 8
General discussion
Chapter 8

The prevalence of anxiety and depressive symptoms following acquired brain injury (ABI) is high. Previous
research has concluded that there is a need to optimize treatment strategies for people experiencing these
symptoms. The aim of this thesis was to improve the treatment for people with ABI-related anxiety and
depressive symptoms. First, we developed a clinical prediction tool for people with post-stroke depressive
symptoms. Additionally, we developed the BrainACT intervention; Acceptance and Commitment Therapy
(ACT) adapted to the needs and possible cognitive deficits of people with ABI. Last, we investigated the
feasibility and effectiveness of BrainACT for anxiety and depressive symptoms in people with ABI.

Main findings reported in this thesis

Chapter 2 describes the results of a study in which we developed a prognostic index for patients with post-
stroke depressive symptoms. This was done for two outcome domains: post-stroke depressive symptoms
and experienced restrictions regarding participation, using data from a randomized controlled trial (RCT)
investigating cognitive behavioural therapy (CBT) and computerized cognitive training (CCT) for post-
stroke depression. The results showed that many variables predict the outcome of post-stroke depressive
symptoms, including characteristics of the stroke, the patients, and their spouses. Fewer variables predicted
the outcome related to participation. The personalized predictions (prognostic index scores) of treatment
outcome show promising results, which, after further replication and validation, could aid clinicians with
treatment selection.
In order to validly measure the effect of ACT for people with ABI, chapter 3 shows the results of
a validation study investigating the psychometric properties of the Dutch versions of the Acceptance
and Action Questionnaire for Acquired Brain Injury (AAQ-ABI; measuring psychological flexibility related
to thoughts and feelings about ABI) and the Cognitive Fusion Questionnaire (CFQ-7; measuring cognitive
defusion). It was concluded that these measures have acceptable to good psychometric properties when
measuring psychological flexibility and cognitive defusion in Dutch individuals with ABI. In chapter 4, the
rationale and description of the BrainACT treatment are presented. The BrainACT treatment is an ACT
intervention adapted to the possible cognitive deficits and needs of people with ABI. General alterations
are the use of visual materials, summaries, and repetition. ACT-specific adaptions include the Bus of Life
metaphor as a recurrent exercise, shorter mindfulness exercises, a focus on experiential exercises, and the
monitoring of committed actions. The intervention consists of eight one-hour face-to-face sessions. The
order of the sessions, metaphors, and exercises can be tailored to the needs of the patients. In chapter
5 the effectiveness of the BrainACT treatment was investigated in four people with ABI using a single
case experimental design (SCED). Three out of four patients showed a significant decrease in anxiety and
depressive symptoms. In addition, clinically significant improvements were observed regarding cognitive
fusion, quality of life, and stress. No improvements were observed regarding psychological flexibility, value-
driven behaviour, and social participation. In chapter 6 the protocol of the BrainACT RCT is described. This
study is a multicentre, randomized, controlled, two-arm parallel trial. People who survived a stroke or
traumatic brain injury (TBI) are randomized into an ACT or control (i.e. psycho-education and relaxation)

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 General discussion

intervention. The primary outcome measures are the Hospital Anxiety and Depression Scale (HADS) and the
Depression Anxiety Stress Scale (DASS-21). Secondary outcomes are psychological flexibility, valued living,
cognitive defusion, social participation, and quality of life. Outcomes are assessed pre-treatment, during
treatment, post-treatment, and at 7 and 12 months. In chapter 7 the results of a process evaluation of the
BrainACT treatment are presented. The BrainACT treatment was found to be feasible. The attendance rates
were high and the compliance rate was relatively high. Participants and therapists rated the intervention
positively, were satisfied, and identified several facilitators (such as the structured and experiential nature
of the intervention). A clear barrier identified by the therapists was that the content of the sessions was
too extensive. Adding two extra sessions was therefore recommended. The follow-up measurements of
the BrainACT RCT are currently being conducted and will be finalized by the end of 2022. Results on the
effectiveness of the BrainACT treatment as investigated by the BrainACT RCT are therefore not presented
in this thesis.

Optimizing the treatment of depressive symptoms following acquired brain injury

Predicting psychotherapy outcome
Previous reviews have indicated that the effectiveness of psychotherapy for people experiencing depressive
symptoms following an ABI is unclear (1, 2). Is it possible to gain additional insights from these trials that have
already been conducted? In chapter 2 we re-analysed the data of a RCT comparing CCT with CBT in a group of 8
patients with stroke and depressive symptoms (3). No significant group differences were found on the main
outcome measure, the depression scale of the HADS, at any of the measurement moments. The average scores
can be seen in figure 1. However, after adding the individual scores to the graph, as in figure 2, a different
picture emerges. The variability between the participants becomes apparent. Some participants profited from
the treatment, while others did not. A recent article by Kaiser et al. (4) found that there is indeed heterogeneity
in the treatment response in people who receive psychotherapy. A group average does not tell clinicians what
to do with the patient that sits in front of them, as the ‘average patient’ does not exist (5). Hence, the use of
personalized treatment approaches might help to improve treatment response.

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Figure 1. Results of the RCT investigating CBT for post-stroke depressive symptoms, adapted from Kootker et al. (3)

Figure 2. The individual scores in the CBT and CCT groups

For that reason, we developed a clinical prediction model for depressive symptoms and experienced restrictions
regarding participation for people with post-stroke depression. The goal of personalized medicine and prediction
models is to find the best fit between a patient and a certain treatment (6). Both the clinical prediction model
for depression and the model for participation explained around 50% of the variance in the data. It raised the
question which additional variables could influence the treatment outcome and therefore could be included
in future studies as predictors. In people with depressive symptoms without ABI, no biomarkers have been
found to be related to treatment response or dropout (7, 8). The predictive value of biomarkers in people
with ABI might be higher. Biological mechanisms are likely to contribute to the development of depressive
symptoms post-ABI. Previous studies identified biomarkers related to oxidative stress, lipids, and inflammation,
which are predictive for the development of post-stroke depressive symptoms (9-11). Other variables which
might influence the outcome of psychotherapy for people with ABI are deficits in self-awareness and cognitive
functioning such as memory, attention, and executive difficulties. These factors are experienced as challenging
by therapists when providing psychotherapy to people with ABI (12).

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 General discussion

Moreover, next to predicting the treatment outcome related to depression and participation, future
studies could consider additional outcomes as well. Even though a reduction in depressive symptoms can be an
indication of a successful treatment, it is not the whole picture (13). Not all patients who improved according
to a self-report depression questionnaire also experience this improvement following psychotherapy (13,
14). For instance, patients describe a ‘good outcome’ as feeling empowered and finding balance when
experiencing personal struggles (13). Solely focussing on remission based on depressive symptoms does not
reflect the multidimensional nature of depression and the experience of patients receiving psychotherapy.
Hence, clinical prediction models should be developed related to other outcomes as well. These could include
quality of life or the feeling of purpose and empowerment, which would align with the idea of positive
health (15). Taking the personalized medicine approach even a step further, the meaning of a successful
outcome differs between patients (13). For some, it would mean a reduction in complaints while for others
it would mean an increase in valued activities. It would be interesting to investigate if it is possible to match
different primary outcomes to different patients. Moreover, when providing third-wave behavioural therapy
such as ACT, outcomes such as mindfulness, psychological flexibility, and value-driven behaviour could be
considered. These measures, however, also have some disadvantages as will be discussed later.
In people with depression but without ABI, clinical prediction models are in a further developmental
phase as more studies have been performed (16). Nonetheless, they have not reached a stage in which
they can be implemented in clinical practice yet, since these models need further validation. The use of
prediction models for people with ABI is even further away. As we found that ABI-related variables, such as 8
lesion location, have a predictive value, models developed with data from people without ABI will likely not
be readily applicable for people with ABI. Therefore, it is important to further develop and validate these
models specifically for people with ABI.

Randomized controlled trials in psychotherapy research

RCTs are often considered the gold standard in investigating the effectiveness of psychotherapies or any
other intervention (17). They are used to study the cause-effect relationship between a treatment and
outcome (18). Next to comparing the average effects of different treatment outcomes, process measures
can be used to study the mechanisms by which the outcome is reached (i.e. moderating and mediating
effects). For instance, by including process measures in the BrainACT RCT, namely cognitive defusion, value-
based behaviour, and psychological flexibility, it can be investigated if these changed as hypothesized.
Nevertheless, RCTs also have some disadvantages. They are costly and time-consuming (19).
Furthermore, the recruitment of people with ABI is challenging and many RCTs in the field have small
sample sizes (20-22). Consequently, it is interesting to explore additional study designs as they have
some substantive advantages. SCED designs can form a viable alternative or addition to psychotherapy
research. Single case research is increasingly included in evidence standards by, for instance, the American
Psychological Association (23, 24). An obvious advantage of SCED studies is that no large sample sizes
are needed. Hence, they are less time-consuming and easier to implement in clinical practice. SCEDs can

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bridge the gap between research and everyday clinical practice and fit with the idea of evidence-based
clinical-practice (25). In addition, insights into how and why individuals change during the treatment can be
evaluated in a more detailed manner. A result of repeated assessing outcomes over multiple experimental
phases is that individual change patterns in the data can be investigated as well as the temporal relation
with mediators (26, 27). Lastly, due to the rapidly developing statistical techniques, such as meta-analytic
procedures, results can be generalized to specific populations (28).
As RCTs and SCED studies have different properties and strengths they can complement each other.
This is demonstrated in the BrainACT studies in this thesis. The SCED study in chapter 5 was used as an
initial exploration on the effectiveness and feasibility of the BrainACT treatment, before testing it in a
larger sample. Next to a SCED design, qualitative studies can provide valuable insights into psychological
mechanisms related to the effect of psychotherapy, which cannot be fully captured in questionnaires. In
addition, qualitative studies can help to unravel how psychotherapies aid people in the adaptation process
following ABI. Next to studying effectiveness, it is important to also study the feasibility, implementation,
and delivery of the intervention by means of a process evaluation as this will help to interpret the results on
effectiveness (29). Utilizing different types of research designs can complement each other in order to better
understand how and why people with ABI benefit from psychotherapy (17).

Acceptance and Commitment Therapy for people with acquired brain injury
In the studies in chapters 3 to 7, the effect of ACT in people with ABI was investigated, adaptations of ACT
for cognitive impairments were investigated, and the effectiveness and feasibility of ACT for people with ABI
were assessed. Both anxiety and depressive symptoms were considered since these often co-occur in people
with ABI (30) and because ACT is a transdiagnostic treatment (31).

Measuring the outcome of ACT

In the BrainACT RCT the primary outcome measures are anxiety and depressive symptoms. When looking at
the psychological flexibility model, a decrease in mood symptoms is expected despite it not being the main
treatment aim (it is however viewed as a beneficial treatment outcome) (32). The control strategies people
use to decrease thoughts, feelings, and sensations, such as avoidance or numbing, often cause suffering. If
people accept their thoughts, feelings, and sensations instead of trying to control them, one would expect
that suffering would become less and that mood symptoms would decrease as a result. Also, an increase
in psychological flexibility is often related to a decrease in mood symptoms (33, 34). This corresponds with
the results of chapter 5, where (clinically) significant improvements were found on repeated measures of
anxiety and depression, the HADS (35), and DASS-21 (36) following the BrainACT intervention. Furthermore,
Whiting et al. (37), Sander et al. (38), and Majumdar and Morris (39) found significant improvements in
mood symptoms in people with ABI in the ACT condition compared to the control condition. Using the HADS
and DASS-21 as primary outcome measures aids comparability with other studies investigating interventions
for anxiety and depressive complaints following ABI.

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Next to measuring outcomes related to symptom reduction, it is important to measure outcomes

related to the theoretical mechanisms of change. Consequently, in the BrainACT studies, several ACT process
measures are included, namely cognitive defusion, valued living, and psychological flexibility. In chapter
5 participants experienced a clinically significant increase in cognitive defusion. However, not all process
outcomes measured change.
Valued living. Surprisingly, we found no clinically significant changes regarding valued living (chapter
5), while the BrainACT treatment places extra emphasis on values and committed actions (chapter 3). Whiting
et al. (37) also found no significant differences regarding value-directed behaviour in the ACT intervention
compared to the control intervention. Additionally, a study researching an intervention developed to increase
valued living following ABI, found no improvements regarding value-driven behaviour (40). The measure
that was used in chapter 5 to measure value-driven behaviour is the Valued Living Questionnaire (VLQ).
The VLQ consists of ten broad value domains which are not exhaustive and people might show more value-
consistent behaviour related to different values which is then not reflected in the score on the questionnaire
(41). Additionally, a recent study found that the VLQ is not suitable for people with ABI (42). People with ABI
experienced confusion due to the phrasing and structure of the questions and made errors while rating the
value-consistency of actions in the last week. This measure was also used in the study by Sathananthan et
al. (40) and the authors reasoned that it likely explained the lack of improvement in valued living following
their intervention targeting valued living. After the commencement of our RCT, a version of the VLQ adapted
for people with cognitive deficits was developed and the use of this measure is recommended in future 8
studies researching ACT for people with ABI (43). Furthermore, processes related to psychological flexibility
will often be novel for people. For instance, people might believe they are living consistently with what is
important to them prior to the start of an ACT intervention. However, during the value exploration, they
might realize they have different values which are being neglected. Wilson et al. (41) suggested this might
even lead to a decrease in scores on a value questionnaire without behaviour being altered. A decrease in
scores on the VLQ was observed for three out of the four participants on the post-treatment measurement
in chapter 5, albeit not clinically significant. At the follow-up measures, the scores did increase somewhat
again, but only slightly. Moreover, measuring ACT processes can be an intervention in and of itself. One of
the participants mentioned that the measuring moments of the RCT gave her increased insights (chapter 7):

“This also came back with the measuring moments; how have you acted on your values lately?
That did make me aware again that I had to pay more attention to my husband, for example. That
insight helped.”

As people in the control condition also complete ACT questionnaires this might reduce the effects in the RCT,
but does not explain the lack of effects in the SCED study.
Psychological flexibility. The AAQ-ABI was included in the studies in this thesis as a measure of
psychological inflexibility related to thoughts and feelings about ABI (44, 45). Population-specific outcomes
can measure the change in how flexible patients can cope with the symptoms or complaints for which

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they sought help. They, therefore, might outperform more generic measures of psychological flexibility
regarding treatment sensitivity and incremental validity (46). In chapter 3 the psychometric properties of
the AAQ-ABI and the CFQ-7, measuring cognitive defusion were investigated in Dutch individuals with ABI.
For both measures, good psychometric properties were found. However, in chapter 5 no clinically significant
differences were found on the AAQ-ABI or the original questionnaire, the AAQ-II. Likewise, Whiting et al.
(37) found no significant improvements in the psychological flexibility on both the AAQ-II and the AAQ-ABI
compared to the control intervention. This could be attributed to the small sample size in the study of people
with severe TBI. A study with a larger sample size by Sander et al. (38) did find significant improvements on
the AAQ-II compared to the control condition in people with TBI. Another possible explanation for these
mixed findings might be found in the outcomes used to measure psychological flexibility processes. As
discussed earlier in this thesis, the AAQ-II, the most used measure of psychological inflexibility, has been
criticized for its validity, specifically the discriminant validity (33, 47). Given the concerns regarding the
discriminant validity of the AAQ-II, the discriminant validity of the AAQ-ABI should be further investigated.
This should be kept in mind when using the AAQ-ABI and the AAQ-II. The AAQ-ABI is currently the only
available measure for psychological flexibility related to thoughts and feelings about ABI and can thus be
considered the best option, although its limitations should be kept in mind.

Flexibility processes
As ACT does improve psychological flexibility and valued living, as measured by the AAQ-II and VLQ in other
populations, there could be additional explanations for the lack of effects in our and other studies regarding
these processes. Perhaps, the possible cognitive deficits experienced by people with ABI play a role, such
as deficits in cognitive flexibility (34, 48). Cognitive flexibility is a subcomponent of executive functioning
and is defined as the ability to change behaviour in accordance with environmental change (49). This
concept likely partly overlaps with psychological flexibility. Both are dynamic, related to behavioural change
processes, and describe the interplay between behaviour (thoughts and actions) and the environmental
context. However, the conceptualization of psychological flexibility is more comprehensive and includes the
psychological processes of acceptance and self-as-context which cognitive flexibility does not (48). Cognitive
and psychological flexibility stem from different conceptual backgrounds; cognitive flexibility originates from
neuropsychology and psychological flexibility is most often studied in relation to ACT. Tyrberg et al. (50)
performed a study on the intersection of these two fields. The authors studied the Wisconsin Card Sorting
Test (a commonly used task of cognitive flexibility) using a behavioural analytic approach. During the task
when cognitive flexibility was most needed (switches) the behaviour of participants was based on temporal
and deictic framing, while this was less for coordination and spatial framing. It would be interesting to
know whether the relational frames that are dominant in the behaviour of people with deficits in cognitive
flexibility would differ. There is some evidence that cognitive and psychological flexibility are related. The
study of Grant and Cassidy (51) found that self-report cognitive flexibility is related to psychological flexibility,
but task-based cognitive flexibility is not. Following an ABI people often experience deficits in executive

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functioning and cognitive flexibility (52). What this implies for improving psychological flexibility in people
with impaired cognitive flexibility is unclear. People with deficits in cognitive flexibility might have difficulties
adapting their behaviour based on contextual changes and their values, which therefore might explain
the lack of improvements in psychological flexibility and value-driven behaviour. Given the impairments in
cognitive flexibility in people with ABI, it is likely beneficial to pay increased attention to behavioural change
strategies when providing ACT to this patient population. Moreover, while values and committed actions are
introduced early on in the BrainACT treatment and receive attention in the following sessions, this might not
be sufficient for everyone to elicit behavioural change.

Adapting ACT for people with ABI

As is shown in the previous paragraph, the treatment of anxiety and depressive complaints following
ABI is still complex. Many factors influence treatment response (chapter 2) and standard psychological
interventions are not suitable for people with ABI. Psychotherapy needs alteration for possible cognitive
deficits when provided to people with ABI. When adapting psychotherapeutic interventions several
recourses can be consulted such as recommendations from the literature, clinical experience of therapists
working with this population, and the patients themselves. Furthermore, it seems important to pilot the
adapted psychotherapy and further adjust it based on feedback from patients and therapists. Some major
changes were made to the BrainACT treatment based on the results of the pilot study (chapter 5), such as
decreasing the amount of content and length of the sessions and offering the possibility to change the order
8
of the sessions to the patients’ needs (as described in chapter 4). The studies in this thesis illustrate that it is
possible to adapt ACT for people with ABI. When providing ACT to this patient population, it seems essential
to integrate concepts from contextual behavioural science and clinical neuropsychology. Therapists should
therefore be knowledgeable on both the psychotherapeutic processes they are providing as well as the
possible consequences of an ABI.
Moreover, the results in chapter 7 demonstrate that the BrainACT treatment was found feasible for
people with ABI. Participants implemented the different ACT processes, with acceptance being an important
outcome mentioned by participants, indicating that people with ABI were able to comprehend and utilize
ACT skills. Key strengths of the BrainACT intervention are the experiential nature of the intervention, the
simplified materials in the workbook and homework, and the structured nature of the protocol by means of
the bus of life metaphor. It emphasizes the importance of repetition, structure, and a focus on behavioural
activation strategies which confirms the recommendations made by previous articles (48, 53, 54). These
recommendations could be considered when adapting interventions for people with ABI.

Psychological flexibility in rehabilitation

Several reviews have pointed out that psychological flexibility has likely been studied before but under
different names, such as ego resilience, executive control, response modulation, or self-regulation (33, 34).

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Over the past years, rehabilitation programmes for people with ABI have increasingly been aimed at improving
these concepts, which might be an explanation for the popularity of ACT for people with ABI. An example
of a potential overlap between underlying concepts can be taken from the literature on post-traumatic
growth, which describes that following a traumatic event, people can experience positive psychological
growth (55). It is a concept that has been studied intensively in relation to ABI (56). Lyon et al. (57) found that
following ABI people can experience positive changes related to acceptance, strengthened relations with
others, and discovering a new meaning and perspective on life. These themes seem to overlap with several
core components of the psychological flexibility model. Post-traumatic growth is related to value-directed
living (58), which might indicate that when people experience post-traumatic growth, they have identified
new values and live more in alignment with these values. Moreover, acceptance and resilience (a concept
closely related to psychological flexibility) have been studied in people with ABI and are seen as important
outcomes related to rehabilitation (59, 60). It seems that components of the psychological flexibility model
have been part of rehabilitation following ABI for a longer period of time. The studies in this thesis stress that
interventions targeting these processes can be beneficial to recovery after ABI.

Clinical recommendations
Before implementing the BrainACT treatment in the clinic, the effectiveness should be confirmed by means
of the BrainACT RCT. However, clinicians can use the BrainACT treatment protocol as described in chapter
4 to provide the treatment to patients with similar patient profiles as the three participants for whom the
BrainACT treatment was found effective in chapter 5. The BrainACT treatment can then be adapted according
to the recommendations in chapter 7. When the content of the sessions is too much for a patient, the
BrainACT treatment can be provided in ten sessions instead of eight. Moreover, when face-to-face sessions
are not possible, the BrainACT treatment can be provided through video-conferencing as this was found
feasible in chapter 7. However, face-to-face is the preferred treatment format.
No clear clinical recommendations can yet be made on what the best timing of the BrainACT treatment
following an ABI would be. During the span of our research, many clinicians have mentioned that ACT seems
most appropriate for people in the more chronic phase following ABI when they might be struggling with
acceptance. However, others have discussed to provide ACT as early as possible (as a preventative intervention)
and that it is never too late to provide ACT (61). In chapter 2 we found that time since injury influenced the
outcome of depressive symptoms following CBT or CCT. There was a greater reduction in depressive symptoms
after the treatment if time since injury was longer. This effect was, however, very small.

Strengths and methodological considerations

The studies in this thesis utilized a wide variety of designs, measurement techniques, and novel analysis
techniques. A questionnaire measuring ACT processes was developed specifically for people with ABI and
an ACT intervention was specifically developed for this patient population. Chapter 5 was the first study

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 General discussion

utilizing a SCED design to investigate ACT (or psychotherapy) for people with ABI. The process evaluation in
chapter 7 reveals a more qualitative perspective on the experience of the therapists and participants who,
respectively, provided and received the BrainACT intervention. Finally, the results of the BrainACT RCT will
provide information on the effectiveness on a group level, although the data will also be analysed from an
individual perspective by calculating if participants surpassed the threshold of minimally important, reliable,
or clinically significant change. Finally, a novel variable selection approach (i.e. elastic net regression) was
used to develop a clinical prediction model.
Several methodological considerations have already been discussed above, such as the strengths and
limitations of a RCT and the measurement of ACT processes. Furthermore, as can be seen in the patient
characteristics of the sample included in the study in chapter 7, most participants acquired a stroke.
Therefore the results of the feasibility study and the RCT might not be as generalizable for people with TBI
as for people with a stroke. Nevertheless, it seems that levels and aetiology of depressive symptoms do
not greatly vary between people with stroke or TBI (62), nor does their coping style (63). Levels of anxiety
might be higher for patients with a stroke since they can experience fear of stroke recurrence (64, 65).
Moreover, the participants included in the SCED study in chapter 5 were relatively young and three had a
high education level. Looking at their case descriptions, the experienced consequences following ABI were
not very severe. The results might therefore not generalize to older people with a lower education level and
with more severe (cognitive) deficits. Additionally, previous studies have shown that psychotherapies can
also elicit negative effects such as worsening of symptoms or the emergence of new symptoms (66) which 8
often receive little attention in clinical trials. This also holds for the BrainACT RCT. While adverse events are
registered, negative therapeutic effects are not. In the SCED study, these negative effects would have been
noticed since the participants were closely monitored. To our knowledge, no studies have been performed
on the negative side effects of ACT. Future studies should be attentive and register these effects.

Future directions
The studies in this thesis give rise to several recommendations and leads for future studies.

Developing and validating clinical prediction models

The first step towards a more personalized approach to the treatment of anxiety and depressive
symptoms was made in chapter 2. Our developed prediction model could be replicated and externally
validated. Most likely the BrainACT treatment will not be effective for all participants included in
the BrainACT RCT. It would therefore be interesting to identify which patients benefited from the
BrainACT and psycho-education and relaxation intervention by developing a clinical prediction model
for both treatments and investigating which characteristics are related to these beneficial effects.

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BrainACT for people with ABI, other populations, and in different formats
The results in chapters 5 and 7 are promising and together with the existing data permit further investigation
into the effectiveness of ACT for people with ABI. Future studies could investigate the effect of ACT from a
qualitative perspective building upon the work of Large et al. (67), who examined the experiences of people
with stroke following a group ACT intervention. Furthermore, theoretical and clinical processes underlying
treatment effects should be investigated, utilizing moderation and mediation analyses. This could lead the
way towards process-based therapy targeting these mediators and moderators (68).
After evaluation of the long-term effect of ACT for people with ABI, future studies could investigate
the added effect of booster sessions and their usefulness for implementing ACT skills in daily life in the long
term. Moreover, while the BrainACT treatment is specifically developed for people with ABI, it might also
be of use for other populations with cognitive deficits, such as people with multiple sclerosis, mild cognitive
impairment, or Parkinson’s disease. The references to brain injury would have to be altered, but no major
changes to the protocol would be necessary. Additionally, the studies in this thesis focus on people with an
objectified ABI. However, clinicians from participating centres indicated that they often see patients with
ABI which is not objectified, such as a mild TBI or concussion. Patients with mild TBI were excluded from
participation in the BrainACT studies but there are indications that psychological flexibility plays a role in
persistent post-concussion symptoms (69). Therefore, the potential of ACT for people with persistent post-
concussion symptoms following mild TBI or a transient ischemic attack should be further investigated.
One of the outcomes of the process evaluation in chapter 7 was that the BrainACT treatment could
be investigated for its effectiveness and feasibility as a group intervention. At Maastricht University Medical
Centre, the first ACT group based on the BrainACT treatment was provided to people with ABI as a pilot.
While not empirically investigated, the BrainACT treatment seemed appropriate to be provided in a group
format and patients were satisfied with the intervention. Another format which could be considered is to
provide the BrainACT treatment in a dyadic format. A study by Kraus et al. (70) found it beneficial when
people with dementia followed a CBT intervention together with a caregiver. The caregivers could help
patients learn and practice skills between sessions. This could be an interesting option for people with ABI
and more severe cognitive deficits or for instance aphasia. Future research could investigate BrainACT in a
dyadic format, especially since ACT seems to be helpful for caregivers of people with ABI as well (71).

Conceptualizing and measuring psychological flexibility

The concept of psychological flexibility seems a vital process in relation to mental health and has a clear
clinical implications (34). However, more research is needed on its conceptualization and assessment.
Approaches and perspectives from neuropsychology could help in this regard. The association between
cognitive and psychological flexibility could, for instance, be further investigated. Moreover, alternative
manners of measuring psychological flexibility could be explored. Wolgast (47) mentioned that because
psychological flexibility is a dynamic, context-dependent, and shifting psychological process, it might be

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difficult to fully capture it in a static and global self-report measure. Therefore, measuring psychological
flexibility through different outcome modalities, next to self-report measures, might increase our
understanding of the construct. Malo et al. (72) propose to do this from a transdiagnostic perspective utilizing
virtual reality and qualitative techniques. It would be interesting to investigate if it is possible to develop a
behavioural measure of psychological flexibility. Additionally, the experience sampling method could be an
interesting approach to studying psychological flexibility and related ACT processes in a real‐world context,
by investigating how these concepts are related to different contexts and mood states. Furthermore, in the
SCED study in chapter 5, we measured anxiety and depressive symptoms repeatedly over time. It would be
interesting to use a SCED design to investigate how ACT processes evolve and change during the BrainACT
intervention. The temporal relation between mood and process measures could be studied, for instance,
a decrease in experiential avoidance would be expected before a decrease in mood symptoms. The Brief
Acceptance Measure, as used by Hulbert-Williams et al. (73), seems appropriate to assess the ACT processes
repeatedly over time. This is a three-item measure of psychological flexibility related to the three pillars of
ACT openness, awareness, and engagement. However, the psychometric properties of this measure should
be further investigated.

Concluding remarks
The puzzle of helping people with anxiety and depressive symptoms following ABI is far from solved. With
this thesis, we hope to have added some pieces to the puzzle. By successfully developing a clinical prediction
8
model, the first step towards a more personalized treatment approach for post-stroke depressive symptoms
was made. Moreover, the studies in this thesis add to the existing knowledge that people with ABI can
benefit from ACT. The BrainACT treatment is feasible for people with ABI and can improve anxiety and
depressive complaints. These findings will be strengthened if the BrainACT treatment is found to be effective
in the BrainACT RCT. The outcomes of this thesis are promising and we hope our studies will contribute to a
further advancement in the treatment of anxiety and depressive symptoms in people with ABI.

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Chapter 8

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ADDENDUM
Addendum

Summary
People with acquired brain injury (ABI) often experience anxiety and depressive symptoms. Previous studies
have concluded that there is a need to optimize treatment strategies for people with ABI-related anxiety and
depressive symptoms. The aim of this thesis therefore was to improve treatment for people experiencing
anxiety and depressive symptoms following ABI. We first developed a clinical prediction tool for people
with post-stroke depressive symptoms (i.e. whom to treat). Furthermore, the BrainACT intervention was
developed; Acceptance and Commitment Therapy (ACT) adapted for the needs and possible cognitive
deficits of people with ABI. We investigated the feasibility and effectiveness of BrainACT for anxiety and
depressive symptoms post-ABI.
Chapter 2 describes the results of the study in which we developed a prognostic index for patients
with post-stroke depressive symptoms. This was done for two outcome domains: post-stroke depressive
symptoms and experienced restrictions regarding participation, using the data of a randomized controlled
trial (RCT) investigating cognitive behavioural therapy and computerized cognitive training for post-stroke
depression. From 18 pre-treatment variables of patients and caregivers, predictors were selected using elastic
net regression analyses. Based on this selection, prognostic index scores (i.e. predictions) for both outcome
domains were computed for each individual patient. The depression model included all pre-treatment
variables, explaining 44% of the variance. The strongest predictors were lesion location, employment status,
participation, comorbidities, mobility, sex, and presence of pre-treatment depression. Six predictors of post-
treatment participation were identified, explaining 51% of the variance: mobility, pre-treatment level of
participation, age, satisfaction with participation, caregiver strain, and psychological distress of the spouse.
The cross-validated prognostic index scores correlated highly with the actual outcome scores. From this
study, it can be concluded that post-stroke depressive symptoms form a complex and multifactorial problem.
Treatment outcome is influenced by the characteristics of the stroke, the patients, and their spouses. The
results show that psychological distress is probably no obstacle when attempting to improve participation.
The personalized predictions (prognostic index scores) of treatment outcome show promising results, which,
after further replication and validation, could aid clinicians and patients with treatment selection.
Furthermore, in order to measure psychological flexibility related to thoughts and feelings about
ABI, the Acceptance and Action Questionnaire for Acquired Brain Injury (AAQ-ABI) was developed.
Population-specific outcomes can measure the change in how flexible patients can deal with the symptoms
or complaints for which they sought help. They, therefore, might outperform more generic measures of
psychological flexibility regarding treatment sensitivity and incremental validity. In chapter 3 the results of a
validation study investigating the psychometric properties of the Dutch versions of the AAQ-ABI (measuring
psychological flexibility related to thoughts and feelings about ABI) and the Cognitive Fusion Questionnaire
(CFQ-7; measuring cognitive defusion) are presented. Score distribution, reliability, and convergent validity
of the AAQ-ABI and the CFQ-7 were examined in Dutch individuals with ABI. In total 73 patients with ABI
were included. The AAQ-ABI showed good reliability and the CFQ-7 excellent reliability. Both did not show
a floor or ceiling effect, nor a skewed distribution. There were strong to moderate correlations between the

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 Summary

questionnaires and measures of psychological flexibility, mood, quality of life, and value-driven behaviour.
Inter-item total correlations indicate that the questions within each questionnaire measure the same
construct. This study shows that the Dutch AAQ-ABI and CFQ-7 have acceptable to good psychometric
properties when measuring psychological flexibility and cognitive defusion in patients with ABI.
Chapter 4 describes the theoretical underpinning, development, and content of the BrainACT
intervention. Existing ACT protocols were adapted for the needs and potential cognitive deficits of people
with ABI. General alterations are the use of visual materials, summaries, and repetition. ACT-specific
adaptions include the Bus of Life metaphor as a recurrent exercise, shorter mindfulness exercises, simplified
explanations, a focus on experiential exercises, and the monitoring of committed actions. The intervention
consists of eight one-hour face-to-face sessions provided by a psychologist who has experience with ACT and
in working with people with ABI. The order of the sessions, metaphors, and exercises can be tailored to the
needs of the patients. The BrainACT intervention is expected to be a feasible and effective intervention for
people with anxiety or depressive symptoms following ABI.
To evaluate the effect of ACT for people with ABI, in chapter 5 a non-concurrent multiple baseline
design study across four cases is described. Participants were randomly assigned to a baseline period,
followed by a treatment phase using the BrainACT protocol, and a follow-up phase. Anxiety and depressive
symptoms were repeatedly measured. During six measurement moments over a year, participants filled
in questionnaires measuring anxiety, depression, stress, participation, quality of life, and ACT-related
processes. Randomization tests and NAP (non-overlap of all pairs) scores were used to calculate the level of
change across phases. The clinically significant change as measured by the questionnaires was defined with
the Reliable Change Index. Three out of four participants showed medium to large decreases in anxiety and
depressive symptoms. Furthermore, participants showed improvements regarding stress, cognitive fusion,
A
and quality of life. There were no improvements regarding psychological flexibility, value-driven behaviour,
or social participation. It can be concluded that ACT is possibly an effective treatment option for people
experiencing ABI-related anxiety and depression symptoms.
In chapter 6 the protocol of the BrainACT RCT is described. The study is a multicentre, randomized,
controlled, two-arm parallel trial. In total, 80 patients who survived an ABI will be randomized into the
BrainACT or control (i.e. psycho-education and relaxation) intervention. BrainACT and the control intervention
are offered by psychologists in Dutch hospitals and rehabilitation centres during regular care. Measurements
are conducted by the researchers. The primary outcome measures are the Hospital Anxiety and Depression
Scale and the Depression Anxiety Stress Scale. Secondary outcomes are psychological flexibility, valued
living, cognitive defusion, social participation, and quality of life. Outcomes will be assessed by trained
assessors, blinded to treatment condition, pre-treatment, during treatment, post-treatment, and at 7 and
12 months. At the moment (July 2022) the follow-up measurements of the RCT are being conducted. Data
on the effectiveness of BrainACT are therefore not presented in this thesis.
The study described in chapter 7 aimed to evaluate the feasibility of BrainACT for people with ABI.
In addition, the feasibility of providing the BrainACT treatment through videoconferencing during COVID-19

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lockdowns was investigated. Therefore, a process evaluation of the BrainACT treatment was conducted. The
attendance and compliance rates, engagement with the protocol, satisfaction of participants and therapists,
and perceived barriers and facilitators for delivery in clinical practice were investigated using therapy logs
and semi-structured interviews with participants and therapists. Qualitative data were categorized based
on content. Quantitative data were reported using descriptive statistics. Twenty-seven participants and 11
therapists participated in the study. We found high attendance rates and both participants and therapists
were satisfied with the intervention. Moreover, participants were motivated and engaged in homework
exercises. The compliance rate, however, was relatively low. After finishing the treatment, patients reported
to still apply the ACT skills obtained during the BrainACT intervention. Key strengths are the structure
provided with the Bus of Life metaphor, the experiential nature of the intervention, and the materials and
homework exercises. Although participants and therapists often preferred face-to-face sessions, it is feasible
to deliver ACT through video conferencing for people with ABI. In conclusion, the BrainACT treatment is a
feasible intervention for people with anxiety and depressive symptoms following ABI. However, for patients
for whom the content of the sessions is too extensive, it is recommended to add two extra sessions. In case
the BrainACT treatment appears to be effective in the accompanying RCT, we recommend implementation
in clinical practice.
Chapter 8 describes the main findings of this thesis and provides a general discussion, including
methodological considerations as well as implications for future research. The studies in this thesis
demonstrated that ACT can be a suitable treatment option for people with ABI-related anxiety and
depressive symptoms. These findings will be strengthened if the BrainACT treatment is found to be effective
in the BrainACT RCT. By successfully developing a clinical prediction model, the first step towards a more
personalized treatment approach for post-stroke depressive symptoms was taken. This can be further
explored in future studies. The outcomes of this thesis are promising and we hope they will contribute to a
further advancement in the treatment of anxiety and depressive symptoms in people with ABI.

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Addendum

Nederlandse samenvatting (dutch summary)

Mensen met niet-aangeboren hersenletsel ervaren vaak stemmingsklachten, zoals angst- of depressieve
gevoelens. We weten uit eerder onderzoek dat er behoefte is aan het verbeteren van de behandeling voor
mensen met hersenletselgerelateerde angst- en depressieve symptomen. Het doel van het onderzoek in
dit proefschrift was daarom het verbeteren van de behandeling voor mensen die angst- en depressieve
symptomen ervaren na een hersenletsel. Op basis van een eerder uitgevoerde studie, ontwikkelden we een
klinisch voorspellingsmodel voor mensen met depressieve symptomen na een beroerte. Dit zou kunnen
helpen bij het koppelen van de juiste behandeling aan de juiste persoon. Vervolgens ontwikkelden we de
BreinACT-behandeling op basis van Acceptance and Commitment Therapy (ACT). ACT is een psychologische
behandeling met als belangrijkste behandeldoel het verhogen van psychologische flexibiliteit. Psychologische
flexibiliteit, oftewel veerkracht, betekent dat je flexibel om kunt gaan met gedachten, gevoelens of
lichamelijke gewaarwordingen, ook als ze moeilijk of pijnlijk zijn - en dat je tegelijkertijd keuzes kunt maken
op basis van wat echt belangrijk voor je is (je waarden). We pasten de BreinACT-behandeling op zo’n manier
aan dat het beter past bij de behoeften en veelvoorkomende problemen van mensen met een hersenletsel,
zoals cognitieve klachten. We onderzochten of de BreinACT-behandeling een haalbare interventie is en of
het angst- en depressieve symptomen na hersenletsel vermindert.
Hoofdstuk 2 beschrijft de resultaten van een studie waarin we een prognostische index (klinisch
voorspellingsinstrument) ontwikkelden voor patiënten met depressieve symptomen na een beroerte. Dit
deden we voor twee uitkomstdomeinen: depressieve symptomen na een beroerte en ervaren beperkingen
met betrekking tot sociale participatie. We maakten gebruik van de gegevens van een gerandomiseerde
gecontroleerde studie waarin cognitieve gedragstherapie en cognitieve training op de computer werden
onderzocht als behandeling voor depressie na een beroerte. Uit 18 pre-behandelingsvariabelen van
patiënten en partners werden voorspellers geselecteerd met behulp van een elastic net regressie-analyse.
Op basis van deze selectie werden prognostische indexscores (voorspellingen) voor beide uitkomstdomeinen
berekend voor elke individuele patiënt. In het depressiemodel werden alle pre-behandelingsvariabelen
geselecteerd en het model verklaarde 44% van de variantie. De sterkste voorspellers waren: locatie van
de laesie, werkstatus, participatie, comorbiditeiten, mobiliteit, geslacht en het niveau van depressie voor
de behandeling. Er werden zes voorspellers van participatie na de behandeling vastgesteld, die 51% van
de variantie verklaarden: mobiliteit, niveau van participatie vóór de behandeling, leeftijd, tevredenheid
met participatie, belasting en stemmingsklachten van de partner. De kruis-gevalideerde prognostische
indexscores correleerden sterk met de werkelijke uitkomstscores. Uit deze studie kan worden geconcludeerd
dat depressieve symptomen na een beroerte een complex en multifactorieel probleem vormen. Het resultaat
van de behandeling wordt beïnvloed door de kenmerken van de beroerte, de patiënten en hun partners.
De resultaten laten zien dat stemmingsklachten waarschijnlijk geen belemmering vormen bij pogingen om
de participatie te verbeteren. De gepersonaliseerde voorspellingen (prognostische indexscores) van het
behandelresultaat zijn veelbelovend en kunnen na verdere replicatie en validatie zowel clinici als patiënten
helpen bij de keuze voor de meest geschikte behandeling.

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 Nederlandse samenvatting (Dutch summary)

In hoofdstuk 3 worden de resultaten gepresenteerd van een validatieonderzoek naar de

psychometrische eigenschappen van twee Nederlandse vragenlijsten namelijk; de Acceptance and Action
Questionnaire voor Niet-Aangeboren Hersenletsel (AAQ-NAH; deze meet psychologische flexibiliteit met
betrekking tot gedachten en gevoelens over hersenletsel) en de Cognitive Fusion Questionnaire (CFQ-7; deze
meet cognitieve defusie). Scoreverdeling, betrouwbaarheid en convergente validiteit van de AAQ-NAH en de
CFQ-7 werden onderzocht bij Nederlandse personen met hersenletsel. In totaal werden 73 patiënten met
hersenletsel geïncludeerd. De AAQ-NAH toonde een goede betrouwbaarheid en de CFQ-7 een uitstekende
betrouwbaarheid. Beide vertoonden geen bodem- of plafondeffect, noch een scheve verdeling. Er werden
sterke tot matige correlaties tussen de vragenlijsten en maten van psychologische flexibiliteit, stemming,
kwaliteit van leven en waardegericht gedrag gevonden. Inter-item totaalcorrelaties lieten zien dat de vragen
binnen elke vragenlijst hetzelfde construct meten. Dit onderzoek laat zien dat de Nederlandse AAQ-NAH en
CFQ-7 acceptabele tot goede psychometrische eigenschappen hebben bij het meten van psychologische
flexibiliteit en cognitieve defusie bij patiënten met hersenletsel.
Hoofdstuk 4 beschrijft de theoretische onderbouwing, de ontwikkeling en de inhoud van de BreinACT-
interventie. Bestaande ACT-protocollen werden aangepast aan de behoeften en potentiële cognitieve
problemen van mensen met een hersenletsel. Algemene aanpassingen zijn het gebruik van visuele
materialen, samenvattingen en herhaling. ACT-specifieke aanpassingen omvatten de levensbusmetafoor
als rode draad in de behandeling, kortere mindfulnessoefeningen, vereenvoudigde uitleg, een focus op
ervaringsgerichte oefeningen en het monitoren van waardengerichte acties. De interventie bestaat uit acht
face-to-face sessies van een uur met een psycholoog, ervaren in ACT en in het werken met mensen met
een hersenletsel. De volgorde van de sessies, de metaforen en de oefeningen kunnen worden aangepast
aan de behoeften van de patiënten. Verwacht wordt dat de BreinACT-interventie een haalbare en effectieve
A
interventie is voor mensen met angst- en/of depressieve symptomen na een hersenletsel.
Om het effect van de BreinACT-interventie voor mensen met een hersenletsel te evalueren, wordt in
hoofdstuk 5 een studie beschreven met een non-concurrent multiple baseline design waar vier mensen met
hersenletsel aan hebben deelgenomen. Participanten startten met een gerandomiseerde baselineperiode,
die werd gevolgd door de BreinACT-behandeling en vervolgens een follow-upfase. Angst- en depressieve
symptomen werden herhaaldelijk gemeten. Tijdens zes meetmomenten, gedurende het jaar dat de
participanten deelnamen aan de studie, vulden ze vragenlijsten in die angst, depressie, stress, participatie,
kwaliteit van leven en ACT-gerelateerde processen maten. Randomisatietests en NAP-scores (non-overlap
of all pairs) werden gebruikt om het niveau van veranderingen over de fases heen te berekenen. Klinisch
significante veranderingen werden berekend met de Reliable Change Index. Drie van de vier deelnemers
vertoonden een gemiddelde tot grote afname van angst- en depressieve symptomen. Verder vertoonden
de deelnemers verbeteringen met betrekking tot stress, cognitieve fusie en kwaliteit van leven. Er waren
geen verbeteringen met betrekking tot psychologische flexibiliteit, waardengericht gedrag of sociale
participatie. Geconcludeerd kan worden dat ACT mogelijk een effectieve behandeloptie is voor mensen met
hersenletselgerelateerde angst- en depressiesymptomen.

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Addendum

In hoofdstuk 6 wordt het protocol van de gerandomiseerde gecontroleerde studie naar de

haalbaarheid en effectiviteit van BreinACT beschreven. De studie is een multicenter parallelle studie met
twee groepen. In totaal worden 80 patiënten met hersenletsel gerandomiseerd in de BreinACT-behandeling
of de controlebehandeling (een behandeling die bestaat uit psycho-educatie en relaxatietraining). De
BreinACT- en controlebehandeling worden aangeboden door psychologen in Nederlandse ziekenhuizen en
revalidatiecentra tijdens de reguliere zorg. Uitkomstmetingen worden uitgevoerd door de onderzoekers. De
primaire uitkomstmaten zijn de Hospital Anxiety and Depression Scale en de Depression Anxiety Stress Scale.
Secundaire uitkomsten zijn psychologische flexibiliteit, waardengericht leven, cognitieve defusie, sociale
participatie en kwaliteit van leven. Uitkomsten zullen worden beoordeeld door getrainde beoordelaars die
blind zijn voor de behandelconditie. Zij meten voor de behandeling, tijdens de behandeling, direct na de
behandeling en 7 en 12 maanden na start van de studie. Op dit moment (juli 2022) worden de follow-
up metingen van de RCT uitgevoerd. Gegevens over de effectiviteit van de BreinACT-behandeling worden
daarom in dit proefschrift niet gepresenteerd.
Het doel van de in hoofdstuk 7 beschreven studie was om de haalbaarheid van de BreinACT-
behandeling voor mensen met hersenletsel te evalueren. Daarnaast werd de haalbaarheid onderzocht
van het aanbieden van de BreinACT-behandeling via beeldbellen tijdens de COVID-19-lockdowns. Daarom
werd er een procesevaluatie van de BreinACT-behandeling uitgevoerd. Aanwezigheid, therapietrouw,
betrokkenheid bij het protocol, tevredenheid van deelnemers en therapeuten, en barrières en faciliterende
factoren bij het implementeren van de behandeling in de klinische praktijk werden onderzocht met behulp
van therapielogboeken en semigestructureerde interviews met deelnemers en therapeuten. Kwalitatieve
gegevens werden gecategoriseerd op basis van inhoud. Kwantitatieve gegevens werden gerapporteerd met
behulp van beschrijvende statistieken. Zevenentwintig deelnemers en 11 therapeuten namen deel aan het
onderzoek. We vonden een hoge opkomst en zowel deelnemers als therapeuten waren tevreden over de
interventie. Bovendien waren de deelnemers gemotiveerd en betrokken bij de huiswerkoefeningen. De
therapietrouw was echter relatief laag. Na afloop van de behandeling gaven patiënten aan dat ze de ACT-
vaardigheden die ze tijdens de interventie leerden nog steeds toepassen. Belangrijke sterke punten zijn de
geboden structuur met de levensbusmetafoor, de ervaringsgerichte aard van de interventie en de materialen
en huiswerkoefeningen. Hoewel deelnemers en therapeuten vaak de voorkeur gaven aan face-to-face
sessies, is het voor mensen met hersenletsel haalbaar om ACT via beeldbellen aan te bieden. Concluderend
is de BreinACT-behandeling een haalbare interventie voor mensen met angst- en depressieve symptomen
na hersenletsel. Echter, voor patiënten voor wie de inhoud van de sessies te uitgebreid is, kunnen twee
extra sessies worden toegevoegd. Indien de BreinACT-behandeling effectief blijkt te zijn in de BreinACT-RCT,
bevelen wij implementatie in de klinische praktijk aan.
Hoofdstuk 8 beschrijft de belangrijkste bevindingen van dit proefschrift en geeft een algemene
discussie, inclusief methodologische overwegingen en implicaties voor toekomstig onderzoek. De
studies in dit proefschrift toonden aan dat ACT een geschikte behandeloptie kan zijn voor mensen met
hersenletselgerelateerde angst- en depressieve symptomen. Deze bevindingen zullen worden versterkt

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 Nederlandse samenvatting (Dutch summary)

als de BreinACT-behandeling effectief blijkt te zijn in de BreinACT-RCT. Door met succes een klinisch
voorspellingsmodel te ontwikkelen is de eerste stap gezet naar een meer gepersonaliseerde behandelaanpak
voor depressieve symptomen na een beroerte. Dit kan in toekomstige studies verder worden onderzocht. De
resultaten van dit proefschrift zijn veelbelovend. We hopen dan ook dat ze zullen bijdragen aan een verdere
vooruitgang in de behandeling van angst- en depressieve symptomen bij mensen met een hersenletsel.

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Addendum

Impact paragraph
Acquired brain injury (ABI), such as stroke or traumatic brain injury due to a fall or accident, can lead to
physical disabilities (e.g. problems with walking), persistent cognitive deficits (e.g. forgetfulness), behavioural
dysregulations (e.g. impulsivity), and emotional consequences (e.g. depression and anxiety). People with
ABI are at an increased risk of developing symptoms of depression and anxiety. These symptoms are related
to decreased participation in society (dependency in daily life and lower return-to-work rates), higher re-
hospitalization rates, and increased cognitive and physical impairments. Furthermore, anxiety and depressive
symptoms following ABI are determined by many different factors related to the injury to the brain, but also
to personal factors such as coping style and environmental factors such as social support. Therefore, the
treatment of ABI-related anxiety and depressive symptoms is challenging. The effectiveness of psychological
treatments for depression is less robust for patients with ABI than for patients with depression but without
an ABI. For that reason, the studies in this thesis aimed to improve the treatment for people experiencing
anxiety and depressive symptoms following ABI.

Main findings
First, it was examined whether it was possible to predict the treatment outcome for individuals who survived
a stroke and have received psychological treatment for depressive symptoms. A statistical model (clinical
prediction model) was developed to predict the level of depressive symptoms and social participation for
individual patients following the treatment. We found that characteristics of the stroke (e.g. location of
the stroke in the brain), patients themselves (e.g. presence of depression before the stroke), and their
caregivers (e.g. level of burden) were predictive of treatment outcome. Second, we investigated Acceptance
and Commitment Therapy (ACT) as a possible treatment option for people with ABI-related anxiety and
depressive symptoms. ACT is a psychological treatment which focuses on the acceptance of thoughts and
feelings and on living according to your values. Such a treatment should lead to an increase in psychological
flexibility, which is the main treatment goal of ACT and is described as “the ability to contact the present
moment more fully as a conscious human being and to change, or persist in, behaviour when doing so
serves valued ends”. In order to measure the effectiveness of ACT for people with ABI, we translated
two questionnaires measuring ACT processes into Dutch. The questionnaires measure cognitive defusion
(creating a distance from thoughts) and psychological flexibility related to thoughts and feelings about ABI.
Subsequently, their performance was investigated which was found to be good. Furthermore, we developed
an ACT intervention adapted for the needs and possible cognitive deficits (e.g. memory problems) of
people with ABI: the BrainACT treatment. Existing ACT treatments were adapted based on suggestions
made in previous studies, recommendations by clinicians, and feedback from patients and therapists
who, respectively, received and provided the treatment during a pilot study. The BrainACT treatment is
simple, structured, and includes many behavioural and experiential exercises. We found that the BrainACT
treatment is feasible for people with ABI. Both participants and therapists were satisfied with the treatment.

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 Impact paragraph

Patients engaged with the protocol and even after the intervention patients reported to still apply the ACT
skills obtained during therapy. Furthermore, we studied the effectiveness of the new BrainACT treatment
in four individuals with brain injury and we found that the BrainACT treatment can reduce stress, anxiety
and depressive symptoms and improve cognitive fusion and quality of life. No improvements were observed
regarding psychological flexibility, value-driven behaviour, and social participation. We are performing a
large-scale experiment in which we compare BrainACT to an education and relaxation treatment to further
evaluate the effectiveness of ACT for people with ABI. The follow-up measurements are currently (July 2022)
being conducted and will be finalized by the end of 2022. The results of the large-scale experiment are
therefore not presented in this thesis.

Scientific and societal impact

The studies described in this thesis have been published or submitted to international peer-reviewed scientific
journals. Chapters 2, 3, 5, and 6 have been published open access which makes them freely available to
researchers across the world. Chapters 4 and 7 will be made freely available once accepted for publication.
The statistical model to predict the level of depressive symptoms and social participation for
individual patients could be further explored by researchers and the developed model could be validated
using different data. When these clinical prediction models are ready for use in clinical practice, they can
optimize the care for people with ABI-related anxiety and depressive complaints. The models can help
psychologists decide which psychological treatment would be the best option for a particular patient.
In current practice, the decision which treatment a patient will receive is mostly based on therapist and
patient preferences. Consequently, patients may receive different treatments before the intended outcome A
is reached. The clinical prediction models might enable more patients to be provided with personalized
treatment that could alleviate their depressive symptoms. As a result, treatment trajectories will become
shorter, mental health care will become more efficient and cost-effective, and most importantly, it would
improve the quality of life of people with ABI and ABI-related anxiety and depressive symptoms.
Additionally, the results of this study permit further investigation into the effectiveness of ACT for
people with ABI. The detailed description of the BrainACT treatment described in chapter 4, can be used by
other researchers to replicate and build upon the studies in this thesis. Moreover, a collaboration between
the BrainACT Team and MindLink Psychology in Perth, Australia was started to evaluate the feasibility and
effectiveness of the BrainACT treatment in a Western Australian context. Therefore, the BrainACT protocol
will also become available in English for researchers and clinicians. Furthermore, researchers could use
the BrainACT treatment protocol to investigate the effectiveness of ACT for other patients who might
experience cognitive complaints, such as people with multiple sclerosis, Parkinson’s disease, and mild
cognitive impairment. Moreover, the adaptations that were made to adjust ACT for people with ABI could
be used for further research to adjust other psychological interventions for this patient population as well.
During the span of our research, clinicians have repeatedly inquired about the availability of the
BrainACT treatment. It shows the need for evidence-based psychological treatments adapted for people

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Addendum

with ABI. When the BrainACT treatment is found to be effective in the large-scale BrainACT study, it can
be implemented in the clinical practice. The BrainACT treatment protocol will become freely available. At
the moment clinicians can use the BrainACT treatment protocol as described in chapter 4 to provide the
treatment to patients with the same patient profile as one of the three participants for which the BrainACT
treatment was found effective in chapter 5. The BrainACT treatment can then be adapted according to the
recommendations in chapter 7 and based on the severity of cognitive deficits of patients, as for instance
objectified by a neuropsychological assessment. Furthermore, since the BrainACT treatment was found
feasible to be delivered through a video-conferencing format, it can be provided to patients during a
lockdown or when patients are not able to come to the hospital, rehabilitation, or mental health care facility.
Anxiety and depressive complaints are common in people with ABI; around 1 out of 3 people will experience
them. The BrainACT treatment, therefore, has the potential to help a large number of patients with ABI.
Moreover, the Dutch questionnaires measuring cognitive defusion and psychological flexibility related
to thoughts and feelings are made available and can already be used in future studies and clinical practice.
These questionnaires can help clinicians to monitor patients with ABI during an ACT intervention and can
help evaluate the treatment. Furthermore, they can give patients insight into their treatment process. Both
questionnaires are available at www.hersenletsellimburg.nl.
As a result, the studies in this thesis provide clinicians with many materials ready to use in the clinical
practise. This includes the BrainACT treatment protocol with the content of the sessions, homework and
mindfulness exercises specially designed for patients with ABI. In addition, two Dutch questionnaires are
available to be used in clinical and research settings. These products will hopefully be integrated into care
for people with ABI and therefore will help people in the adaptation process following ABI.

Dissemination activities
The results from the studies in this thesis have been and will be communicated in several ways. The results
have been presented at national and international conferences, such as the Association for Contextual
Behavioral Science (ACBS) Conference, the 6th Pacific Rim Conference, the ACT in Actie conference, the
Conference in Neuropsychological Rehabilitation of the Special Interest Group of the WFNR, and at webinars
of the Limburg Brain Injury Centre. Besides, we provided training for therapists who participate in the
BrainACT study to familiarize them with the BrainACT treatment protocol. Participating sites and other
people who have shown their interest in the BrainACT treatment were (and still are) kept informed on
the development and results of the BrainACT studies through the BrainACT newsletters. The mailing list
now includes 125 clinicians, researchers, and lay experts. Furthermore, webinars and masterclasses were
organized for members of the Dutch ACBS chapter, the association for cognitive therapists, and participants
of the ACT in Actie training. Moreover, findings were shared via online platforms such as LinkedIn, Twitter,
and Facebook. Besides, results were shared and discussed with colleagues via research days and informal
interactions. The results were shared with people with ABI and their partners, caregivers, and relatives at
Brain cafes in Kerkrade and Sittard. Finally, a blog post on the meaning of health was written and shared on the

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 Impact paragraph

website of the Limburg Brain Injury Centre (https://www.hersenletsellimburg.nl/ehl-blog-hersenkronkels/

wanneer-ben-je-gezond).
The results of the large-scale BrainACT study that we are currently conducting will be communicated via the
same organizations and (social) media. The BrainACT treatment protocol will be made available for psychologists
experienced in ACT and in working with people with ABI if the new treatment is found to be effective.

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Curriculum vitae

Curriculum vitae
Johanne Rauwenhoff werd geboren op 28 november 1993 te Leicester, Groot-Brittannië. In 2011, behaalde
ze haar diploma Algemeen Secundair Onderwijs binnen de studierichting Humane Wetenschappen aan het
Heilig Graf College in Turnhout, België. Hierna ging zij een jaar studeren aan Elizabethtown College in de
Verenigde Staten. In 2012 begon zij aan de studie Psychologie aan de Universiteit Leiden. Tijdens haar bachelor
werd zij geselecteerd om deel te nemen aan het Honours Research Bachelor Project. Deze ervaring wakkerde
haar interesse in het onderzoek aan. In 2015 verhuisde Johanne naar Maastricht voor de Research Master
in Cognitive and Clinical Neuroscience. Naast het cursorisch onderwijs koos zij voor een combistage. Deze
bestond uit een klinische stage bij de afdeling Medische Psychologie van het Zuyderland Medisch Centrum
te Sittard/Geleen en een onderzoeksstage bij de Universiteit Maastricht. Johanne schreef haar master thesis
over hoe angst en catastroferen over mentale activiteiten gerelateerd is aan vreesvermijdendgedrag. In 2017
studeerde Johanne af en begon aan haar promotietraject. Zij werd onderdeel van het Expertisecentrum
Hersenletsel Limburg (EHL), waar zij onderzoek deed naar het behandelen van stemmingsklachten bij
mensen met hersenletsel. Dit deed zij onder supervisie van haar promotieteam bestaande uit Prof.
Dr. Caroline van Heugten, Prof. Dr. Frenk Peeters en Dr. Yvonne Bol. Johanne ontving de Van der Gaag-
beurs van de Koninklijke Nederlandse Academie van Wetenschappen (KNAW) om onderzoek te doen bij
het Ingham Institute for Applied Medical Research en MindLink Psychology in Australië. Dit werkbezoek
ging helaas niet door vanwege de Covid-19 pandemie. In het laatste jaar van haar promotietraject werkte
Johanne twee dagen in de week als basispsycholoog bij de Geestelijke Gezondheidszorg Eindhoven in de
Kliniek Neuropsychiatrie. Momenteel werkt zij als postdoctoraal onderzoeker bij de afdeling Psychiatrie en
Neuropsychologie aan de Universiteit Maastricht en bij het EHL.

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 List of publications

List of publications
Rauwenhoff J., Peeters F., Bol Y. & Van Heugten C. (2019). The BrainACT study: Acceptance and Commitment
Therapy for depressive and anxiety symptoms following acquired brain injury: study protocol for a
randomized controlled trial. Trials.

Rauwenhoff J., Bronswijk S., Peeters F., Bol Y., Geurts A. C. & Van Heugten C. (2020). Personalized predictions
of treatment outcome in patients with post-stroke depressive symptoms. Journal of Rehabilitation Medicine.

Wijenberg M.*, Rauwenhoff J.*, Stapert S., Verbunt J. & Van Heugten C. (2021). Do fear and catastrophizing
about mental activities relate to fear-avoidance behavior in a community sample? An experimental study.
Journal of Clinical Experimental Neuropsychology.
*Co-first authorship

Rauwenhoff J., Peeters F., Bol Y. & Van Heugten C. (2021). Measuring psychological flexibility and cognitive
defusion in individuals with acquired brain injury. Brain Injury.

Rauwenhoff J., Bol Y., Peeters F., Van den Hout A., Geusgens C. & Van Heugten C. (2022). Acceptance and
Commitment Therapy for individuals with depressive and anxiety symptoms following acquired brain injury:
a non-concurrent multiple baseline design across four cases. Neuropsychological Rehabilitation.

Rauwenhoff J.*, Bol Y.*, Van Heugten C., Batink T., Geusgens C., Van den Hout A., Smits P., Verwegen C.,
Visser A. & Peeters F. (2022). Acceptance and Commitment Therapy for people with acquired brain injury:
rationale and description of the BrainACT treatment. Under revision.
A
*Co-first authorship

Rauwenhoff J., Peeters F., Bol Y. & Van Heugten C. (2022). Acceptance and Commitment Therapy is feasible
for people with acquired brain injury: a process evaluation of the BrainACT treatment. Submitted for
publication.

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PhD defences MHeNs

PhD defences at the school for mental health and neuroscience (MHeNs)
Previous and upcoming PhD defences can be found at the website of MHeNs which can be reached through
the following QR-code.

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 Dankwoord

Dankwoord
Zo het zit erop! Reflecterend op de afgelopen vijf jaar, kan ik alleen maar dankbaar zijn voor alle mooie
mensen die ik heb mogen ontmoeten en met wie ik heb mogen samenwerken. Ik zou dan ook graag wat
mensen willen bedanken.

Als eerste wil ik alle deelnemers aan de verschillende studies in dit proefschrift bedanken. Dank jullie wel dat
jullie je kostbare energie aan dit onderzoek wilden besteden. Jullie bijdrage is zondermeer heel waardevol.

Dan wil ik natuurlijk ook graag mijn promotieteam bedanken. De weg hiernaartoe was niet vrij van obstakels.
Echter, ook op momenten dat het einde onbereikbaar leek, gaven jullie blijk van een rotsvast vertrouwen in
een goede afloop. Caroline, er zijn weinig mensen die hun werk met zoveel gedrevenheid uitvoeren als jij
dat doet. Het enthousiasme waarmee jij de wetenschap bedrijft werkt dan ook aanstekelijk. In de afgelopen
jaren heb ik veel van je mogen leren. Frenk, tijdens promotieoverleggen speelde jij vaak de advocaat van de
duivel. Al waren je kritische vragen niet altijd even makkelijk te beantwoorden, ze zette me wel altijd aan het
denken. Ik heb veel bewondering voor hoe jij altijd met een overstijgende blik naar een manuscript of studie
kan kijken. Yvonne, jij zorgde ervoor dat we tijdens het onderzoek de patiënt zelf niet uit het oog verloren. Ik
bewonder hoe jij het academische en klinische werk met elkaar combineert en als scientist practitioner ben
je dan ook echt een voorbeeld voor mij.

Mijn dank gaat uit naar de leden van de beoordelingscommissie voor het lezen en beoordelen van dit
proefschrift: Prof. dr. Marleen Rijkeboer, Prof. dr. Koen Schruers, Dr. Diane Whiting en Dr. Dirk Bertens.

Emmy dankjewel voor het schilderij van de Hoge Fronten dat op de kaft van dit proefschrift prijkt. A
Een RCT is (gelukkig) niet een klusje dat je in je eentje klaart. Ik wil dan ook heel graag de hoofdonderzoekers
van de deelnemende instellingen in de BreinACT studie bedanken. Astrid, Marieke, Simone, Melloney, Esther,
Marleen, Annelien, Niels, Peter, Hester en Annemarie dank jullie wel dat jullie naast de drukte van de kliniek
tijd hebben gemaakt voor de vele administratieve rompslomp die een RCT met zich meebrengt en dat jullie
mijn vele remindermails hebben doorstaan. Daarnaast hebben er nog heel veel mensen meegeholpen met
het includeren van patiënten en het geven van de behandelingen, mijn dank is groot. Roos, Jeroen, Andreïna,
Rianne, Gea, Anaïs, Twan, Anouk, Dana en Ilse samen hebben we honderden metingen en eindeloos veel
data ingevoerd. Heel erg bedankt voor jullie hulp!

Graag wil ik ook de collega’s bedanken met wie ik heb mogen samenwerken tijdens mijn promotietraject.
Chantal, Anja, Peter en Christianne dank jullie wel voor jullie waardevolle input en hulp bij het ontwikkelen
van de BreinACT-behandeling. Tim, jouw enthousiasme voor alles ACT werkt aanstekelijk. Bedankt voor je
advies en de vele gelegenheden die je me gaf om mijn onderzoek onder de aandacht te brengen. Suzanne,
dankjewel dat je me meenam langs random forests en elastic nets, er ging een wereld voor me open!
Melloney, van stagiaire naar coauteur, dankjewel voor je betrokkenheid en fijne samenwerking. Jolein, wat is

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Addendum

het leuk om in de laatste fase van mijn promotie een nieuw project te starten en al helemaal om het samen
met zo’n enthousiast en gedreven persoon als jij te doen!

Pascalle, Liz, and other colleagues at MindLink Psychology, thank you for your perseverance in getting the
BrainACT Western-Australia project on the road. I really enjoy our collaboration. Diane, thank you for the advice
at the beginning of the BrainACT project. It has been lovely to build upon your work. I hope to still visit both Perth
and Sydney in the future. I would also like to thank all the people from the NeuroACT community. I thoroughly
enjoyed all the presentations and discussions, with as a highlight our symposium at the ACBS conference.

Anneke, Annemarie, Brenda, Caroline, Christine, Fleur, Ieke, Jenny, Jessica, Jill, Marilien, Pauline, Roos,
Mona, Skye en Tom, bedankt voor alle koffiemomentjes, lunchwandelingen, coronaquizzen en natuurlijk
de legendarische congresfeesten in Praag, Granada en Maastricht. Wat is het een voorrecht om deel uit te
mogen maken van zo’n gezellig en gedreven onderzoeksteam!

Ook wil ik graag alle collega’s bedanken van de afdeling Neuropsychiatrie en Psychologie. Ron en Joost,
dank voor jullie technische ondersteuning. Daniëlle dank voor je hulp en alle gezellige babbels. Jeanette en
Annelien, ik vond het een hele leuke ervaring om samen met jullie de BreinACT-behandeling uit te proberen
in een groepsformat. Dat klinische werk smaakte meteen naar meer! Mignon, vier jaar hebben we een
kantoor gedeeld. Vele dagen hebben we daar natuurlijk hard zitten zwoegen, maar stiekem hebben we ook
heel veel gekletst, hard gelachen en veel vlaoi gegeten.

Graag wil ik ook mijn collega’s van de GGz Eindhoven bedanken. Dank jullie wel voor het hele gezellige, maar
zeker ook bijzonder leerzame jaar in de kliniek.

Lieve irrelevantjes, dadelijk een vriendengroepje met (als het goed gaat) alleen maar gepromoveerde mensen,
dat is wel ernstig… Olin, kantoorgenootje, buurvrouw, hondenuitlaatservice, editor in chief (met ijzeren bril)
en bovenal heel lief vriendinnetje. Je bezegelde ons paranimfschap al zo’n vijf jaar geleden en in de tussentijd
hebben we zoveel meegemaakt. Ik geniet altijd van jouw kijk op het leven, je spontanitiet en excentriciteit,
met jou is het altijd avontuur! Dankjewel voor je steun, lieve kaartjes en dat ik altijd bij jou terecht kan. Ik
had deze rit niet zonder jou willen maken. Fleurpie, mijn bourgondische Brabantse schone, kenner van wijn
en hondenrassen. Met jou kan ik zowel (of ja toch bijna?) een review schrijven als (on)vergetelijke nachten
beleven in Complex. Jij bent bescheiden (vaak te), vol passie en creativiteit en je hebt altijd oog voor hoe het
gaat met de mensen om je heen, dankjewel daarvoor. Bert, ook al raken we soms verstrikt in onze eigen mopjes
en sarcasme, waardeer ik onze vriendschap enorm. Van zorgeloos dansen op de maan tot vogels spotten en
weekendjes weg met al onze meiden. Meer van dat alles graag! Annemarie, dankjewel voor je Groningse
nuchterheid en je meer dan aanstekelijke lach. Jouw relativeringsvermogen heeft me meer dan eens geholpen
en dankzij jou zie ik nu overal foutief spatiegebruik (ik weet niet of dat een vloek of een zegen is?). Daan, wat
heerlijk om een vriend te hebben met wie ik tijdens een lange wandeling de politiek kan doornemen, onze kijk
op de klinische praktijk kan bespreken en ook gewoon heel hard kan lachen. Ik vind het heel fijn om te zien
hoe je helemaal op je plek bent terecht gekomen daar in Nijmegen. Lieve Leo, jij weet altijd de juiste vragen

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 Dankwoord

te stellen. Dankjewel voor de gesprekken over twijfels, boeken en buitenlandse avonturen. Liselot, dankzij jou
komen we nooit te laat op een feestje (wel vaak te vroeg) en hebben we altijd een kluisje. Jij waardeert als geen
ander de kleine dingen in het leven. Dankjewel voor je dilemma’s, mopjes en gedichtjes.

Olof, dankjewel voor alle gezellige etentjes, spelletjesavonden en weekendjes in Friesland en de Veluwe.
Vaak hebben we onze promotieperikelen met elkaar gedeeld. Laten we maar zeggen, gedeelde PhD smart
is halve PhD smart. Wellicht vormen wij samen het meest warrige duo op aarde, maar dat maakt onze
vriendschap des te waardevoller.

Lieve Batterijen, er was geen mooiere plek om aan dit avontuur te beginnen dan de Batterijstraat. Wat kijk ik
met veel plezier en nostalgie terug op onze tijd daar. Lieve mama Mikels dankjewel dat je er altijd bent. Sinds
mijn aankomst in Maastricht stond jij me (letterlijk) op te wachten en ben je een constante factor geweest
waar ik altijd op kan terugvallen. Ik koester onze vriendschap enorm! En vergeet niet ‘sjeif votte sjiete auch!’.
Lieve Robje en Sjill, ook al wonen jullie niet meer hier jullie horen bij mijn Maastrichtfamilie en ik kijk al uit
naar het volgende Batterijenweekendje.

Dan natuurlijk mijn lieve familie, met als eerste papa en mama. Jullie hebben ons vanaf jonge leeftijd
aangemoedigd om te ontdekken en nieuwschierig te zijn, maar ook om kritisch te kijken naar de wereld
om ons heen. Ook gaven jullie ons mee om goed voor de mensen te zorgen die we liefhebben en kansen
te pakken als deze zich voor doen. Dank jullie wel voor jullie onuitputtelijke liefde, steun en vertrouwen.
Maartje, ik vind het altijd heerlijk om te zien hoe onbezonnen jij in het leven staat, maar tegelijkertijd vol
enthousiasme en passie de dingen doet die belangrijk voor je zijn. Ik mag mezelf gelukkig prijzen dat ik mijn
kleine zusje zo dicht bij me heb hier in Maastricht. Lodewijk, van elkaar in de haren vliegen naar discussiëren A
over de politiek en liedjes van Merol luisteren, bijzonder hoe niet alleen wij maar ook onze relatie (soort van)
is opgegroeid. En dankjewel voor het ontwerpen van het BreinACT-logo! Lieve kleine opa en oma, jullie zullen
dit boekje niet meer begrijpen, maar jullie liefde voor het leven draag ik met me mee. Sopje, wij hebben
maar een paar woorden (of klopjes) nodig om elkaar te begrijpen en dat is oh zo fijn. Lieve tante Lotje,
dankjewel voor al jouw zorgzaamheid. Dankjewel voor de vele uren die ik schrijvend aan dit proefschrift
mocht doorbrengen op West Raven. Ik kijk er al naar uit om daar bij jullie te logeren! Lieve schoonfamilie,
Marjet, Peter, Guusje en Joep dank jullie wel voor alle gezellige uitjes, etentjes en Sinterklaasavondjes.

Ik zou liegen als ik zeg dat de knuffels en wandelingen met mijn lieve hond Pom niet hebben bijgedragen aan de
afgelopen periode. Een proefschrift schrijven is nou eenmaal fijner met een hond die op je voeten ligt. Tijdens
wandelingen in de Hoge Fronten kan ik mijn hoofd legen of kom ik juist op nieuwe ideeën. Vaak loopt er dan
iemand naast mij met wie ik die ideeën, overpeinzingen, vreugde en verdriet deel. Lieve Loes, jij voelt vaak beter
aan wat ik nodig heb dan ikzelf, als mijn bus zich in de mist bevindt laat jij me altijd met heel veel geduld zien
waar het pad is. Bij jou kan ik helemaal mezelf zijn en samen met jou is alles fijn of we nou thuiswerken tijdens
een lockdown of op avontuur zijn in Noorwegen. Ik voel me zo dankbaar dat ik al zoveel mooie momenten met
jou heb mogen delen en kan niet wachten wat het leven nog meer voor ons in petto heeft.

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Addendum

Lieve grote opa en oma, jullie hadden het fantastisch gevonden, een doctor in de familie. Lieve oma, ik had
je graag dit boekje gegeven om toe te voegen aan jouw indrukwekkende boekencollectie. Een passie voor
lezen en tuinieren heb ik niet van een vreemde. Lieve opa, van jou leerde ik om altijd nieuwsgierig te blijven
en aandachtig te luisteren naar de meningen van anderen. Ik heb vaak aan je gedacht tijdens het schrijven
van dit proefschrift.

Terwijl ik dit schrijf en terugkijk voel ik me vooral heel dankbaar. Jullie zijn de mensen die deze rit waardevol
hebben gemaakt!

178
Anxiety and depression in people
with acquired brain injury
Acceptance and Commitment Therapy
as a possible intervention

Johanne Rauwenhoff