C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotrop... more C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotropic glutamate type 5 receptors (mGluR5). The use of this tracer has identified receptor binding changes in clinical populations, and has been informative in drug occupancy studies. However, previous studies have found significant increases in [ 11 C]ABP688 binding in the later scan of same-day comparisons, and estimates of test-retest reliability under consistent scanning conditions are not available. The objective of this study was to assess the variability of [ 11 C]ABP688 binding in healthy people in scans performed at the same time of day. Two [ 11 C]ABP688 scans were acquired in eight healthy volunteers (6 women, 2 men) using a highresolution research tomograph (HRRT). Scans were acquired 3 weeks apart with start times between 10:00am and 1:30pm. Mean mGluR5 binding potential (BPND) values were calculated across cortical, striatal and limbic brain regions. Participants reported on subjective mood state after each scan and blood samples were drawn for cortisol analysis. No significant change in BPND between scans was observed. Variability in BPND values of 11 to 21% was observed across regions, with the greatest change in the hippocampus and amygdala. Reliability was low to moderate. BPND was not statistically related to scan start time, subjective anxiety, serum cortisol levels, or menstrual phase in women. Overall, [ 11 C]ABP688 BPND estimates show moderate variability in healthy people. Reliability is fair in cortical and striatal regions, and lower in limbic regions. Future research using this ligand should account for this in study design and analysis.
In October 2015 Canadians elected a federal government that proposes to legalize marijuana for re... more In October 2015 Canadians elected a federal government that proposes to legalize marijuana for recreational use following in the footsteps of 4 American states (Alaska, Colorado, Oregon and Washington) and the District of Columbia. Is this a good idea, and how might we decide?
Axon guidance molecules direct growing axons toward their targets, assembling the intricate wirin... more Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.
This study aimed to investigate the relationship between navigational strategies and the use of a... more This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition.
medRxiv (Cold Spring Harbor Laboratory), Feb 13, 2024
In vitro data from primates provide conflicting evidence about the cerebellum's suitability as a ... more In vitro data from primates provide conflicting evidence about the cerebellum's suitability as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET). To address this, we first measured mGluR5 density in postmortem human cerebellum using [ 3 H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next, in vivo experiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [ 11 C]ABP688 binding potential (BP ND ) values obtained with reference tissue methods and the two-tissue compartment model vs. metabolite-corrected arterial input function. The postmortem data showed that, relative to the hippocampus, the cerebellum had 26% less mGluR5 immunoreactivity and 94% fewer [ 3 H]ABP688 binding sites. In vivo brain regional [ 11 C]ABP688 BP ND values using the cerebellum as a reference region were highly correlated with BP ND values and distribution volumes derived by arterial input methods (R 2 > 0.9). The absence of cerebellar allosteric binding sites might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these results support the proposition that [ 11 C]ABP688 BP ND using cerebellum as a reference region provides accurate quantification of mGluR5 allosteric binding in vivo.
Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessat... more Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessation aids show only modest efficacy, new interventions are needed. Given the evidence that stress is a potent trigger for smoking, the present randomized clinical trial tested whether stress could augment the effects of a memory updating (retrieval-extinction) intervention. Nontreatment seeking smokers (n = 76) were assigned to one of four conditions composed of either a stressful or non-stressful psychosocial challenge followed by either smoking or neutral cues. Ten minutes after this manipulation, all underwent a 60-minute extinction procedure during which they viewed smoking-related videos and images and manipulated smoking paraphernalia. Compared to participants who were not exposed to the laboratory stressor, the stressor-exposed groups exhibited greater psychophysiological responses during their intervention and greater decreases in cigarette use at two-and six-weeks follow-up independent of smoking cue exposure. Together, these findings suggest that the ability of stress to activate cigarette seeking processes can be exploited to decrease cigarette use. With replication, the stress-based intervention could become a novel strategy for decreasing cigarette use in non-treatment seeking smokers. Clinicaltrials.gov identifier: NCT04843969.
Self-disturbances constitute a hallmark of psychosis, but it remains unclear whether these altera... more Self-disturbances constitute a hallmark of psychosis, but it remains unclear whether these alterations are present in at-risk populations, and therefore their role in the development of psychosis has yet to be confirmed. The present study addressed this question by measuring neural correlates of selfother processing in youth belonging to three developmental trajectories of psychotic experiences. Eighty-six youths were recruited from a longitudinal cohort of over 3800 adolescents based on their trajectories of Psychotic-Like Experiences from 12 to 16 years of age. Participants underwent neuroimaging at 17 years of age (mean). A functional neuroimaging task evaluating self-and otherrelated trait judgments was used to measure whole-brain activation and connectivity. Youth who showed an increasing trajectory displayed hypoactivation of the dorsomedial prefrontal cortex and hypoconnectivity with the cerebellum. By contrast, youth who showed a decreasing trajectory displayed decreased activation of the superior temporal gyrus, the inferior frontal gyrus, and the middle occipital gyrus. These findings suggest that the increasing trajectory is associated with alterations that might erode distinctions between self and other, influencing the emergence of symptoms such as hallucinations. The decreasing trajectory, in comparison, was associated with hypoactivations in areas influencing attention and basic information processing more generally. These alterations might affect the trajectories' susceptibilities to positive vs. negative symptoms, respectively. Psychosis risk is understood as existing on a continuum 1 with, at one end, schizophrenia; at the intermediate, a treatment-seeking Clinical High Risk syndrome characterized by "attenuated" or "brief " symptoms that do not necessarily meet full diagnostic criteria; and, at the lower end, Psychotic-Like Experiences (PLEs). PLEs are defined as subclinical positive psychotic symptoms that can be observed in the general population, including 17% of children aged 9-12 and over 7% of adolescents 2. While most PLEs are transient in nature and do not extend into adulthood, persistent PLEs confer a four-to tenfold increased risk for psychosis 3-5. Recent cohort studies provide evidence of heterogeneous PLE developmental trajectories during adolescence. In 2566 youths from the general population followed between the ages of 13 and 16, three trajectories were identified: 84% of adolescents (n = 2152) exhibited a typical trajectory of low PLE levels that decreased further over time, 8% (n = 203) exhibited high PLE levels that subsequently decreased, and another 8% (n = 211) reported moderate PLE levels that increased 6. These trajectories have been replicated in multiple samples 7-9 , supporting their relevance in adolescent development. While the increasing trajectory is thought to be associated with increased risk of psychosis 10 , outcomes in the decreasing trajectory have been little investigated. Our own studies suggest that both trajectories can develop problems, with the increasing trajectory exhibiting progressively more
Drug-induced sensitization is said to occur when a drug regimen leads to larger responses to the ... more Drug-induced sensitization is said to occur when a drug regimen leads to larger responses to the same dose or measurable responses to a previously ineffective low dose. Sensitization hypotheses of problematic substance use further propose that these effects facilitate the development of incentive responses to drug-paired cues. 1 These effects are well-established in rodents, 2-5 but, in some circles, it remains controversial whether they occur in primates (Box 1). What is the evidence? Stimulant drug-induced behavioural sensitization in healthy humans The first 2 attempts to demonstrate stimulant drug-induced behavioural sensitization in humans were unsuccessful. 42,43 Both administered low doses of d-amphetamine (5 or 10 mg, orally). In comparison, 80 % of studies (8 of 10) administering at least 20 mg of d-amphetamine found evidence of sensitization. 44-51 Among the 6 studies that administered at least 3 doses of 20 mg or more, 100 % found an effect. 44-47,49,50 The most consistent changes were to the drug's behaviourally energizing effects 12,13 with augmented responses continuing for at least a year 49 (Table 1). Stimulant drug-induced behavioural sensitization in nonhuman primates There is consistent evidence of cocaine and amphetamineinduced behavioural sensitization in nonhuman primates. 54-69 As in humans, augmented responses have been seen for psycho motor stimulation, but psychosis-like phenomena can emerge following high-dose regimens. The effects can last for more than 2 years 60 (Table 2). Stimulant drug-induced behavioural sensitization in people with addictions Clinical observations at least raise the possibility that people with stimulant drug addictions exhibit behavioural sensitization; e.g., markedly elevated incentive (drug-seeking) responses to small doses of the drug and drug-related cues. These observations noted, perhaps the most compelling demonstration that extensive substance use can lead to sensitization in humans investigated alcohol. In this 10-year prospective study, young adult drinkers (n = 163) received an alcohol challenge (0.8 g/kg, orally) at baseline and 5 and 10 years later. 38 Among those who developed an alcohol use disorder (AUD; n = 39), the self-reported alcohol-induced "wanting" and "stimulation" responses became progressively larger. The larger the wanting and stimulation responses, the greater the likelihood of developing an AUD and the greater the number of AUD symptoms.
Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary su... more Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary support for this hypothesis has been provided by recent neuroimaging studies. While most effects remain to be replicated, there is now evidence that, compared to healthy controls, people at familial risk for substance use disorders exhibit both increases and decreases in striatal dopamine function. The following review assesses the strength of this evidence, considers explanations for discrepant results, and discusses potential implications for understanding pathways to addiction. * Family history of substance use disorders (SUDs): An affected 1 st degree relative equals 1. An affected 2 nd degree relative equals 0.5. ** Did not differentiate between first and second-degree relatives. DA: dopamine.
Dysregulation of the stress response system is a potential etiological factor in the development ... more Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent D-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to D-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [ 11 C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated D-amphetamine (3 × 0.3 mg kg − 1 , by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the D-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the D-amphetamine regimen, the stress-induced cortisol responses were augmented (P o 0.04), and voxel-based analyses showed larger stress-induced decreases in [ 11 C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [ 11 C]raclopride binding, primarily in the sensorimotor striatum (P o 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.
The aim of this study was to investigate the neural bases of facial emotion processing before the... more The aim of this study was to investigate the neural bases of facial emotion processing before the onset of clinical psychotic symptoms in youth belonging to well-defined developmental trajectories of psychotic-like experiences (PLEs). A unique sample of 86 youths was recruited from a population-based sample of over 3800 adolescents who had been followed from 13 to 17 years of age. Three groups were identified based on validated developmental trajectories: a control trajectory with low and decreasing PLEs, and two atypical trajectories with moderate to elevated baseline PLEs that subsequently decreased or increased. All had functional magnetic resonance imaging data collected during a facial emotion processing task. Functional activation and connectivity data were analyzed for different contrasts. The increasing PLE trajectory displayed more positive psychotic symptoms while the decreasing trajectory exhibited more negative symptoms relative to the control group. During face processi...
Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lea... more Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine‐related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d‐amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue‐induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue‐induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS‐11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d‐amphetamine did not augment the cue‐induced activations, but, in cocaine users, drug cue‐induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.
Functional neuroimaging studies of patients with Parkinson’s disease (PD) have repeatedly identif... more Functional neuroimaging studies of patients with Parkinson’s disease (PD) have repeatedly identified over-activations in midline structures (medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, and precuneus), especially in those without comorbid dementia. Here, we investigated whether the different cognitive profiles in PD were linked to measures of diffusion microstructure in medial regions of the brain. Using magnetic resonance based diffusion weighted imaging (DWI) in healthy volunteers (HV) and PD patients with and without mild cognitive impairment (PD-nonMCI and PD-MCI), applying diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) techniques, we observed: 1) increased fractional anisotropy (FA) in the precuneus and the anterior cingulate in the PD-nonMCI participants compared with the HV; 2) an association between precuneus FA and executive and memory function, respectively, in PD and HV; 3) a negative correlation be...
Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous ... more Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous studies suggest that this differential vulnerability commonly reflects a developmental trajectory characterized by diverse externalizing behaviors. In this study, we examined the relation between child and adolescent externalizing behaviors and adolescent substance use in a prospectively followed Canadian birth cohort, accounting for the temporal sequence of a wide variety of contributing factors. Methods: Two hundred and forty-two adolescents followed since birth (date range: 1996 to 2012) were assessed on externalizing behavior (age 17 months to 16 years), alcohol and cannabis use at age 16, age of alcohol use onset, family history of substance use problems, family functioning (age 11 to 15), sensation seeking (age 16), prenatal substance exposure, socioeconomic status (age 1 to 9), and sex. Results: Age of alcohol use onset was predicted by a family history of substance use problems, ...
Neurotransmitter receptors support the propagation of signals in the human brain. How receptor sy... more Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all f...
This chapter describes the use of positron emission tomography (PET) for in vivo imaging of brain... more This chapter describes the use of positron emission tomography (PET) for in vivo imaging of brain regional type 5 metabotropic glutamate (mGlu5) receptors. Two mGlu5 PET tracers have been well-validated, [ 11 C]ABP688 and [ 18 F]FPEB. They have been used, in laboratory animals and humans, to study diverse illnesses including Parkinson's disease, Alzheimer's disease, addictions, depression, and schizophrenia. The shorter half-life of [ 11 C]ABP688 makes it easier to conduct multiple scans on the same day in the same participant. The longer half-life of 18 F-labeled tracers allows its use in centers without an on-site production facility. Additional details about each tracer's development, advantages, and disadvantages are described.
C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotrop... more C]ABP688 is a positron emission tomography (PET) radioligand that binds selectively to metabotropic glutamate type 5 receptors (mGluR5). The use of this tracer has identified receptor binding changes in clinical populations, and has been informative in drug occupancy studies. However, previous studies have found significant increases in [ 11 C]ABP688 binding in the later scan of same-day comparisons, and estimates of test-retest reliability under consistent scanning conditions are not available. The objective of this study was to assess the variability of [ 11 C]ABP688 binding in healthy people in scans performed at the same time of day. Two [ 11 C]ABP688 scans were acquired in eight healthy volunteers (6 women, 2 men) using a highresolution research tomograph (HRRT). Scans were acquired 3 weeks apart with start times between 10:00am and 1:30pm. Mean mGluR5 binding potential (BPND) values were calculated across cortical, striatal and limbic brain regions. Participants reported on subjective mood state after each scan and blood samples were drawn for cortisol analysis. No significant change in BPND between scans was observed. Variability in BPND values of 11 to 21% was observed across regions, with the greatest change in the hippocampus and amygdala. Reliability was low to moderate. BPND was not statistically related to scan start time, subjective anxiety, serum cortisol levels, or menstrual phase in women. Overall, [ 11 C]ABP688 BPND estimates show moderate variability in healthy people. Reliability is fair in cortical and striatal regions, and lower in limbic regions. Future research using this ligand should account for this in study design and analysis.
In October 2015 Canadians elected a federal government that proposes to legalize marijuana for re... more In October 2015 Canadians elected a federal government that proposes to legalize marijuana for recreational use following in the footsteps of 4 American states (Alaska, Colorado, Oregon and Washington) and the District of Columbia. Is this a good idea, and how might we decide?
Axon guidance molecules direct growing axons toward their targets, assembling the intricate wirin... more Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.
This study aimed to investigate the relationship between navigational strategies and the use of a... more This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition.
medRxiv (Cold Spring Harbor Laboratory), Feb 13, 2024
In vitro data from primates provide conflicting evidence about the cerebellum's suitability as a ... more In vitro data from primates provide conflicting evidence about the cerebellum's suitability as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET). To address this, we first measured mGluR5 density in postmortem human cerebellum using [ 3 H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next, in vivo experiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [ 11 C]ABP688 binding potential (BP ND ) values obtained with reference tissue methods and the two-tissue compartment model vs. metabolite-corrected arterial input function. The postmortem data showed that, relative to the hippocampus, the cerebellum had 26% less mGluR5 immunoreactivity and 94% fewer [ 3 H]ABP688 binding sites. In vivo brain regional [ 11 C]ABP688 BP ND values using the cerebellum as a reference region were highly correlated with BP ND values and distribution volumes derived by arterial input methods (R 2 > 0.9). The absence of cerebellar allosteric binding sites might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these results support the proposition that [ 11 C]ABP688 BP ND using cerebellum as a reference region provides accurate quantification of mGluR5 allosteric binding in vivo.
Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessat... more Tobacco use is the leading cause of preventable mortality worldwide. Since current smoking cessation aids show only modest efficacy, new interventions are needed. Given the evidence that stress is a potent trigger for smoking, the present randomized clinical trial tested whether stress could augment the effects of a memory updating (retrieval-extinction) intervention. Nontreatment seeking smokers (n = 76) were assigned to one of four conditions composed of either a stressful or non-stressful psychosocial challenge followed by either smoking or neutral cues. Ten minutes after this manipulation, all underwent a 60-minute extinction procedure during which they viewed smoking-related videos and images and manipulated smoking paraphernalia. Compared to participants who were not exposed to the laboratory stressor, the stressor-exposed groups exhibited greater psychophysiological responses during their intervention and greater decreases in cigarette use at two-and six-weeks follow-up independent of smoking cue exposure. Together, these findings suggest that the ability of stress to activate cigarette seeking processes can be exploited to decrease cigarette use. With replication, the stress-based intervention could become a novel strategy for decreasing cigarette use in non-treatment seeking smokers. Clinicaltrials.gov identifier: NCT04843969.
Self-disturbances constitute a hallmark of psychosis, but it remains unclear whether these altera... more Self-disturbances constitute a hallmark of psychosis, but it remains unclear whether these alterations are present in at-risk populations, and therefore their role in the development of psychosis has yet to be confirmed. The present study addressed this question by measuring neural correlates of selfother processing in youth belonging to three developmental trajectories of psychotic experiences. Eighty-six youths were recruited from a longitudinal cohort of over 3800 adolescents based on their trajectories of Psychotic-Like Experiences from 12 to 16 years of age. Participants underwent neuroimaging at 17 years of age (mean). A functional neuroimaging task evaluating self-and otherrelated trait judgments was used to measure whole-brain activation and connectivity. Youth who showed an increasing trajectory displayed hypoactivation of the dorsomedial prefrontal cortex and hypoconnectivity with the cerebellum. By contrast, youth who showed a decreasing trajectory displayed decreased activation of the superior temporal gyrus, the inferior frontal gyrus, and the middle occipital gyrus. These findings suggest that the increasing trajectory is associated with alterations that might erode distinctions between self and other, influencing the emergence of symptoms such as hallucinations. The decreasing trajectory, in comparison, was associated with hypoactivations in areas influencing attention and basic information processing more generally. These alterations might affect the trajectories' susceptibilities to positive vs. negative symptoms, respectively. Psychosis risk is understood as existing on a continuum 1 with, at one end, schizophrenia; at the intermediate, a treatment-seeking Clinical High Risk syndrome characterized by "attenuated" or "brief " symptoms that do not necessarily meet full diagnostic criteria; and, at the lower end, Psychotic-Like Experiences (PLEs). PLEs are defined as subclinical positive psychotic symptoms that can be observed in the general population, including 17% of children aged 9-12 and over 7% of adolescents 2. While most PLEs are transient in nature and do not extend into adulthood, persistent PLEs confer a four-to tenfold increased risk for psychosis 3-5. Recent cohort studies provide evidence of heterogeneous PLE developmental trajectories during adolescence. In 2566 youths from the general population followed between the ages of 13 and 16, three trajectories were identified: 84% of adolescents (n = 2152) exhibited a typical trajectory of low PLE levels that decreased further over time, 8% (n = 203) exhibited high PLE levels that subsequently decreased, and another 8% (n = 211) reported moderate PLE levels that increased 6. These trajectories have been replicated in multiple samples 7-9 , supporting their relevance in adolescent development. While the increasing trajectory is thought to be associated with increased risk of psychosis 10 , outcomes in the decreasing trajectory have been little investigated. Our own studies suggest that both trajectories can develop problems, with the increasing trajectory exhibiting progressively more
Drug-induced sensitization is said to occur when a drug regimen leads to larger responses to the ... more Drug-induced sensitization is said to occur when a drug regimen leads to larger responses to the same dose or measurable responses to a previously ineffective low dose. Sensitization hypotheses of problematic substance use further propose that these effects facilitate the development of incentive responses to drug-paired cues. 1 These effects are well-established in rodents, 2-5 but, in some circles, it remains controversial whether they occur in primates (Box 1). What is the evidence? Stimulant drug-induced behavioural sensitization in healthy humans The first 2 attempts to demonstrate stimulant drug-induced behavioural sensitization in humans were unsuccessful. 42,43 Both administered low doses of d-amphetamine (5 or 10 mg, orally). In comparison, 80 % of studies (8 of 10) administering at least 20 mg of d-amphetamine found evidence of sensitization. 44-51 Among the 6 studies that administered at least 3 doses of 20 mg or more, 100 % found an effect. 44-47,49,50 The most consistent changes were to the drug's behaviourally energizing effects 12,13 with augmented responses continuing for at least a year 49 (Table 1). Stimulant drug-induced behavioural sensitization in nonhuman primates There is consistent evidence of cocaine and amphetamineinduced behavioural sensitization in nonhuman primates. 54-69 As in humans, augmented responses have been seen for psycho motor stimulation, but psychosis-like phenomena can emerge following high-dose regimens. The effects can last for more than 2 years 60 (Table 2). Stimulant drug-induced behavioural sensitization in people with addictions Clinical observations at least raise the possibility that people with stimulant drug addictions exhibit behavioural sensitization; e.g., markedly elevated incentive (drug-seeking) responses to small doses of the drug and drug-related cues. These observations noted, perhaps the most compelling demonstration that extensive substance use can lead to sensitization in humans investigated alcohol. In this 10-year prospective study, young adult drinkers (n = 163) received an alcohol challenge (0.8 g/kg, orally) at baseline and 5 and 10 years later. 38 Among those who developed an alcohol use disorder (AUD; n = 39), the self-reported alcohol-induced "wanting" and "stimulation" responses became progressively larger. The larger the wanting and stimulation responses, the greater the likelihood of developing an AUD and the greater the number of AUD symptoms.
Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary su... more Is altered dopamine transmission a pre-existing vulnerability trait for addiction? Preliminary support for this hypothesis has been provided by recent neuroimaging studies. While most effects remain to be replicated, there is now evidence that, compared to healthy controls, people at familial risk for substance use disorders exhibit both increases and decreases in striatal dopamine function. The following review assesses the strength of this evidence, considers explanations for discrepant results, and discusses potential implications for understanding pathways to addiction. * Family history of substance use disorders (SUDs): An affected 1 st degree relative equals 1. An affected 2 nd degree relative equals 0.5. ** Did not differentiate between first and second-degree relatives. DA: dopamine.
Dysregulation of the stress response system is a potential etiological factor in the development ... more Dysregulation of the stress response system is a potential etiological factor in the development of and relapse to multiple neuropsychiatric disorders. Previously we reported that repeated intermittent D-amphetamine administration can lead to progressively greater dopamine release, thereby providing evidence of drug-induced neurochemical sensitization. Here, we test the hypothesis that repeated exposure to D-amphetamine increases dopaminergic responses to stress; that is, produces cross-sensitization. Using positron emission tomography, we measured in 17 healthy male volunteers (mean ± s.d. = 22.1 ± 3.4 years) [ 11 C]raclopride binding responses to a validated psychosocial stress task before and 2 weeks after a regimen of repeated D-amphetamine (3 × 0.3 mg kg − 1 , by mouth; n = 8) or placebo (3 × lactose, by mouth; n = 9). Mood and physiological measurements were recorded throughout each session. Before the D-amphetamine regimen, exposure to the stress task increased behavioral and physiological indices of stress (anxiety, heart rate, cortisol, all P ⩽ 0.05). Following the D-amphetamine regimen, the stress-induced cortisol responses were augmented (P o 0.04), and voxel-based analyses showed larger stress-induced decreases in [ 11 C]raclopride non-displaceable binding potential across the striatum. In the placebo group, re-exposure to stress led to smaller clusters of decreased [ 11 C]raclopride binding, primarily in the sensorimotor striatum (P o 0.05). Together, this study provides evidence for drug × stress cross-sensitization; moreover, random exposure to stimulants and/or stress cumulatively, while enhancing dopamine release in striatal areas, may contribute to a lowered set point for psychopathologies in which altered dopamine neurotransmission is invoked.
The aim of this study was to investigate the neural bases of facial emotion processing before the... more The aim of this study was to investigate the neural bases of facial emotion processing before the onset of clinical psychotic symptoms in youth belonging to well-defined developmental trajectories of psychotic-like experiences (PLEs). A unique sample of 86 youths was recruited from a population-based sample of over 3800 adolescents who had been followed from 13 to 17 years of age. Three groups were identified based on validated developmental trajectories: a control trajectory with low and decreasing PLEs, and two atypical trajectories with moderate to elevated baseline PLEs that subsequently decreased or increased. All had functional magnetic resonance imaging data collected during a facial emotion processing task. Functional activation and connectivity data were analyzed for different contrasts. The increasing PLE trajectory displayed more positive psychotic symptoms while the decreasing trajectory exhibited more negative symptoms relative to the control group. During face processi...
Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lea... more Stimulant drug‐paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine‐related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d‐amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue‐induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue‐induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS‐11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d‐amphetamine did not augment the cue‐induced activations, but, in cocaine users, drug cue‐induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.
Functional neuroimaging studies of patients with Parkinson’s disease (PD) have repeatedly identif... more Functional neuroimaging studies of patients with Parkinson’s disease (PD) have repeatedly identified over-activations in midline structures (medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex, and precuneus), especially in those without comorbid dementia. Here, we investigated whether the different cognitive profiles in PD were linked to measures of diffusion microstructure in medial regions of the brain. Using magnetic resonance based diffusion weighted imaging (DWI) in healthy volunteers (HV) and PD patients with and without mild cognitive impairment (PD-nonMCI and PD-MCI), applying diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) techniques, we observed: 1) increased fractional anisotropy (FA) in the precuneus and the anterior cingulate in the PD-nonMCI participants compared with the HV; 2) an association between precuneus FA and executive and memory function, respectively, in PD and HV; 3) a negative correlation be...
Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous ... more Objective: Only a minority of drug and alcohol users develops a substance use disorder. Previous studies suggest that this differential vulnerability commonly reflects a developmental trajectory characterized by diverse externalizing behaviors. In this study, we examined the relation between child and adolescent externalizing behaviors and adolescent substance use in a prospectively followed Canadian birth cohort, accounting for the temporal sequence of a wide variety of contributing factors. Methods: Two hundred and forty-two adolescents followed since birth (date range: 1996 to 2012) were assessed on externalizing behavior (age 17 months to 16 years), alcohol and cannabis use at age 16, age of alcohol use onset, family history of substance use problems, family functioning (age 11 to 15), sensation seeking (age 16), prenatal substance exposure, socioeconomic status (age 1 to 9), and sex. Results: Age of alcohol use onset was predicted by a family history of substance use problems, ...
Neurotransmitter receptors support the propagation of signals in the human brain. How receptor sy... more Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all f...
This chapter describes the use of positron emission tomography (PET) for in vivo imaging of brain... more This chapter describes the use of positron emission tomography (PET) for in vivo imaging of brain regional type 5 metabotropic glutamate (mGlu5) receptors. Two mGlu5 PET tracers have been well-validated, [ 11 C]ABP688 and [ 18 F]FPEB. They have been used, in laboratory animals and humans, to study diverse illnesses including Parkinson's disease, Alzheimer's disease, addictions, depression, and schizophrenia. The shorter half-life of [ 11 C]ABP688 makes it easier to conduct multiple scans on the same day in the same participant. The longer half-life of 18 F-labeled tracers allows its use in centers without an on-site production facility. Additional details about each tracer's development, advantages, and disadvantages are described.
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Papers by Marco Leyton