Hindawi

Case Reports in Psychiatry

Volume 2021, Article ID 5563017, 5 pages
https://doi.org/10.1155/2021/5563017

Case Report
High-Frequency and Low-Intensity Patterned Transcranial
Magnetic Stimulation over Left Dorsolateral Prefrontal Cortex as
Treatment for Major Depressive Disorder: A Report of 3 Cases

Lizbeth Castillo-Aguilar,1 Alma E. Ríos-Ponce ,1 Edson Albano de Mendonca,2

and Gabriel Villafuerte 3
1
Clínica Coyoacán, Mexico City, Mexico
2
Hospital Psiquiátrico “Dr. Samuel Ramírez Moreno”, State of Mexico, Mexico
3
Plan de Estudios Combinados en Medicina (PECEM), Facultad de Medicina, Universidad Nacional Autónoma de México,
Mexico City, Mexico

Correspondence should be addressed to Gabriel Villafuerte; gabv105@gmail.com

Received 2 February 2021; Revised 8 March 2021; Accepted 13 March 2021; Published 20 March 2021

Academic Editor: Jeronimo Saiz Ruiz

Copyright © 2021 Lizbeth Castillo-Aguilar et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.

Current transcranial magnetic stimulation devices apply intense (near 1 tesla) repetitive magnetic pulses over a specific area of the
skull at relatively lower frequencies (1-50 Hz). Nevertheless, different studies have shown that very small magnetic fields, at higher
frequencies (50-1000 Hz.), produce therapeutic effects in major depressive disorder. We report the application of high-frequency
and low-intensity patterned magnetic pulses over the left prefrontal dorsolateral cortex in three subjects diagnosed with clinical
major depressive disorder. All three patients showed sharp changes in their self-reports as well as in the standardized clinical
assessment. Hypothesized mechanisms of action of this new variant of magnetic stimulation are discussed.

1. Introduction therapeutic effects in some nervous system pathologies [5, 6].

Rohan et al. published a study where they applied low-
Repetitive transcranial magnetic stimulation (rTMS) is a intensity magnetic fields (around 2 militeslas) at 1000 Hz
noninvasive neuromodulation technique that has shown to producing an antidepressant effect in patients with bipolar
be effective for the treatment of major depressive disorder depression [5]. However, this same protocol was used in
(MDD), especially in subjects in which pharmacological patients with MDD having mixed results [7, 8]. Another
treatment has failed to improve depressive symptoms [1]. protocol using similar parameters, applied with 7 coils to
Current rTMS devices apply intense (near 1 tesla) repetitive the whole brain was also used for the treatment of MDD with
magnetic pulses over a specific area of the skull at relatively good results [9].
lower frequencies (1-50 Hz). These rapidly changing and In this paper, we report the application of high-frequency
intense magnetic pulses produce their biological activity by and low-intensity patterned magnetic pulses with a circular
inducing an electric current inside the brain [2]. Nevertheless, coil of 60 mm of diameter over the F3 coordinate of the 10-
the threshold for pulsed magnetic field effects on biological 20 EEG system (left prefrontal dorsolateral cortex) in three
systems has been estimated to be at much lower intensities subjects diagnosed with clinical MDD. The coil used in this
(1 × 10−7 teslas) [3] and different studies have shown that very protocol was selected over a figure 8 coil as the intensities
small magnetic fields, at higher frequencies (50-1000 Hz), do used in the present study are not able to produce a motor
produce measurable changes in brain’s activity [4] and even threshold; without a motor threshold and in order to assure
2 Case Reports in Psychiatry

Stimulation train

3 s on 1 s off

0 1 2 3 4 5 6 7 8 9 10 11

Figure 1: Stimulation pattern. The stimulation was divided in trains; each train consisted of a 3-second period of burst stimulation at
550-600 Hz and a 1-second period without stimulation. A total of 675 trains were applied during each session over the left prefrontal
dorsolateral cortex.

that the prefrontal cortex was indeed stimulated, a circular (BAI), 12 item General Health Questionnaire (GHQ-12),
coil with a larger area of stimulation was used. Mini-Mental State Examination (MMSE), and the Athens
The device used to apply the magnetic stimulation was Insomnia Scale (AIS). Moderate depression was found
designed and manufactured exclusively for this study by through the MADRS and the BDI with a score of 24 and 26
Actipulse Neuroscience (Boston, USA). The pulses were points, respectively, while on the BAI, severe anxiety was
applied in trains: each train consisted of 3-second bursts of found (score of 32 points), as well as the presence of insomnia
high-frequency pulses (550-600 Hz) alternated with 1 second (score of 9). Cognition was preserved, demonstrated through
without stimulation (see Figure 1 for more details about the the application of the MMSE (score of 28 points).
stimulation pattern); a total of 675 trains (45 minutes of stim-
ulation) were applied in each session. Each pulse had an 2.4. Follow-Up and Outcomes. All tests were reassessed after
approximate magnetic field intensity of 0.5 milliteslas. Ses- 15 sessions of HFLI TMS, and an improvement in all mea-
sions were applied to each patient once daily for 5 days each sures was observed. On the other hand, both the MADRS
week, making a total of 15 sessions distributed in 3 weeks. (score of 10 points) and the BDI (score of 13 points) reduced
their scores, indicating a change from moderate to mild
2. Case 1 depression, as well as the BAI, which indicated the presence
of moderate anxiety (score of 23 points). Meanwhile, insom-
2.1. Patient Information. Case 1 was a male, 69 years old, with nia (AIS = 6) and cognition scores (MMSE = 30) were also
Latin American ethnicity and with a family history of diabe- improved, returning to normal values. In the self-report,
tes mellitus and colon cancer. The patient has a history of the patient reported a clear improvement in mood, anxiety,
aortic valve calcification due to which he had to have an aor- and sleep disturbances.
tic valve surgery 5 years prior to this evaluation. During the
aortic valve surgery, the patient suffered a cardiorespiratory
arrest and, as consequence, he developed chronic posthy- 3. Case 2
poxic myoclonus affecting his head, trunk, and superior
limbs. After discharge, depressive symptoms started and 3.1. Patient Information. Case 2 was a female, 27 years old,
were mainly associated with a feeling of worthlessness due with Latin American ethnicity and with a family history of
to motor function impairment. Four years ago, the patient cardiac disease, asthma, diabetes mellitus, and pulmonary
attended a psychiatric evaluation for the first time, referring emphysema. She was diagnosed with attention deficit and
depressed mood nearly every day, anhedonia, alexithymia, hyperactivity disorder 10 years prior to the evaluation; 9
social isolation, insomnia, and anxiety symptoms, for which years prior, a hygroma was found incidentally in an MRI scan
he was prescribed sertraline and clonazepam at unknown performed for other reasons. She has a positive history of
doses showing mild response. tobacco and drug use including cannabis, cocaine, LSD,
methamphetamine, ecstasy, and hallucinogens. The onset of
2.2. Clinical Findings. The patient was conscious and ori- psychiatric symptoms was at age 12 with anhedonia, social
ented. He presented postural and action tremor in the upper isolation, apathy, emotional liability, and sleeping problems;
limbs with an accentuation on the left side of the body, while at the age of 18, she had a suicide attempt and was institu-
on the lower limbs, he presented bradykinesia. The patient tionalized for a month. Trials with different medications
also presented gait changes including reduced stride length (fluoxetine, sertraline, carbamazepine, valproate, and clonaz-
and speed, reduced arm movement, and deviation to the right epam) had a poor effect in remission of depressive symptoms
side. At the time of assessment and treatment, the patient was and complete remission was never achieved.
taking sertraline, primidone, acenocumarol, clonazepam,
metoprolol, paracetamol, losartan, and atorvastatin. 3.2. Clinical Findings. The patient was conscious and ori-
ented. She presents with anxiety-related tachycardia, as well
2.3. Diagnostic Assessment. The patient was assessed using the as excessive sweat and paresthesia. At the time of assessment
Montgomery–Åsberg Depression Rating Scale (MADRS), and treatment, the patient was taking a stable dose of venla-
Beck Depression Inventory (BDI), Beck Anxiety Inventory faxine for over 3 months.
Case Reports in Psychiatry 3

Pre and post HFLIP TMS scores in several scales

50

40

30
Scores

20

10

0
Pre Post Pre Post Pre Post Pre Post Pre Post
MARDS BDI BAI GHQ-12 AIS
Scales

Figure 2: Pre- and post-HFLIP TMS scores in several scales. Several clinimetric scores were performed before and after HFLIP TMS:
Montgomery–Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), 12 item
General Health Questionnaire (GHQ-12), Mini-Mental State Examination (MMSE), and the Athens Insomnia Scale (AIS). All three
subjects showed improvement in all measured scales.

3.3. Diagnostic Assessment. The patient was assessed with the for the first time at 18 years of age. At 21 years old, she was
same scales and inventories as the first case. On depression diagnosed with postpartum depression after symptoms of
tests, the patient presented moderate depression through isolation, anhedonia, and emotional lability augmented. She
the MADRS (score of 30 points), while on the BDI, she pre- had two suicide attempts at age 24 and 28, both of which were
sented severe depression (score of 46 points). On the other followed by the hospitalization of the patient. Since age 24,
hand, severe anxiety was found (BAI score of 37 points), as she had received several antidepressants intermittently
well as the presence of insomnia (score of 21 points in (mainly fluoxetine and sertraline), with poor improvement
AIS). Cognition was fully preserved, demonstrated through of symptoms. Two months ago, depressive symptoms
a flawless MMSE score (30 points). increased, and she started fluoxetine 40 mg daily by herself.
Poor symptomatic response was achieved, and she continued
3.4. Follow-Up and Outcomes. Tests were reassessed after 15 with anhedonia, hopelessness, sleeping problems, irritability,
sessions of HFLI TMS, and an improvement in all measures and anxiety.
was observed, reaching minimum levels. Both the MADRS
(score of 5 points) and the BDI (score of 0 points) reduced 4.2. Clinical Findings. The patient was conscious and ori-
their scores, indicating the absence or minimum presence ented. She complained of occasional tachycardia and lower
of depressive symptoms. While the BAI indicated a mini- limb paresthesia while being stressed, as well as acid reflux
mum presence of anxiety (score of 7 points) and the AIS with every meal, leading to a diminishment in daily food
(score of 6 points) showed an absence of insomnia symp- intake; additionally, the patient appears to be sleepy and
toms. Finally, the cognitive score was decreased by two points tired. At the time of assessment and treatment, the patient
(MMSE = 28 points); however, it remained within normal had suspended medication without physician supervision.
values. The self-report of the patient corroborated the
reported clinimetric changes; the patient reported minimum 4.3. Diagnostic Assessment. The patient was assessed with the
depressive, anxiety, and insomnia symptoms. same scales and inventories as in previous cases. The
MADRS showed moderate depression (score of 28 points),
4. Case 3 and the BDI indicated the presence of severe depression
(score of 42 points). Meanwhile, the BAI indicated the pres-
4.1. Patient Information. Case was a 38-year-old Latin Amer- ence of severe anxiety (score of 37 points), as well as the pres-
ican female with a family history of cardiac disease, arterial ence of insomnia (score of 10 in AIS). Finally, the MMSE
hypertension, pulmonary, and testicular cancer. The patient indicated no impairment; however, the score is on a limit
was diagnosed 2 years prior to evaluation with borderline cut-off value (score of 24 points).
personality disorder and had positive tobacco and alcohol
use, reaching inebriation at least once every 15 days. The 4.4. Follow-Up and Outcomes. Reassessment was performed
patient presented depressive symptoms with labile mood after 15 sessions of HFLI TMS, showing an improvement in
4 Case Reports in Psychiatry

all measures. The BDI (score of 9 points) demonstrated a Taking into count those previous studies, we designed a
reduction of depressive symptoms, reaching minimum levels stimulation protocol that acknowledged three main points
of depression, while the MADRS (score of 10 points) score from previously reported protocols.
reduction reached mild depression levels. The BAI also indi- Firstly, as classical rTMS devices, we decided to focus the
cated a minimum presence of anxiety (score of 5 points), and stimulation just in one area of the brain instead of applying a
the AIS (score of 7 points) showed a minimum presence of diffuse and global magnetic field to the whole skull. Patho-
insomnia symptoms. Finally, the cognitive score improved physiologically, we considered it important to focus the
by five points (MMSE = 29 points), which could indicate that magnetic stimulation on one area known to be affected in
baseline evaluation could be influenced by concurrent MDD. MDD such as the left prefrontal dorsolateral cortex [17].
The changes in the scales were corroborated by the self- Secondly, the pattern of stimulation seems to be very impor-
report of the patient. tant in determining the effects of both classical [18] and low-
Before and after changes in scales for the three subjects intensity magnetic stimulation [19]. That is why we chose a
are presented in Figure 2. novel pattern of stimulation that has been shown to modify
the brain’s activity in both animal models (unpublished data)
5. Discussion and humans. This novel stimulation pattern has shown to
improve mood and insomnia symptoms in healthy young
In this report, three patients with different history and clini- people [20].
cal presentation of MDD were treated with high-frequency Lastly, while neuroplastic changes can occur after just
and low-intensity magnetic patterned pulses over the left one session of rTMS [18], lasting and clinically relevant
dorsolateral prefrontal cortex and showed remarkable clini- changes typically occur after at least 10 sessions of classical
cal improvement after 15 sessions of stimulation. rTMS devices [21]; we hypothesized that applying a similar
While each patient presented a different clinical back- number of sessions as classical rTMS stimulation could lead
ground, all three patients showed sharp changes in their to a more pronounced and consistent antidepressant effect
self-report and in the standardized clinical assessments. The compared to other low-intensity protocols.
mechanisms responsible for the observed clinical changes We advise to regard this report with caution, as only
in these patients are almost certainly different from those three cases without proper controls are described, so
produced by classical TMS devices. The pulse intensity placebo effects could not be evaluated. Also, the size of the
applied by this device is several orders of magnitude lower group and its heterogeneity could have influenced the results
than the one required to generate a motor evoked potential, obtained in this work, as patients were very different amongst
so direct depolarization of neurons does not seem like a via- themselves.
ble mechanism of the observed antidepressant effect [10]. To reach stronger conclusions about the effect of HFLIP
Even if there is no direct depolarization of neurons, magnetic TMS, the group size must be augmented, and their heteroge-
pulses at a low subthreshold intensity and relatively high fre- neity reduced by the application of strict selection criteria,
quency have demonstrated to change cortical excitability rather than a sample selected by convenience. Moving
[11], modify brain metabolism [12], and change neurocogni- forward, clinical trials using this new HFLIP TMS protocol
tive function in humans [13]. How does these kinds of should be performed with appropriate sham control to
magnetic fields modify the brain’s activity is not completely correctly assess the clinical efficacy, as well as to clarify if
understood, but animal and human evidence have shown the placebo effect could play a role in the improvement seen
an increase in plasticity [14], BDNF [15], and an anti- on the patients or other effects this technique could generate
inflammatory effect [16], which, coincidentally, are normally in MDD subjects.
affected in MDD [10].
Other studies using magnetic pulses have reported mixed
results in the antidepressant effects of magnetic stimulation Data Availability
in a similar window of frequencies and intensities. Rohan Anonymized data of the applied scores are available upon
et al. first published that the application of magnetic pulses request.
at 1000 Hz and an intensity of no more than 2 milliteslas to
the whole brain reduced depressive symptoms in patients
with bipolar disorder and MDD compared to sham stimula- Disclosure
tion with just one session of stimulation [5]. Years after, a
double-blind proof of concept clinical trial showed no differ- The research was partly performed as part of the employ-
ence between sham and real stimulation with this same stim- ment of two authors (VG and RA). The employer (Actipulse
ulation protocol and device in improving depression scores Neuroscience) was not involved in the manuscript writing,
in subjects with unipolar MDD, leading to the conclusion editing, approval, or decision to publish.
that more sessions of stimulation and longer exposure time
could explain the lack of efficacy of this trial [7]. A new and Conflicts of Interest
more recent double-blind clinical trial using this same
stimulation protocol showed improvement in mood scores VG and RA are currently working in the research department
in real stimulation compared with sham with three sessions of Actipulse Neuroscience. Dr. Albano has been a speaker for
of stimulation [8]. Actipulse Neuroscience educational events.
Case Reports in Psychiatry 5

Acknowledgments exposure on cognitive functions: results of a meta-analysis,”

Bioelectromagnetics, vol. 31, pp. 173–179, 2010.
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magnetic stimulation device here used. We thank Sandra “Effects of exposure to an extremely low frequency electro-
Sotelo for her full support in this project. magnetic field on hippocampal long-term potentiation in
rat,” Brain Research, vol. 1564, pp. 1–8, 2014.
[15] L. Xiao, C. U. Correll, L. Feng et al., “Rhythmic low-field mag-
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See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/335962807

The effectiveness of exogenous melatonin versus transcranial magnetic

stimulation on the quality of sleep, memory and mood of young adult people

Article · August 2019

DOI: 10.15406/ppij.2019.07.00250

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 Pharmacy & Pharmacology International Journal

Research Article Open Access

The effectiveness of exogenous melatonin versus

transcranial magnetic stimulation on the quality of
sleep, memory and mood of young adult people
Abstract Volume 7 Issue 4 - 2019
Melatonin is a neurohormone that is secreted in the brain and which is associated with
the sleep cycle, its clinical uses have been focused on sleep disorders, as well as on the Sánchez-Betancourt Javier,1,2 Meza-Amaya
improvement of cognitive performance and people’s mood. Likewise, Transcranial Arturo,1 Muñiz-Salazar Raquel,3 Guzmán-
Magnetic Stimulation (TMS) has been used in the same areas. The objective of this research Cortes Jorge,2 Cárdenas-Bautista Dilayaxy3
was to analyze for two weeks, in young adults with an average age of 24 (the minimum
1
Facultad de Ciencias Administrativas y Sociales, carrera de
age was 18 and the maximum was 32), which of the two treatments was more effective in psicología, Unidad Valle Dorado, Universidad Autónoma de Baja
inducing improvements in sleep quality, memory and mood. Four groups were formed, the California, México
2
Facultad de Estudios Superiores Iztacala, Laboratorio de
placebo group (n=28), the sham group (n=28), the melatonin group (n=25) and the TMS
Neuromorfología, Universidad Nacional Autónoma de México,
group (n=16). All groups had a pre-test evaluation of sleep quality, memory, depression
México
and anxiety. The experimental phase lasted 2 weeks and consisted of placebo exposure, 3
Laboratorio de Epidemiología y Ecología Molecular, Escuela de
sham stimulation, melatonin consumption (10 mg) and TMS (128 Hz). After this period, the Ciencias de la Salud, Unidad Valle Dorado, Universidad Autónoma
post-test evaluation was carried out. The results showed that both treatments were equally de Baja California, México
effective in improving sleep quality, although TMS was more effective in improving
memory and anxiety symptoms. It is inferred that both treatments are effective, although Correspondence: Javier Sánchez-Betancourt, Facultad de
the question arises about their long-term use and the maintenance of the improvements. Ciencias Administrativas y Sociales, carrera de psicología Unidad
Valle Dorado, Universidad Autónoma de Baja California, Ensenada,
Keywords: melatonin, TMS, depression, anxiety, sleep quality, memory Baja California 22890, México, Tel +52 646 176 66 00 ext 151,
Email

Received: July 24, 2019 | Published: August 07, 2019

Abbreviations: TMS, transcranial magnetic stimulation submitted to the ethics committee of the School of Health Sciences
of the Autonomous University of Baja California. Each participant
Introduction was given an informed consent where he or she was aware of
the objective of the investigation and was told that it could be
Melatonin (N-Methyl-5-Methoxytryptamine) is a neurohormone distributed randomly in the different experimental conditions. The
that is synthesized in the pineal gland as well as in other organs of average age of the participants was 24, the percentage of women
the body and their functions are crucial to vertebrate’s life since they and men was 36% and 64%, respectively. Participants who were
include the regulation of circadian rhythms by facilitating sleep and under psychopharmacological and/or psychological treatment were
being a free radical scavenger in the brain.1‒6 Moreover, the intake excluded from the study.
of exogenous melatonin has been associated with more complex
functions such as being effective in improving the conditions of Materials/equipment 
animals in depression/anxiety models as well as in patients with mood
disorders.7‒10 To evaluate the working memory, the computerized version of
the memory span and digit span tests were applied using the PEBL
In addition to being effective in treating insomnia problems in platform. To measure the quality of sleep, a Pittsburgh sleep quality
older adults,11 melatonin is also effective in improving cognitive inventory was applied. Burns inventories were used to detect levels of
functions such as memory.12‒15 Although it is not clearly known how depression and anxiety. The anxiety inventory has a score of 0 to 100
exogenous melatonin promotes such improvement, both in humans
and the classification of minimum anxiety (0-4), limit (5-10), light
and in laboratory animals, it has been found to promote the expression
of antioxidant enzyme,16 the increase in concentration of trophic (11-20), moderate (21-30), severe (41-50) and extreme (51-100). The
factors14 as well as increased neurogenesis in the hippocampus.17 inventory of depression has a score of 0 to 100 and is classified in
the categories of non-deprecated (0-5), normal but unhappy (6-10),
On the other hand, it is also known that transcranial magnetic minimal depression (11-25), moderate depression (26-50), severe
stimulation is effective in treating similar disorders in which depression (51-75) and extreme depression (76-100).21
melatonin has been effective.18‒20 That is the reason why the question
arises of which of the two therapies is more effective in treating Melatonin: 10 mg sublingual melatonin tablets from the Eurovital
both sleep disorders and cognitive functioning. Thus, the objective nutraceuticals brand were used. Participants were asked to ingest the
of this investigation was to evaluate the independent effect of the pill a few minutes before sleeping for two consecutive weeks.
administration of exogenous melatonin and transcranial magnetic
stimulation on the quality of sleep, memory and mood in young adults. Transcranial magnetic stimulation: The portable version of the
Actipulse Home-depression device was used. The stimulation protocol
consisted of placing the diadem to the participants for 30 minutes a
Material and methods day, from Monday to Friday for two weeks. The electromagnetic
Participants; 100 young people from the city of Ensenada, Baja impulses generated by the main unit of the stimulator are square
California were asked to participate in the research, which was then waves with an emission frequency of approximately 128 Hertz (Hz).

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© 2019 Sánchez-Betancourt et al. This is an open access article distributed under the terms of the Creative Commons Attribution
License, which permits unrestricted use, distribution, and build upon your work non-commercially.
The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on the quality of sleep, Copyright:
©2019 Sánchez-Betancourt et al. 189
memory and mood of young adult people

Procedure: the participants were randomly distributed to one of the however, the TMS group showed significant differences in the post-
following groups (it was a double-blind study); 1. Placebo group test phase [F(3,60)=6,92, p<0.01], which indicates an increase in
(n=28) (this group only received strawberry flavor pills and had the ability to remember images. In the digit span test, no significant
psychometric tests); 2. Sham group (n=28) (this group wore the differences were found due to the time factor, experimental condition
stimulation headband and it was placed without any current and or the interaction of both, however, an increase in the average of items
the tests were performed) 3. Melatonin group (n=25) (this group remembered can be seen (see Figure 3). For example, the Melatonin
received 10 mg melatonin tablets that were ingested a few minutes group had an average of 5.5 and 6.5 of items in the pre-test and post-
before sleeping for 2 weeks, the formerly mentioned tests were test evaluations, respectively; on the other hand, the TMS group had an
applied before and after the experiment) and 4. TMS (n=16) (this average of 5.8 and 8 items before and after stimulation, respectively.
group received transcranial magnetic stimulation through a diadem Memory span
30 minutes a day for two weeks and the tests were also applied before
and after the experiment). All groups had a pre-test evaluation of sleep
quality, memory, depression and anxiety. The experimental phase
lasted 2 weeks and consisted of placebo exposure, sham stimulation,
melatonin consumption (10 mg) and TMS (128 Hz). After this period,
the post-test evaluation was carried out.

Statistical analysis
The two-factor ANOVA was used where the dependent variables
were quality of sleep, memory, depression and anxiety: the factors
included in the analysis were “time” (that is, before and after the
experimental intervention) and the “experimental condition” (that is,
the group to which it belonged to). For multiple comparisons the data
was analyzed using the Tukey test. The statistical program Graph Pad Figure 2 Shows the average of correct answers in the Mspan test in the
Pris 8 for Mac was used. four groups before and after receiving the treatment. While in the placebo,
sham and melatonin groups there are no changes in the pre-test and post-test
Results evaluations in the TMS group, the two-way ANOVA revealed a significant effect
of the “experimental condition” factor [F (3, 60) = 6,922]. * Versus control, p
In the applied quality of sleep scale, values close to 0 indicate <0.001
quality of sleep while those close to 21 indicate poor quality of sleep.
According to the cut-off point of the instrument, values above 5 Digit Span
indicate poor sleep quality. As can be seen in Figure 1, both in the
placebo group and in the sham group the average quality of sleep
exceeds the cut-off point and remained similar in the pre-test and
post-test phase of the experiment. In the melatonin and TMS groups,
an improvement in sleep quality was observed in both groups, with
both of them approaching a 5. The two factor ANOVA showed that
time, experimental condition as well as interaction of both groups
were significant [F(3,80)=7,285, p<0.01]. The analysis of multiple
comparisons confirmed that the melatonin and TMS groups showed
the reported improvement in sleep quality.
Sleep Quality

Figure 3 Shows the average number of correct answers obtained in the Dspan
test in the four groups before and after receiving the treatments. Statistical
analyzes did not reveal significant changes after treatments. However, it can be
seen in the experimental groups a tendency to improve in the execution of
said test. * Versus control, p <0.001
The average levels of depression found in the pre-test phase in the
four groups were similar and according to the interpretation of the
Burns depression inventory corresponded to the levels of moderate
depression (Figure 4). In the post-test phase, this trend was maintained
with the exception of the melatonin group, where there was a
combined effect of the “time” factor and “experimental condition” to
Figure 1 Shows the quality of sleep in the four groups before and after significantly reduce depression values [F(3,98)=3,103, p<0.01]. The
receiving the treatments; In the melatonin and TMS groups there was an average levels of depression in this group after melatonin treatment
improvement in sleep quality. The interaction between the “time” factor and corresponded to those of minimal depression.
“experimental condition” was significant in these groups [F (3, 80) = 7,285]. *
Versus control, p <0.001 Anxiety in the placebo and sham groups was similar in the pre-test
and post-test evaluations (Figure 5). According to the classification
Regarding the execution of the memory tests, it can be seen in Figure of the Burns anxiety inventory in both groups, it was detected that
2 that in the memory span test the placebo, sham and melatonin the average score corresponded to a moderate level of anxiety. In the
groups had similar averages in the pre-test and post-test phases; case of the melatonin group, the pre-test evaluation showed moderate

Citation: Sánchez-Betancourt J, Meza-Amaya A, Muñiz-Salazar R, et al. The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on
the quality of sleep, memory and mood of young adult people. Pharm Pharmacol Int J. 2019;7(4):188‒191. DOI: 10.15406/ppij.2019.07.00250
The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on the quality of sleep, Copyright:
©2019 Sánchez-Betancourt et al. 190
memory and mood of young adult people

anxiety and in the post-test evaluation the participants’ scores shown that it induces the propagation of slow waves, similar to those
corresponded to those of light anxiety. Statistical analysis showed of the deep sleep phase.25
that the experimental condition factor had a significant reduction in
anxiety in the TMS group [F(3, 96)=4,23, p<0.01]. Memory improvement can be clearly seen in the memory span
test in the group that received TMS for two weeks. These results
Depression agree with reports where TMS in the motor cortex is able to improve
the learning of motor sequences in 22 year olds.26 Similarly, they
agree with memory improvement in mice exposed to microgravity
conditions (which causes cognitive damage); in that case, 15 Hz TMS
was applied for 14 consecutive days.27 In this investigation, memory
improvement was associated with an increase in dendritic spine
density of the dentate gyrus of the hippocampus, as well as an increase
in the expression of postsynaptic proteins NR2A, NR2B, PSD95
(associated with memory formation ) as well as an increase in BNDF/
TrkB growth factors. On the other hand, although melatonin was not
able to significantly improve performance in memory tests, although
if there is a tendency to increase the average number of successes in
both tests and it seems that the effects on this function are observed
with more days of treatment, at least for two more weeks.28
The depression variable was the one that got benefited the most
Figure 4 Depression levels in the melatonin group significantly decreased by the melatonin treatment. This is consistent with research in which
after the two week treatment [F (3, 98) = 3,103]. * Versus control, p <0.001 mice that received the 10 mg/k intraperitoneal injection of melatonin
and that had been pretreated with liposaccharides had a reduction
Anxiety in depressive symptoms induced by such drugs. This improvement
was associated with the increase in glutathione antioxidant enzyme,
increase in BNDF and decrease in TNF-a in the hippocampus.29
On the other hand, these results are consistent with the fact that
the administration of 10 mg/k melatonin in rats was able to reverse
depressive symptoms induced by continuous stress. Neurochemical
analyzes confirmed that this improvement was related to an increase
in norepinephrine levels in the hippocampus.30 Furthermore, our
results agree with preclinical studies where melatonin has shown
antidepressant properties. Although statistical analyzes did not show
a reduction in depression levels in the TMS group if a tendency to
decrease can be seen, which would be consistent with reports of the
effectiveness of this treatment for depression.31,32
Anxiety showed high values in all the groups evaluated and
decreased with experimental conditions. This data is consistent
Figure 5 Shows the anxiety levels before and after the experimental phase.As with reports where TMS was effective for the treatment of anxiety
can be seen, anxiety levels had a decrease in the TMS group; Statistical analyzes disorders.2,3 It should be noted that the group that had higher levels
showed that the experimental condition factor had a significant effect on [F (3, of anxiety before the experiment was that of TMS and after that
96) = 4,227]. * Versus control, p <0.001 treatment the anxiety levels decreased significantly, so it is likely that
TMS use has higher anxiolytic properties than that of melatonin’s.
Discussion
Sleep quality is a condition that was affected in all participants Conclusion
of this research. However, the melatonin treatment as well as the After two weeks of treatment, both melatonin and TMS were
magnetic stimulation treatment was effective in improving the quality effective in improving the sleep quality of young adults. TMS was
of sleep as reported by the participants. This data is consistent with more effective than melatonin for relieving anxiety symptoms and
reports where exogenous melatonin is useful and widely used to treat for improving memory test scores. On the other hand, the melatonin
sleep disorders.22 Thus, for example, there is evidence where relatively treatment was more effective in reducing the symptoms of depression.
low doses of melatonin (1mg/day) administered for 5 weeks (of which However, there is still the question of knowing how the effectiveness
2 received placebo) were effective in reducing the difficulty of waking of such treatments would be long-term (one or two months) and
up, reducing sleep during school hours and increasing sleep time in knowing if these effects are maintained after the end of the treatment.
adolescents whose ages ranged from 14 to 19.23 Our data also agreed
with studies where patients who were in a treatment against heroin Funding details
addiction and who underwent a 10 Hz stimulation protocol for six
weeks reported a significant improvement in sleep quality.24 While My research project was partially or fully sponsored by (PRODEP)
melatonin was more effective in improving sleep quality, statistical with grant number (UABC-PTC-691).
analyzes did not show that one treatment was more effective than the
other. These results could be explained because melatonin has the Acknowledgments
natural function of regulating sleep cycles, increasing the REM sleep
cycle and decreasing sleep latency.2 In the case of TMS, it has been None.

Citation: Sánchez-Betancourt J, Meza-Amaya A, Muñiz-Salazar R, et al. The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on
the quality of sleep, memory and mood of young adult people. Pharm Pharmacol Int J. 2019;7(4):188‒191. DOI: 10.15406/ppij.2019.07.00250
The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on the quality of sleep, Copyright:
©2019 Sánchez-Betancourt et al. 191
memory and mood of young adult people

Conflicts of interest 17. Ruksee N, Tongjaroenbuangam W, Mahanam T, et al. Melatonin pretreat-

ment prevented the effect of dexamethasone negative alterations on beha-
The authors declare no conflict of interest. vior and hippocampal neurogenesis in the mouse brain. J Steroid Biochem
Mol Biol. 2014;143:72–80.
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Citation: Sánchez-Betancourt J, Meza-Amaya A, Muñiz-Salazar R, et al. The effectiveness of exogenous melatonin versus transcranial magnetic stimulation on
the quality of sleep, memory and mood of young adult people. Pharm Pharmacol Int J. 2019;7(4):188‒191. DOI: 10.15406/ppij.2019.07.00250

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