Functional neuroanatomy of mania

Funding Information: GC is supported by Fundação para a Ciência e Tecnologia (FCT) through a PhD Scholarship (SFRH/BD/130210/2017). AJO-M is supported by grant FCT-PTDC/MEC-PSQ/ 30302/2017-IC&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020—Programa Operacional Regional de Lisboa, and the BOUNCE (grant agreement number 777167) and FAITH (grant agreement number 875358) projects, funded by the European Union’s Horizon 2020 research and innovation programme. GC and AJO-M are supported by grant FCT-PTDC/MED-NEU/31331/2017, funded by FCT/MCTES. Funding Information: AJO-M was national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019-2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348-25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). None of the aforementioned agencies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. Publisher Copyright: © 2022, The Author(s).Mania, the diagnostic hallmark of bipolar disorder, is an episodic disturbance of mood, sleep, behavior, and perception. Improved understanding of the neurobiology of mania is expected to allow for novel avenues to address current challenges in its diagnosis and treatment. Previous research focusing on the impairment of functional neuronal circuits and brain networks has resulted in heterogenous findings, possibly due to a focus on bipolar disorder and its several phases, rather than on the unique context of mania. Here we present a comprehensive overview of the evidence regarding the functional neuroanatomy of mania. Our interpretation of the best available evidence is consistent with a convergent model of lateralized circuit dysfunction in mania, with hypoactivity of the ventral prefrontal cortex in the right hemisphere, and hyperactivity of the amygdala, basal ganglia, and anterior cingulate cortex in the left hemisphere of the brain. Clarification of dysfunctional neuroanatomic substrates of mania may contribute not only to improve understanding of the neurobiology of bipolar disorder overall, but also highlights potential avenues for new circuit-based therapeutic approaches in the treatment of mania.publishersversionpublishe

Future Perspectives From a Case Report of Transcranial Magnetic Stimulation, Cognitive Behavioral Therapy, and Psychopharmacological Treatment for Post-traumatic Stress Disorder

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In Older Adults the Antidepressant Effect of Repetitive Transcranial Magnetic Stimulation Is Similar but Occurs Later Than in Younger Adults

BackgroundTreatment resistant depression is common in older adults and treatment is often complicated by medical comorbidities and polypharmacy. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for this group due to its favorable profile. However, early influential studies suggested that rTMS is less effective in older adults. This evidence remains controversial.MethodsHere, we evaluated the rTMS treatment outcomes in a large international multicenter naturalistic cohort of >500 patients comparing older vs. younger adults.ResultsWe show that older adults, while having similar antidepressant response to younger adults, respond more slowly, which may help to explain differences from earlier studies when the duration of a treatment course was shorter.ConclusionsSuch evidence helps to resolve a long-standing controversy in treating older depressed patients with rTMS. Moreover, these findings provide an important data point in the call to revise policy decisions from major insurance providers that have unfairly excluded older adults

Regulatory Clearance and Approval of Therapeutic Protocols of Transcranial Magnetic Stimulation for Psychiatric Disorders

Funding Information: G.C. was funded by Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD scholarship (SFRH/BD/130210/2017. G.C. and A.J.O.-M. were supported by grant PTDC/MED-NEU/31331/2017 from FCT. A.J.O.-M. was supported by grant PTDC/MEC-PSQ/30302/2017-IC&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT and co-funded by FEDER, under the Partnership Agreement Lisboa 2020—Programa Operacional Regional de Lisboa, and by a Starting Grant from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 950357). A.J.O.-M. was also supported by the BOUNCE project (grant agreement no. 777167) and by the FAITH project (grant agreement no. 875358), both funded by the European Union’s Horizon 2020 Research and Innovation Programme. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the Fundação para a Ciência e Tecnologia or the European Research Council. Publisher Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland.Non-invasive brain stimulation techniques (NIBS) have been widely used in both clinical and research contexts in neuropsychiatry. They are safe and well-tolerated, making NIBS an interest-ing option for application in different settings. Transcranial magnetic stimulation (TMS) is one of these strategies. It uses electromagnetic pulses for focal modulate ion of neuronal activity in brain cortical regions. When pulses are applied repeatedly (repetitive transcranial magnetic stimulation—rTMS), they are thought to induce long-lasting neuroplastic effects, proposed to be a therapeutic mechanism for rTMS, with efficacy and safety initially demonstrated for treatment-resistant depression (TRD). Since then, many rTMS treatment protocols emerged for other difficult to treat psychiatric conditions. Moreover, multiple clinical studies, including large multi-center trials and several meta-analyses, have confirmed its clinical efficacy in different neuropsychiatric disorders, resulting in evidence-based guidelines and recommendations. Currently, rTMS is cleared by multiple regulatory agencies for the treatment of TRD, depression with comorbid anxiety disorders, obsessive compulsive disorder, and substance use disorders, such as smoking cessation. Importantly, current research supports the potential future use of rTMS for other psychiatric syndromes, including the negative symptoms of schizophrenia and post-traumatic stress disorder. More precise knowledge of formal indications for rTMS therapeutic use in psychiatry is critical to enhance clinical decision making in this area.publishersversionpublishe

Hemispheric asymmetry of motor cortex excitability in mood disorders – Evidence from a systematic review and meta-analysis

Funding Information: Funding: GC was supported by Fundação para a Ciência e Tecnologia (FCT) through a PhD Scholarship (SFRH/BD/130210/2017). AJO-M is supported by grant FCT-PTDC/MEC-PSQ/30302/2017-IC&DT-LIS BOA-01-0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020 - Programa Operacional Regional de Lisboa. GC and AJO-M are supported by grant FCT-PTDC/MED-NEU/31331/2017, funded by FCT/MCTES. This project was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 777167. AJO-M was national coordinator for Portugal of a noninterventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019–2020), is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36 and 2020-001348- 25), and of esketamine for treatment-resistant depression, sponsored by Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33).Objective: Mood disorders have been associated with lateralized brain dysfunction, on the left-side for depression and right-side for mania. Consistently, asymmetry of cortical excitability, as measured by transcranial magnetic stimulation (TMS) has been reported. Here, we reviewed and summarized work assessing such measures bilaterally in mood disorders. Methods: We performed a systematic review and extracted data to perform meta-analyses of interhemispheric asymmetry of motor cortex excitability, assessed with TMS, across different mood disorders and in healthy subjects. Additionally, potential predictors of interhemispheric asymmetry were explored. Results: Asymmetry of resting motor threshold (MT) among healthy volunteers was significant, favoring lower right relative to left-hemisphere excitability. MT was also significantly asymmetric in major depressive disorder (MDD), but with lower excitability of the left -hemisphere, when compared to the right, no longer observed in recovered patients. Findings on intracortical facilitation were similar. The few trials including bipolar depression revealed similar trends for imbalance, but with lower right hemisphere excitability, relative to the left. Conclusions: There is interhemispheric asymmetry of motor cortical excitability in MDD, with lower excitability on left when compared to right-side. Interhemispheric asymmetry, with lower right relative to left-sided excitability, was found for bipolar depression and was also suggested for healthy volunteers, in a pattern that is clearly distinct from MDD. Significance: Mood disorders display asymmetric motor cortical excitability that is distinct from that found in healthy volunteers, supporting the presence of lateralized brain dysfunction in these disorders.publishersversionpublishe

In Older Adults the Antidepressant Effect of Repetitive Transcranial Magnetic Stimulation Is Similar but Occurs Later Than in Younger Adults

Funding Information: AJO-M was the national coordinator for Portugal of a non-interventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd (2019–2020), is the recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is the national coordinator for Portugal of trials of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd (EudraCT number 2017-003288-36), and of esketamine for treatment-resistant depression, sponsored by the Janssen-Cilag, Ltd (EudraCT NUMBER: 2019-002992-33). AP-L is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Magstim Inc., Radiant Hearts, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of non-invasive brain stimulation with electroencephalography and magnetic resonance imaging. None of the aforementioned agencies or companies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Information: GC was funded by the Fundação para a Ciência e Tecnologia (FCT; Portugal) through a PhD Scholarship (SFRH/BD/130210/2017). AB was supported by the NIH (NS114405-02, MH120441-01). AJO-M was funded by the FCT (Portugal) through a Junior Research and Career Development Award from the Harvard Medical School—Portugal Program (HMSP-ICJ/0020/2011). GC and AJO-M were supported by grant PTDC/MED-NEU/31331/2017, and AJO-M by grant PTDC/MED-NEU/30302/2017, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020—Programa Operacional Regional de Lisboa. AJO-M was also funded by a Starting Grant from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 950357). Publisher Copyright: Copyright © 2022 Cotovio, Boes, Press, Oliveira-Maia and Pascual-Leone.Background: Treatment resistant depression is common in older adults and treatment is often complicated by medical comorbidities and polypharmacy. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for this group due to its favorable profile. However, early influential studies suggested that rTMS is less effective in older adults. This evidence remains controversial. Methods: Here, we evaluated the rTMS treatment outcomes in a large international multicenter naturalistic cohort of >500 patients comparing older vs. younger adults. Results: We show that older adults, while having similar antidepressant response to younger adults, respond more slowly, which may help to explain differences from earlier studies when the duration of a treatment course was shorter. Conclusions: Such evidence helps to resolve a long-standing controversy in treating older depressed patients with rTMS. Moreover, these findings provide an important data point in the call to revise policy decisions from major insurance providers that have unfairly excluded older adults.publishersversionpublishe

a systematic review and meta-analysis

OKThere is significant evidence linking a 'reward deficiency syndrome' (RDS), comprising decreased availability of striatal dopamine D2-like receptors (DD2lR) and addiction-like behaviors underlying substance use disorders and obesity. Regarding obesity, a systematic review of the literature with a meta-analysis of such data is lacking. Following a systematic review of the literature, we performed random-effects meta-analyses to determine group differences in case-control studies comparing DD2lR between individuals with obesity and non-obese controls and prospective studies of pre- to post-bariatric surgery DD2lR changes. Cohen's d was used to measure effect size. Additionally, we explored factors potentially associated with group differences in DD2lR availability, such as obesity severity, using univariate meta-regression. In a meta-analysis including positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies, striatal DD2lR availability did not significantly differ between obesity and controls. However, in studies comprising patients with class III obesity or higher, group differences were significant, favoring lower DD2lR availability in the obesity group. This effect of obesity severity was corroborated by meta-regressions showing inverse associations between the body mass index (BMI) of the obesity group and DD2lR availability. Post-bariatric changes in DD2lR availability were not found, although a limited number of studies were included in this meta-analysis. These results support lower DD2lR in higher classes of obesity which is a more targeted population to explore unanswered questions regarding the RDS.publishersversionpublishe

Motor cortical inhibitory deficits in patients with obsessive-compulsive disorder–A systematic review and meta-analysis of transcranial magnetic stimulation literature

Funding Information: DR was supported by H2020-SC1-DTH-2019-875358-FAITH. AM and GC are supported by Fundação para a Ciência e Tecnologia (FCT) through Ph.D. Scholarships (respectively, SFRH/BD/144508/2019 and SFRH/BD/130210/2017). GC and AO-M are supported by grant FCT-PTDC/MED-NEU/31331/2017, funded by FCT/MCTES. AO-M was funded by a Starting Grant from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 950357). JB-C and AO-M were supported by grant FCT-PTDC/MEC-PSQ/30302/2017-IC&DT-LISBOA-01-0145-FEDER, funded by national funds from FCT/MCTES and co-funded by FEDER, under the Partnership Agreement Lisboa 2020–Programa Operacional Regional de Lisboa. JO was supported by BBRF-27595-2018 NARSAD. None of the agencies had a role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, in the preparation, review, or approval of the manuscript, nor in the decision to submit the manuscript for publication. Publisher Copyright: Copyright © 2022 Rodrigues da Silva, Maia, Cotovio, Oliveira, Oliveira-Maia and Barahona-Corrêa.Introduction: Obsessive-compulsive disorder (OCD) is a highly prevalent chronic disorder, often refractory to treatment. While remaining elusive, a full understanding of the pathophysiology of OCD is crucial to optimize treatment. Transcranial magnetic stimulation (TMS) is a non-invasive technique that, paired with other neurophysiological techniques, such as electromyography, allows for in vivo assessment of human corticospinal neurophysiology. It has been used in clinical populations, including comparisons of patients with OCD and control volunteers. Results are often contradictory, and it is unclear if such measures change after treatment. Here we summarize research comparing corticospinal excitability between patients with OCD and control volunteers, and explore the effects of treatment with repetitive TMS (rTMS) on these excitability measures. Methods: We conducted a systematic review and meta-analysis of case-control studies comparing various motor cortical excitability measures in patients with OCD and control volunteers. Whenever possible, we meta-analyzed motor cortical excitability changes after rTMS treatment. Results: From 1,282 articles, 17 reporting motor cortex excitability measures were included in quantitative analyses. Meta-analysis regarding cortical silent period shows inhibitory deficits in patients with OCD, when compared to control volunteers. We found no statistically significant differences in the remaining meta-analyses, and no evidence, in patients with OCD, of pre- to post-rTMS changes in resting motor threshold, the only excitability measure for which longitudinal data were reported. Discussion: Our work suggests an inhibitory deficit of motor cortex excitability in patients with OCD when compared to control volunteers. Cortical silent period is believed to reflect activity of GABAB receptors, which is in line with neuroimaging research, showing GABAergic deficits in patients with OCD. Regardless of its effect on OCD symptoms, rTMS apparently does not modify Resting Motor Threshold, possibly because this measure reflects glutamatergic synaptic transmission, while rTMS is believed to mainly influence GABAergic function. Our meta-analyses are limited by the small number of studies included, and their methodological heterogeneity. Nonetheless, cortical silent period is a reliable and easily implementable measurement to assess neurophysiology in humans, in vivo. The present review illustrates the importance of pursuing the study of OCD pathophysiology using cortical silent period and other easily accessible, non-invasive measures of cortical excitability. Systematic review registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020201764], identifier [CRD42020201764].publishersversionpublishe