Correction: Cotovio et al. Regulatory Clearance and Approval of Therapeutic Protocols of Transcranial Magnetic Stimulation for Psychiatric Disorders. Brain Sci. 2023, 13, 1029.

Missing Citation [...].

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

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 interesting 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.

Replicability of motor cortex-excitability modulation by intermittent theta burst stimulation.

OBJECTIVE: Transcranial Magnetic Stimulation (TMS) allows for cortical-excitability (CE) assessment and its modulation has been associated with neuroplasticity-like phenomena, thought to be impaired in neuropsychiatric disorders. However, the stability of these measures has been challenged, defying their potential as biomarkers. This study aimed to test the temporal stability of cortical-excitability modulation and study the impact of individual and methodological factors in determining within- and between-subject variability. METHODS: We recruited healthy-subjects to assess motor cortex (MC) excitability modulation, collecting motor evoked potentials (MEP) from both hemispheres, before and after left-sided intermittent theta burst stimulation (iTBS), to obtain a measure of MEPs change (delta-MEPs). To assess stability across-time, the protocol was repeated after 6 weeks. Socio-demographic and psychological variables were collected to test association with delta-MEPs. RESULTS: We found modulatory effects on left MC and not on right hemisphere following iTBS of left MC. Left delta-MEP was stable across-time when performed immediately after iTBS (ICC = 0.69), only when obtained first in left hemisphere. We discovered similar results in a replication cohort testing only left MC (ICC = 0.68). No meaningful associations were found between demographic and psychological factors and delta-MEPs. CONCLUSIONS: Delta-MEP is stable immediately after modulation and not impacted by different individual factors, including expectation about TMS-effect. SIGNIFICANCE: Motor cortex excitability modulation immediately after iTBS should be further explored as a potential biomarker for neuropsychiatric diseases.

Striatal dopamine D2-like receptors availability in obesity and its modulation by bariatric surgery: a systematic review and meta-analysis.

There 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.

Functional neuroanatomy of mania.

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.

Lesion network mapping of mania using different normative connectomes.

Lesion network mapping is a neuroimaging technique that explores the network of regions functionally connected to lesions causing a common syndrome. The technique uses resting state functional connectivity from large databases of healthy individuals, i.e., connectomes, and has allowed for important insight into the potential network mechanisms underlying several neuropsychiatric disorders. However, concerns regarding reproducibility have arisen, that may be due to the use of different connectomes, with variable MRI acquisition parameters and preprocessing methods. Here, we tested the impact of using different connectomes on the results of lesion network mapping for mania. We found results were reliable and consistent independent of the connectome used.

An Argument in Favor of Deep Brain Stimulation for Uncommon Movement Disorders: The Case for N-of-1 Trials in Holmes Tremor.

Deep brain stimulation (DBS) is part of state-of-the-art treatment for medically refractory Parkinson's disease, essential tremor or primary dystonia. However, there are multiple movement disorders that present after a static brain lesion and that are frequently refractory to medical treatment. Using Holmes tremor (HT) as an example, we discuss the effectiveness of currently available treatments and, performing simulations using a Markov Chain approach, propose that DBS with iterative parameter optimization is expected to be more effective than an approach based on sequential trials of pharmacological agents. Since, in DBS studies for HT, the thalamus is a frequently chosen target, using data from previous studies of lesion connectivity mapping in HT, we compared the connectivity of thalamic and non-thalamic targets with a proxy of the HT network, and found a significantly higher connectivity of thalamic DBS targets in HT. The understanding of brain networks provided by analysis of functional connectivity may thus provide an informed framework for proper surgical targeting of individual patients. Based on these findings, we argue that there is an ethical imperative to at least consider surgical options in patients with uncommon movement disorders, while simultaneously providing consistent information regarding the expected effectiveness and risks, even in a scenario of surgical-risk aversion. An approach based on n-of-1 DBS trials may ultimately significantly improve outcomes while informing on optimal therapeutic targets and parameter settings for HT and other disabling and rare movement disorders.

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

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.

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

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.

Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Older Adults: Systematic Review and Meta-analysis.

BACKGROUND: Major depressive disorder (MDD) in older adults is a serious public health concern. Repetitive transcranial magnetic stimulation (rTMS) is a nonpharmacological intervention approved for MDD treatment in adults, but its value in older adults remains unknown. This study aims to systematically review and meta-analyze evidence of rTMS efficacy in MDD treatment among older adults. METHODS: We systematically reviewed the literature for randomized controlled trials (RCTs) and open-label studies assessing rTMS for the treatment of MDD in patients older than 50 years, published until June 2020. Random-effects meta-analyses using standardized mean differences (SMDs) were conducted to assess change in depression severity score (primary outcome), while odds ratios (ORs) were used to assess secondary categorical outcomes (response and remission). Additionally, univariate meta-regression analyses were performed to identify potential predictors of change in depression severity scores. RESULTS: Fourteen RCTs were included in meta-analyses and 26 studies (10 RCTs and 16 open-label studies) in meta-regression. Active rTMS was significantly superior to sham treatment for reduction of severity (SMD = 0.36; 95% CI = 0.13-0.60), as well as response (OR = 3.26; 95% CI = 2.11-5.04) and remission (OR = 4.63; 95% CI = 2.24-9.55). Studies were of moderate to high quality, with funnel plots and Egger's regression test not suggestive of publication bias. In meta-regressions, higher mean age and number of sessions were significantly associated with greater improvement. CONCLUSIONS: Our results support that rTMS is an effective, safe, and well-tolerated treatment for MDD in older adults and that it should be considered in the treatment of this vulnerable population.

Symptom provocation for treatment of obsessive-compulsive disorder using transcranial magnetic stimulation: A step-by-step guide for professional training.

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that was cleared by the Food and Drug Administration (FDA) for the treatment of Obsessive-Compulsive Disorder (OCD) in 2018. The approved protocol includes individualized symptom provocation before each stimulation session, to elicit a moderate level of obsessional distress. Although symptom provocation can be a delicate, demanding, and uncomfortable procedure, structured training methods for those who are going to apply it are not available. Here, we describe a model for training in symptom provocation for TMS technicians, developed at the Champalimaud Clinical Centre in Lisbon, Portugal. Our programme includes two-sessions dedicated to clinical communication and symptom provocation techniques from a theoretical and practical perspective. Additionally, supervision meetings are conducted during treatment of patients, allowing regular case discussion and redefinition of symptom provocation hierarchy, as needed. In addition to having a strong practical component, our training program is short and pragmatic, allowing for easy implementation and fluid transition to clinical practice. By sharing our experience, we hope to contribute to systematize training procedures required for symptom provocation in the context of TMS, and to qualitatively describe a methodology that can be used for implementation of TMS programmes for the treatment of OCD.

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

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].

Translation and Validation of the Clinician Administered PTSD Scale (CAPS-CA-5) for Portuguese Children and Adolescents.

INTRODUCTION: The aim of this study was to translate and validate into European Portuguese the CAPS-CA-5 (Clinician Administered PTSD Scale for Children and Adolescents), a semi-structured scale for the diagnosis of post-traumatic stress disorder in children and adolescents, according to the DSM-5 criteria. MATERIAL AND METHODS: This study was developed in three stages. In the first stage, the translation and back-translation of CAPS-CA-5 into European Portuguese was carried out. In the second stage, the version obtained in the previous step was subjected to a pre-test. In the third stage, the final version of CAPS-CA-5, the KIDCOPE questionnaires and the Depression, Anxiety and Stress Scale-Children were applied to 101 children who had experienced at least one potentially traumatic event. The children included in this study were between seven and 18 years old and had a follow-up period in a Child Psychiatry or Pediatrics Clinic in one of the three hospitals involved in this project of at least one month. RESULTS: Regarding the confirmatory factor analysis, our results show that the CAPS-CA-5 is a suitable psychometric instrument to assess the diagnosis and symptoms severity of post-traumatic stress disorder according to DSM-5. Convergent validity was comparable to its original version. Although there were negative relationships with almost all of its clusters, these were not statistically significant when applied with the positive coping strategies of the KIDCOPE. The European Portuguese version of the CAPS-CA-5 showed a good internal consistency (Cronbach's α for the total scale was 0.89). CONCLUSION: The European Portuguese version of CAPS-CA-5 has similar psychometric properties to its original version.

Introdução: O objetivo deste estudo foi traduzir e validar para português europeu a CAPS-CA-5 (Clinician Administered PTSD Scale for Children and Adolescents), uma escala semiestruturada para o diagnóstico de perturbação de stress pós-traumático em crianças e adolescentes, de acordo com os critérios do DSM-5. Material e Métodos: Este estudo foi desenvolvido em três etapas. Na primeira, foi realizada a tradução e contra-tradução da CAPS-CA-5 para português europeu. Na segunda etapa, a versão obtida anteriormente foi submetida a um pré-teste. Na terceira etapa, a versão final da CAPS-CA-5, os questionários KIDCOPE e a Escala de Depressão, Ansiedade e Stresse - Crianças foram aplicados em 101 crianças que experienciaram pelo menos um evento potencialmente traumático. As crianças incluídas neste estudo tinham entre sete e 18 anos e tinham um período de acompanhamento em consulta de Psiquiatria Infantil ou Pediatria de pelo menos um mês, num dos três hospitais envolvidos neste projeto. Resultados: Em relação à análise fatorial confirmatória, os nossos resultados mostram que a CAPS-CA-5 é um instrumento psicométrico adequado para avaliar o diagnóstico e a gravidade dos sintomas de perturbação de stresse pós-traumático de acordo com o DSM-5. A validade convergente foi comparável à versão original. Embora tenha havido relações negativas com quase todos os seus clusters, estas não foram estatisticamente significativas quando aplicadas com as estratégias de coping positivo do KIDCOPE. A versão em português europeu da CAPS-CA-5 apresentou boa consistência interna (α de Cronbach para a escala total foi de 0,89). Conclusão: A versão em português europeu do CAPS-CA-5 possui propriedades psicométricas semelhantes à sua versão original.

Diagnosis and Treatment of Neuroleptic Malignant Syndrome in the Intensive Care Unit: A Case Report.

Neuroleptic malignant syndrome is a neurological emergency caused by dysregulation of dopaminergic neurotransmission. While it is typically characterized by muscle rigidity, fever and altered mental status, it may have a heterogeneous and non-specific presentation, leading to delays in diagnosis and treatment. Treatment involves cessation of dopamine-receptor antagonists and supportive measures, but in more severe cases, bromocriptine, dantrolene, benzodiazepines and/or electroconvulsive therapy should be considered. We present the case of a 66-year-old man with severe neuroleptic malignant syndrome, diagnosed due to need for continuous invasive ventilation in an Intensive Care Unit, after successful treatment for respiratory sepsis. The patient recovered after electroconvulsive therapy and administration of bromocriptine. This unusually severe case illustrates the need for a high level of suspicion for neuroleptic malignant syndrome in critically ill patients with malignant catatonic syndromes, allowing for an early diagnosis and potentially lifesavingtreatment.

A síndrome maligna dos neurolépticos é uma emergência neurológica causada pela desregulação da neurotransmissão dopaminérgica. Apesar de habitualmente caracterizada por rigidez muscular, febre e alteração do estado mental, pode apresentar-se de forma inespecífica e heterogénea, atrasando o diagnóstico e tratamento. O tratamento engloba a interrupção de antagonistas dos receptores dopaminérgicos, medidas de suporte e, em casos mais graves, bromocriptina, dantroleno, benzodiazepinas e/ou terapia electroconvulsiva. Neste artigo descrevemos o caso clínico de um homem de 66 anos com síndrome maligna dos neurolépticos grave, diagnosticada devido à necessidade de ventilação artificial continuada na Unidade de Cuidados Intensivos, após tratamento de uma sépsis respiratória. O doente melhorou significativamente após terapia electroconvulsiva e administração de bromocriptina. Este caso, de gravidade particular, sublinha a necessidade de manter um elevado nível de suspeita de síndrome maligna dos neurolépticos em doentes em estado crítico com síndromes catatónicos malignos, permitindo assim um diagnóstico precoce e tratamento dirigido.

Reward-related gustatory and psychometric predictors of weight loss following bariatric surgery: a multicenter cohort study.

BACKGROUND: Reward sensitivity has been proposed as a potential mediator of outcomes for bariatric surgery. OBJECTIVES: We aimed to determine whether gustatory and psychometric measures of reward-related feeding are predictors of bariatric-induced weight loss. METHODS: A multicenter longitudinal cohort study was conducted in patients scheduled for bariatric surgery (surgical group), assessed at baseline and 2 follow-up assessments. Predictions of % weight loss from baseline (%WL) according to baseline gustatory measures, including intensity and pleasantness ratings of sweet and other tastants, and psychometric measures of reward-related feeding behavior, including hedonic hunger scores, were assessed with multivariable linear regression. Exploratory analyses were conducted to test for associations between %WL and changes in gustatory and psychophysical measures, as well as for comparisons with data from patients on the surgery waiting list (control group). RESULTS: We included 212 patients, of whom 96 in the surgical group and 50 in the control group were prospectively assessed. The groups were similar at baseline and, as expected, bariatric surgery resulted in higher %WL (BTreatment-Time  = 2.4; 95% CI: 2.1-2.8; P  < 0.0001). While variation in gustatory measures did not differ between groups, in the surgery group baseline sweet intensity predicted %WL at the primary endpoint (11 to 18 months postoperatively; ß = 0.2; B = 0.2, 95% CI: 0.02 to 0.3; P  = 0.02), as did hedonic hunger scores (ß = -0.2; B = -2.0, 95% CI: -3.8 to -0.3; P  = 0.02). Furthermore, at this endpoint, postsurgical reduction of sweet taste intensity and acceptance of sweet foods were associated with %WL (ß = -0.3; B = -3.5, 95% CI: -5.8 to -1.3; P  = 0.003, and ß = -0.2; B = -4.7, 95% CI: -8.5 to -0.8; P  = 0.02, respectively). The use of sweet intensity as a predictor of weight change was confirmed in another bariatric cohort. CONCLUSIONS: Sweet intensity ratings and hedonic hunger scores predict %WL after surgery. The variability of sweet intensity ratings is also associated with %WL, further suggesting they may reflect physiological processes that are variably modulated by bariatric surgery, influencing clinical outcomes.

Day-to-day variability in motor threshold during rTMS treatment for depression: Clinical implications.

BACKGROUND: When repetitive transcranial magnetic stimulation (rTMS) is used to treat medication refractory depression, the treatment pulse intensity is individualized according to motor threshold (MT). This measure is often acquired only on the first day of treatment, as per the protocol currently approved by Food and Drug Administration. OBJECTIVE: Here, we aimed to assess daily MT variability across an rTMS treatment course and simulate the effects of different schedules of MT assessment on treatment intensity. METHODS: We conducted a naturalistic retrospective study with 374 patients from a therapeutic rTMS program for depression that measures MT daily. RESULTS: For each patient, in almost half the TMS sessions, MT varied on average more than 5% as compared to the baseline MT acquired in the first treatment day. Such variability was only minimally impacted by having different TMS technicians acquiring MT in different days. In a smaller cohort of healthy individuals, we confirmed that the motor hotspot localization method, a critical step for accurate MT assessment, was stable in different days, arguing that daily MT variability reflects physiological variability, rather than an artifact of measurement error. Finally, in simulations of the effect of one-time MT measurement, we found that half of sessions would have been 5% or more above or below target intensity, with almost 5% of sessions 25% above target intensity. The simulated effects of weekly MT measurements were significantly improved. CONCLUSIONS: In conclusion, MT varies significantly across days, not fully dependent on methods of MT acquisition. This finding may have important implications for therapeutic rTMS practice regarding safety and suggests that regular MT assessments, daily or at least weekly, would ameliorate the effect.

Right-sided brain lesions predominate among patients with lesional mania: evidence from a systematic review and pooled lesion analysis.

Despite claims that lesional mania is associated with right-hemisphere lesions, supporting evidence is scarce, and association with specific brain areas has not been demonstrated. Here, we aimed to test whether focal brain lesions in lesional mania are more often right- than left-sided, and if lesions converge on areas relevant to mood regulation. We thus performed a systematic literature search (PROSPERO registration CRD42016053675) on PubMed and Web-Of-Science, using terms that reflect diagnoses and structures of interest, as well as lesional mechanisms. Two researchers reviewed the articles separately according to PRISMA Guidelines, selecting reports of adult-onset hypomania, mania or mixed state following a focal brain lesion, for pooled-analyses of individual patient data. Eligible lesion images were manually traced onto the corresponding MNI space slices, and lesion topography analyzed using standard brain atlases. Using this approach, data from 211 lesional mania patients was extracted from 114 reports. Among 201 cases with focal lesions, more patients had lesions involving exclusively the right (60.7%) than exclusively the left (11.4%) hemisphere. In further analyses of 56 eligible lesion images, while findings should be considered cautiously given the potential for selection bias of published lesion images, right-sided predominance of lesions was confirmed across multiple brain regions, including the temporal lobe, fusiform gyrus and thalamus. These, and several frontal lobe areas, were also identified as preferential lesion sites in comparisons with control lesions. Such pooled-analyses, based on the most comprehensive dataset of lesional mania available to date, confirm a preferential association with right-hemisphere lesions, while suggesting that several brain areas/circuits, relevant to mood regulation, are most frequently affected.

Mapping mania symptoms based on focal brain damage.

BACKGROUNDAlthough mania is characteristic of bipolar disorder, it can also occur following focal brain damage. Such cases may provide unique insight into brain regions responsible for mania symptoms and identify therapeutic targets.METHODSLesion locations associated with mania were identified using a systematic literature search (n = 41) and mapped onto a common brain atlas. The network of brain regions functionally connected to each lesion location was computed using normative human connectome data (resting-state functional MRI, n = 1000) and contrasted with those obtained from lesion locations not associated with mania (n = 79). Reproducibility was assessed using independent cohorts of mania lesions derived from clinical chart review (n = 15) and of control lesions (n = 490). Results were compared with brain stimulation sites previously reported to induce or relieve mania symptoms.RESULTSLesion locations associated with mania were heterogeneous and no single brain region was lesioned in all, or even most, cases. However, these lesion locations showed a unique pattern of functional connectivity to the right orbitofrontal cortex, right inferior temporal gyrus, and right frontal pole. This connectivity profile was reproducible across independent lesion cohorts and aligned with the effects of therapeutic brain stimulation on mania symptoms.CONCLUSIONBrain lesions associated with mania are characterized by a specific pattern of brain connectivity that lends insight into localization of mania symptoms and potential therapeutic targets.FUNDINGFundação para a Ciência e Tecnologia (FCT), Harvard Medical School DuPont-Warren Fellowship, Portuguese national funds from FCT and Fundo Europeu de Desenvolvimento Regional, Child Neurology Foundation Shields Research, Sidney R. Baer, Jr. Foundation, Nancy Lurie Marks Foundation, Mather's Foundation, and the NIH.