No Consistent Antidepressant Effects of Deep Brain Stimulation of the Bed Nucleus of the Stria Terminalis.

BACKGROUND: Applying deep brain stimulation (DBS) to several brain regions has been investigated in attempts to treat highly treatment-resistant depression, with variable results. Our initial pilot data suggested that the bed nucleus of the stria terminalis (BNST) could be a promising therapeutic target. OBJECTIVE: The aim of this study was to gather blinded data exploring the efficacy of applying DBS to the BNST in patients with highly refractory depression. METHOD: Eight patients with chronic severe treatment-resistant depression underwent DBS to the BNST. A randomised, double-blind crossover study design with fixed stimulation parameters was followed and followed by a period of open-label stimulation. RESULTS: During the double-blind crossover phase, no consistent antidepressant effects were seen with any of the four stimulation parameters applied, and no patients achieved response or remission criteria during the blinded crossover phase or during a subsequent period of three months of blinded stimulation. Stimulation-related side effects, especially agitation, were reported by a number of patients and were reversible with adjustment of the stimulation parameters. CONCLUSIONS: The results of this study do not support the application of DBS to the BNST in patients with highly resistant depression or ongoing research utilising stimulation at this brain site. The blocked randomised study design utilising fixed stimulation parameters was poorly tolerated by the participants and does not appear suitable for assessing the efficacy of DBS at this location.

Electroencephalographic Connectivity: A Fundamental Guide and Checklist for Optimal Study Design and Evaluation.

Brain connectivity can be estimated through many analyses applied to electroencephalography (EEG) data. However, substantial heterogeneity in the implementation of connectivity methods exists. Heterogeneity in conceptualization of connectivity measures, data collection, or data preprocessing may be associated with variability in robustness of measurement. While it is difficult to compare the results of studies using different EEG connectivity measures, standardization of processing and reporting may facilitate the task. We discuss how factors such as referencing, epoch length and number, controls for volume conduction, artifact removal, and statistical control of multiple comparisons influence the EEG connectivity estimate for connectivity measures, and what can be done to control for potential confounds associated with these factors. Based on the results reported in previous literature, this article presents recommendations and a novel checklist developed for quality assessment of EEG connectivity studies. This checklist and its recommendations are made in an effort to draw attention to factors that may influence connectivity estimates and factors that need to be improved in future research. Standardization of procedures and reporting in EEG connectivity may lead to EEG connectivity studies being made more synthesizable and comparable despite variations in the methodology underlying connectivity estimates.

Repetitive Transcranial Magnetic Stimulation for Obsessive-Compulsive Disorder: A Meta-analysis of Randomized, Sham-Controlled Trials.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic, disabling mental health condition with limited treatment options available to date. Numerous randomized controlled trials have explored the efficacy of repetitive transcranial magnetic stimulation (rTMS) in OCD. This meta-analysis synthesized data from selected randomized controlled trials and examined the impact of different treatment parameters to generate hypotheses that would direct future randomized controlled trials. METHODS: A database search was performed to identify studies published in English up to October 2020. Randomized, sham-controlled studies that used rTMS to treat OCD were included. Effect sizes were calculated using Hedges' g for pre- to post-treatment Yale-Brown Obsessive Compulsive Scale scores. Subgroup analyses were conducted to assess the effects of variations in rTMS treatment parameters. RESULTS: A total of 26 studies with 781 participants were included. Overall, rTMS demonstrated a modest effect on reduction of Yale-Brown Obsessive Compulsive Scale scores (Hedges' g = 0.64, 95% confidence interval = 0.39-0.89; p < .0001). The largest significant effect size was obtained by targeting the bilateral dorsolateral prefrontal cortex. High- and low-frequency rTMS showed comparable effects. Studies with follow-up data suggested that the effects of active rTMS remain significantly superior to those of sham 4 weeks after treatment. CONCLUSIONS: The therapeutic effects of rTMS are superior to those of sham in the treatment of OCD. Targeting the bilateral dorsolateral prefrontal cortex was the most favorable approach in administering rTMS. Further research is required to determine the optimal frequency, total pulses per session, and duration of treatment with rTMS for OCD.

Potential predictors of depressive relapse following repetitive Transcranial Magnetic Stimulation: A systematic review.

BACKGROUND: Repetitive Transcranial Magnetic Stimulation (rTMS) is widely approved treatment for major depressive disorder (MDD). However, around 50% of individuals who recover from depression following rTMS interventions experience a relapse of depressive symptomatology by 12 months. The short-term durability of the rTMS treatment effect has been systematically investigated. However, variables relating to the long-term durability of the antidepressant effect produced by rTMS are less understood. Therefore, the current review systematically assessed the research on variables relating to relapse following rTMS. METHOD: This systematic review was performed according to PRISMA guidelines. A comprehensive electronic literature search for terms related to relapse following rTMS treatment for MDD was performed on studies published before the end of October 2018. RESULTS: A total of 18 studies assessing relapse related variables were identified. While there is some indication that comorbid anxiety, acute response, and residual symptomatology may hold predictive potential for depressive relapse following rTMS treatment, findings were not sufficient to draw reliable conclusions. DISCUSSION: Identified studies assessed three main categories of variables including demographic information, clinical characteristics and rating scale scores, and rTMS treatment specific factors. Only a small number of studies were available, and considerable inconsistency exists between studies, only limited conclusions were able to be drawn. CONCLUSION: More studies assessing a wider range of predictor variables such as cognitive or neuroimaging markers are needed.

A Pilot Investigation of Repetitive Transcranial Magnetic Stimulation for Post-Traumatic Brain Injury Depression: Safety, Tolerability, and Efficacy.

Depression following a traumatic brain injury (TBI) is common and difficult to treat using standard approaches. The current study investigated, for the first time, transcranial magnetic stimulation (TMS) for the treatment of post TBI depression. We specifically assessed the safety, tolerability, and efficacy of TMS in this patient population. We also explored cognitive outcomes. Twenty-one patients with a current episode of major depression subsequent to a TBI participated in a randomized double-blind placebo-controlled trial of repetitive TMS (rTMS). Sequential bilateral rTMS (to the left and right dorsolateral prefrontal cortex) was provided in 20 treatments over a period of 4 weeks. Patients were randomly allocated to receive either active or sham stimulation. There were no adverse effects and treatment was well tolerated. There was no significant effect of rTMS on post-TBI depression, with all patients showing a significant improvement in depressive symptoms irrespective of their treatment group (p = 0.002). There were significant improvements in cognition following active rTMS in the areas of working memory (p = 0.021) and executive function (p = 0.029). rTMS was shown to be safe and well tolerated in patients who had developed depression after a TBI. We did not find a therapeutic effect for post-TBI depression; however, this approach may have some utility in improving cognitive function. Future research should focus on alternative rTMS treatment approaches for post-TBI depression and the direct investigation of rTMS as a treatment for cognitive impairment in TBI.

Electrophysiology of obsessive compulsive disorder: A systematic review of the electroencephalographic literature.

Obsessive-compulsive disorder (OCD) is a chronic disease that causes significant decline in the quality of life of those affected. Due to our limited understanding of the underlying pathophysiology of OCD, successful treatment remains elusive. Although many have studied the pathophysiology of OCD through electroencephalography (EEG), limited attempts have been made to synthesize and interpret their findings. To bridge this gap, we conducted a comprehensive literature review using Medline/PubMed and considered the 65 most relevant studies published before June 2018. The findings are categorised into quantitative EEG, sleep related EEG and event related potentials (ERPs). Increased frontal asymmetry, frontal slowing and an enhancement in the ERP known as error related negativity (ERN) were consistent findings in OCD. However, sleep EEG and other ERP (P3 and N2) findings were inconsistent. Additionally, we analysed the usefulness of ERN as a potential candidate endophenotype. We hypothesize that dysfunctional frontal circuitry and overactive performance monitoring are the major underlying impairments in OCD. Additionally, we conceptualized that defective fronto-striato-thalamic circuitry causing poor cerebral functional connectivity gives rise to the OCD behavioural manifestations. Finally, we have discussed transcranial magnetic stimulation and EEG (TMS-EEG) applications in future research to further our knowledge of the underlying pathophysiology of OCD.

Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder.

BACKGROUND: Electroconvulsive therapy (ECT) is a very commonly used treatment for patients with severe and treatment-resistant depression. Although effective, this treatment is complicated by a number of side effects including cognitive impairment motivating attempts to develop treatment alternatives. Magnetic seizure therapy (MST) is a brain stimulation technique using a high-powered transcranial magnetic stimulation device to produce therapeutic seizures. Preliminary research suggests that MST has antidepressant activity in the absence of cognitive side effects. The aim of this study was therefore to investigate the therapeutic efficacy and cognitive profile of MST provided at high frequency (100 Hz) and potentially longer stimulation trains and longer treatment courses than have been previously investigated. METHODS: Thirteen patients participated in an open-label clinical trial of up to 18 treatment sessions with 100-Hz MST. Assessments of depression severity and cognitive functioning were performed before and after treatment. RESULTS: Of the 13 patients who completed the study, five met clinical response criteria at study end. There was an overall group reduction in depression severity and no evidence of any impairment of orientation, memory, or other elements of cognition after MST treatment. The major limitation of the study was its lack of sham control. CONCLUSIONS: In conclusion, MST shows antidepressant efficacy without apparent cognitive side effects. However, substantial research is required to understand the optimal conditions for stimulation and to compare MST to established treatments including ECT.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression.

OBJECTIVE: A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD: Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS: In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS: This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.

Symptom correlates of static and dynamic facial affect processing in schizophrenia: evidence of a double dissociation?

Schizophrenia patients have been shown to be compromised in their ability to recognize facial emotion. This deficit has been shown to be related to negative symptoms severity. However, to date, most studies have used static rather than dynamic depictions of faces. Nineteen patients with schizophrenia were compared with seventeen controls on 2 tasks; the first involving the discrimination of facial identity, emotion, and butterfly wings; the second testing emotion recognition using both static and dynamic stimuli. In the first task, the patients performed more poorly than controls for emotion discrimination only, confirming a specific deficit in facial emotion recognition. In the second task, patients performed more poorly in both static and dynamic facial emotion processing. An interesting pattern of associations suggestive of a possible double dissociation emerged in relation to correlations with symptom ratings: high negative symptom ratings were associated with poorer recognition of static displays of emotion, whereas high positive symptom ratings were associated with poorer recognition of dynamic displays of emotion. However, while the strength of associations between negative symptom ratings and accuracy during static and dynamic facial emotion processing was significantly different, those between positive symptom ratings and task performance were not. The results confirm a facial emotion-processing deficit in schizophrenia using more ecologically valid dynamic expressions of emotion. The pattern of findings may reflect differential patterns of cortical dysfunction associated with negative and positive symptoms of schizophrenia in the context of differential neural mechanisms for the processing of static and dynamic displays of facial emotion.

Mirror neuron activation is associated with facial emotion processing.

Theoretical accounts suggest that mirror neurons play a crucial role in social cognition. The current study used transcranial magnetic stimulation (TMS) to investigate the association between mirror neuron activation and facial emotion processing, a fundamental aspect of social cognition, among healthy adults (n=20). Facial emotion processing of static (but not dynamic) images correlated significantly with an enhanced motor response, proposed to reflect mirror neuron activation. These correlations did not appear to reflect general facial processing or pattern recognition, and provide support to current theoretical accounts linking the mirror neuron system to aspects of social cognition. We discuss the mechanism by which mirror neurons might facilitate facial emotion recognition.

Reduced motor facilitation during action observation in schizophrenia: a mirror neuron deficit?

Impairments in social cognitive functioning are well documented in schizophrenia, however the neural basis of these deficits is unclear. A recent explanatory model of social cognition centers upon the activity of mirror neurons, which are cortical brain cells that become active during both the performance and observation of behavior. Here, we test for the first time whether mirror neuron functioning is reduced in schizophrenia. Fifteen individuals with schizophrenia or schizoaffective disorder and fifteen healthy controls completed a transcranial magnetic stimulation (TMS) experiment designed to assess mirror neuron activation. While patients demonstrated no abnormalities in cortical excitability, motor facilitation during action observation, putatively reflecting mirror neuron activity, was reduced in schizophrenia. Dysfunction within the mirror neuron system may contribute to the pathophysiology of schizophrenia.