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.

Exploring Theta Burst Stimulation for Post-traumatic Stress Disorder in Australian Veterans-A Pilot Study.

INTRODUCTION: Post-traumatic stress disorder (PTSD) is a severe and debilitating condition affecting a significant proportion of the veteran community. A substantial number of veterans with PTSD fail to benefit from trauma-focused psychological therapies or pharmacotherapy or are left with residual symptoms, and therefore, investigation of new and innovative treatment is required. Theta Burst Stimulation (TBS) is a novel form of Repetitive Transcranial Magnetic Stimulation, which has been shown to improve depression symptoms and associated cognitive deficits. The current pilot study aimed to explore the acceptability, safety, and tolerability of intermittent TBS (iTBS) as a treatment for PTSD in Australian veterans. MATERIALS AND METHODS: This study employed a case series, repeated-measures design. Eight Australian Defence Force veterans with PTSD received 20 bilateral iTBS treatments (1 session per day, 5 days per week over a 4-week period) and were assessed on a range of mental health and neuropsychological measures, including the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and Hamilton Depression Rating Scale (HAM-D), at pretreatment, post-treatment, and a 3-month follow-up. RESULTS: Treatment was generally welltolerated, with reported side-effects including mild to moderate site-specific cranial pain and headaches during stimulation, which were relieved with the use of low dose analgesics. No serious side effects or adverse events were reported. Participants exhibited reductions in both PTSD and depression symptom severity (the repeated-measures effect size [dRM] for the CAPS-5 was -1.78, and the HAM-D was -1.16 post-treatment), as well as improvements in working memory and processing speed. Although significance cannot be inferred, these preliminary estimates of effect size indicate change over time. CONCLUSIONS: Bilateral iTBS appears to be welltolerated by Australian veterans. Within this repeated-measures case series, iTBS treatment shows promise in reducing both PTSD and mood symptoms, as well as improving cognitive difficulties associated with these disorders. Large-scale randomized controlled trials of this promising treatment are warranted.

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.

A pilot study of bed nucleus of the stria terminalis deep brain stimulation in treatment-resistant depression.

BACKGROUND: Studies are increasingly investigating the therapeutic effects of deep brain stimulation (DBS) applied to a variety of brain regions in the treatment of patients with highly treatment refractory depression. Limited research to date has investigated the therapeutic potential of DBS applied to the Bed Nucleus Of Stria Terminalis (BNST). OBJECTIVE: The aim of this study was to explore the therapeutic potential of DBS applied to the BNST. METHOD: Five patients with highly treatment resistant depression underwent DBS to the BNST in an open label case series design. RESULTS: BNST DBS resulted in sustained remission of depression in two of the five patients, provided substantial therapeutic improvement two further patients, and had minimal antidepressant effect for the final patient. There were no operative complications and stimulation related side effects were limited and reversible with adjustment of stimulation. However, the time to achieve and complexity of programming required to achieve optimal therapeutic outcomes varied substantially between patients. CONCLUSION: DBS applied to the BNST as therapeutic potential in patients with highly refractory depression and warrants exploration in larger clinical studies.

Use of clinical guidelines in remote Australia: A realist evaluation.

AIM: The aim of this evaluation was to assess the acceptability, accessibility, and compliance with the 2014 editions of the Remote Primary Health Care Manuals (RPHCM) in health care centres across remote areas of Northern and Central Australia. METHOD: To undertake a comprehensive evaluation that considered context, the evaluation used a realist evaluation framework. The evaluation used a variety of methods including interviews and survey to develop and test a programme theory. RESULTS: Many remote health practitioners have adopted standardized, evidence-based practice because of the use of the RPHCM. The mechanisms that led to the use of the manuals include acceptance of the worth of the protocols to their clinical practice, reliance on manual content to guide their practice, the perception of credibility, the applicability of RPHCM content to the context, and a fear of the consequences of not using the RPHCMs. Some remote health practitioners are less inclined to use the RPHCM regularly because of a perception that the content is less suited to their needs and daily practice or it is hard to navigate or understand. CONCLUSION: The evaluation concluded that there is work to be done to widen the RPHCM user base, and organizations need to increase support for their staff to use the RPHCM protocols better. These measures are expected to enable standardized clinical practice in the remote context.

Identifying an appropriate Content Management System to develop Clinical Practice Guidelines: A perspective.

Clinical Practice Guidelines are widely used to inform and improve the quality and consistency of clinical practice. Developing and publishing Clinical Practice Guidelines is a complex task involving multiple components. Electronic Content Management Systems are increasingly employed to make this task more manageable. The Content Management System market offers a variety of options for publishing content on the Internet. However, there are limited products that comprehensively address the requirements of publishing Clinical Practice Guidelines. The authors are involved in publishing guidelines for remote clinical practitioners in Australia and present their perspective about identifying an appropriate Content Management System. Several elements essential to addressing their unique editing needs are defined in this article. Unfortunately, customisation is very expensive and laborious: few Content Management System providers can comprehensively meet the needs of Clinical Practice Guidelines publishing. Being pragmatic about the level of functionality a product can offer to support publication is essential.

Evaluating impact of clinical guidelines using a realist evaluation framework.

RATIONALE, AIMS AND OBJECTIVES: The Remote Primary Health Care Manuals (RPHCM) project team manages the development and publication of clinical protocols and procedures for primary care clinicians practicing in remote Australia. The Central Australian Rural Practitioners Association Standard Treatment Manual, the flagship manual of the RPHCM suite, has been evaluated for accessibility and acceptability in remote clinics three times in its 20-year history. These evaluations did not consider a theory-based framework or a programme theory, resulting in some limitations with the evaluation findings. With the RPHCM having an aim of enabling evidence-based practice in remote clinics and anecdotally reported to do so, testing this empirically for the full suite is vital for both stakeholders and future editions of the RPHCM. METHODS: The project team utilized a realist evaluation framework to assess how, why and for what the RPHCM were being used by remote practitioners. A theory regarding the circumstances in which the manuals have and have not enabled evidence-based practice in the remote clinical context was tested. The project assessed this theory for all the manuals in the RPHCM suite, across government and aboriginal community-controlled clinics, in three regions of Australia. CONCLUSION: Implementing a realist evaluation framework to generate robust findings in this context has required innovation in the evaluation design and adaptation by researchers. This article captures the RPHCM team's experience in designing this evaluation.

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.

Transcranial magnetic stimulation for depression after a traumatic brain injury: a case study.

Depression after a traumatic brain injury (TBI) is very common, yet there is a lack of evidence-based treatment options for people who experience depression after a TBI. Traditionally, a history of TBI has been considered an exclusion criterion for transcranial magnetic stimulation trials because of the increased risk of seizure after a TBI. We present what we believe to be the first case of a patient with depression after a TBI treated with transcranial magnetic stimulation.

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.

A study of the effectiveness of high-frequency left prefrontal cortex transcranial magnetic stimulation in major depression in patients who have not responded to right-sided stimulation.

The objective of this study was to explore the response rate to high-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) in patients who had failed to respond to right-sided low-frequency stimulation, and to investigate whether there was differential efficacy between stimulation at 5 or 10 Hz. Data from two randomized controlled trials were pooled. In both studies a group of patients were randomized to receive either 5- or 10-Hz left prefrontal rTMS after failing to respond to right-sided stimulation. These patients received blinded 5- or 10-Hz stimulation (but without a sham control) for a period of up to 4 weeks and outcomes were compared. There was a small but significant overall response to left-sided rTMS but no difference in response between the 5- and 10-Hz treatment conditions. There appears to be a significant but modest likelihood of response to left-sided TMS in patients who fail right-sided stimulation, but there is no difference in efficacy between 5- and 10-Hz stimulation.

A randomized trial of rTMS targeted with MRI based neuro-navigation in treatment-resistant depression.

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subject's MRI scan. There was an overall significant reduction in the Montgomery-Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

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.