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In this article, we describe the case of a patient who, under the direction of a multidisciplinary case committee, underwent both an ablative cingulotomy and subsequent bilateral deep brain stimulation placement in the Cg25 area. Review of this case provides a means of comparing the two techniques and of illustrating what we feel are some important advantages to using stimulation in the treatment of major depression. This report also provides potential insight into common and unique mechanisms mediating the two procedures.

Despite being the most common group of mental disorders in later life, anxiety disorders in the elderly have historically been a neglected area of research. While clinically important, there have been few studies of anxiety disorders specifically in older persons. However, in recent years, there has been increasing interest and a growing base of studies addressing the epidemiology, comorbidity and treatment of late-life anxiety. The literature on panic disorder in the elderly is illustrative of this trend. Although clinicians who treat panic disorder in the elderly have been left to extrapolate from data derived from younger individuals with panic disorder, the last decade has witnessed the first trials of psychotherapeutic and pharmacological treatments performed exclusively in older patients. Although much work remains to be done in terms of testing both psychosocial and medication treatment strategies in rigorously designed studies, preliminary evidence suggests that both psychotherapeutic and pharmacological treatment can be effective for panic disorder in the elderly.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.

s / Brain Stimulation 8 (2015) 395e411 396 included age, gender, years with disease, doses of L-DOPA, dyskinesias, stadium by Hoehn and Yahr. rTMS was performed with a Magstim Rapid2, 5 consecutive days, for 3 months, resting 3 weeks per month, 100 pulses, 25 Hz, 80% of motor threshold. Results: We recruited a total of 2 men and 2 women, stadium Hoehn and Yahr 1.5-3, age 67 8. 76, 7.75 2. 5 years with PD, basal doses of L-dopa 850 270.80 with dyskinesias type 3 in 3 patients and basal UPDR of 53 26.99. After the third week of rTMS, patients were able to score by UPDRS 40.75 20.23, and revealed a dose reduction in L-DOPA of 578.12 93.74. Conclusions: According with the clinical features of our patients, the predominant type of dyskinesias is type 3. Preliminary results in response to rTMS treatment showa reduction in the UPDRS scale, as well as a decrease in L-DOPA dosage, which could be reduced monthly in all 4 patients.

Obsessive-compulsive disorder (OCD) is a disabling illness with high rates of nonresponse to conventional treatments. OCD pathophysiology is believed to involve abnormalities in cortico-striatal-thalamic-cortical circuits through regions such as dorsomedial prefrontal cortex (dmPFC) and ventral striatum. These regions may constitute therapeutic targets for neuromodulation treatments, such as repetitive transcranial magnetic stimulation (rTMS). However, the neurobiological predictors and correlates of successful rTMS treatment for OCD are unclear. Here, we used resting-state functional magnetic resonance imaging (fMRI) to identify neural predictors and correlates of response to 20–30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls as baseline comparators. A region of interest in the dmPFC was used to generate whole-brain functional connectivity maps pre-treatment and post treatment. Ten of 20 patients met the response criteria (⩾50% improvement on Yale-Brown Obsessive-Compulsive Scale, YBOCS); response to dmPFC-rTMS was sharply bimodal. dmPFC-rTMS responders had higher dmPFC-ventral striatal connectivity at baseline. The degree of reduction in this connectivity, from pre- to post-treatment, correlated to the degree of YBOCS symptomatic improvement. Baseline clinical and psychometric data did not predict treatment response. In summary, reductions in fronto-striatal hyperconnectivity were associated with treatment response to dmPFC-rTMS in OCD. This finding is consistent with previous fMRI studies of deep brain stimulation in OCD, but opposite to previous reports on mechanisms of dmPFC-rTMS in major depression. fMRI could prove useful in predicting the response to dmPFC-rTMS in OCD.

The last decade has seen a significant rise in interest in the use of deep brain stimulation (DBS) for the management of obsessive-compulsive disorder (OCD), one of psychiatry's most challenging conditions. The prominent role of both thought (obsessions) and motor (compulsions) dysfunction in OCD place the condition at the border between the neurological and the psychiatric. This is supported by a growing body of literature that implicates structures in decision-making, reward, and action-selection circuits in the disorder. Here, we provide an overview of the neurocircuitry of OCD while reviewing the DBS literature to date for the condition. Results of DBS trials in treatment- resistant OCD have been remarkably similar, with clinical response rates in the range of 40-60%, despite the use of a diverse range of targets. These results imply that a common underlying circuit is being modulated, and moreover that there is room for improvement, and debate, in the development of an evidence-driven DBS treatment for this chronic, debilitating illness.

Major depressive disorder is among the most prevalent psychiatric disorders and is a leading cause of morbidity and lost productivity.[1][1] The 1-year prevalence of major depressive disorder in the Canadian population is 3.2%–4.6%.[2][2] A large, multisite prospective trial showed that only 28%

Recently, deep brain stimulation (DBS) has been evaluated as an experimental therapy for treatment-resistant depression. Although there have been encouraging results in open-label trials, about half of the patients fail to achieve meaningful benefit. Although progress has been made in understanding the neurobiology of MDD, the ability to characterize differences in brain dynamics between those who do and do not benefit from DBS is lacking. In this study, we investigated EEG resting-state data recorded from 12 patients that have undergone DBS surgery. Of those, six patients were classified as responders to DBS, defined as an improvement of 50% or more on the 17-item Hamilton Rating Scale for Depression (HAMD-17). We compared hemispheric frontal theta and parietal alpha power asymmetry and synchronization asymmetry between responders and non-responders. Hemispheric power asymmetry showed statistically significant differences between responders and non-responders with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry was characterized by an increase in frontal theta in the right hemisphere relative to the left combined with an increase in parietal alpha in the left hemisphere relative to the right in non-responders compared with responders. Hemispheric mean synchronization asymmetry showed a statistically significant difference between responders and non-responders in the theta band, with healthy controls showing an asymmetry similar to responders but opposite to non-responders. This asymmetry resulted from an increase in frontal synchronization in the right hemisphere relative to the left combined with an increase in parietal synchronization in the left hemisphere relative to the right in non-responders compared with responders. Connectivity diagrams revealed long-range differences in frontal/central-parietal connectivity between the two groups in the theta band. This pattern was observed irrespective of whether EEG data were collected with active DBS or with the DBS stimulation turned off, suggesting stable functional and possibly structural modifications that may be attributed to plasticity.

Despite its high toll on society, there has been little recent improvement in treatment efficacy for major depressive disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting-state functional connectivity predicted response to treatment with repetitive transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty-five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting-state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal, and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased subgenual cingulate cortex-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Background: Major Depressive Disorder (MDD) is a leading cause of disability globally. Currently available treatments have limited efficacy and combination strategies are frequently used. Several lines of research have demonstrated that MDD patients experience impairments in various components of affective processing, including regulation of affective states. Aim: To identify baseline and 1-week neuroimaging predictors of response to a 6-week trial of fluoxetine/ olanzapine combination treatment during an affective processing task. Methods: Twenty-one MDD patients and 18 healthy controls were enrolled in the study. MDD patients were treated for 6 weeks with fluoxetine (40–60 mg/day) and olanzapine (5–12.5 mg/day). All participants viewed images from the International Affective Picture Rating System during a functional magnetic resonance (fMRI) scan at baseline and 1 week. Results: There was a 57% response rate (defined as a 50% decrease in Hamilton Rating Scale for Depression17 item) at 6 weeks. At baseline, responders had increased premotor activity while viewing negative images compared to non-responders and healthy controls. Higher baseline premotor activity was also predictive of greater percent change on the HAMD-17 and improvement in negative disposition and behavioral drive. Non-responders exhibited increased insular activity at baseline compared to responders. Higher activity in the posterior cingulate cortex was also predictive of greater percent change on the HAMD-17. Change from baseline to 1 week did not produce any significant predictive findings. Conclusions: Treatment with fluoxetine/olanzapine demonstrated similar biomarkers of response to monotherapeutic strategies. In particular, posterior cingulate cortex, anterior insula, and premotor cortex may show predictive differences in their response to affective images prior to treatment. Further research needs to be conducted to determine the utility of early changes in emotion circuitry in predicting antidepressant response.

The last decade has seen a significant rise in interest in the use of deep brain stimulation (DBS) for the management of obsessive–compulsive disorder (OCD), one of psychiatry’s most challenging conditions. The prominent role of both thought (obsessions) and motor (compulsions) dysfunction in OCD place the condition at the border between the neurological and the psychiatric. This is supported by a growing body of literature that implicates structures in decision-making, reward, and action-selection circuits in the disorder. Here, we provide an overview of the neurocircuitry of OCD while reviewing the DBS literature to date for the condition. Results of DBS trials in treatment- resistant OCD have been remarkably similar, with clinical response rates in the range of 40–60%, despite the use of a diverse range of targets. These results imply that a common underlying circuit is being modulated, and moreover that there is room for improvement, and debate, in the development of an evidence-driven DBS treatment for this chronic, debilitating illness.

A woman with severe, refractory bulimia nervosa underwent treatment for comorbid depression using repetitive transcranial magnetic stimulation (rTMS) of the dorsomedial prefrontal cortex (DMPFC) using a novel technique. Unexpectedly, she showed a rapid, dramatic remission from bulimia nervosa. For 5 months pre-treatment, she had reported two 5-hour binge-purge episodes per day. After rTMS session 2 the episodes stopped entirely for 1 week; after session 10 there were no further recurrences. Depression scores improved more gradually to remission at session 10. Full remission from depression and binge-eating/purging episodes was sustained more than 2 months after treatment completion. In neuroimaging studies, the DMPFC is important in impulse control, and is underactive in bulimia nervosa. DMPFC-rTMS may have enhanced the patient’s ability to deploy previously acquired strategies to avoid binge-eating and purging via a reduction in her impulsivity. A larger sham-controlled trial of DMPFC-rTMS for binge-eating and purging behavior may be warranted.

Antidepressant treatments, including pharmacotherapy and psychotherapy, do not result in remission for the majority of patients with major depressive disorder. The high prevalence of treatment resistant depression (TRD) poses a significant issue for patients as well as both societal and economic costs. Due to the limited efficacy of existing therapies in this sub-population, alternative somatic treatments are being explored. Both vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are neurostimulation treatments for TRD. While VNS has Food Drug Administration approval as an adjunctive therapy for MDD, DBS is still in the experimental stages. This article will review the evidence supporting the clinical utility of these therapies.

Deep brain stimulation (DBS) has been recently investigated as a treatment for major depression. One of the proposed targets for this application is the subcallosal cingulate gyrus (SCG). To date, promising results after SCG DBS have been reported by a single center. In the present study the authors investigated whether these findings may be replicated at different institutions. They conducted a 3-center prospective open-label trial of SCG DBS for 12 months in patients with treatment-resistant depression.Twenty-one patients underwent implantation of bilateral SCG electrodes. The authors examined the reduction in Hamilton Rating Scale for Depression (HRSD-17) score from baseline (RESP50).Patients treated with SCG DBS had an RESP50 of 57% at 1 month, 48% at 6 months, and 29% at 12 months. The response rate after 12 months of DBS, however, increased to 62% when defined as a reduction in the baseline HRSD-17 of 40% or more. Reductions in depressive symptomatology were associated with amelioration in disease severity in patients who responded to surgery.Overall, findings from this study corroborate the results of previous reports showing that outcome of SCG DBS may be replicated across centers.

Advances in neuromodulation and an improved understanding of the anatomy and circuitry of psychopathology have led to a resurgence of interest in surgery for psychiatric disease. Clinical trials exploring deep brain stimulation (DBS), a focally targeted, adjustable and reversible form of neurosurgery, are being developed to address the use of this technology in highly selected patient populations. Psychiatric patients deemed eligible for surgical intervention, such as DBS, typically meet stringent inclusion criteria, including demonstrated severity, chronicity and a failure of conventional therapy. Although a humanitarian device exemption by the US Food and Drug Administration exists for its use in obsessive-compulsive disorder, DBS remains a largely experimental treatment in the psychiatric context, with its use currently limited to clinical trials and investigative studies. The combination of a patient population at the limits of conventional therapy and a novel technology in a new indication poses interesting challenges to the informed consent process as it relates to clinical trial enrollment. These challenges can be divided into those that relate to the patient, their disease and the technology, with each illustrating how traditional conceptualisations of research consent may be inadequate in the surgical psychiatry context. With specific reference to risk analysis, patient autonomy, voluntariness and the duty of the clinician-researcher, this paper will discuss the unique challenges that clinical trials of surgery for refractory psychiatric disease present to the consent process. Recommendations are also made for an ethical approach to clinical trial consent acquisition in this unique patient population.

A prevalence of at least 30% for treatment-resistant depression has prompted the investigation of alternative treatment strategies. Deep brain stimulation (DBS) is a promising targeted approach involving the bilateral placement of electrodes at specific neuroanatomical sites. Given the invasive and experimental nature of DBS for treatment-resistant depression, it is important to obtain both short-term and long-term effectiveness and safety data. This report represents an extended follow-up of 20 patients with treatment-resistant depression who received DBS to the subcallosal cingulate gyrus (Brodmann's area 25).After an initial 12-month study of DBS, patients were seen annually and at a last follow-up visit to assess depression severity, functional outcomes, and adverse events.The average response rates 1, 2, and 3 years after DBS implantation were 62.5%, 46.2%, and 75%, respectively. At the last follow-up visit (range=3-6 years), the average response rate was 64.3%. Functional impairment in the areas of physical health and social functioning progressively improved up to the last follow-up visit. No significant adverse events were reported during this follow-up, although two patients died by suicide during depressive relapses.These data suggest that in the long term, DBS remains a safe and effective treatment for treatment-resistant depression. Additional trials with larger samples are needed to confirm these findings.

Bipolar disorder (BD) is a complex psychiatric disorder that is often underrecognized, misdiagnosed, and challenging to detect. During the past decade, substantial progress has been made in the development of pharmacotherapeutic and psychosocial interventions for various phases of BD. Notwithstanding these developments, the majority of BD individuals, and particularly patients with bipolar depression, receiving guideline concordant care do not experience syndromal or functional recovery, underscoring the need for novel treatments. Early success with deep brain stimulation (DBS) in the treatment of major depressive episodes as part of major depressive disorder (MDD) has provided the impetus to explore its application in other treatment-resistant psychiatric disorders, notably BD. Herein, we provide the rationale for employing DBS as an alternative treatment avenue in individuals with bipolar depression.We conducted a PubMed literature search, focusing on English language articles beginning in 1950 to the present day, and employed the following search terms: bipolar disorder, neurosurgery, deep brain stimulation, neuroimaging, and circuitry. Search results were then manually reviewed and relevant articles selected for analysis. Relevance was determined by author consensus and overall manuscript quality. We also reviewed articles on currently available treatment options for BD in order to develop a coherent and practical definition of treatment resistance with a focus on surgical intervention.Several lines of evidence indicate that although mania is the defining feature of bipolar I disorder, depressive symptoms and episodes dominate the longitudinal course, account for most of the illness burden including premature mortality, and are least responsive to contemporary treatments. Disease models in bipolar depression implicate abnormalities in the structure and function of discrete neural circuits that subserve affective processing and cognitive function with the subgenual cingulate cortex occupying a central role. Modulation of the cingulate cortex with DBS in treatment-resistant MDD populations has proven to offer acute and sustained antidepressant effects, suggesting possible benefits for other mood disorder populations.A surgical intervention for bipolar depression would not only be a proof of concept regarding disease modeling but also an important and novel treatment avenue for individuals affected by bipolar depression.

Therapy-resistant depression (TRD) is highly prevalent and has major health and economic implications. Although it is associated with psychiatric and medical comorbidity, there does not appear to be any common underlying biological substrate: more likely TRD represents a final pathway for various subpopulations of major depressive disorder patients. Sequential treatment studies indicate that over 40% of patients have not achieved remission after 2 adequate trials. Atypical antipsychotics and neurostimulation therapies are the most recently applied approaches to TRD, each with considerable success. Nevertheless, there is an urgent need to characterize the subtypes of TRD (at neurotransmitter, neural circuitry or neuroanatomical levels) with the aim of providing a personalized medicine approach to treatment.

Object Deep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG), including Brodmann area 25, is currently being investigated for the treatment of major depressive disorder (MDD). As a potential emerging therapy, optimal target selection within the SCG has still to be determined. The authors compared the location of the electrode contacts in responders and nonresponders to DBS of the SCG and correlated the results with clinical outcome to help in identifying the optimal target within the region. Based on the location of the active contacts used for long-term stimulation in responders, the authors suggest a standardized method of targeting the SCG in patients with MDD. Methods Postoperative MR imaging studies of 20 patients with MDD treated with DBS of the SCG were analyzed. The authors assessed the location of the active contacts relative to the midcommissural point and in relation to anatomical landmarks within the medial aspect of the frontal lobe. For this, a grid with 2 main lines was designed, with 1 line in the anterior-posterior and 1 line in the dorsal-ventral axis. Each of these lines was divided into 100 units, and data were converted into percentages. The anterior-posterior line extended from the anterior commissure (AC) to the projection of the anterior aspect of the corpus callosum (CCa). The dorsal-ventral line extended from the inferior portion of the CC (CCi) to the most ventral aspect of the frontal lobe (abbreviated “Fr” for the formula). Results Because the surgical technique did not vary across patients, differences in stereotactic coordinates between responders and nonresponders did not exceed 1.5 mm in any axis (x, y, or z). In patients who responded to the procedure, contacts used for long-term stimulation were in close approximation within the SCG. In the anterior-posterior line, these contacts were located within a 73.2 ± 7.7 percentile distance from the AC (with the AC center being 0% and the line crossing the CCa being 100%). In the dorsal-ventral line, active contacts in responders were located within a 26.2 ± 13.8 percentile distance from the CCi (with the CCi edge being 0% and the Fr inferior limit being 100%). In the medial-lateral plane, most electrode tips were in the transition between the gray and white matter of SCG. Conclusions Active contacts in patients who responded to DBS were relatively clustered within the SCG. Because of the anatomical variability in the size and shape of the SCG, the authors developed a method to standardize the targeting of this region.

Given the profound negative public health effects of major depressive disorder (MDD), and data suggesting only modest effectiveness of existing psychological and pharmacological treatments for this condition, there has been increasing interest in exploring the antidepressant potential of non-pharmacological, brain-based interventions, such as deep brain stimulation (DBS). The use of the DBS for psychiatric indications follows a decade of data suggesting that DBS is an effective, evidence-based strategy for the treatment of movement disorders such as Parkinson's disease. At the present time there is open-label case series data to suggest that DBS in the subgenual cingulate gyrus, ventral caudate/ventral striatum, and the nucleus accumbens, is associated with antidepressant effects in individuals who fail to respond to conventional treatments for MDD. However a number of unresolved issues about the optimal use of DBS for MDD remain, such as the optimal anatomical placement of the electrodes and the mechanisms of its antidepressant effects. This review summarizes the clinical experience of DBS for treatment resistant depression (TRD). The rationale for the use of DBS for TRD is reviewed in the context of the growing neuroimaging literatures exploring the biomarkers of antidepressant response, and the neural substrates of emotional regulation in both normal and pathological states.

The failure to achieve remission for patients with Major Depressive Disorder (MDD) represents a major public health concern. Inadequately treated depression is associated with higher rates of relapse, poorer quality of life, deleterious personal and societal economic ramifications, as well as increased mortality rates. Unfortunately, only a minority of patients achieves this goal with initial antidepressant treatment and by convention, failure to achieve response after two adequate trials of antidepressant therapy defines "Treatment Resistant Depression" (TRD). Furthermore, results from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) group of studies suggest that approximately 50% of "real world" patients who meet criteria for MDD fail to achieve remission, even after four carefully monitored sequenced treatments.Given these limitations of existing antidepressant medications alone and in combination, together with improved understanding of the neural circuitry of depression, it is not surprising that there is a renewed interest in neuromodulation strategies for TRD.The purpose of this article is to review the evidence for the inclusion of various non-pharmacological, neuromodulatory strategies for TRD. Specifically, information regarding the mechanism, tolerability and efficacy of electroconvulsive therapy (ECT), magnetic seizure therapy (MST), repetitive transcranial magnetic stimulation (rTMS), vagal nerve stimulation (VNS), and deep brain stimulation (DBS) in ameliorating TRD will be presented.Although these treatments are at various stages of clinical development, they represent a new frontier in expanding the treatment options available for individuals with TRD, as well as contributing to a better understanding the neurobiology of depressive disorders.

s / Brain Stimulation 8 (2015) 326e342 329 factors of SITE (vertex or occiput) and TIME (pre/post rTMS).we found a significant SITE x TIME interaction( F(1,9)1⁄45.595, df1⁄41, P1⁄40.042) in the visual short term memory task(DMS) which was due to the fact that performance improved after V1 stimulation (p1⁄40.048) but not after vertex stimulation. In contrast there was no significant interaction effect in the spatial recognition task, indicating that the effect of V1 stimulation was the same as vertex stimulation. There was a significant main effect of TIME (F (1,9)1⁄4 5.795, df1⁄41, P1⁄40.039), due to the fact that performance of both groups declined after rTMS. These findings provide evidence for the significant role of the V1 in visual short-term memory and that rTMS can affect visual shortterm memory and could be use as a tool for improving cognition function and achievement of peak performance in sport.

Traditionally, the therapeutic approach to treatment-resistant depression (TRD) has relied on pharmacotherapy in various sequences and combinations, in addition to evidence-based psychotherapy or electroconvulsive therapy. Despite refinements to the existing therapeutic modalities, there remains a significant subpopulation of severely ill patients with refractory mood disorders who fail to achieve a clinical response despite aggressive psychosocial and biological treatments. Interest in the use of deep brain stimulation (DBS) for treatment-resistant psychiatric illness has emerged in recent years for a number of reasons: 1) as part of a general re-evaluation of both noninvasive and invasive brain stimulation techniques, 2) because of the demonstrated clinical efficacy of DBS for movement disorders, and 3) as a logical consequence of studies defining the functional neurocircuitry of several psychiatric disorders. This review will examine the progress of DBS in the treatment of Parkinson's disease and the potential implications for its use in TRD, as well as the role of the psychiatrist in selection and ongoing management of patients who receive this procedure.

rTMS is an emerging treatment for major depressive disorder (MDD) refractory to medications and psychotherapy. The conventional target for rTMS in MDD is the dorsolateral prefrontal cortex (DLPFC). However, convergent evidence from lesion, stimulation, and neuroimaging studies suggests that the dorsomedial prefrontal cortex (DMPFC) may play a more central role in emotion regulation. We have recently demonstrated robust and potentially superior antidepressant properties for excitatory rTMS of the DMPFC. However, one of the enduring limitations of rTMS is the long duration of each treatment session under conventional protocols, which require ~40 minutes per day over 20-30 sessions for maximum efficacy using conventional 10 Hz stimulation. More recent studies have suggested that theta-burst stimulation (TBS) protocols can achieve stronger and more durable effects in markedly less time. Intermittent theta-burst stimulation (iTBS) generates robust and long-lasting excitatory effects with 600 pulses over ~3 min. Pilot studies have previously reported antidepressant effects with TBS over the DLPFC. However, TBS over the DMPFC has not previously been studied. Here we report robust antidepressant effects for a 7 min course of iTBS, administered bilaterally over the DMPFC with MRI-guidance at 120% resting motor threshold, over 20-30 sessions, in an open-label series of 40 patients with refractory MDD. Safety, efficacy, and tolerability are comparable to a 10 Hz rTMS protocol requiring 30-40 min of treatment. iTBS of the DMPFC may effectively reduce the duration (and cost) of rTMS >4-fold, thus increasing patient capacity per clinic and improving the overall accessibility of rTMS in refractory MDD.

rTMS is currently being explored as a potential adjunctive treatment for anorexia and bulimia nervosa. Previous studies have found, at best, modest efficacy for rTMS in this setting using the conventional target in the dorsolateral prefrontal cortex (DLPFC). However, neuroimaging studies suggest that the dorsomedial prefrontal cortex (DMPFC) may be more central to inhibiting impulsive thoughts and behaviours such as binge and purge episodes. We have previously reported serendipitous rapid, complete, and durable remission of binge and purge behaviours in a patient with severe bulimia nervosa who was undergoing rTMS of the DMPFC for comorbid major depression (Downar et al., 2012). Here we extend this finding in a larger case series of 15 patients with either anorexia or bulimia nervosa and bingeing and purging behaviours refractory to medications and therapy despite several years of treatment. MRI-guided rTMS of the DMPFC (10 Hz stimulation, 120% resting motor threshold, bilateral, 3000 pulses per hemisphere) achieved full remission from binge and purge episodes in a majority of patients, with parallel improvements in mood and anxiety symptoms. Patients with BMI in the normal range showed a more robust response to treatment. Individual cases also spontaneously reported improvement in comorbid impulse control disorder symptoms, such as kleptomania. Individuals with comorbid obsessive-compulsive disorder (OCD) also reported marked improvements in these symptoms. A subset of patients with lower BMIs showed minimal response. rTMS of the DMPFC may represent an effective adjunct to conventional treatment for binge-purge behaviours. A randomized controlled trial of this approach may be warranted.

Patients with Obsessive-Compulsive Disorder (OCD) often show minimal response to either pharmacotherapy or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is being explored as a new treatment for OCD. rTMS targeting the dorsolateral prefrontal cortex (DLPFC) has not shown robust efficacy; however, neuroimaging studies of OCD have shown more consistent volumetric grey matter reductions along the medial rather than the lateral prefrontal cortex, specifically in the dorsomedial prefrontal cortex (DMPFC). rTMS targeting medial motor areas such as the supplementary motor area (SMA) and pre-SMA has shown some efficacy in OCD. However, the DMPFC proper, just anterior to the pre-SMA, has not previously been targeted. We have previously used a novel rTMS technique to target DMPFC with robust effects in refractory depression. Here we apply this technique in an open-label series of 10 consecutive patients with refractory OCD. Under MRI-guidance, patients received bilateral DMPFC-rTMS at 10 Hz, 120% resting motor threshold, 6000 pulses per day for 20 - 30 sessions over 4-6 weeks. Robust improvements were achieved, with YBOCS scores dropping by more than half in the large majority of cases and full remission achieved in several cases. Scores continued dropping after treatment in some cases, suggesting durable improvements in capacity to suppress intrusive thoughts and behaviours. Improvements were durable at 3-6 months. Pre- and post-treatment functional MRI revealed changes in resting-state connectivity to DMPFC following treatment. A sham-controlled trial may be warranted as a next step. If successful, DMPFC-rTMS may represent a new, effective therapeutic option in refractory OCD.

Background Depression is a heterogeneous mental illness. Neurostimulation treatments, by targeting specific nodes within the brain's emotion-regulation network, may be useful both as therapies and as probes for identifying clinically relevant depression subtypes. Methods Here, we applied 20 sessions of magnetic resonance imaging-guided repetitive transcranial magnetic stimulation (rTMS) to the dorsomedial prefrontal cortex in 47 unipolar or bipolar patients with a medication-resistant major depressive episode. Results Treatment response was strongly bimodal, with individual patients showing either minimal or marked improvement. Compared with responders, nonresponders showed markedly higher baseline anhedonia symptomatology (including pessimism, loss of pleasure, and loss of interest in previously enjoyed activities) on item-by-item examination of Beck Depression Inventory-II and Quick Inventory of Depressive Symptomatology ratings. Congruently, on baseline functional magnetic resonance imaging, nonresponders showed significantly lower connectivity through a classical reward pathway comprising ventral tegmental area, striatum, and a region in ventromedial prefrontal cortex. Responders and nonresponders also showed opposite patterns of hemispheric lateralization in the connectivity of dorsomedial and dorsolateral regions to this same ventromedial region. Conclusions The results suggest distinct depression subtypes, one with preserved hedonic function and responsive to dorsomedial rTMS and another with disrupted hedonic function, abnormally lateralized connectivity through ventromedial prefrontal cortex, and unresponsive to dorsomedial rTMS. Future research directly comparing the effects of rTMS at different targets, guided by neuroimaging and clinical presentation, may clarify whether hedonia/reward circuit integrity is a reliable marker for optimizing rTMS target selection.

Background: The dorsolateral prefrontal cortex (DLPFC) is a common target for repetitive transcranial magnetic stimulation (rTMS) in major depression, but the conventional “5 cm rule” misses DLPFC in >1/3 cases. Another heuristic, BeamF3, locates the F3 EEG site from scalp measurements. MRI-guided neuronavigation is more onerous, but can target a specific DLPFC stereotaxic coordinate directly. The concordance between these two approaches has not previously been assessed. Objective: To quantify the discrepancy in scalp site between BeamF3 versus MRI-guided neuronavigation for left DLPFC. Methods: Using 100 pre-treatment MRIs from subjects undergoing left DLPFC-rTMS, we localized the scalp site at minimum Euclidean distance from a target MNI coordinate (X − 38 Y + 44 Z + 26) derived from our previous work. We performed nasion-inion, tragus–tragus, and head-circumference measurements on the same subjects' MRIs, and applied the BeamF3 heuristic. We then compared the distance between BeamF3 and MRI-guided scalp sites. Results: BeamF3-to-MRI-guided discrepancies were