Marc Dubin

Default Mode Network Mechanisms of Transcranial Magnetic Stimulation in Depression

BACKGROUND Repetitive transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for depression, but its underlying mechanism of action remains unknown. Abnormalities in two large-scale neuronal networks-the frontoparietal central executive network (CEN) and the medial prefrontal-medial parietal default mode network (DMN)-are consistent findings in depression and potential therapeutic targets for TMS. Here, we assessed the impact of TMS on activity in these networks and their relation to treatment response. METHODS We used resting state functional magnetic resonance imaging to measure functional connectivity within and between the DMN and CEN in 17 depressed patients, before and after a 5-week course of TMS. Motivated by prior reports, we focused on connectivity seeded from the DLPFC and the subgenual cingulate, a key region closely aligned with the DMN in depression. Connectivity was also compared with a cohort of 35 healthy control subjects. RESULTS Before treatment, functional connectivity in depressed patients was abnormally elevated within the DMN and diminished within the CEN, and connectivity between these two networks was altered. Transcranial magnetic stimulation normalized depression-related subgenual hyperconnectivity in the DMN but did not alter connectivity in the CEN. Transcranial magnetic stimulation also induced anticorrelated connectivity between the DLPFC and medial prefrontal DMN nodes. Baseline subgenual connectivity predicted subsequent clinical improvement. CONCLUSIONS Transcranial magnetic stimulation selectively modulates functional connectivity both within and between the CEN and DMN, and modulation of subgenual cingulate connectivity may play an important mechanistic role in alleviating depression. The results also highlight potential neuroimaging biomarkers for predicting treatment response.

Transcranial Magnetic Stimulation of Left Dorsolateral Prefrontal Cortex Induces Brain Morphological Changes in Regions Associated with a Treatment Resistant Major Depressive Episode: An Exploratory Analysis

BACKGROUND Repetitive transcranial magnetic stimulation (TMS) is an FDA-approved antidepressant treatment but little is known of its mechanism of action. Specifically, downstream effects of TMS remain to be elucidated. OBJECTIVE/HYPOTHESIS This study aims to identify brain structural changes from TMS treatment of a treatment resistant depressive episode through an exploratory analysis. METHODS Twenty-seven subjects in a DSM-IV current major depressive episode and on a stable medication regimen had a 3T magnetic resonance T1 structural scan before and after five weeks of standard TMS treatment to the left dorsolateral prefrontal cortex. Twenty-seven healthy volunteer (HVs) subjects had the same brain MRI acquisition. Voxel-based morphometry was performed using high dimensional non-linear diffusomorphic anatomical registration (DARTEL). RESULTS Six clusters of gray matter volume (GMV) that were lower in pre-treatment MRIs of depressed subjects than in HVs. GMV in four of these regions increased in MDD after TMS treatment by 3.5-11.2%. The four brain regions that changed with treatment were centered in the left anterior cingulate cortex, the left insula, the left superior temporal gyrus and the right angular gyrus. Increases in the anterior cingulate GMV with TMS correlated with improvement in depression severity. CONCLUSIONS To our knowledge, this is the first study of brain structural changes during TMS treatment of depression. The affected brain areas are involved in cognitive appraisal, decision-making and subjective experience of emotion. These effects may have potential relevance for the antidepressant action of TMS.

Prefrontal cortical blood flow predicts response of depression to rTMS.

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for resistant major depressive disorder. The response rate of rTMS for depression is modest, motivating the search for biomarkers predictive of treatment response. METHODS Thirteen patients (mean age 45 years, three males) with current major depression resistant to at least one antidepressant trial in the current episode were treated with a 25 day course of rTMS over the left dorsolateral prefrontal cortex (DLPFC). Resting state cerebral perfusion was measured prior to the first day of treatment and after the final day of treatment. Treatment response was measured using the Hamilton Depression Rating Scale-24 Item (Ham-D). Baseline cerebral perfusion was compared in responders to non-responders. In addition, post-treatment cerebral perfusion was compared to pre-treatment in responders as well as in non-responders. RESULTS Six individuals responded to rTMS. Responders had greater resting state blood flow in the left DLPFC (the target site) at baseline compared to non-responders. Non-responders showed greater baseline activity in the left medial frontal cortex. Neither group exhibited changes during treatment, nor did the combined group. LIMITATIONS This study suffers from low sample size and resulting small responder and non-responder subgroups. The sample was not balanced to gender. A normal control group was not included. CONCLUSIONS We believe this is the first study to compare pre-treatment brain perfusion patterns of depressed individuals who responded to rTMS to those who did not. Our results suggest stronger left DLPFC perfusion in responders and stronger medial prefrontal perfusion in non-responders both at baseline and post-treatment. These results await confirmation in a larger, prospective, placebo-controlled study.

Identification of a circuit-based endophenotype for familial depression

Frontal and parietal lesions may cause depression, and cortical thinning of the right frontal and parietal lobes has been shown to be a marker of risk for familial major depression. We studied biological offspring within a three-generation cohort, in which risk was defined by the depression status of the first generation, to identify regional volume differences associated with risk for depression throughout the cerebrum. We found reduced frontal and parietal white matter volumes in the high-risk group, including in persons without any personal history of depression, suggesting that hypoplasia of frontal and parietal white matter is an endophenotype for familial depression. In addition, white matter volumes in these regions correlated with current severity of symptoms of depression, inattention, and impulsivity. White matter volumes also correlated strongly with the degree of thinning in the right parietal cortex. These findings support a model of pathogenesis in which hypoplasia within a neural network for attention and emotional processing predisposes to depression.

Age-Related Repetitive Transcranial Magnetic Stimulation Effects on Executive Function in Depression: A Systematic Review

OBJECTIVE The aims of the current review were to: 1) examine whether the rTMS effects on executive function increase as age advances; 2) to examine the potential of rTMS to remediate executive function in older depressed patients; and 3) to assess the relationship between the executive function and mood benefits from rTMS in depression. METHODS Randomized or matched-groups, blind, sham-controlled studies (12 studies, 347 participants) on excitatory rTMS applied to left DLPFC in depression were reviewed. RESULTS A series of meta-regressions found no evidence of greater rTMS effects on executive functions as age advances. Similarly, meta-analyses showed no significant rTMS effects on executive functions in older depressed individuals. However, meta-regression analyses showed that the size of the executive function benefits from rTMS in depression are positively related to the effect size of mood symptom reduction. Despite its correlational nature, this finding is consistent with the idea that improvement in executive function may play a critical role in depression recovery. CONCLUSIONS The authors consider these findings preliminary because of the modest number of available studies. Based on a qualitative review, the authors describe methodologic modifications that may increase rTMS efficacy for both executive functions and mood in late-life depression.

Improving the correction of eddy current-induced distortion in diffusion-weighted images by excluding signals from the cerebral spinal fluid

Iterative cross-correlation (ICC) is the most popularly used schema for correcting eddy current (EC)-induced distortion in diffusion-weighted imaging data, however, it cannot process data acquired at high b-values. We analyzed the error sources and affecting factors in parameter estimation, and propose an efficient algorithm by expanding the ICC framework with a number of techniques: (1) pattern recognition for excluding brain ventricles; (2) ICC with the extracted ventricle for parameter initialization; (3) gradient-based entropy correlation coefficient (GECC) for optimal and finer registration. Experiments demonstrated that our method is robust with high accuracy and error tolerance, and outperforms other ICC-family algorithms and popular approaches currently in use.

Network-Guided Transcranial Magnetic Stimulation for Depression

Purpose of ReviewFirst, we will identify candidate predictive biomarkers of antidepressant response of TMS based on the neuroimaging literature. Next, we will review the effects of TMS on networks involved in depression. Finally, we will discuss ways in which our current understanding of network engagement by TMS may be used to optimize its antidepressant effect.Recent FindingsThe past few years has seen significant interest in the antidepressant mechanisms of TMS. Studies using functional neuroimaging and neurochemical imaging have demonstrated engagement of networks known to be important in depression. Current evidence supports a model whereby TMS normalizes network function gradually over the course of several treatments. This may, in turn, mediate its antidepressant effect.SummaryOne strategy to optimize the antidepressant effect of TMS is to more precisely target networks relevant in depression. We propose methods to achieve this using functional and neurochemical imaging.

A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) was approved in 2008 in the United States, and there are relatively few studies describing its use in regular clinical practice since approval. METHODS From April 2011 to October 2014, ten sites within the National Network of Depression Centers (NNDC) provided data on 62 evaluable patients with a depressive episode. Treatment was determined naturalistically. Response was assessed by the Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR) as the primary outcome, and the Patient Health Questionnaire-9 (PHQ-9) and the clinician-rated Clinical Global Impression (CGI) as secondary depression measures. RESULTS Enrolled patients exhibited significant treatment resistance, with 70.2% reporting more than 4 prior depressive episodes. Most patients received treatment with standard parameters (10Hz over the left dorsolateral prefrontal cortex), although 22.6% of the patients received 1 or 5Hz stimulation at some point. Over 6 weeks of treatment, response and remission rates were 29.4% and 5.9%, respectively, for the QIDS-SR; 39.2% and 15.7%, respectively, for the PHQ-9; and 50.9% and 17.9%, respectively, for the CGI. Moderator analyses revealed no effect of prior depressive episodes, history of ECT or gender, although early life stress predicted a better response to rTMS therapy. LIMITATIONS The study was an open-label, registry trial, with relatively coarse clinical data, reflecting practice only in academic, depression-specialty centers. Because of the relatively small size and heterogeneity of the sample, type 2 errors are possible and positive findings are in need of replication. CONCLUSION rTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies.

A Woman With Major Depression With Psychotic Features Requesting a Termination of Pregnancy

Case Presentation Ms. A, a married, pregnant 31-year-old woman with a history of major depressive disorder, was admitted to an inpatient psychiatric unit with dysphoria, ruminative worries about her work performance, difficulty sleeping,doubtsaboutherpotentialtobeagoodmother, and suicidal impulses to jump out of her apartment window. On the day before admission, she impulsively punched herself in the abdomen with the hope of inducing a miscarriage. Acti ng on the advice of her out

Imaging TMS: antidepressant mechanisms and treatment optimization

Abstract With the antidepressant efficacy of Transcranial Magnetic Stimulation well-established by several meta-analyses, there is growing interest in its mechanism of action. TMS has been shown to engage, and in some cases, normalize functional connectivity and neurotransmitter levels within networks dysfunctional in the depressed state. In this review, I will suggest candidate biomarkers, based on neuroimaging, that may be predictive of response to TMS. I will then review the effects of TMS on networks and neurotransmitter systems involved in depression. Throughout, I will also discuss how our current understanding of response predication and network engagement may be used to personalize treatment and optimize its efficacy.