Mahendra T. Bhati

All Publications

• The genetics of severe depression. Molecular psychiatry Franklin, C. E., Achtyes, E., Altinay, M., Bailey, K., Bhati, M. T., Carr, B. R., Conroy, S. K., Husain, M. M., Khurshid, K. A., Lencz, T., McDonald, W. M., Mickey, B. J., Murrough, J., Nestor, S., Nickl-Jockschat, T., Nikayin, S., Reeves, K., Reti, I. M., Selek, S., Sanacora, G., Trapp, N. T., Viswanath, B., Wright, J. H., Sullivan, P., Zandi, P. P., Potash, J. B. 2024

  Abstract

  Genome-wide association studies (GWASs) of major depressive disorder (MDD) have recently achieved extremely large sample sizes and yielded substantial numbers of genome-wide significant loci. Because of the approach to ascertainment and assessment in many of these studies, some of these loci appear to be associated with dysphoria rather than with MDD, potentially decreasing the clinical relevance of the findings. An alternative approach to MDD GWAS is to focus on the most severe forms of MDD, with the hope that this will enrich for loci of larger effect, rendering their identification plausible, and providing potentially more clinically actionable findings. Here we review the genetics of severe depression by using clinical markers of severity including: age of onset, recurrence, degree of impairment, and treatment with ECT. There is evidence for increased family-based and Single Nucleotide Polymorphism (SNP)-based estimates of heritability in recurrent and early-onset illness as well as severe functional impariment. GWAS have been performed looking at severe forms of MDD and a few genome-wide loci have been identified. Several whole exome sequencing studies have also been performed, identifying associated rare variants. Although these findings have not yet been rigorously replicated, the elevated heritability seen in severe MDD phenotypes suggests the value of pursuing additional genome-wide interrogation of samples from this population. The challenge now is generating a cohort of adequate size with consistent phenotyping that will allow for careful and robust classifications and distinctions to be made. We are currently pursuing such a strategy in our 50-site worldwide Gen-ECT-ics consortium.

  View details for DOI 10.1038/s41380-024-02731-1

  View details for PubMedID 39406997

  View details for PubMedCentralID 3387670

• Frontostriatal salience network expansion in individuals in depression. Nature Lynch, C. J., Elbau, I. G., Ng, T., Ayaz, A., Zhu, S., Wolk, D., Manfredi, N., Johnson, M., Chang, M., Chou, J., Summerville, I., Ho, C., Lueckel, M., Bukhari, H., Buchanan, D., Victoria, L. W., Solomonov, N., Goldwaser, E., Moia, S., Caballero-Gaudes, C., Downar, J., Vila-Rodriguez, F., Daskalakis, Z. J., Blumberger, D. M., Kay, K., Aloysi, A., Gordon, E. M., Bhati, M. T., Williams, N., Power, J. D., Zebley, B., Grosenick, L., Gunning, F. M., Liston, C. 2024

  Abstract

  Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset1. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2-4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

  View details for DOI 10.1038/s41586-024-07805-2

  View details for PubMedID 39232159

  View details for PubMedCentralID 9330277

• Dual Treatment of Refractory Focal Epilepsy and Obsessive-Compulsive Disorder With Intracranial Responsive Neurostimulation. Neurology. Clinical practice Kellogg, M. A., Ernst, L. D., Spencer, D. C., Datta, P., Klein, E., Bhati, M. T., Shivacharan, R. S., Nho, Y., Barbosa, D. A., Halpern, C. H., Raslan, A. 2024; 14 (4): e200318

  Abstract

  Purpose of the Review: Intracranial neurostimulation is a well-established treatment of neurologic conditions such as drug-resistant epilepsy (DRE) and movement disorders, and there is emerging evidence for using deep brain stimulation to treat obsessive-compulsive disorder (OCD) and depression. Nearly all published reports of intracranial neurostimulation have focused on implanting a single device to treat a single condition. The purpose of this review was to educate neurology clinicians on the background literature informing dual treatment of 2 comorbid neuropsychiatric conditions epilepsy and OCD, discuss ethical and logistical challenges to dual neuropsychiatric treatment with a single device, and demonstrate the promise and pitfalls of this approach through discussion of the first-in-human closed-looped responsive neurostimulator (RNS) implanted to treat both DRE (on-label) and OCD (off-label).Recent Findings: We report the first implantation of an intracranial closed-loop neurostimulation device (the RNS system) with the primary goal of treating DRE and a secondary exploratory goal of managing treatment-refractory OCD. The RNS system detects electrophysiologic activity and delivers electrical stimulation through 1 or 2 electrodes implanted into a patient's seizure-onset zones (SOZs). In this case report, we describe a patient with treatment-refractory epilepsy and OCD where the first lead was implanted in the right superior temporal gyrus to target the most active SOZ based on stereotactic EEG (sEEG) recordings and semiology. The second lead was implanted to target the right anterior peri-insular region (a secondary SOZ on sEEG) with the distal-most contacts in the right nucleus accumbens, a putative target for OCD neurostimulation treatment. The RNS system was programmed to detect and record the unique electrophysiologic signature of both the patient's seizures and compulsions and then deliver tailored electrical pulses to disrupt the pathologic circuitry.Summary: Dual treatment of refractory focal epilepsy and OCD with an intracranial closed-loop neurostimulation device is feasible, safe, and potentially effective. However, there are logistical challenges and ethical considerations to this novel approach to treatment, which require complex care coordination by a large multidisciplinary team.

  View details for DOI 10.1212/CPJ.0000000000200318

  View details for PubMedID 38846467

• Proposed curriculum for an interventional psychiatry fellowship program Interventional Psychiatry: Road to Novel Therapeutics Lan, L., Raj, K. S., Bhati, M. Elsevier. 2024: 17-28
• Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion. Neuron Nho, Y. H., Rolle, C. E., Topalovic, U., Shivacharan, R. S., Cunningham, T. N., Hiller, S., Batista, D., Feng, A., Espil, F. M., Kratter, I. H., Bhati, M. T., Kellogg, M., Raslan, A. M., Williams, N. R., Garnett, J., Pesaran, B., Oathes, D. J., Suthana, N., Barbosa, D. A., Halpern, C. H. 2023

  Abstract

  Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.

  View details for DOI 10.1016/j.neuron.2023.09.034

  View details for PubMedID 37865084

• Pilot study of responsive nucleus accumbens deep brain stimulation for loss-of-control eating. Nature medicine Shivacharan, R. S., Rolle, C. E., Barbosa, D. A., Cunningham, T. N., Feng, A., Johnson, N. D., Safer, D. L., Bohon, C., Keller, C., Buch, V. P., Parker, J. J., Azagury, D. E., Tass, P. A., Bhati, M. T., Malenka, R. C., Lock, J. D., Halpern, C. H. 2022

  Abstract

  Cravings that precede loss of control (LOC) over food consumption present an opportunity for intervention in patients with the binge eating disorder (BED). In this pilot study, we used responsive deep brain stimulation (DBS) to record nucleus accumbens (NAc) electrophysiology during food cravings preceding LOC eating in two patients with BED and severe obesity (trial registration no. NCT03868670). Increased NAc low-frequency oscillations, prominent during food cravings, were used to guide DBS delivery. Over 6 months, we observed improved self-control of food intake and weight loss. These findings provide early support for restoring inhibitory control with electrophysiologically-guided NAc DBS. Further work with increased sample sizes is required to determine the scalability of this approach.

  View details for DOI 10.1038/s41591-022-01941-w

  View details for PubMedID 36038628

• Aberrant impulse control circuitry in obesity. Molecular psychiatry Barbosa, D. A., Kuijper, F. M., Duda, J., Wang, A. R., Cartmell, S. C., Saluja, S., Cunningham, T., Shivacharan, R. S., Bhati, M. T., Safer, D. L., Lock, J. D., Malenka, R. C., de Oliveira-Souza, R., Williams, N. R., Grossman, M., Gee, J. C., McNab, J. A., Bohon, C., Halpern, C. H. 2022

  Abstract

  The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

  View details for DOI 10.1038/s41380-022-01640-5

  View details for PubMedID 35697760

• National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy. The journal of ECT Zandi, P. P., Morreale, M., Reti, I. M., Maixner, D. F., McDonald, W. M., Patel, P. D., Achtyes, E., Bhati, M. T., Carr, B. R., Conroy, S. K., Cristancho, M., Dubin, M. J., Francis, A., Glazer, K., Ingram, W., Khurshid, K., McClintock, S. M., Pinjari, O. F., Reeves, K., Rodriguez, N. F., Sampson, S., Seiner, S. J., Selek, S., Sheline, Y., Smetana, R. W., Soda, T., Trapp, N. T., Wright, J. H., Husain, M., Weiner, R. D. 2022

  Abstract

  Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

  View details for DOI 10.1097/YCT.0000000000000840

  View details for PubMedID 35704844

• Interventional Neuropsychiatry Concise Guide to Neuropsychiatry and Behavioral Neurology Coetzee, J. P., Kratter, I. H., Bhati, M. T., Williams, N. R. American Psychiatric Association Publishing. 2022; 3: 439-449
• Natural language processing methods are sensitive to sub-clinical linguistic differences in schizophrenia spectrum disorders. NPJ schizophrenia Tang, S. X., Kriz, R., Cho, S., Park, S. J., Harowitz, J., Gur, R. E., Bhati, M. T., Wolf, D. H., Sedoc, J., Liberman, M. Y. 2021; 7 (1): 25

  Abstract

  Computerized natural language processing (NLP) allows for objective and sensitive detection of speech disturbance, a hallmark of schizophrenia spectrum disorders (SSD). We explored several methods for characterizing speech changes in SSD (n=20) compared to healthy control (HC) participants (n=11) and approached linguistic phenotyping on three levels: individual words, parts-of-speech (POS), and sentence-level coherence. NLP features were compared with a clinical gold standard, the Scale for the Assessment of Thought, Language and Communication (TLC). We utilized Bidirectional Encoder Representations from Transformers (BERT), a state-of-the-art embedding algorithm incorporating bidirectional context. Through the POS approach, we found that SSD used more pronouns but fewer adverbs, adjectives, and determiners (e.g., "the," "a,"). Analysis of individual word usage was notable for more frequent use of first-person singular pronouns among individuals with SSD and first-person plural pronouns among HC. There was a striking increase in incomplete words among SSD. Sentence-level analysis using BERT reflected increased tangentiality among SSD with greater sentence embedding distances. The SSD sample had low speech disturbance on average and there was no difference in group means for TLC scores. However, NLP measures of language disturbance appear to be sensitive to these subclinical differences and showed greater ability to discriminate between HC and SSD than a model based on clinical ratings alone. These intriguing exploratory results from a small sample prompt further inquiry into NLP methods for characterizing language disturbance in SSD and suggest that NLP measures may yield clinically relevant and informative biomarkers.

  View details for DOI 10.1038/s41537-021-00154-3

  View details for PubMedID 33990615

• Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression: A Decade of Clinical Follow-Up. The Journal of clinical psychiatry Hitti, F. L., Cristancho, M. A., Yang, A. I., O'Reardon, J. P., Bhati, M. T., Baltuch, G. H. 2021; 82 (6)

  Abstract

  Objective: Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD) that has shown variable efficacy. This report describes long-term outcomes of DBS for TRD.Methods: A consecutive series of 8 patients with TRD were implanted with ventral capsule/ventral striatum (VC/VS) DBS systems as part of the Reclaim clinical trial. Outcomes from 2009 to 2020 were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Demographic information, MADRS scores, and data on adverse events were collected via retrospective chart review. MADRS scores were integrated over time using an area-under-the-curve technique.Results: This cohort of patients had severe TRD-all had failed trials of ECT, and all had failed a minimum of 4 adequate medication trials. Mean ± SD follow-up for patients who continued to receive stimulation was 11.0 ± 0.4 years (7.8 ± 4.3 years for the entire cohort). At last follow-up, mean improvement in MADRS scores was 44.9% ± 42.7%. Response (≥ 50% improvement) and remission (MADRS score ≤ 10) rates at last follow-up were 50% and 25%, respectively. Two patients discontinued stimulation due to lack of efficacy, and another patient committed suicide after stimulation was discontinued due to recurrent mania. The majority of the cohort (63%) continued to receive stimulation through the end of the study.Conclusions: While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this small open-label study demonstrates that some patients achieve meaningful and sustained clinical benefit. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including patient selection, integrative outcome measures, and long-term observation is essential for future trial design.Trial Registration: ClinicalTrials.gov identifier: NCT00837486.

  View details for DOI 10.4088/JCP.21m13973

  View details for PubMedID 34670026

• Deep Transcranial Magnetic Stimulation Combined With Brief Exposure for Posttraumatic Stress Disorder: A Prospective Multisite Randomized Trial. Biological psychiatry Isserles, M., Tendler, A., Roth, Y., Bystritsky, A., Blumberger, D. M., Ward, H., Feifel, D., Viner, L., Duffy, W., Zohar, J., Keller, C. J., Bhati, M. T., Etkin, A., George, M. S., Filipcic, I., Lapidus, K., Casuto, L., Vaishnavi, S., Stein, A., Deutsch, L., Deutsch, F., Morales, O., Daskalakis, Z. J., Zangen, A., Ressler, K. J. 2021

  Abstract

  Posttraumatic stress disorder (PTSD) is both prevalent and debilitating. While deep transcranial magnetic stimulation (dTMS) has shown preliminary efficacy, exposure therapy remains the most efficacious, though limited, treatment in PTSD. The medial prefrontal cortex (mPFC) is implicated in extinction learning, suggesting that concurrent mPFC stimulation may enhance exposure therapy. In this randomized controlled multicenter trial, the efficacy and safety of mPFC dTMS combined with a brief exposure procedure were studied in patients with PTSD.Immediately following exposure to their trauma narrative, 125 outpatients were randomly assigned to receive dTMS or sham. Twelve sessions were administered over 4 weeks, with a primary end point of change in 5-week Clinician-Administered PTSD Scale for DSM-5 score. This clinical study did not include biological markers.Clinician-Administered PTSD Scale for DSM-5 score improved significantly in both groups at 5 weeks, though the improvement was smaller in the dTMS group (16.32) compared with the sham group (20.52; p = .027). At 9 weeks, improvement continued in Clinician-Administered PTSD Scale for DSM-5 score in both groups but remained smaller in dTMS (19.0) versus sham (24.4; p = .024).Both groups showed significant PTSD symptom improvement, possibly from the brief script-driven imagery exposure. While our design was unable to rule out placebo effects, the magnitude and durability of improvement suggest that repeated ultrabrief exposure therapy alone may be an effective treatment for PTSD, warranting additional study. The surprising and unexpected effect in the dTMS group also suggests that repeated mPFC stimulation with the H7 coil may interfere with trauma memory-mediated extinction. Our results provide new insight for dTMS approaches for possible future avenues to treat PTSD.

  View details for DOI 10.1016/j.biopsych.2021.04.019

  View details for PubMedID 34274108

• Decreased Speech Coherence Captured by Novel Natural Language Processing Methods in Two Cohorts of Individuals With Schizophrenia Tang, S., Kriz, R., Cho, S., Sedoc, J., Park, S., Harowitz, J., Bhati, M., Gur, R., Wolf, D., Liberman, M. ELSEVIER SCIENCE INC. 2020: S379–S380

  View details for Web of Science ID 000535308201172

• Brain-Responsive Neurostimulation for Loss of Control Eating: Early Feasibility Study. Neurosurgery Wu, H. n., Adler, S. n., Azagury, D. E., Bohon, C. n., Safer, D. L., Barbosa, D. A., Bhati, M. T., Williams, N. R., Dunn, L. B., Tass, P. A., Knutson, B. D., Yutsis, M. n., Fraser, A. n., Cunningham, T. n., Richardson, K. n., Skarpaas, T. L., Tcheng, T. K., Morrell, M. J., Roberts, L. W., Malenka, R. C., Lock, J. D., Halpern, C. H. 2020

  Abstract

  Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study.To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity.This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed.Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation.This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.

  View details for DOI 10.1093/neuros/nyaa300

  View details for PubMedID 32717033

• Comparison of head pose tracking methods for mixed-reality neuronavigation for transcranial magnetic stimulation SPIE Medical Imaging Sathyanarayana, S., Leuze, C., Hargreaves, B., Daniel, B. L., Wetzstein, G., Etkin, A., Bhati, M. T., McNab, J. A. 2020

  View details for DOI 10.1117/12.2547917

• Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: a meta-analytic study JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Kumar, K. K., Appelboom, G., Lamsam, L., Caplan, A. L., Williams, N. R., Bhati, M. T., Stein, S. C., Halpern, C. H. 2019; 90 (4): 469–73

  View details for DOI 10.1136/jnnp-2018-319318

  View details for Web of Science ID 000471115600019

• MR-Guided Focused Ultrasound Versus Radiofrequency Capsulotomy for Treatment-Refractory Obsessive-Compulsive Disorder: A Cost-Effectiveness Threshold Analysis FRONTIERS IN NEUROSCIENCE Kumar, K. K., Bhati, M. T., Ravikumar, V. K., Ghanouni, P., Stein, S. C., Halpern, C. H. 2019; 13

  View details for DOI 10.3389/fnins.2019.00066

  View details for Web of Science ID 000458081000001

• Adjunctive repetitive transcranial magnetic stimulation delivers superior quality of life for focal epilepsy compared to anti-epileptic drugs: A meta-analytic utility prediction study. Brain stimulation Mahajan, U. V., Parker, J. J., Williams, N. R., Bhati, M. T., Ku, S. n., Grant, G. n., Fisher, R. S., Stein, S. C., Halpern, C. H. 2019

  View details for DOI 10.1016/j.brs.2019.12.006

  View details for PubMedID 31874798

• Brain Stimulation Therapies AMERICAN PSYCHIATRIC ASSOCIATION PUBLISHING TEXTBOOK OF PSYCHIATRY, 7TH EDITION Keller, C., Bhati, M. T., Downar, J., Etkin, A., Roberts, L. W. 2019: 861–98

  View details for Web of Science ID 000550979400032

• Naturalistic Clinical Monitoring of rTMS-Induced Plasticity With TMS-EEG Keller, C., Wu, W., Sarhadi, K., Zhang, Y., Kerwin, L., Bhati, M., Etkin, A. ELSEVIER SCIENCE INC. 2018: S195

  View details for Web of Science ID 000432466300487

• Deep Brain Stimulation for Alzheimer's Disease: Ethical Challenges for Clinical Research. Journal of Alzheimer's disease : JAD Siegel, A. M., Barrett, M. S., Bhati, M. T. 2017; 56 (2): 429-439

  Abstract

  Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer's disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment.

  View details for DOI 10.3233/JAD-160356

  View details for PubMedID 27983548

• Deciphering deep brain stimulation for depression. The lancet. Psychiatry Bhati, M. T., Halpern, C. H. 2017

  View details for PubMedID 28988905

• A naturalistic, multi-site study of repetitive transcranial magnetic stimulation therapy for depression. Journal of affective disorders Taylor, S. F., Bhati, M. T., Dubin, M. J., Hawkins, J. M., Lisanby, S. H., Morales, O., Reti, I. M., Sampson, S., Short, E. B., Spino, C., Watcharotone, K., Wright, J. 2016; 208: 284-290

  Abstract

  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.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.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.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.rTMS demonstrates effectiveness in clinical practice within the NNDC, although remission rates appear slightly lower in comparison with other recent naturalistic studies.

  View details for DOI 10.1016/j.jad.2016.08.049

  View details for PubMedID 27794252

• Cognitive outcome after ventral capsule/ventral striatum stimulation for treatment-resistant major depression. Journal of neurology, neurosurgery, and psychiatry Kubu, C. S., Brelje, T., Butters, M. A., Deckersbach, T., Malloy, P., Moberg, P., Tröster, A. I., Williamson, E., Baltuch, G. H., Bhati, M. T., Carpenter, L. L., Dougherty, D. D., Howland, R. H., Rezai, A. R., Malone, D. A. 2016

  Abstract

  We report the neuropsychological outcome of 25 patients with treatment-resistant major depressive disorder (TRD) who participated in an Institutional Review Board (IRB)-approved randomised double-blind trial comparing active to sham deep brain stimulation (DBS) in the anterior limb of the ventral capsule/ventral striatum (VC/VS).Participants were randomised to active (n=12) versus sham (n=13) DBS for 16 weeks. Data were analysed at the individual and group levels. Group differences were analysed using repeated measures ANOVAs. Relationships between depression severity and cognition were examined using partial correlations. The false discovery rate method controlled for multiple analyses.No significant interactions comparing active versus sham stimulation over time were evident. Change in depression was unrelated to change in neuropsychological measures. Twenty patients declined by ≥1 SD on at least one measure (41.3% of declines occurred in active group participants; 63.0% in older participants regardless of stimulation status). Twenty-two patients exhibited improvements >1 SD on neuropsychological measures (47.7% in the active group; 63.1% in younger participants).These data suggest that VC/VS DBS in patients with TRD does not significantly affect neuropsychological function. Age at surgery, regardless of stimulation status, may be related to cognitive outcome at the individual patient level.NCT00837486; Results.

  View details for DOI 10.1136/jnnp-2016-313803

  View details for PubMedID 27659923

• A Commentary on Attitudes Towards Deep Brain Stimulation for Addiction. Journal of neurology & neuromedicine Lee, K. E., Bhati, M. T., Halpern, C. H. 2016; 1 (8): 1–3

  Abstract

  Deep brain stimulation (DBS) has proven to be an effective treatment for neurologic disorders such as Parkinson's disease, and is currently being investigated as a therapy for psychiatric diseases such as addiction, major depressive disorder, and obsessive compulsive disorder. In this commentary, we review and discuss the findings presented in the Letter to the Editor entitled "Attitudes towards treating addiction with deep brain stimulation," written by Ali et al(1). The survey presented in this Letter reported general approval for examining the effects of DBS on addictive disorders in a clinical trial, but highlighted critical areas of concern including informed consent, patient autonomy, appropriate medical practice, passing of clinical trial milestones, and implications on law enforcement.

  View details for PubMedID 28620655

• A Randomized Sham-Controlled Trial of Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Chronic Treatment-Resistant Depression BIOLOGICAL PSYCHIATRY Dougherty, D. D., Rezai, A. R., Carpenter, L. L., Howland, R. H., Bhati, M. T., O'Reardon, J. P., Eskandar, E. N., Baltuch, G. H., Machado, A. D., Kondziolka, D., Cusin, C., Evans, K. C., Price, L. H., Jacobs, K., Pandya, M., Denko, T., Tyrka, A. R., Brelje, T., Deckersbach, T., Kubu, C., Malone, D. A. 2015; 78 (4): 240-248

  Abstract

  Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published.Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery-Åsberg Depression Rating Scale from baseline.There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively.The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed.

  View details for DOI 10.1016/j.biopsych.2014.11.023

  View details for Web of Science ID 000358084200010

  View details for PubMedID 25726497

• Efficacy and Safety of Low-field Synchronized Transcranial Magnetic Stimulation (sTMS) for Treatment of Major Depression BRAIN STIMULATION Leuchter, A. F., Cook, I. A., Feifel, D., Goethe, J. W., Husain, M., Carpenter, L. L., Thase, M. E., Krystal, A. D., Philip, N. S., Bhati, M. T., Burke, W. J., Howland, R. H., Sheline, Y. I., Aaronson, S. T., Iosifescu, D. V., O'Reardon, J. P., Gilmer, W. S., Jain, R., Burgoyne, K. S., Phillips, B., Manberg, P. J., Massaro, J., Hunter, A. M., Lisanby, S. H., George, M. S. 2015; 8 (4): 787-794

  Abstract

  Transcranial Magnetic Stimulation (TMS) customarily uses high-field electromagnets to achieve therapeutic efficacy in Major Depressive Disorder (MDD). Low-field magnetic stimulation also may be useful for treatment of MDD, with fewer treatment-emergent adverse events.To examine efficacy, safety, and tolerability of low-field magnetic stimulation synchronized to an individual's alpha frequency (IAF) (synchronized TMS, or sTMS) for treatment of MDD.Six-week double-blind sham-controlled treatment trial of a novel device that used three rotating neodymium magnets to deliver sTMS treatment. IAF was determined from a single-channel EEG prior to first treatment. Subjects had baseline 17-item Hamilton Depression Rating Scale (HamD17) ≥ 17.202 subjects comprised the intent-to-treat (ITT) sample, and 120 subjects completed treatment per-protocol (PP). There was no difference in efficacy between active and sham in the ITT sample. Subjects in the PP sample (N = 59), however, had significantly greater mean decrease in HamD17 than sham (N = 60) (-9.00 vs. -6.56, P = 0.033). PP subjects with a history of poor response or intolerance to medication showed greater improvement with sTMS than did treatment-naïve subjects (-8.58 vs. -4.25, P = 0.017). Efficacy in the PP sample reflects exclusion of subjects who received fewer than 80% of scheduled treatments or were inadvertently treated at the incorrect IAF; these subgroups failed to separate from sham. There was no difference in adverse events between sTMS and sham, and no serious adverse events attributable to sTMS.Results suggest that sTMS may be effective, safe, and well tolerated for treating MDD when administered as intended.

  View details for DOI 10.1016/j.brs.2015.05.005

  View details for Web of Science ID 000357542100014

  View details for PubMedID 26143022

• Defining Psychosis: The Evolution of DSM-5 Schizophrenia Spectrum Disorders CURRENT PSYCHIATRY REPORTS Bhati, M. T. 2013; 15 (11)

  Abstract

  Descriptions of mental illness exist throughout recorded history. However, until the mid-twentieth century, there was no standard nosology or diagnostic standard for mental disorders. This limited understanding of these disorders and development of better treatments. As conditions such as dementia praecox and schizophrenia were being described, collaborative efforts were made in the twentieth century to develop the first Diagnostic and Statistical Manual of Mental Disorders (DSM). This review provides an overview of the history of psychiatric diagnosis with a focus on the history of schizophrenia as a diagnosis in the DSM. DSM-5 updates to diagnostic criteria for schizophrenia and related disorders are provided. Limitations to diagnostic validity and reliability are discussed in addition to changes in diagnostic approaches to schizophrenia spectrum and other psychotic disorders in an effort to improve diagnostic validity and reliability. The DSM-5 reflects the culmination of an ongoing collaborative effort to improve the diagnosis of mental disorders, and future research in Research Domain Criteria (RDoC) will help provide convergent validity when understanding and treating mental illnesses.

  View details for DOI 10.1007/s11920-013-0409-9

  View details for Web of Science ID 000326187300006

  View details for PubMedID 24057160

• Effect of retrieval effort and switching demand on fMRI activation during semantic word generation in schizophrenia SCHIZOPHRENIA RESEARCH Ragland, J. D., Moelter, S. T., Bhati, M. T., Valdez, J. N., Kohlerc, C. G., Siegel, S. J., Gur, R. C., Gur, R. E. 2008; 99 (1-3): 312-323

  Abstract

  Verbal fluency deficits in schizophrenia are difficult to interpret because the tasks are multi-factorial and groups differ in total words generated. We manipulated retrieval and switching demands by requiring alternation between over-learned sequences in which retrieval is relatively automatic (OS) and semantic categories requiring increased retrieval effort (SC). Controlled processing was also manipulated by including switching and non-switching conditions, and formal thought disorder (FTD) was assessed with the communication disorders index (CDI). The OS/SC semantic fluency paradigm was administered during fMRI to 13 patients with schizophrenia and 14 matched controls. Images were acquired on a 3 Tesla Siemens scanner using compressed image acquisition to allow for cued overt word production. Subjects alternated between OS, SC, OS-switch, SC-switch, and baseline blocks. Images were pre-processed in SPM-2, and a two-stage random effects analysis tested within and between group contrasts. There were no group performance differences. fMRI analysis did not reveal any group differences during the OS non-switching condition. Both groups produced expected activation in bilateral prefrontal and inferior parietal regions. However, during the SC condition patients had greater activation than controls in left prefrontal, right anterior cingulate, right superior temporal, bilateral thalamus, and left parietal regions. There was also evidence of patient over-activation in prefrontal, superior temporal, superior parietal, and visual association areas when a switching component was added. FTD was negatively correlated with BOLD response in the right anterior cingulate, cuneus and superior frontal gyrus during increased retrieval demand, and positively correlated with fMRI activation in the left lingual gyrus, right fusiform gyrus and left superior parietal lobule during increased switching demand. These results indicate that patients are able to successfully perform effortful semantic fluency tasks during non-speeded conditions. When retrieval is relatively automatic there does not appear to be an effect of schizophrenia on fMRI response. However, when retrieval and controlled processing demands increase, patients have greater activation than controls despite unimpaired task performance. This inefficient BOLD response may explain why patients are slower and less accurate on standard self-paced fluency tasks.

  View details for Web of Science ID 000254306600037

  View details for PubMedID 18155880

• Facial emotion recognition in schizophrenia: When and why does it go awry? SCHIZOPHRENIA RESEARCH Turetsky, B. I., Kohler, C. G., Indersmitten, T., Bhati, M. T., Charbonnier, D., Gur, R. C. 2007; 94 (1-3): 253-263

  Abstract

  Schizophrenia patients demonstrate impaired emotional processing that may be due, in part, to impaired facial emotion recognition. This study examined event-related potential (ERP) responses to emotional faces in schizophrenia patients and controls to determine when, in the temporal processing stream, patient abnormalities occur.16 patients and 16 healthy control participants performed a facial emotion recognition task. Very sad, somewhat sad, neutral, somewhat happy, and very happy faces were each presented for 100 ms. Subjects indicated whether each face was "Happy", "Neutral", or "Sad". Evoked potential data were obtained using a 32-channel EEG system.Controls performed better than patients in recognizing facial emotions. In patients, better recognition of happy faces correlated with less severe negative symptoms. Four ERP components corresponding to the P100, N170, N250, and P300 were identified. Group differences were noted for the N170 "face processing" component that underlies the structural encoding of facial features, but not for the subsequent N250 "affect modulation" component. Higher amplitude of the N170 response to sad faces was correlated with less severe delusional symptoms. Although P300 abnormalities were found, the variance of this component was explained by the earlier N170 response.Patients with schizophrenia demonstrate abnormalities in early visual encoding of facial features that precedes the ERP response typically associated with facial affect recognition. This suggests that affect recognition deficits, at least for happy and sad discrimination, are secondary to faulty structural encoding of faces. The association of abnormal face encoding with delusions may denote the physiological basis for clinical misidentification syndromes.

  View details for DOI 10.1016/j.schres.2007.05.001

  View details for Web of Science ID 000248638500032

  View details for PubMedID 17583481

• Clinical manifestations, diagnosis, and empirical treatments for catatonia. Psychiatry (Edgmont (Pa. : Township)) Bhati, M. T., Datto, C. J., O'Reardon, J. P. 2007; 4 (3): 46-52

  Abstract

  Review the medical literature on the history and clinical features of catatonia so as to provide a contemporary clinical guide for successfully diagnosing and treating the various clinical forms of catatonia.RESULTS of MEDLINE computerized searches using search terms 'catatonia', 'treatment of catatonia', 'electroconvulsive therapy and catatonia', 'benzodiazepines and catatonia', clinical case reports, and book chapters covering the medical and psychiatric literature relevant to catatonia and its associated treatments were examined.Academic medical center.None.None.Catatonia is a common but under-recognized clinical syndrome. No large-scale, controlled studies exist to determine the relative effectiveness of current treatments, including sedative-hypnotic medications (benzodiazepines or barbiturates), and electroconvulsive therapy (ECT).Despite the lack of large-scale, controlled studies, benzodiazepines appear to be an effective first-line treatment for catatonia. ECT is now often reserved as a second-line treatment despite more than 60 years of documented efficacy and safety. However, ECT should be viewed as a first-line intervention in cases of severe or malignant catatonias.

  View details for PubMedID 20805910

• Catatonia and prediction of response to ECT Psychiatric Annals Caroff, S. N., Ungvari, G. S., Bhati, M. T., Datto, C. J., O'Reardon, J. P. 2007; 32 (1): 57-64
• The brain, language, and schizophrenia. Current psychiatry reports Bhati, M. T. 2005; 7 (4): 297-303

  Abstract

  Language is a defining and prominent feature in humans. This faculty is impaired in those with schizophrenia. Individuals with schizophrenia show numerous abnormalities in language function, including symptoms of disorganized speech, auditory hallucinations, thought disorders, and verbal memory impairments. Structural and functional brain imaging with neurocognitive testing shows various aspects of brain structure and function associated with language that also are abnormal in schizophrenia. This article comparatively reviews this research and relates it to understanding the symptoms and pathophysiologic features of schizophrenia. Understanding the neural basis of language and its disruption in schizophrenia provides a guide for diagnosis, subtyping, treatment, and future research.

  View details for PubMedID 16098284

• What makes aripiprazole the ‘different’ antipsychotic. Current Psychiatry Bhati, M. T. 2005; 4 (7): 51-60