Publications by authors named "Helen S Mayberg"

161 Publications

A connectomic analysis of deep brain stimulation for treatment-resistant depression.

Brain Stimul 2021 Sep-Oct;14(5):1226-1233. Epub 2021 Aug 13.

Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, 310009, China. Electronic address:

Objective: Deep brain stimulation (DBS) has been used as a treatment of last resort for treatment-resistant depression (TRD) for more than a decade. Many DBS targets have been proposed and tested clinically, but the underlying circuit mechanisms remain unclear. Uncovering white matter tracts (WMT) activated by DBS targets may provide crucial information about the circuit substrates mediating DBS efficacy in ameliorating TRD.

Methods: We performed probabilistic tractography using diffusion magnetic resonance imaging datas from 100 healthy volunteers in Human Connectome Project datasets to analyze the structural connectivity patterns of stimulation targeting currently-used DBS target for TRD. We generated mean and binary fiber distribution maps and calculated the numbers of WMT streamlines in the dataset.

Results: Probabilistic tracking results revealed that activation of distinct DBS targets demonstrated modulation of overlapping but considerably distinct pathways. DBS targets were categorized into 4 groups: Cortical, Striatal, Thalamic, and Medial Forebrain Bundle according to their main modulated WMT and brain areas. Our data also revealed that Brodmann area 10 and amygdala are hub structures that are associated with all DBS targets.

Conclusions: Our results together suggest that the distinct mechanism of DBS targets implies individualized target selection and formulation in the future of DBS treatment for TRD. The modulation of Brodmann area 10 and amygdala may be critical for the efficacy of DBS-mediated treatment of TRD.
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http://dx.doi.org/10.1016/j.brs.2021.08.010DOI Listing
August 2021

ANA Investigates: Neural Circuit Concepts Connecting Neurology and Psychiatry.

Ann Neurol 2021 Oct 24;90(4):568-569. Epub 2021 Aug 24.

Departments of Neurology, Neurosurgery, Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY.

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http://dx.doi.org/10.1002/ana.26190DOI Listing
October 2021

Dynamic Functional Connectivity Predicts Treatment Response to Electroconvulsive Therapy in Major Depressive Disorder.

Front Hum Neurosci 2021 6;15:689488. Epub 2021 Jul 6.

Wallace H. Coulter Department of Biomedical Engineering at Georgia Institute of Technology and Emory University, Atlanta, GA, United States.

Electroconvulsive therapy (ECT) is one of the most effective treatments for major depressive disorder. Recently, there has been increasing attention to evaluate the effect of ECT on resting-state functional magnetic resonance imaging (rs-fMRI). This study aims to compare rs-fMRI of depressive disorder (DEP) patients with healthy participants, investigate whether pre-ECT dynamic functional network connectivity network (dFNC) estimated from patients rs-fMRI is associated with an eventual ECT outcome, and explore the effect of ECT on brain network states. Resting-state functional magnetic resonance imaging (fMRI) data were collected from 119 patients with depression or depressive disorder (DEP) (76 females), and 61 healthy (HC) participants (34 females), with an age mean of 52.25 ( = 180) years old. The pre-ECT and post-ECT Hamilton Depression Rating Scale (HDRS) were 25.59 ± 6.14 and 11.48 ± 9.07, respectively. Twenty-four independent components from default mode (DMN) and cognitive control network (CCN) were extracted, using group-independent component analysis from pre-ECT and post-ECT rs-fMRI. Then, the sliding window approach was used to estimate the pre-and post-ECT dFNC of each subject. Next, k-means clustering was separately applied to pre-ECT dFNC and post-ECT dFNC to assess three distinct states from each participant. We calculated the amount of time each subject spends in each state, which is called "occupancy rate" or OCR. Next, we compared OCR values between HC and DEP participants. We also calculated the partial correlation between pre-ECT OCRs and HDRS change while controlling for age, gender, and site. Finally, we evaluated the effectiveness of ECT by comparing pre- and post-ECT OCR of DEP and HC participants. The main findings include (1) depressive disorder (DEP) patients had significantly lower OCR values than the HC group in state 2, where connectivity between cognitive control network (CCN) and default mode network (DMN) was relatively higher than other states (corrected = 0.015), (2) Pre-ECT OCR of state, with more negative connectivity between CCN and DMN components, is linked with the HDRS changes (R = 0.23 corrected = 0.03). This means that those DEP patients who spent less time in this state showed more HDRS change, and (3) The post-ECT OCR analysis suggested that ECT increased the amount of time DEP patients spent in state 2 (corrected = 0.03). Our finding suggests that dynamic functional network connectivity (dFNC) features, estimated from CCN and DMN, show promise as a predictive biomarker of the ECT outcome of DEP patients. Also, this study identifies a possible underlying mechanism associated with the ECT effect on DEP patients.
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http://dx.doi.org/10.3389/fnhum.2021.689488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291148PMC
July 2021

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease.

Nat Hum Behav 2021 Jul 8. Epub 2021 Jul 8.

Center for Brain Circuit Therapeutics, Brigham and Women's Hospital, Boston, MA, USA.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.
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http://dx.doi.org/10.1038/s41562-021-01161-1DOI Listing
July 2021

Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies.

Front Hum Neurosci 2021 19;15:644593. Epub 2021 Apr 19.

Neurologischen Klinik Universitätsklinikum Würzburg, Würzburg, Germany.

We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.
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http://dx.doi.org/10.3389/fnhum.2021.644593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092047PMC
April 2021

Establishing Evidence for Clinical Utility of a Neuroimaging Biomarker in Major Depressive Disorder: Prospective Testing and Implementation Challenges.

Biol Psychiatry 2021 08 26;90(4):236-242. Epub 2021 Feb 26.

Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York.

Background: Although a number of neuroimaging biomarkers for response have been proposed, none have been tested prospectively for direct effects on treatment outcomes. To the best of our knowledge, this is the first prospective test of the clinical utility of the use of an imaging biomarker to select treatment for patients with major depressive disorder.

Methods: Eligible participants (n = 60) had a primary diagnosis of major depressive disorder and were assigned to either escitalopram or cognitive behavioral therapy based on fluorodeoxyglucose positron emission tomography activity in the right anterior insula. The overall study remission rate after 12 weeks of treatment, based on the end point Hamilton Depression Rating Scale score, was then examined for futility and benefit of the strategy.

Results: Remission rates demonstrated lack of futility at the end of stage 1 (37%, 10/27), and the study proceeded to stage 2. After adjustment for the change in stage 2 sample size, the complete remission rate did not demonstrate evidence of benefit (37.7%, 95% confidence interval, 26.3%-51.4%, p = .38). However, total remission rates (complete and partial remission) did reach significance in post hoc analysis (49.1%, 95% confidence interval, 37.6%-60.7%, p = .020).

Conclusions: The study shows some evidence for a role of the right anterior insula in the clinical choice of major depressive disorder monotherapy. The effect size, however, is insufficient for the use of insula activity as a sole predictive biomarker of remission. The study also demonstrates the logistical difficulties in establishing clinical utility of biomarkers.
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http://dx.doi.org/10.1016/j.biopsych.2021.02.966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324510PMC
August 2021

Single-cell molecular profiling of all three components of the HPA axis reveals adrenal ABCB1 as a regulator of stress adaptation.

Sci Adv 2021 Jan 27;7(5). Epub 2021 Jan 27.

Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Bavaria 80804, Germany.

Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type-specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing's syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism's nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.
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http://dx.doi.org/10.1126/sciadv.abe4497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840126PMC
January 2021

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age.

Transl Psychiatry 2021 02 1;11(1):88. Epub 2021 Feb 1.

Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.
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http://dx.doi.org/10.1038/s41398-020-01147-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851167PMC
February 2021

International Legal Approaches to Neurosurgery for Psychiatric Disorders.

Front Hum Neurosci 2020 13;14:588458. Epub 2021 Jan 13.

Department of Neurosurgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Neurosurgery for psychiatric disorders (NPD), also sometimes referred to as psychosurgery, is rapidly evolving, with new techniques and indications being investigated actively. Many within the field have suggested that some form of guidelines or regulations are needed to help ensure that a promising field develops safely. Multiple countries have enacted specific laws regulating NPD. This article reviews NPD-specific laws drawn from North and South America, Asia and Europe, in order to identify the typical form and contents of these laws and to set the groundwork for the design of an optimal regulation for the field. Key challenges for this design that are revealed by the review are how to define the scope of the law (what should be regulated), what types of regulations are required (eligibility criteria, approval procedures, data collection, and oversight mechanisms), and how to approach international harmonization given the potential migration of researchers and patients.
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http://dx.doi.org/10.3389/fnhum.2020.588458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838635PMC
January 2021

A Standards Organization for Open and FAIR Neuroscience: the International Neuroinformatics Coordinating Facility.

Neuroinformatics 2021 Jan 27. Epub 2021 Jan 27.

Department of Neuroscience, School of Medicine, University of California, San Diego, La Jolla, CA, USA.

There is great need for coordination around standards and best practices in neuroscience to support efforts to make neuroscience a data-centric discipline. Major brain initiatives launched around the world are poised to generate huge stores of neuroscience data. At the same time, neuroscience, like many domains in biomedicine, is confronting the issues of transparency, rigor, and reproducibility. Widely used, validated standards and best practices are key to addressing the challenges in both big and small data science, as they are essential for integrating diverse data and for developing a robust, effective, and sustainable infrastructure to support open and reproducible neuroscience. However, developing community standards and gaining their adoption is difficult. The current landscape is characterized both by a lack of robust, validated standards and a plethora of overlapping, underdeveloped, untested and underutilized standards and best practices. The International Neuroinformatics Coordinating Facility (INCF), an independent organization dedicated to promoting data sharing through the coordination of infrastructure and standards, has recently implemented a formal procedure for evaluating and endorsing community standards and best practices in support of the FAIR principles. By formally serving as a standards organization dedicated to open and FAIR neuroscience, INCF helps evaluate, promulgate, and coordinate standards and best practices across neuroscience. Here, we provide an overview of the process and discuss how neuroscience can benefit from having a dedicated standards body.
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http://dx.doi.org/10.1007/s12021-020-09509-0DOI Listing
January 2021

ERICH3: vesicular association and antidepressant treatment response.

Mol Psychiatry 2021 06 23;26(6):2415-2428. Epub 2020 Nov 23.

Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.
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http://dx.doi.org/10.1038/s41380-020-00940-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141066PMC
June 2021

Replicable effects of deep brain stimulation for obsessive-compulsive disorder.

Brain Stimul 2021 Jan-Feb;14(1):1-3. Epub 2020 Oct 28.

Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine, New York, NY, United States. Electronic address:

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http://dx.doi.org/10.1016/j.brs.2020.10.016DOI Listing
August 2021

Classifying Major Depressive Disorder and Response to Deep Brain Stimulation Over Time by Analyzing Facial Expressions.

IEEE Trans Biomed Eng 2021 02 21;68(2):664-672. Epub 2021 Jan 21.

Objective: Major depressive disorder (MDD) is a common psychiatric disorder that leads to persistent changes in mood and interest among other signs and symptoms. We hypothesized that convolutional neural network (CNN) based automated facial expression recognition, pre-trained on an enormous auxiliary public dataset, could provide improve generalizable approach to MDD automatic assessment from videos, and classify remission or response to treatment.

Methods: We evaluated a novel deep neural network framework on 365 video interviews (88 hours) from a cohort of 12 depressed patients before and after deep brain stimulation (DBS) treatment. Seven basic emotions were extracted with a Regional CNN detector and an Imagenet pre-trained CNN, both of which were trained on large-scale public datasets (comprising over a million images). Facial action units were also extracted with the Openface toolbox. Statistics of the temporal evolution of these image features over each recording were extracted and used to classify MDD remission and response to DBS treatment.

Results: An Area Under the Curve of 0.72 was achieved using leave-one-subject-out cross-validation for remission classification and 0.75 for response to treatment.

Conclusion: This work demonstrates the potential for the classification of MDD remission and response to DBS treatment from passively acquired video captured during unstructured, unscripted psychiatric interviews.

Significance: This novel MDD evaluation could be used to augment current psychiatric evaluations and allow automatic, low-cost, frequent use when an expert isn't readily available or the patient is unwilling or unable to engage. Potentially, the framework may also be applied to other psychiatric disorders.
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http://dx.doi.org/10.1109/TBME.2020.3010472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891869PMC
February 2021

Analyzing Non-verbal Behavior Throughout Recovery in a Sample of Depressed Patients Receiving Deep Brain Stimulation.

Neurol Psychiatry Brain Res 2020 Sep 11;37:33-40. Epub 2020 Jun 11.

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences.

Background: Traditional rating scales for depression rely heavily on patient self-report, and lack detailed measurement of non-verbal behavior. However, there is evidence that depression is associated with distinct non-verbal behaviors, assessment of which may provide useful information about recovery. This study examines non-verbal behavior in a sample of patients receiving Deep Brain Stimulation (DBS) treatment of depression, with the purpose to investigate the relationship between non-verbal behaviors and reported symptom severity.

Methods: Videotaped clinical interviews of twelve patients participating in a study of DBS for treatment-resistant depression were analyzed at three time points (before treatment and after 3 months and 6 months of treatment), using an ethogram to assess the frequencies of 42 non-verbal behaviors. The Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS-17) were also collected at all time points.

Results: Factor analysis grouped non-verbal behaviors into three factors: , and . Two-way repeated measures ANOVA showed that scores on the three factors change differently from each other over time. Mixed effects modelling assessed the relationship between BDI score and frequency of non-verbal behaviors, and provided evidence that the frequency of behaviors related to reactivity and engagement increase as BDI score decreases.

Limitations: This study assesses a narrow sample of patients with a distinct clinical profile at limited time points.

Conclusions: Non-verbal behavior provides information about clinical states and may be reliably quantified using ethograms. Non-verbal behavior may provide distinct information compared to self-report.
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http://dx.doi.org/10.1016/j.npbr.2020.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375407PMC
September 2020

Psychotherapy or medication for depression? Using individual symptom meta-analyses to derive a Symptom-Oriented Therapy (SOrT) metric for a personalised psychiatry.

BMC Med 2020 06 5;18(1):170. Epub 2020 Jun 5.

Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.

Background: Antidepressant medication (ADM) and psychotherapy are effective treatments for major depressive disorder (MDD). It is unclear, however, if treatments differ in their effectiveness at the symptom level and whether symptom information can be utilised to inform treatment allocation. The present study synthesises comparative effectiveness information from randomised controlled trials (RCTs) of ADM versus psychotherapy for MDD at the symptom level and develops and tests the Symptom-Oriented Therapy (SOrT) metric for precision treatment allocation.

Methods: First, we conducted systematic review and meta-analyses of RCTs comparing ADM and psychotherapy at the individual symptom level. We searched PubMed Medline, PsycINFO, and the Cochrane Central Register of Controlled Trials databases, a database specific for psychotherapy RCTs, and looked for unpublished RCTs. Random-effects meta-analyses were applied on sum-scores and for individual symptoms for the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) measures. Second, we computed the SOrT metric, which combines meta-analytic effect sizes with patients' symptom profiles. The SOrT metric was evaluated using data from the Munich Antidepressant Response Signature (MARS) study (n = 407) and the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study (n = 234).

Results: The systematic review identified 38 RCTs for qualitative inclusion, 27 and 19 for quantitative inclusion at the sum-score level, and 9 and 4 for quantitative inclusion on individual symptom level for the HAM-D and BDI, respectively. Neither meta-analytic strategy revealed significant differences in the effectiveness of ADM and psychotherapy across the two depression measures. The SOrT metric did not show meaningful associations with other clinical variables in the MARS sample, and there was no indication of utility of the metric for better treatment allocation from PReDICT data.

Conclusions: This registered report showed no differences of ADM and psychotherapy for the treatment of MDD at sum-score and symptom levels. Symptom-based metrics such as the proposed SOrT metric do not inform allocation to these treatments, but predictive value of symptom information requires further testing for other treatment comparisons.
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http://dx.doi.org/10.1186/s12916-020-01623-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273646PMC
June 2020

Rapid Antidepressant Effects of Deep Brain Stimulation and Their Relation to Surgical Protocol.

Biol Psychiatry 2020 10 14;88(8):e37-e39. Epub 2020 May 14.

Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York.

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http://dx.doi.org/10.1016/j.biopsych.2020.03.017DOI Listing
October 2020

Impulsivity and Compulsivity After Subthalamic Deep Brain Stimulation for Parkinson's Disease.

Front Behav Neurosci 2020 23;14:47. Epub 2020 Apr 23.

Nash Family Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States.

Impulsivity and compulsivity are prominent non-motor problems in Parkinson's disease (PD). Despite 20 years of research, there is still an ongoing debate as to whether subthalamic deep brain stimulation (STN DBS) for PD exacerbates or improves these symptoms. Here, we review how STN DBS affects clinical symptoms and neurocognitive aspects of impulsivity and compulsivity. When comparing patients post- to pre-surgery, in the majority of studies STN DBS for PD is associated with a decrease in clinically diagnosed impulse-control disorders and disorders of compulsivity. To avoid confounds, such as post-surgical decreases in dopaminergic medication doses, comparisons can also be made between DBS "On" versus "Off" conditions. These experimentally assayed effects of STN DBS with respect to neurocognitive aspects of impulsivity and compulsivity are more mixed. STN DBS improves behavioral flexibility without impairing negative feedback learning, delay discounting, or inhibitory control, as long as stimulation is restricted to the dorsal STN. However, STN DBS may drive impulsive actions when a subject is faced with competing choices. We discuss how motivated responses may be either enhanced or impaired by STN DBS depending on engagement of dorsal or ventral STN-mediated circuits. Future studies should combine structural and functional circuit measures with behavioral testing in PD patients on and off medication and stimulation. A more sophisticated understanding of how to modulate cortico-striatal-thalamo-cortical loops will increase the likelihood that these circuit manipulation techniques can successfully be applied to a wider range of neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fnbeh.2020.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191054PMC
April 2020

Concordance between clinician-rated and patient reported outcome measures of depressive symptoms in treatment resistant depression.

J Affect Disord 2020 04 22;266:22-29. Epub 2020 Jan 22.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 12 Executive Park Drive NE 3rd Floor, Atlanta, GA 30329, USA. Electronic address:

Background: Calls to implement measurement-based care (MBC) in psychiatry are increasing. A recent Cochrane meta-analysis concluded that there is insufficient evidence that routine application of patient reported outcomes (PROs) improves treatment outcomes for common psychiatric disorders. There is a particular paucity of this information in patients with treatment resistant depression (TRD).

Methods: A TRD sample (n = 302) and a treatment-naïve sample with major depression (n = 344) were assessed for the level of agreement in depression severity between two PROs (the Beck Depression Inventory, BDI, and the Quick Inventory of Depressive Symptomatology Self-report, QIDS-SR) and two Clinician Rated (CRs) measures (Hamilton Depression Rating Scale, HDRS, and the Montgomery-Asberg Depression Rating Scale, MADRS).

Results: Correlations between CR and PRO total scores in the TRD sample ranged from 0.57 (HDRS-QIDS-SR) to 0.68 (MADRS-BDI), reflecting a moderate-to-strong relationship between assessment tools. Correlations in the treatment naïve sample were non-significantly lower for most comparisons, ranging from 0.51 (HDRS-QIDS-SR) to 0.64 (MADRS-BDI). Few predictors of discordance between CRs and PROs were identified, though chronicity of the current episode in treatment-naïve patients was associated with greater agreement.

Limitations: Inter-rater reliability of the clinician interviews was conducted separately within the two studies so we could not determine the reliability between the two groups of raters used in the studies.

Conclusion: Findings generally supported acceptably high levels of agreement between patient and clinician ratings of baseline depression severity. More work is needed to determine the extent to which PROs can improve outcomes in MBC for depression and, more specifically, TRD.
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http://dx.doi.org/10.1016/j.jad.2020.01.108DOI Listing
April 2020

From bed to bench side: Reverse translation to optimize neuromodulation for mood disorders.

Proc Natl Acad Sci U S A 2019 Dec 23. Epub 2019 Dec 23.

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029

The advent of neuroimaging has provided foundational insights into the neural basis of psychiatric conditions, such as major depression. Across countless studies, dysfunction has been localized to distinct parts of the limbic system. Specific knowledge about affected locations has led to the development of circuit modulation therapies to correct dysfunction, notably deep brain stimulation (DBS). This and other emerging neuromodulation approaches have shown great promise, but their refinement has been slow and fundamental questions about their mechanisms of action remain. Here, we argue that their continued development requires reverse translation to animal models with close homology to humans, namely, nonhuman primates. With a particular focus on DBS approaches for depression, we highlight the parts of the brain that have been targeted by neuromodulation in humans, their efficacy, and why nonhuman primates are the most suitable model in which to conduct their refinement. We finish by highlighting key gaps in our knowledge that need to be filled to allow more rapid progress toward effective therapies in patients for whom all other treatment attempts have failed.
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http://dx.doi.org/10.1073/pnas.1902287116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936427PMC
December 2019

Somatic symptoms in treatment-naïve Hispanic and non-Hispanic patients with major depression.

Depress Anxiety 2020 02 12;37(2):156-165. Epub 2019 Dec 12.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.

Background: Somatic complaints are a major driver of health care costs among patients with major depressive disorder (MDD). Some epidemiologic and clinical data suggest that Hispanic and non-Hispanic Black patients with MDD endorse higher levels of somatic symptoms than non-Hispanic White patients.

Methods: Somatic symptoms in 102 Hispanic, 61 non-Hispanic Black, and 156 non-Hispanic White patients with treatment-naïve MDD were evaluated using the somatic symptom subscale of the Hamilton anxiety rating scale (HAM-A). The other seven items of the HAM-A comprise the psychic anxiety subscale, which was also evaluated across ethnicities.

Results: Hispanic patients reported significantly greater levels of somatic symptoms than non-Hispanic patients, but levels of psychic anxiety symptoms did not differ by ethnicity. Levels of somatic symptoms did not significantly differ between Black and White non-Hispanic patients. Within the Hispanic sample, somatic symptom levels were higher only among those who were evaluated in Spanish; Hispanics who spoke English showed no significant differences versus non-Hispanics.

Conclusions: In this medically healthy sample of patients with MDD, monolingual Spanish-speaking Hispanic patients endorsed high levels of somatic symptoms. Clinicians should be mindful that the depressive experience may manifest somatically and be judicious in determining when additional medical work-up is warranted for somatic complaints.
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http://dx.doi.org/10.1002/da.22984DOI Listing
February 2020

Cingulate-mediated depressive symptoms in neurologic disease and therapeutics.

Handb Clin Neurol 2019 ;166:371-379

Departments of Neurology, Neurosurgery, Psychiatry, and Neuroscience, Center of Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Electronic address:

The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially showing volumetric changes, followed by the insights that functional imaging and physiology contributed to neuroscience and psychiatry, the distinct areas of the cingulate subdivisions were seen to have unique contributions. The subcallosal cingulate, with its functional responsivity to mood states and to antidepressant therapies, has been identified as a central node within the mood regulation network. In this chapter, detailed descriptions of the anatomic and functional changes that are seen in depression will be discussed. Finally, a focus on the development of deep brain stimulation in the subcallosal cingulate area will be used to emphasize the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed to treat depression.
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http://dx.doi.org/10.1016/B978-0-444-64196-0.00021-2DOI Listing
April 2020

Investigation of MORC1 DNA methylation as biomarker of early life stress and depressive symptoms.

J Psychiatr Res 2020 01 26;120:154-162. Epub 2019 Oct 26.

Department of Psychiatry and Psychotherapy, University Hospital Tübingen, Calwerstr. 14, 72070, Tübingen, Germany.

Early life stress (ELS) is associated with an increased risk of depression and this association may be mediated by epigenetic mechanisms. A previous epigenome-wide DNA methylation (DNAm) study investigating human newborns and two animal models of ELS suggested that the epigenetic regulator MORC1 is differentially methylated following ELS. The ELS-induced DNAm alterations were long-lasting in the animal models. However, whether this finding is also transferable to humans experiencing ELS in childhood was not investigated. Further, MORC1 may provide a link between ELS and adult depression, as MORC1 DNAm and genetic variants were found to be associated with depressive symptoms in humans. In the present study, we investigated the validity of MORC1 DNAm as a biomarker of ELS in humans and its role in linking ELS to depression later in life by studying childhood maltreatment. We analyzed whole blood MORC1 DNAm in an adult cohort (N = 151) that was characterized for both the presence of depressive symptoms and childhood maltreatment. Further, we investigated the association between MORC1 DNAm, depressive symptoms and childhood maltreatment in two additional cohorts (N = 299, N = 310). Overall, our data do not indicate an association of MORC1 DNAm with childhood maltreatment. An association of MORC1 DNAm with depressive symptoms was present in all cohorts, but was inconsistent in the specific CpG sites associated and the direction of effect (Tuebingen cohort: standardized β = 0.16, unstandardized β = 0.01, 95% CI [-0.0004, -0.0179], p = 0.061, PReDICT cohort: standardized β = -0.12, unstandardized β = -0.01, 95% CI [-0.0258, -0.0003], p = 0.045), Grady cohort: standardized β = 0.16, unstandardized β = 0.008, 95% CI [0.0019, 0.0143], p = 0.01). Our study thus suggests that peripheral MORC1 DNAm cannot serve as biomarker of childhood maltreatment in adults, but does provide further indication for the association of MORC1 DNAm with depressive symptoms.
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http://dx.doi.org/10.1016/j.jpsychires.2019.10.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6866669PMC
January 2020

Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.

Am J Psychiatry 2019 11 4;176(11):949-956. Epub 2019 Oct 4.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta (Crowell, Riva-Posse, Denison, Quinn); Departments of Psychiatry and Surgery, Geisel School of Medicine at Dartmouth, Lebanon, N.H. (Holtzheimer); Department of Psychiatry, University of Wisconsin Madison School of Medicine and Public Health, Madison, Wisc. (Garlow); Department of Biostatistics and Bioinformatics, Emory University, Atlanta (Kelley); Department of Neurosurgery, Emory University School of Medicine, Atlanta (Gross); and Departments of Neurology, Neurosurgery, Psychiatry, and Neuroscience and Center for Advanced Circuit Therapeutics, Icahn School of Medicine at Mount Sinai, New York (Mayberg).

Objective: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression.

Methods: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years.

Results: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides.

Conclusions: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.
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http://dx.doi.org/10.1176/appi.ajp.2019.18121427DOI Listing
November 2019

Proceedings of the Sixth Deep Brain Stimulation Think Tank Modulation of Brain Networks and Application of Advanced Neuroimaging, Neurophysiology, and Optogenetics.

Front Neurosci 2019 12;13:936. Epub 2019 Sep 12.

Department of Neurology, Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States.

The annual deep brain stimulation (DBS) Think Tank aims to create an opportunity for a multidisciplinary discussion in the field of neuromodulation to examine developments, opportunities and challenges in the field. The proceedings of the Sixth Annual Think Tank recapitulate progress in applications of neurotechnology, neurophysiology, and emerging techniques for the treatment of a range of psychiatric and neurological conditions including Parkinson's disease, essential tremor, Tourette syndrome, epilepsy, cognitive disorders, and addiction. Each section of this overview provides insight about the understanding of neuromodulation for specific disease and discusses current challenges and future directions. This year's report addresses key issues in implementing advanced neurophysiological techniques, evolving use of novel modulation techniques to deliver DBS, ans improved neuroimaging techniques. The proceedings also offer insights into the new era of brain network neuromodulation and connectomic DBS to define and target dysfunctional brain networks. The proceedings also focused on innovations in applications and understanding of adaptive DBS (closed-loop systems), the use and applications of optogenetics in the field of neurostimulation and the need to develop databases for DBS indications. Finally, updates on neuroethical, legal, social, and policy issues relevant to DBS research are discussed.
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http://dx.doi.org/10.3389/fnins.2019.00936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751331PMC
September 2019

Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment.

Front Neurosci 2019 12;13:926. Epub 2019 Sep 12.

Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States.

Major depressive disorder (MDD) is a common and disabling syndrome with multiple etiologies that is defined by clinically elicited signs and symptoms. In hopes of developing a list of candidate biological measures that reflect and relate closely to the severity of depressive symptoms, so-called "state-dependent" biomarkers of depression, this pilot study explored the biochemical underpinnings of treatment response to cognitive behavior therapy (CBT) in medication-free MDD outpatients. Plasma samples were collected at baseline and week 12 from a subset of MDD patients ( = 26) who completed a course of CBT treatment as part of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study. Targeted metabolomic profiling using the AbsoluteIDQ p180 Kit and LC-MS identified eight "co-expressed" metabolomic modules. Of these eight, three were significantly associated with change in depressive symptoms over the course of the 12-weeks. Metabolites found to be most strongly correlated with change in depressive symptoms were branched chain amino acids, acylcarnitines, methionine sulfoxide, and α-aminoadipic acid (negative correlations with symptom change) as well as several lipids, particularly the phosphatidlylcholines (positive correlation). These results implicate disturbed bioenergetics as an important state marker in the pathobiology of MDD. Exploratory analyses contrasting remitters to CBT versus those who failed the treatment further suggest these metabolites may serve as mediators of recovery during CBT treatment. Larger studies examining metabolomic change patterns in patients treated with pharmacotherapy or psychotherapy will be necessary to elucidate the biological underpinnings of MDD and the -specific biologies of treatment response.
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http://dx.doi.org/10.3389/fnins.2019.00926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751322PMC
September 2019

Do Relational and Self-Definitional Traits Influence Deep Brain Stimulation Device Preference?

Psychoanal Psychol 2019 Oct;36(4):313-320

Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences.

Personality psychodynamics have been shown to influence individual responses to psychiatric treatments, including medication. Increasingly, neuromodulation therapies have become available for severe and treatment-resistant depression. This study aims to evaluate patient response to an implanted neurostimulator battery within the framework of relational versus self-definitional personality traits. Relational development is interpersonally oriented and disruptions along this pathway lead to dependency on others for a sense of security and self-worth. Self-definitional development is characterized by autonomy strivings and disruptions lead to self-critical feelings of failing to meet expectations. Patients drawn from a larger study of deep brain stimulation (DBS) for treatment-resistant depression were switched from a non-rechargeable to a rechargeable battery type to maintain stimulation therapy. This switch entailed taking greater personal responsibility for device maintenance and allowed for fewer battery replacement surgeries. Twenty-six patients completed the Depressive Experiences Questionnaire (DEQ) and a questionnaire surveying their preference for DBS battery type. Results show that the DEQ dependency subscale, and more specifically the neediness component of the subscale, is associated with patient preference for the non-rechargeable battery. This suggests that individuals with higher relational needs prefer treatment options that increase contact with and need for medical caregivers and may prioritize this aspect of an intervention over alternative considerations. In contrast, individuals with more self-critical personality traits did not have a battery type preference, indicating that self-definitional needs were not predictive of battery preference. The link between an individual's personality psychodynamics and response to biomedical interventions, including neuromodulation and treatments that incorporate medical devices, deserves further attention.
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http://dx.doi.org/10.1037/pap0000249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989068PMC
October 2019

Neuroanatomical predictors of response to subcallosal cingulate deep brain stimulation for treatment-resistant depression

J Psychiatry Neurosci 2020 01;45(1):45-54

From the Division of Neurosurgery, University of Alberta, Edmonton, Alberta, Canada (Sankar); the Department of Psychiatry, McGill University, Montreal, Quebec, Canada (Chakravarty); the Department of Biological and Biomedical Engineering, McGill University, Montreal, Quebec, Canada (Chakravarty); the Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada (Jawa, Li, Hamani, Lozano); the Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (Giacobbe, Kennedy, Rizvi); and the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States (Mayberg).

Background: Deep brain stimulation targeting the subcallosal cingulate gyrus (SCG DBS) improves the symptoms of treatment-resistant depression in some patients, but not in others. We hypothesized that there are pre-existing structural brain differences between responders and nonresponders to SCG DBS, detectable using structural MRI.

Methods: We studied preoperative, T1-weighted MRI scans of 27 patients treated with SCG DBS from 2003 to 2011. Responders (n = 15) were patients with a >50% improvement in Hamilton Rating Scale for Depression score following 12 months of SCG DBS. Preoperative subcallosal cingulate gyrus grey matter volume was obtained using manual segmentation by a trained observer blinded to patient identity. Volumes of hippocampus, thalamus, amygdala, whole-brain cortical grey matter and white matter volume were obtained using automated techniques.

Results: Preoperative subcallosal cingulate gyrus, thalamic and amygdalar volumes were significantly larger in patients who went on to respond to SCG-DBS. Hippocampal volume did not differ between groups. Cortical grey matter volume was significantly smaller in responders, and cortical grey matter:white matter ratio distinguished between responders and nonresponders with high sensitivity and specificity.

Limitations: Normalization by intracranial volume nullified some between-group differences in volumetric measures.

Conclusion: There are structural brain differences between patients with treatment-resistant depression who respond to SCG DBS and those who do not. Specifically, the structural integrity of the subcallosal cingulate gyrus target region and its connected subcortical areas, and variations in cortical volume across the entire brain, appear to be important determinants of response. Structural MRI shows promise as a biomarker in deep brain stimulation for depression, and may play a role in refining patient selection for future trials.
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http://dx.doi.org/10.1503/jpn.180207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919920PMC
January 2020

A difference degree test for comparing brain networks.

Hum Brain Mapp 2019 10 26;40(15):4518-4536. Epub 2019 Jul 26.

Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia.

Recently, there has been a proliferation of methods investigating functional connectivity as a biomarker for mental disorders. Typical approaches include massive univariate testing at each edge or comparisons of network metrics to identify differing topological features. Limitations of these methods include low statistical power due to the large number of comparisons and difficulty attributing overall differences in networks to local variation. We propose a method to capture the difference degree, which is the number of edges incident to each region in the difference network. Our difference degree test (DDT) is a two-step procedure for identifying brain regions incident to a significant number of differentially weighted edges (DWEs). First, we select a data-adaptive threshold which identifies the DWEs followed by a statistical test for the number of DWEs incident to each brain region. We achieve this by generating an appropriate set of null networks which are matched on the first and second moments of the observed difference network using the Hirschberger-Qi-Steuer algorithm. This formulation permits separation of the network's true topology from the nuisance topology induced by the correlation measure that alters interregional connectivity in ways unrelated to brain function. In simulations, the proposed approach outperforms competing methods in detecting differentially connected regions of interest. Application of DDT to a major depressive disorder dataset leads to the identification of brain regions in the default mode network commonly implicated in this ruminative disorder.
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http://dx.doi.org/10.1002/hbm.24718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865740PMC
October 2019
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