Search

BACKGROUND: Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome. METHODS: To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8). RESULTS: Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices. LIMITATIONS: Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses. CONCLUSION: Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate preservation of cognitive function after deep brain stimulation (DBS) of the subgenual cingulate (Cg25) for treatment-resistant depression (TRD). We have previously reported on the treatment methods, safety, and 6-month clinical outcome (Mayberg et al., Neuron. 2005;45:651-660). Comprehensive neuropsychological assessments tapping 4 domains of frontal lobe function, and general cognitive abilities, were completed before implantation and at 3, 6, and 12 months postonset of continuous DBS in 6 TRD patients. No adverse neuropsychological effects were noted following surgery, onset and maintenance of DBS with the exception of transient motor slowing noted at 3 and 6 months that improved to normative levels by 12 months. Several areas of cognition that were below average or impaired at baseline improved over follow-up, and these changes were not correlated with improvements in mood. Though the sample size is small, these results support cognitive safety of Cg25 DBS for TRD. [ABSTRACT FROM AUTHOR]

Objective: The authors previously identified depression-specific differences in brain responses to an emotional challenge in patients with bipolar and unipolar mood disorder. In this study, potential markers of bipolar risk and resilience were examined in a new cohort of lithium-responsive bipolar patients and their healthy siblings. Method: Changes in regional cerebral blood flow (rCBF) were measured with [(15)O]water positron emission tomography after induction of transient sadness in nine euthymic lithium responders and nine healthy siblings. The patterns of change in these groups were compared, and then they were contrasted with previous findings on bipolar responders to valproate. Results: Common to all three groups with induced sadness were rCBF increases in the dorsal/rostral anterior cingulate and anterior insula and decreases in the orbitofrontal and inferior temporal cortices. Distinguishing the groups were decreases in the medial frontal cortex in the patients but an increase in this region in the siblings. Discussion: Common changes with emotional challenge were identified in bipolar patients and their healthy siblings. These were not seen previously in healthy subjects without a family history of mood disorder, suggesting a potential marker of bipolar risk. The siblings' unique increases in the medial frontal cortex appear to identify a compensatory response in this at-risk group, as this pattern was not seen previously in healthy subjects without depression risk factors. This differential change pattern in patients and their siblings highlights the role of the anterior cingulate and medial frontal regions in mediating resiliency and vulnerability in bipolar disorder families. [ABSTRACT FROM AUTHOR]

This study sought to further evaluate an observational measure of rumination that occurs during psychotherapy (i.e., in-session rumination). Specifically, the study aimed to replicate the reliability of an observational rating procedure in new therapy sessions and a new sample, clarify the relationship between in-session rumination and depressive symptoms, and evaluate for the first time the relationship between in-session rumination and self-reported rumination. A team of trained research assistants produced observational ratings of in-session rumination occurring during video-taped sessions of CBT from two separate treatment studies. Thirty-five patients with major depressive disorder (MDD) from one study had their final session rated, and 17 patients with MDD from another study had their first session rated. Results showed that the observational ratings were reliable, and that in-session rumination generally correlated with depressive symptom severity as expected, with higher in-session rumination predicting higher depressive symptom levels both cross-sectionally and longitudinally. Preliminary evidence also found that in-session rumination correlated with self-reported rumination, and exploratory analyses provided preliminary evidence supporting the incremental validity of in-session rumination for predicting depression severity after treatment. The results indicate that in-session rumination can be reliably identified during CBT sessions and consistently predicts higher depressive severity, both of which support efforts to develop treatments that specifically target rumination.

Background: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate., Methods: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region., Results: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression., Conclusions: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) is an emerging therapeutic option for treatment resistant neurological and psychiatric disorders, most notably depression. Despite this, little is known about the anatomical and functional mechanisms that underlie this therapy. Here we targeted stimulation to the white matter adjacent to the subcallosal anterior cingulate cortex (SCC-DBS) in macaques, modeling the location in the brain proven effective for depression. We demonstrate that SCC-DBS has a selective effect on white matter macro- and micro-structure in the cingulum bundle distant to where stimulation was delivered. SCC-DBS also decreased functional connectivity between subcallosal and posterior cingulate cortex, two areas linked by the cingulum bundle and implicated in depression. Our data reveal that white matter remodeling as well as functional effects contribute to DBS's therapeutic efficacy., Competing Interests: Conflict of interest: HSM and KC receive consulting fees from Abbott Neuromodulation. The other authors declare no competing financial interest. SHF, AF, CE, AS, EA, GV, WGJ, LF, DF, BER and PER have no competing interests.

Little is known about the effects of common daily experiences in patients with major depressive disorder (MDD). The Daily Hassles and Uplifts Scale (HUPS) was assessed in 142 treatment-naïve adult MDD outpatients randomized to 12 weeks of treatment with either antidepressant medication (ADM) or Cognitive Behavior Therapy (CBT). Three HUPS measures were analyzed: hassle frequency (HF), uplift frequency (UF), and the mean hassle intensity to mean uplift intensity ratio (MHI:MUI). Remission after treatment was not predicted by these baseline HUPS measures and did not moderate outcomes by treatment type. In contrast, HUPS measures significantly changed with treatment and were impacted by remission status. Specifically, HF and MHI:MUI decreased and UF increased from baseline to week 12, with remission leading to significantly greater decreases in HF and MHI:MUI compared to non-remission. ADM-treated patients demonstrated significant improvements on all three HUPS measures regardless of remission status. In contrast, remitters to CBT demonstrated significant improvements in HF and MHI:MUI but not UF; among CBT non-remitters the only significant change was a reduction in HF. The changes in HUPS measures are consistent with how affective biases are impacted by treatments and support the potential value of increasing attention to positive events in CBT., Competing Interests: Declaration of competing interest Dr. Craighead serves on the National Advisory Board for the George West Mental Health Foundation, as a board member of Hugarheill ehf (an Icelandic company dedicated to the prevention of depression), and as a scientific advisory board member for AIM for Mental Health and the Anxiety and Depression Association of America; he is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations; and he receives book royalties from John Wiley. Dr. Mayberg has received consulting and intellectual property licensing fees from Abbott Neuromodulation. Dr. Nemeroff has served as a consultant for AbbVie, ANeuroTech (division of Anima BV), Signant Health, Magstim, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Sage, Silo Pharma, EmbarcNeuro, Engrail Therapeutics, Pasithea Therapeutic Corp., GoodCap Pharmaceuticals, Inc., Senseye, Clexio, EmbarkNeuro, SynapseBio, BioXcel Therapeutics, and Relmada Therapeutics; he has served on scientific advisory boards ANeuroTech (division of Anima BV), Brain and Behavior Research Foundation (BBRF), Anxiety and Depression Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc., Heading Health, Pasithea Therapeutic Corp., and Sage; he holds stock in Seattle Genetics, Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, Precisement Health, Relmada Therapeutics; he serves on the Board of Directors for Gratitude America, ADAA, and Lucy Scientific Discovery, Inc.; and he is named on U.S. patents 6,375,990B1 and 7,148,027B2. Dr. Dunlop has received research support from Boehringer Ingelheim, Compass Pathways, NIMH, Otsuka, Sage, Usona Institute, and Takeda and has served as a consultant for Biohaven, Cerebral Therapeutics, Myriad Neuroscience, NRx Pharmaceuticals, Otsuka, and Sage. Mr. Furman and Ms. Mletzko report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Subcallosal cingulate (SCC) deep brain stimulation (DBS) is an emerging therapy for refractory depression. Good clinical outcomes are associated with the activation of white matter adjacent to the SCC. This activation produces a signature cortical evoked potential (EP), but it is unclear which of the many pathways in the vicinity of SCC is responsible for driving this response. Individualized biophysical models were built to achieve selective engagement of two target bundles: either the forceps minor (FM) or cingulum bundle (CB). Unilateral 2 Hz stimulation was performed in seven patients with treatment-resistant depression who responded to SCC DBS, and EPs were recorded using 256-sensor scalp electroencephalography. Two distinct EPs were observed: a 120 ms symmetric response spanning both hemispheres and a 60 ms asymmetrical EP. Activation of FM correlated with the symmetrical EPs, while activation of CB was correlated with the asymmetrical EPs. These results support prior model predictions that these two pathways are predominantly activated by clinical SCC DBS and provide first evidence of a link between cortical EPs and selective fiber bundle activation., Competing Interests: Competing interests statement:C.C.M. is a paid consultant for Boston Scientific, Co., receives royalties from Hologram Consultants, Neuros Medical, Ceraxis, and Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, CereGate, Cardionomic, Enspire DBS. All other authors declare that they have no competing interests. H.S.M. receives consulting and IP licensing fees from Abbott Labs. K.S.C. is a paid consultant for Abbott Labs.

Dopamine and serotonin are hypothesized to guide social behaviours. In humans, however, we have not yet been able to study neuromodulator dynamics as social interaction unfolds. Here, we obtained subsecond estimates of dopamine and serotonin from human substantia nigra pars reticulata during the ultimatum game. Participants, who were patients with Parkinson's disease undergoing awake brain surgery, had to accept or reject monetary offers of varying fairness from human and computer players. They rejected more offers in the human than the computer condition, an effect of social context associated with higher overall levels of dopamine but not serotonin. Regardless of the social context, relative changes in dopamine tracked trial-by-trial changes in offer value-akin to reward prediction errors-whereas serotonin tracked the current offer value. These results show that dopamine and serotonin fluctuations in one of the basal ganglia's main output structures reflect distinct social context and value signals., (© 2024. The Author(s).)

Deep brain stimulation (DBS) has emerged as a promising treatment for select patients with refractory major depressive disorder (MDD). The clinical effectiveness of DBS for MDD has been demonstrated in meta-analyses, open-label studies, and a few controlled studies. However, randomized controlled trials have yielded mixed outcomes, highlighting challenges that must be addressed prior to widespread adoption of DBS for MDD. These challenges include tracking MDD symptoms objectively to evaluate the clinical effectiveness of DBS with sensitivity and specificity, identifying the patient population that is most likely to benefit from DBS, selecting the optimal patient-specific surgical target and stimulation parameters, and understanding the mechanisms underpinning the therapeutic benefits of DBS in the context of MDD pathophysiology. In this review, we provide an overview of the latest clinical evidence of MDD DBS effectiveness and the recent technological advancements that could transform our understanding of MDD pathophysiology, improve the clinical outcomes for MDD DBS, and establish a path forward to develop more effective neuromodulation therapies to alleviate depressive symptoms., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Depression is prevalent in epilepsy patients and their intracranial brain activity recordings can be used to determine the types of brain activity that are associated with comorbid depression. We performed case-control comparison of spectral power and phase amplitude coupling (PAC) in 34 invasively monitored drug resistant epilepsy patients' brain recordings. The values of spectral power and PAC for one-minute segments out of every hour in a patient's study were correlated with pre-operative assessment of depressive symptoms by Beck Depression Inventory-II (BDI). We identified an elevated PAC signal (theta-alpha-beta phase (5-25 Hz)/gamma frequency (80-100 Hz) band) that is present in high BDI scores but not low BDI scores adult epilepsy patients in brain regions implicated in primary depression, including anterior cingulate cortex, amygdala and orbitofrontal cortex. Our results showed the application of PAC as a network-specific, electrophysiologic biomarker candidate for comorbid depression and its potential as treatment target for neuromodulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Deep Brain Stimulation (DBS) Think Tank XI was held on August 9-11, 2023 in Gainesville, Florida with the theme of "Pushing the Forefront of Neuromodulation". The keynote speaker was Dr. Nico Dosenbach from Washington University in St. Louis, Missouri. He presented his research recently published in Nature inn a collaboration with Dr. Evan Gordon to identify and characterize the somato-cognitive action network (SCAN), which has redefined the motor homunculus and has led to new hypotheses about the integrative networks underpinning therapeutic DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers, and researchers (from industry and academia) can freely discuss current and emerging DBS technologies, as well as logistical and ethical issues facing the field. The group estimated that globally more than 263,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: cutting-edge translational neuromodulation, cutting-edge physiology, advances in neuromodulation from Europe and Asia, neuroethical dilemmas, artificial intelligence and computational modeling, time scales in DBS for mood disorders, and advances in future neuromodulation devices., Competing Interests: ND has a financial interest in Turing Medical Inc. and may financially benefit if the company is successful in marketing FIRMM motion monitoring software products, may receive royalty income based on FIRMM technology developed at Washington University School of Medicine and Oregon Health and Sciences University and licensed to Turing Medical Inc, and is a co-founder of Turing Medical Inc. These potential conflicts of interest have been reviewed and are managed by Washington University School of Medicine. AH reports lecture fees for Boston Scientific and is a consultant for FxNeuromodulation and Abbott. RG is an employee of Rune Labs. JO'K is CEO and Founder of Machine Medicine Technologies. W-JN received honoraria for consulting from InBrain – Neuroelectronics that is a neurotechnology company and honoraria for talks from Medtronic that is a manufacturer of deep brain stimulation devices unrelated to this manuscript. SL has received speaking honoraria from Medtronic and is a consultant for Iota Biosciences. SS is a consultant for Zimmer Biomet, Neuropace, Koh Young, Boston Scientfic, Sensoria Therapeutics, Varian Medical; co-founder for Motif Neurotech. LM is an employee of Boston Scientific. AF has stock ownership in Inbrain Pharma and has received payments as consultant and/or speaker from Abbvie, Abbott, Boston Scientific, Ceregate, Dompé Farmaceutici, Inbrain Neuroelectronics, Ipsen, Medtronic, Iota, Syneos Health, Merz, Sunovion, Paladin Labs, UCB, Sunovion, and he has received research support from Abbvie, Boston Scientific, Medtronic, Praxis, ES and receives royalties from Springer. AH-B and RR are employees of Medtronic Inc. LM is an employee of Boston Scientific. YP is an employee of Abbott. DG is an employee of NeuroPace, owns NeuroPace stock, and has NeuroPace stock options. SM is a founder and shareholder of Newronika SpA. LK is the CEO of Newronika. MP-N has received speaker honoraria/travel costs from Medtronic, Boston Scientific, Abbott, Bial, and Abbvie and study reimbursements from Zambon, Licher, Boston Scientific, and Abbott. LC has received research support from National Institutes of Health and the National Network of Depression Centers and serves on the Board of Directors for the International Neuroethics Society (unpaid) as well as on the Advisory Council for the Institute of Neuroethics think and do thank (unpaid). CM is a paid consultant for Boston Scientific Neuromodulation, receives royalties from Hologram Consultants, Neuros Medical, Qr8 Health, and is a shareholder in the following companies: Hologram Consultants, Surgical Information Sciences, BrainDynamics, CereGate, Cardionomic, Enspire DBS. NH is a co-founder of Surgical Information Sciences (SIS), Inc. HM received consulting and IP licensing fees from Abbott Laboratories. AK has stock options in Neurawell and Big Health and is a consultant for Axsome Therapeutics, Big Health, Eisai, Evecxia, Harmony Biosciences, Idorsia, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Millenium Pharmaceuticals, Merck, Neurocrine Biosciences, Neurawell, Pernix, Otsuka Pharmaceuticals, Sage, and Takeda. NP is a consultant for Abbott and Sensoria Therapeutics. PS receives free research devices from Medtronic and fellowship support funding from Medtronic and BSCI and no personal income from anyone. KF reports receiving research support and fellowship support from Medtronic and Boston Scientific and research support from Functional Neuromodulation. MO serves as Medical Advisor the Parkinson's Foundation, and has received research grants from NIH, Parkinson's Foundation, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. MO has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, Perseus, Robert Rose, Oxford and Cambridge (movement disorders books). MO is an associate editor for New England Journal of Medicine Journal, Watch Neurology, and JAMA Neurology. MO has participated in CME and educational activities (past 12-24 months) on movement disorders sponsored by WebMD/Medscape, RMEI Medical Education, American Academy of Neurology, Movement Disorders Society, Mediflix and by Vanderbilt University. The institution and not MO receives grants from industry. MO has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Research projects at the University of Florida receive device and drug donations. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Johnson, Dosenbach, Gordon, Welle, Wilkins, Bronte-Stewart, Voon, Morishita, Sakai, Merner, Lázaro-Muñoz, Williamson, Horn, Gilron, O'Keeffe, Gittis, Neumann, Little, Provenza, Sheth, Fasano, Holt-Becker, Raike, Moore, Pathak, Greene, Marceglia, Krinke, Tan, Bergman, Pötter-Nerger, Sun, Cabrera, McIntyre, Harel, Mayberg, Krystal, Pouratian, Starr, Foote, Okun and Wong.)

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) is an experimental therapy for treatment-resistant depression (TRD). Chronic SCC DBS leads to long-term changes in the electrophysiological dynamics measured from local field potential (LFP) during wakefulness, but it is unclear how it impacts sleep-related brain activity. This is a crucial gap in knowledge, given the link between depression and sleep disturbances, and an emerging interest in the interaction between DBS, sleep, and circadian rhythms. We therefore sought to characterize changes in electrophysiological markers of sleep associated with DBS treatment for depression. We analyzed key electrophysiological signatures of sleep-slow-wave activity (SWA, 0.5-4.5 Hz) and sleep spindles-in LFPs recorded from the SCC of 9 patients who responded to DBS for TRD. This allowed us to compare the electrophysiological changes before and after 24 weeks of therapeutically effective SCC DBS. SWA power was highly correlated between hemispheres, consistent with a global sleep state. Furthermore, SWA occurred earlier in the night after chronic DBS and had a more prominent peak. While we found no evidence for changes to slow-wave power or stability, we found an increase in the density of sleep spindles. Our results represent a first-of-its-kind report on long-term electrophysiological markers of sleep recorded from the SCC in patients with TRD, and provides evidence of earlier NREM sleep and increased sleep spindle activity following clinically effective DBS treatment. Future work is needed to establish the causal relationship between long-term DBS and the neural mechanisms underlying sleep., (© 2024. The Author(s).)

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples ( N  = 1,384) of medication-free individuals with first-episode and recurrent MDD ( N  = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls ( N  = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals ( N  = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter ( N  = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter ( N  = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) ( β  = -18.3, 95% CI (-34.3 to -2.3), P  = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response., Competing Interests: Competing interestsS.R.A. has consulted for Indoc Research Canada. B.W.D. has received research support from Boehringer-Ingelheim, Compass, Pathways, NIMH, Otsuka, and Uson and honoraria for consulting from Aya Biosciences, Myriad Neuroscience, Otsuka, Sophren Therapeutics, Cerebral Therapeutics, Sage. C.H.Y.F. has received grant funding from Brain and Behavior (NARSAD), Eli Lilly and Co. Milken Institute, Flow Neuroscience, MRC, NIMH, Rosetrees Trust, and Wellcome Trust and is Section Editor of Brain Research Bulletin. C.J.H. serves as a consultant for P1vital, Lundbeck, Servier, and Compass Pathways. She holds grant income from Zogenix and J&J. S.H.K. has received funding for consulting or speaking engagements from Abbvie, Boehringer-Ingelheim, Janssen, Lundbeck, Lundbeck Institute, Merck, Otsuka Pfizer, Sunovion, and Servier. He has received research support from Abbott, Brain Canada, CIHR (Canadian Institutes of Health Research), Janssen, Lundbeck, Ontario Brain Institute, Otsuka, Pfizer, and SPOR (Canada’s Strategy for Patient-Oriented Research). He has stock/stock options in Field Trip Health. G.M.K. has received honoraria as a speaker for Sage Biogen and as a consultant for Sanos. H.S.M. has received grant funding from NIH and consulting and IP licenses fees from Abbott Labs. A.M.M. has received research support from Eli Lilly, Janssen, and The Sackler Trust. A.M.M. has also received speaker fees from Illumina and Janssen. W.E.C. serves on the National Advisory Board of the George West Mental health Foundation, as a board member of Hugarheill ehf (an Icelandic company dedicated to the prevention of depression), and on the scientific advisory boards of AIM for Mental Health and the Anxiety and Depression Association of America; he is supported by the Mary and John Brock Foundation, the Pitts Foundation, and the Fuqua family foundations, and he receives book royalties from John Wiley. H.S. has received grant funding from NIH. S.C.S. received research support from Brain Canada, CIHR (Canadian Institutes of Health Research), Ontario Brain Institute, and CFI (Canadian Foundation for Innovation). S.C.S. is a founder and shareholder of ADMdx, Inc. D.T. has received grant funding from NIH. M.H.T. received research support from NIH, PCORI, and AFSP, is a consultant for Alkermes Inc., Alto Neuroscience Inc, Axsome Therapeutics, Boegringer Ingelheim, GH Research, GreenLight VitalSign6 Inc, Heading Health, Inc., Janssen Pharmaceutical, Legion Health, Merck Sharp & Dohme Corp., Mind Medicine Inc., Navitor, Neurocrine Biosciences Inc., Noema Pharma AG, Orexo US Inc., Otsuka Canada Pharmaceutical Inc, Otsuka Pharmaceutical Development & Commercialization, Inc. (MDD section adviser), SAGE Therapeutics, Signant Health, and Takeda Pharmaceuticals Inc and receives editorial compensation from Oxford University Press. A.H.Y. reports the following conflicts of interest: paid lectures and advisory boards for the following companies: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS, Sage, Novartis; consultant to Johnson & Johnson and to Livanova; received honoraria for attending advisory boards and presenting talks at meetings organized by LivaNova; principal investigator in the Restore-Life VNS registry study funded by LivaNova; UK chief investigator for Novartis MDD study MIJ821A12201; principal investigator on ESKETINTRD3004: ‘An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression’; principal investigator on ‘The Effects of Psilocybin on Cognitive Function in Healthy Participants’; principal investigator on ‘The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)’; no shareholdings in pharmaceutical companies; deputy editor of BJPsych Open. Grant funding (past and present): NIMH (USA); CIHR (Canada); NARSAD (USA); Stanley Medical Research Institute (USA); MRC (UK); Wellcome Trust (UK); Royal College of Physicians (Edin); BMA (UK); UBC-VGH Foundation (Canada); WEDC (Canada); CCS Depression Research Fund (Canada); MSFHR (Canada); NIHR (UK); Janssen (UK). R.Z. is a private psychiatrist service provider at The London Depression Institute and co-investigator on a Livanova-funded observational study of vagus nerve stimulation for depression. R.Z. has received honoraria for talks at medical symposia sponsored by Lundbeck as well as Janssen. He has collaborated with EMIS PLC and advises Depsee Ltd. He is affiliated with the D’Or Institute of Research and Education, Rio de Janeiro, and advises the Scients Institute, USA. Authors A. Singh, A. Stolicyn, B.R.G., B.N.F., C.C.F., C.-G.Y., C.D., D.A., D.W., G.E., H.C.W., I.H.G., I.M.A., I.S., J.F.W.D., J.Q., J.S., J.A.G., K.H., K.S.C., K.Q., M.P.P., M.A., M.D.S., M.G., Q.G., R.E., S.H., S.R., T.A.V., T.C., T.W., V.G.F., and Y.F. declare that they have no competing interests., (© The Author(s) 2024.)

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment., (© 2023. The Author(s).)

Recurrent episodes in major depressive disorder (MDD) are common but the neuroimaging features predictive of recurrence are not established. Participants in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study who achieved remission after 12 weeks of treatment withcognitive behavior therapy, duloxetine, or escitalopram were prospectively monitored for up to 21 months for recurrence. Neuroimaging markers predictive of recurrence were identified from week 12 functional magnetic resonance imaging scans by analyzing whole-brain resting state functional connectivity (RSFC) using seeds for four brain networks that are altered in MDD. Neuroimaging correlates of established clinical predictors of recurrence, including the magnitude of depressive (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) symptom severity at time of remission, and a comorbid anxiety disorder were examined for their similarity to the neuroimaging predictors of recurrence. Of the 344 patients randomized in PReDICT, 61 achieved remission and had usable scans for analysis, 9 of whom experienced recurrence during follow-up. Recurrence was predicted by: 1) increased RSFC between subcallosal cingulate cortex (SCC) and right anterior insula, 2) decreased RSFC between SCC and bilateral primary visual cortex, and 3) decreased RSFC between insula and bilateral caudate. Week 12 depression and anxiety scores were negatively correlated with RSFC strength between executive control and default mode networks, but they were not correlated with the three RSFC patterns predicting recurrence. We conclude that altered RSFC in SCC and anterior insula networks are prospective risk factors associated with MDD recurrence, reflecting additional sources of risk beyond clinical measures., (© 2023. American College of Neuropsychopharmacology.)

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD) 1 . However, achieving stable recovery is unpredictable 2 , typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting 3 . We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment., (© 2023. The Author(s).)

Background: Deep brain stimulation of the subcallosal cingulate area (SCC-DBS) is a promising neuromodulatory therapy for treatment-resistant depression (TRD). Biomarkers of optimal target engagement are needed to guide surgical targeting and stimulation parameter selection and to reduce variance in clinical outcome., Objective/hypothesis: We aimed to characterize the relationship between stimulation location, white matter tract engagement, and clinical outcome in a large (n = 60) TRD cohort treated with SCC-DBS. A smaller cohort (n = 22) of SCC-DBS patients with differing primary indications (bipolar disorder/anorexia nervosa) was utilized as an out-of-sample validation cohort., Methods: Volumes of tissue activated (VTAs) were constructed in standard space using high-resolution structural MRI and individual stimulation parameters. VTA-based probabilistic stimulation maps (PSMs) were generated to elucidate voxelwise spatial patterns of efficacious stimulation. A whole-brain tractogram derived from Human Connectome Project diffusion-weighted MRI data was seeded with VTA pairs, and white matter streamlines whose overlap with VTAs related to outcome ('discriminative' streamlines; P uncorrected < 0.05) were identified using t-tests. Linear modelling was used to interrogate the potential clinical relevance of VTA overlap with specific structures., Results: PSMs varied by hemisphere: high-value left-sided voxels were located more anterosuperiorly and squarely in the lateral white matter, while the equivalent right-sided voxels fell more posteroinferiorly and involved a greater proportion of grey matter. Positive discriminative streamlines localized to the bilateral (but primarily left) cingulum bundle, forceps minor/rostrum of corpus callosum, and bilateral uncinate fasciculus. Conversely, negative discriminative streamlines mostly belonged to the right cingulum bundle and bilateral uncinate fasciculus. The best performing linear model, which utilized information about VTA volume overlap with each of the positive discriminative streamline bundles as well as the negative discriminative elements of the right cingulum bundle, explained significant variance in clinical improvement in the primary TRD cohort (R = 0.46, P < 0.001) and survived repeated 10-fold cross-validation (R = 0.50, P = 0.040). This model was also able to predict outcome in the out-of-sample validation cohort (R = 0.43, P = 0.047)., Conclusion(s): These findings reinforce prior indications of the importance of white matter engagement to SCC-DBS treatment success while providing new insights that could inform surgical targeting and stimulation parameter selection decisions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.M.L. is the co-founder of Functional Neuromodulation (a DBS-related company) and is a consultant for Boston Scientific, Medtronic and Abbott (companies that produce DBS hardware). H.S.M., P.G., and S.H.K. are consultants for Abbott. G.J.B.E., A.B., H.S.M, and A.M.L. have intellectual property in the field of DBS. All other authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The field of stereotactic neurosurgery developed more than 70 years ago to address a therapy gap for patients with severe psychiatric disorders. In the decades since, it has matured tremendously, benefiting from advances in clinical and basic sciences. Deep brain stimulation (DBS) for severe, treatment-resistant psychiatric disorders is currently poised to transition from a stage of empiricism to one increasingly rooted in scientific discovery. Current drivers of this transition are advances in neuroimaging, but rapidly emerging ones are neurophysiological-as we understand more about the neural basis of these disorders, we will more successfully be able to use interventions such as invasive stimulation to restore dysfunctional circuits to health. Paralleling this transition is a steady increase in the consistency and quality of outcome data. Here, we focus on obsessive-compulsive disorder and depression, two topics that have received the most attention in terms of trial volume and scientific effort.

Biological assay and imaging techniques have made visible a great deal of the machinery of mental illness. Over fifty years of investigation of mood disorders using these technologies has identified several biological regularities in these disorders. Here we present a narrative connecting genetic, cytokine, neurotransmitter, and neural-systems-level findings in major depressive disorder (MDD). Specifically, we connect recent genome-wide findings in MDD to metabolic and immunological disturbance in this disorder and then detail links between immunological abnormalities and dopaminergic signaling within cortico-striatal circuitry. Following this, we discuss implications of reduced dopaminergic tone for cortico-striatal signal conduction in MDD. Finally, we specify some of the flaws in the current model and propose ways forward for advancing multilevel formulations of MDD most efficiently., (© 2023. The Author(s).)

It remains elusive what language markers derived from psychotherapy sessions are indicative of therapeutic alliance, limiting our capacity to assess and provide feedback on the trusting quality of the patient-clinician relationship. To address this critical knowledge gap, we leveraged feature extraction methods from natural language processing (NLP), a subfield of artificial intelligence, to quantify pronoun and non-fluency language markers that are relevant for communicative and emotional aspects of therapeutic relationships. From twenty-eight transcripts of non-manualized psychotherapy sessions recorded in outpatient clinics, we identified therapists' first-person pronoun usage frequency and patients' speech transition marking relaxed interaction style as potential metrics of alliance. Behavioral data from patients who played an economic game that measures social exchange (i.e. trust game) suggested that therapists' first-person pronoun usage may influence alliance ratings through their diminished trusting behavior toward therapists. Together, this work supports that communicative language features in patient-therapist dialogues could be markers of alliance., Competing Interests: H.S.M. receives consulting and IP licensing fees from Abbott Labs., (© 2023 The Author(s).)

Objective: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) have differential therapeutic effects for Parkinson's disease (PD) that drive patient selection. For example, GPi DBS is preferred for dystonic features and dyskinesia, whereas STN DBS has shown faster tremor control and medication reduction. Connectivity studies comparing these two targets, using patient-specific data, are still lacking. The objective was to find STN and GPi structural connectivity patterns in order to better understand differences in DBS-activated brain circuits between these two stimulation targets and to guide optimal contact selection., Methods: The authors simulated DBS activation along the main axis of both the STN and GPi by using volume of activated tissue (VAT) modeling with known average stimulation parameters (2.8 V and 60 μsec for STN; 3.3 V and 90 μsec for GPi). The authors modeled VATs in the anterior, middle, and posterior STN and the anterior, midanterior, midposterior, and posterior GPi. The authors generated maps of the connections shared by the patients for each VAT by using probabilistic tractography of diffusion-weighted imaging data obtained in 46 PD patients who underwent DBS (26 with STN and 20 with GPi targeting), and differences between VATs for whole-brain and distal regions of interest (prefrontal cortex, supplementary motor area, primary motor cortex, primary sensory cortex, caudate, motor thalamus, and cerebellum) were generated from structural atlases. Differences between maps were quantified and compared., Results: VATs across the STN and GPi had different structural connectivity patterns. The authors found significant connectivity differences between VATs for all regions of interest. Posterior and middle STN showed stronger connectivity to the primary motor cortex and supplementary motor area (SMA) (p < 0.001). Posterior STN had the strongest connectivity to the primary sensory cortex and motor thalamus (p < 0.001). Posterior GPi showed stronger connectivity to the primary motor cortex (p < 0.001). Connectivity to the SMA was similar for the posterior and midposterior GPi (p > 0.05), which was greater than that for the anterior GPi (p < 0.001). When both nuclei were compared, posterior and middle STN had stronger connectivity to the SMA, cerebellum, and motor thalamus than GPi (all p < 0.001). Posterior GPi and STN had similar connectivity to the primary sensory cortex., Conclusions: On patient-specific imaging, structural connectivity differences existed between GPi and STN DBS, as measured with standardized electrical field modeling of the DBS targets. These connectivity differences may correlate with the differential clinical benefits obtained by targeting each of the two nuclei with DBS for PD. Prospective work is needed to relate these differences to clinical outcomes and to inform targeting and programming.

Major depressive disorder (MDD) exhibits diverse symptomology and neuroimaging studies report widespread disruption of key brain areas. Numerous theories underpinning the network degeneration hypothesis (NDH) posit that neuropsychiatric diseases selectively target brain areas via meaningful network mechanisms rather than as indistinct disease effects. The present study tests the hypothesis that MDD is a network-based disorder, both structurally and functionally. Coordinate-based meta-analysis and Activation Likelihood Estimation (CBMA-ALE) were used to assess the convergence of findings from 92 previously published studies in depression. An extension of CBMA-ALE was then used to generate a node-and-edge network model representing the co-alteration of brain areas impacted by MDD. Standardized measures of graph theoretical network architecture were assessed. Co-alteration patterns among the meta-analytic MDD nodes were then tested in independent, clinical T1-weighted structural magnetic resonance imaging (MRI) and resting-state functional (rs-fMRI) data. Differences in co-alteration profiles between MDD patients and healthy controls, as well as between controls and clinical subgroups of MDD patients, were assessed. A 65-node 144-edge co-alteration network model was derived for MDD. Testing of co-alteration profiles in replication data using the MDD nodes provided distinction between MDD and healthy controls in structural data. However, co-alteration profiles were not distinguished between patients and controls in rs-fMRI data. Improved distinction between patients and healthy controls was observed in clinically homogenous MDD subgroups in T1 data. MDD abnormalities demonstrated both structural and functional network architecture, though only structural networks exhibited between-groups differences. Our findings suggest improved utility of structural co-alteration networks for ongoing biomarker development., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The authors sought to determine the shared and unique changes in brain resting-state functional connectivity (rsFC) between patients with major depressive disorder who achieved remission with cognitive-behavioral therapy (CBT) or with antidepressant medication., Methods: The Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) trial randomized adults with treatment-naive major depressive disorder to 12 weeks of treatment with CBT (16 1-hour sessions) or medication (duloxetine 30-60 mg/day or escitalopram 10-20 mg/day). Resting-state functional MRI scans were performed at baseline and at week 12. The primary outcome was change in the whole-brain rsFC of four seeded brain networks among participants who achieved remission., Results: Of the 131 completers with usable MRI data (74 female; mean age, 39.8 years), remission was achieved by 19 of 40 CBT-treated and 45 of 91 medication-treated patients. Three patterns of connectivity changes were observed. First, those who remitted with either treatment shared a pattern of reduction in rsFC between the subcallosal cingulate cortex and the motor cortex. Second, reciprocal rsFC changes were observed across multiple networks, primarily increases in CBT remitters and decreases in medication remitters. And third, in CBT remitters only, rsFC increased within the executive control network and between the executive control network and parietal attention regions., Conclusions: Remission from major depression via treatment with CBT or medication is associated with changes in rsFC that are mostly specific to the treatment modality, providing biological support for the clinical practice of switching between or combining these treatment approaches. Medication is associated with broadly inhibitory effects. In CBT remitters, the increase in rsFC strength between networks involved in cognitive control and attention provides biological support for the theorized mechanism of CBT. Reducing affective network connectivity with motor systems is a shared process important for remission with both CBT and medication.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation . Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS., Competing Interests: HM received consulting and IP licensing fees from Abbott Labs. WG received consulting fees from Biohaven and royalties from Nview, LLC and OCDscales, and LLC. EP had received research support from Mainstay, Medtronic, Neuros Medical, Nevro Corp, ReNeuron, SPR, and Saluda, personal fees from Abbott Neuromodulation, Biotronik, Medtronic Neuromodulation, Nalu, Neuros Medical, Nevro, Presidio Medical, Saluda, and Vertos, and holds stock options from SynerFuse and Neuro42. JV had received consulting fees and grant support by Medtronic and Boston Scientific both manufacturers of DBS systems, consulting fees by Newronika and CereGate and honoraria for lecturing by Abbott. JH was a consultant for Neuralink and serves on the Medical Advisory Board of Enspire DBS. SS was a consultant for Boston Scientific, Zimmer Biomet, NeuroPace, Koh Young, and is a co-founder of Motif Neurotech. RSR was employed by Medtronic Inc. MM was employed by Boston Scientific Neuromodulation Corporation. DG was employed by NeuroPace, Inc. LK, MA, LR, SMa, and AP were employed by Newronika. RG was employed by Rune Labs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wong, Mayberg, Wang, Richardson, Halpern, Krinke, Arlotti, Rossi, Priori, Marceglia, Gilron, Cavanagh, Judy, Miocinovic, Devergnas, Sillitoe, Cernera, Oehrn, Gunduz, Goodman, Petersen, Bronte-Stewart, Raike, Malekmohammadi, Greene, Heiden, Tan, Volkmann, Voon, Li, Sah, Coyne, Silburn, Kubu, Wexler, Chandler, Provenza, Heilbronner, Luciano, Rozell, Fox, de Hemptinne, Henderson, Sheth and Okun.)

Background: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states., Methods: We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants., Results: We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites., Conclusion: We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project., (© 2023. The Author(s).)

Deep brain stimulation (DBS) devices capable of measuring differential local field potentials ( ∂ LFP) enable neural recordings alongside clinical therapy. Efforts to identify oscillatory correlates of various brain disorders, or disease readouts, are growing but must proceed carefully to ensure readouts are not distorted by brain environment. In this report we identified, characterized, and mitigated a major source of distortion in ∂ LFP that we introduce as mismatch compression (MC). Using in vivo, in silico, and in vitro models of MC, we showed that impedance mismatches in the two recording electrodes can yield incomplete rejection of stimulation artifact and subsequent gain compression that distorts oscillatory power. We then developed and validated an opensource mitigation pipeline that mitigates the distortions arising from MC. This work enables more reliable oscillatory readouts for adaptive DBS applications.

The study evaluated if rumination of patients during therapy (i.e., in-session rumination) relates to whether or not they do less well in CBT treatment. We developed a reliably assessed in-session rumination observational measure and evaluated its relationship to depression over the course of CBT. Rated sessions came from 63 treatment-naïve patients with major depressive disorder who participated in CBT in the PReDICT study (Dunlop et al., 2017). In-session rumination was operationalized as repetitive, negative, and passive talking about depressive topics. Trained undergraduates rated the intensity and duration of in-session rumination occurring during 57 initial therapy sessions (i.e., session one) and 45 sessions in the middle of treatment (i.e., session eight). The observational ratings were sufficiently reliable (all ICCs > 0.69). Mixed model results indicated that greater intensity of in-session rumination during the initial treatment session predicted higher levels of subsequent clinician-rated depressive symptoms (p < .023). Regression results indicated that greater intensity and duration of in-session rumination at session 8 significantly predicted higher clinician-rated symptoms at end of treatment (p's < 0.02). In-session rumination intensity and duration were not, however, related to subsequent self-reported depressive symptoms. The results support efforts to identify which patients might benefit from rumination-specific interventions., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Precision targeting of specific white matter bundles that traverse the subcallosal cingulate (SCC) has been linked to efficacy of deep brain stimulation (DBS) for treatment resistant depression (TRD). Methods to confirm optimal target engagement in this heterogenous region are now critical to establish an objective treatment protocol. As yet unexamined are the time-frequency features of the SCC evoked potential (SCC-EP), including spectral power and phase-clustering. We examined these spectral features-evoked power and phase clustering-in a sample of TRD patients ( n = 8) with implanted SCC stimulators. Electroencephalogram (EEG) was recorded during wakeful rest. Location of electrical stimulation in the SCC target region was the experimental manipulation. EEG was analyzed at the surface level with an average reference for a cluster of frontal sensors and at a time window identified by prior study (50-150 ms). Morlet wavelets generated indices of evoked power and inter-trial phase clustering. Enhanced phase clustering at theta frequency (4-7 Hz) was observed in every subject and was significantly correlated with SCC-EP magnitude, but only during left SCC stimulation. Stimulation to dorsal SCC evinced stronger phase clustering than ventral SCC. There was a weak correlation between phase clustering and white matter density. An increase in evoked delta power (2-4 Hz) was also coincident with SCC-EP, but was less consistent across participants. DBS evoked time-frequency features index mm-scale changes to the location of stimulation in the SCC target region and correlate with structural characteristics implicated in treatment optimization. Results also imply a shared generative mechanism (inter-trial phase clustering) between evoked potentials evinced by electrical stimulation and evoked potentials evinced by auditory/visual stimuli and behavioral tasks. Understanding how current injection impacts downstream cortical activity is essential to building new technologies that adapt treatment parameters to individual differences in neurophysiology., Competing Interests: HM received consulting and intellectual property licensing fees from Abbott Labs. KC received consulting fees from Abbott Labs. The terms approved by Emory University and the Icahn School of Medicine in accordance with policies to manage conflict of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Smith, Choi, Veerakumar, Obatusin, Howell, Smith, Tiruvadi, Crowell, Riva-Posse, Alagapan, Rozell, Mayberg and Waters.)

Deep brain stimulation has been extensively studied as a therapeutic option for treatment-resistant depression (TRD). DBS across different targets is associated with on average 60% response rates in previously refractory chronically depressed patients. However, response rates vary greatly between patients and between studies and often require extensive trial-and-error optimizations of stimulation parameters. Emerging evidence from tractography imaging suggests that targeting combinations of white matter tracts, rather than specific grey matter regions, is necessary for meaningful antidepressant response to DBS. In this article, we review efficacy of various DBS targets for TRD, which networks are involved in their therapeutic effects, and how we can use this information to improve targeting and programing of DBS for individual patients. We will also highlight how to integrate these DBS network findings into developing adaptive stimulation and optimal trial designs., (© 2022. The American Society for Experimental NeuroTherapeutics, Inc.)

Background: Major depressive disorder (MDD) is a highly heterogenous disease, both in terms of clinical profiles and pathobiological alterations. Recently, immunometabolic dysregulations were shown to be correlated with atypical, energy-related symptoms but less so with the Melancholic or Anxious distress symptom dimensions of depression in The Netherlands Study of Depression and Anxiety (NESDA) study. In this study, we aimed to replicate these immunometabolic associations and to characterize the metabolomic correlates of each of the three MDD dimensions., Methods: Using three clinical rating scales, Melancholic, and Anxious distress, and Immunometabolic (IMD) dimensions were characterized in 158 patients who participated in the Predictors of Remission to Individual and Combined Treatments (PReDICT) study and from whom plasma and serum samples were available. The NESDA-defined inflammatory index, a composite measure of interleukin-6 and C-reactive protein, was measured from pre-treatment plasma samples and a metabolomic profile was defined using serum samples analyzed on three metabolomics platforms targeting fatty acids and complex lipids, amino acids, acylcarnitines, and gut microbiome-derived metabolites among other metabolites of central metabolism., Results: The IMD clinical dimension and the inflammatory index were positively correlated (r = 0.19, p = 0.019) after controlling for age, sex, and body mass index, whereas the Melancholic and Anxious distress dimensions were not, replicating the previous NESDA findings. The three symptom dimensions had distinct metabolomic signatures using both univariate and set enrichment statistics. IMD severity correlated mainly with gut-derived metabolites and a few acylcarnitines and long chain saturated free fatty acids. Melancholia severity was significantly correlated with several phosphatidylcholines, primarily the ether-linked variety, lysophosphatidylcholines, as well as several amino acids. Anxious distress severity correlated with several medium and long chain free fatty acids, both saturated and polyunsaturated ones, sphingomyelins, as well as several amino acids and bile acids., Conclusion: The IMD dimension of depression appears reliably associated with markers of inflammation. Metabolomics provides powerful tools to inform about depression heterogeneity and molecular mechanisms related to clinical dimensions in MDD, which include a link to gut microbiome and lipids implicated in membrane structure and function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In this perspective article, we consider the critical issue of data and other research object standardisation and, specifically, how international collaboration, and organizations such as the International Neuroinformatics Coordinating Facility (INCF) can encourage that emerging neuroscience data be Findable, Accessible, Interoperable, and Reusable (FAIR). As neuroscientists engaged in the sharing and integration of multi-modal and multiscale data, we see the current insufficiency of standards as a major impediment in the Interoperability and Reusability of research results. We call for increased international collaborative standardisation of neuroscience data to foster integration and efficient reuse of research objects., (© 2021. The Author(s).)

Competing Interests: Declaration of interests HH reports her role as President of the World Psychiatric Association during the period of preparing and submitting the Commission for publication, and support from an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship. VP reports being a co-founder of Librum, a mental health consulting firm, and has consulted with Johnson & Johnson, with no fees received related to the submitted work. His research on depression is supported by the National Institute of Mental Health (NIMH) and the Wellcome Trust. CK is a researcher from Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil, and a UK Academy of Medical Sciences Newton Advanced Fellow. MB reports grants from the NHMRC as Senior Principal Research Fellow, during the conduct of the study; personal fees from Servier, Lundbeck, Livanova, Grunbiotics, Otsuka, RANZCP, ANZJP, and Medisquire India, outside of the submitted work; and three issued patents (Modulation of Physiological processes and agents useful for same, Modulation of diseases of the central nervous system and related disorders, and Xanthone-rich plant extracts or compounds therefrom for modulating diseases of the central nervous system and related disorders issued). CB reports travel support from the Wellcome Trust and personal fees from the University of Melbourne and the World Psychiatric Association, during the conduct of the study. PC reports support for unrelated grants from the European Commission and ZonMw, and receives royalties for books and for occasional workshops and invited addresses. TAF reports grants and personal fees from Mitsubishi-Tanabe and Shionogi, and personal fees from Sony, outside of the submitted work. TAF also has a patent 2020-548587 concerning smartphone cognitive behavioural therapy applications pending, and intellectual properties for Kokoro-application licensed to Tanabe-Mitsubishi. RCK was a consultant for Datastat, Holmusk, RallyPoint Networks, and Sage Pharmaceuticals. He has stock options in Cerebral, Mirah, PYM, and Roga Sciences. CFR reports consultant fees from the Depression and Bipolar Support Alliance, Weill Cornell School of Medicine, UpToDate, The University of Maryland School of Public Health, Psychopharmacology Institute, and Merck; and an honorarium from the American Association for Geriatric Psychiatry, outside of the submitted work; and royalties from the University of Pittsburgh and Oxford University Press. Since 2018, MMW has received research funding from NIMH, Brain and Behavior Foundation, Templeton Foundation, and the Sackler Foundation, and has received book royalties from Perseus Press, Oxford University Press, and APA Publishing and royalties on the social adjustment scale from Multihealth Systems. DC is funded by the African Academy of Sciences and is a founder of Friendship Bench, which is supported by Boehringer Ingelheim, Draper Richards Kaplan Foundation, Mulago Foundation, Africa Visionary Fund, David Weekley Foundation, Grand Challenges Africa, Grand Challenges Canada, Schooner Foundation and Zoom Cares. CD reports grants from National Institute for Health and Social Care (England), personal fees from World Organisation of Family Doctors, personal fees from iheed—Accredited Medical Education Online (Ireland), outside of the submitted work; and as Chair of the Working Party for Mental Health of the World Organisation for Family Doctors, CD advocates for the central role of family doctors in the assessment and management of depression in primary care settings. LMH reports funding from the South London and Maudsley NHS Foundation Trust/King's College London Biomedical Research Centre; the UKRI Collaborative Mental Health Network plus: Violence, Abuse and Mental Health: Opportunities for change (ES/S004424/1); National Institute for Health Research (NIHR) HS&DR ESMI II: The Effectiveness and cost effectiveness of community perinatal Mental health services (17/49/38); and salary support from the South London NIHR Applied Research Collaboration. CWH reports funding from NIMH, National Institute of Drug Abuse, National Heart, Lung, and Blood Institute, Fogarty International Center, and Centers for Disease Control and Prevention–National Institute for Occupational Safety and Health. HSM reports personal fees from Abbott Laboratories, outside of the submitted work; and a patent US 2005/0033379A1 licensed to Abbott Laboratories. BWJHP reports grants from Jansen Research and Boehringer Ingelheim, outside of the submitted work. MT reports personal fees from Acadia Pharmaceuticals, Allergan, Alto Neuroscience, Axsome Therapeutics, Engage Health Media, GreenLight VitalSign6, Janssen, Merck Sharp & Dohme, Myriad Neuroscience, Navitor Pharmaceutical, Otsuka, Perception Neuroscience, SAGE Therapeutics, Signant Health, Academy Health, Akili Interactive, Health Research Associates, Jazz Pharmaceutical, Lundbeck Research USA, Perception Neuroscience Holdings, and Pharmerit International, outside of the submitted work. All other authors declare no competing interests.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury., Competing Interests: RR was employed by Medtronic, Inc. HBo was employed by Boston Scientific Neuromodulation Corporation. DG was employed by the NeuroPace, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wong, Deuschl, Wolke, Bergman, Muthuraman, Groppa, Sheth, Bronte-Stewart, Wilkins, Petrucci, Lambert, Kehnemouyi, Starr, Little, Anso, Gilron, Poree, Kalamangalam, Worrell, Miller, Schiff, Butson, Henderson, Judy, Ramirez-Zamora, Foote, Silburn, Li, Oyama, Kamo, Sekimoto, Hattori, Giordano, DiEuliis, Shook, Doughtery, Widge, Mayberg, Cha, Choi, Heisig, Obatusin, Opri, Kaufman, Shirvalkar, Rozell, Alagapan, Raike, Bokil, Green and Okun.)

Background: Individuals experiencing socioeconomic deprivation consistently demonstrate poorer physical and mental health. Income alone is inadequate as a measure of socioeconomic status (SES); a better measure for assessing the deprivation status of individuals is needed., Methods: The New Zealand Index of Socioeconomic Deprivation for Individuals, a validated, eight-item measure of deprivation, was modified to create the United States Index of Socioeconomic Deprivation for Individuals (USiDep). The questionnaire was administered to patients with major depressive disorder participating in two clinical trials. Spearman's correlation coefficients evaluated associations between USiDep scores with income and other measures associated with deprivation., Results: The USiDep was completed by 118 participants, demonstrating adequate internal consistency (Crohnbach's alpha = 0.766) and strong item-total correlations. USiDep scores were moderately correlated with past-year personal income (Spearman's rho = -0.362, p < .001) and several other measures related to deprivation, including body mass index, level of education, quality of life, severity of childhood traumatic events, self-reported physical health, and negative life events. Patients scoring 5 on the USiDep (the highest possible score, indicating greater deprivation) had significantly lower rates of remission after 12 weeks of treatment than those scoring ≤ 4 (1/12, 8.3% vs 40/98, 40.8%, respectively, p = .03), whereas the lowest income group showed no significant associations with outcomes., Conclusion: The USiDep is a valid, brief questionnaire for assessing SES that has utility for clinical research and may serve as a predictor of treatment outcomes in clinical trials. Validation of the USiDep in healthy controls and other medically and psychiatrically ill populations is warranted.

At the group-level, deep brain stimulation leads to significant therapeutic benefit in a multitude of neurological and neuropsychiatric disorders. At the single-patient level, however, symptoms may sometimes persist despite "optimal" electrode placement at established treatment coordinates. This may be partly explained by limitations of disease-centric strategies that are unable to account for heterogeneous phenotypes and comorbidities observed in clinical practice. Instead, tailoring electrode placement and programming to individual patients' symptom profiles may increase the fraction of top-responding patients. Here, we propose a three-step, circuit-based framework with the aim of developing patient-specific treatment targets that address the unique symptom constellation prevalent in each patient. First, we describe how a symptom network target library could be established by mapping beneficial or undesirable DBS effects to distinct circuits based on (retrospective) group-level data. Second, we suggest ways of matching the resulting symptom networks to circuits defined in the individual patient (template matching). Third, we introduce network blending as a strategy to calculate optimal stimulation targets and parameters by selecting and weighting a set of symptom-specific networks based on the symptom profile and subjective priorities of the individual patient. We integrate the approach with published literature and conclude by discussing limitations and future challenges., (Copyright © 2021 Elsevier Ltd. All rights reserved.)