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Peter S Micalos,1 Mayuresh S Korgaonkar,2 Eric J Drinkwater,3 Jack Cannon,3 Frank E Marino3 1School of Biomedical Sciences, Charles Sturt University, Bathurst, 2Brain Dynamics Centre, Westmead Millennium Institute, University of Sydney Medical School, Sydney, 3School of Human Movement Studies, Charles Sturt University, Bathurst, NSW, Australia Objective: The purpose of this research was to assess the functional brain activity and perceptual rating of innocuous somatic pressure stimulation before and after exercise rehabilitation in patients with chronic pain. Materials and methods: Eleven chronic pain patients and eight healthy pain-free controls completed 12 weeks of supervised aerobic exercise intervention. Perceptual rating of standardized somatic pressure stimulation (2 kg) on the right anterior mid-thigh and brain responses during functional magnetic resonance imaging (fMRI) were assessed at pre- and postexercise rehabilitation. Results: There was a significant difference in the perceptual rating of innocuous somatic pressure stimulation between the chronic pain and control groups (P=0.02) but no difference following exercise rehabilitation. Whole brain voxel-wise analysis with correction for multiple comparisons revealed trends for differences in fMRI responses between the chronic pain and control groups in the superior temporal gyrus (chronic pain > control, corrected P=0.30), thalamus, and caudate (control > chronic, corrected P=0.23). Repeated measures of the regions of interest (5 mm radius) for blood oxygen level-dependent signal response revealed trend differences for superior temporal gyrus (P=0.06), thalamus (P=0.04), and caudate (P=0.21). Group-by-time interactions revealed trend differences in the caudate (P=0.10) and superior temporal gyrus (P=0.29). Conclusion: Augmented perceptual and brain responses to innocuous somatic pressure stimulation were shown in the chronic pain group compared to the control group; however, 12-weeks of exercise rehabilitation did not significantly attenuate these responses. Keywords: fMRI, pain network, central sensitization, BOLD-signal response

Existing work demonstrates that obesity is independently associated with cognitive dysfunction and macrostructural brain changes; however, little is known about the association between obesity and white matter (WM) integrity. We explore this relationship in a large cohort of otherwise healthy subjects. The present study classified 103 adult participants from the Brain Resource International Database between 21 and 86 years of age without history of neurological, medical, or psychiatric illness according to BMI (normal weight, overweight, obese) and subjected them to diffusion tensor imaging (DTI). Resulting fractional anisotropy (FA) indexes for the corpus callosum and fornix were examined in relation to BMI and age in a multiple regression framework. Results indicated that increasing BMI was independently associated with lower FA in the genu, splenium, and fornix, and a BMI × age interaction emerged for FA in the splenium and body of the corpus callosum. When categorized, obese persons demonstrated lower FA than normal and overweight persons for all WM indexes, but no FA differences emerged between overweight and normal persons. Results indicate both a direct association between obesity and reduced WM tract integrity and an interaction between obesity and aging processes on certain WM tracts in otherwise healthy adults. While such findings suggest a possible role for adiposity in WM dysfunction and associated cognitive deficits, prospective studies are needed to clarify the nature of these relationships and elucidate underlying mechanisms. [ABSTRACT FROM AUTHOR]

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry., (© 2024. The Author(s).)

Understanding why some patients with depression remain resistant to antidepressant medication could be elucidated by investigating their associated neural features. Although research has consistently demonstrated abnormalities in the anterior cingulate cortex (ACC) - a region that is part of the default mode network (DMN) - in treatment-resistant depression (TRD), a considerable research gap exists in discerning how these neural networks distinguish TRD from treatment-sensitive depression (TSD). We aimed to evaluate the resting-state functional connectivity (rsFC) of the ACC with other regions of the DMN to better understand the role of this structure in the pathophysiology of TRD. 35 TRD patients, 35 TSD patients, and 38 healthy controls (HC) underwent a resting-state functional MRI protocol. Seed-based functional connectivity analyses were performed, comparing the three groups for the connectivity between two subregions of the ACC (the subgenual ACC (sgACC) and the rostral ACC (rACC)) and the DMN (p < 0.05 FWE corrected). Furthermore, inter-network connectivity of the DMN with other neural networks was explored by independent component (ICA) analyses (p < 0.01, FDR corrected). The results demonstrated hyperconnectivity between the rACC and the posterior cingulate cortex in TRD relative to TSD and HC (F(2,105) = 5.335, p < 0.05). ICA found DMN connectivity to regions of the visual network (TRDTSD), differentiating the two clinical groups. These results provide confirmatory evidence of DMN hyperconnectivity and preliminary evidence for its interactions with other neural networks as key neural mechanisms underlying treatment non-responsiveness., 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. The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Anthony Harris received funding from Takeda Pharmaceutical Company for this project. There are no other financial disclosures related to the work. Mayuresh Korgaonkar received funding from Takeda Pharmaceutical Company for this project. There are no other financial disclosures related to the work. And all other authors have declared 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 The Authors. Published by Elsevier Inc. All rights reserved.)

The amygdala is divided into functional subnuclei which have been challenging to investigate due to functional magnetic resonance imaging (MRI) limitations in mapping small neural structures. Hence their role in the neurobiology of posttraumatic stress disorder (PTSD) remains poorly understood. Examination of covariance of structural MRI measures could be an alternate approach to circumvent this issue. T1-weighted anatomical scans from a 3 T scanner from non-trauma-exposed controls (NEC; n = 71, 75 % female) and PTSD participants (n = 67, 69 % female) were parcellated into 105 brain regions. Pearson's r partial correlations were computed for three and nine bilateral amygdala subnuclei and every other brain region, corrected for age, sex, and total brain volume. Pairwise correlation comparisons were performed to examine subnuclei covariance profiles between-groups. Graph theory was employed to investigate subnuclei network topology. Volumetric measures were compared to investigate structural changes. We found differences between amygdala subnuclei in covariance with the hippocampus for both groups, and additionally with temporal brain regions for the PTSD group. Network topology demonstrated the importance of the right basal nucleus in facilitating network communication only in PTSD. There were no between-group differences for any of the three structural metrics. These findings are in line with previous work that has failed to find structural differences for amygdala subnuclei between PTSD and controls. However, differences between amygdala subnuclei covariance profiles observed in our study highlight the need to investigate amygdala subnuclei functional connectivity in PTSD using higher field strength fMRI for better spatial resolution., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group., Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality., Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance., Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable., Competing Interests: Declaration of Competing Interest Dr. Thompson received partial grant support from Biogen, Inc., and Amazon, Inc., for work unrelated to the current study; Dr. Lebois reports unpaid membership on the Scientific Committee for International Society for the Study of Trauma and Dissociation (ISSTD), grant support from the National Institute of Mental Health, K01 MH118467 and the Julia Kasparian Fund for Neuroscience Research, McLean Hospital. Dr. Lebois also reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. ISSTD and NIMH were not involved in the analysis or preparation of the manuscript; Dr. Etkin reports salary and equity from Alto Neuroscience, equity from Mindstrong Health and Akili Interactive. Other authors have no conflicts of interest to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Speculation exists as to whether lisdexamfetamine dimesylate (LDX) acts on the functional connectivity (FC) of brain networks that modulate appetite, reward, or inhibitory control in binge-eating disorder (BED). Better insights into its action may help guide the development of more targeted therapeutics and identify who will benefit most from this medication. Here, we use a comprehensive data-driven approach to investigate the brain FC changes that underlie the therapeutic action of LDX in patients with BED., Methods: Forty-six participants with moderate to severe BED received LDX titrated to 50 or 70 mg for an 8-week period. Twenty age-matched healthy control participants were also recruited. Resting-state functional magnetic resonance imaging was used to probe changes in brain FC pre- and post treatment and correlated with change in clinical measures., Results: Ninety-seven percent of trial completers ( n  = 31) experienced remission or a reduction to mild BED during the 8-week LDX trial. Widespread neural FC changes occurred, with changes in default mode to limbic, executive control to subcortical, and default mode to executive control networks associated with improvements in clinical outcomes. These connections were not distinct from control participants at pretreatment but were different from control participants following LDX treatment. Pretreatment connectivity did not predict treatment response., Conclusions: FC between networks associated with self-referential processing, executive function, and reward seem to underlie the therapeutic effect of LDX in BED. This suggests that LDX activates change via multiple systems, with most changes in compensatory networks rather than in those characterizing the BED diagnosis., (© 2023 The Authors.)

Importance: Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes., Objective: To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities., Design, Setting, and Participants: This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023., Main Outcomes and Measures: Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging., Results: A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse., Conclusions and Relevance: Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT00693849.

At least one-third posttraumatic stress disorder (PTSD) patients do not respond to trauma-focused psychotherapy (TF-psychotherapy), which is the treatment of choice for PTSD. To clarify the change mechanisms that may be associated with treatment response, this study examined changes in neural activations during affective and non-affective processing that occur with improvement of symptoms after TF-psychotherapy. This study assessed PTSD treatment-seeking patients (n = 27) prior to and after TF-psychotherapy using functional magnetic resonance imaging when they completed three tasks: (a) passive viewing of affective faces, (b) cognitive reappraisal of negative images, and (c) non-affective response inhibition. Patients then underwent 9 sessions of TF-psychotherapy, and were assessed on the Clinician-Administered PTSD Scale following treatment. Changes in neural responses in affect and cognitive processing regions-of-interest for each task were correlated with reduction of PTSD severity from pretreatment to posttreatment in the PTSD cohort. Data from 21 healthy controls was used for comparison. Improvement of symptoms in PTSD were associated with increased activation of left anterior insula, reductions in the left hippocampus and right posterior insula during viewing of supraliminally presented affective images, and reduced connectivity between the left hippocampus with the left amygdala and rostral anterior cingulate. Treatment response was also associated with reduced activation in the left dorsolateral prefrontal cortex during reappraisal of negative images. There were no associations between response and activation change during response inhibition. This pattern of findings indicates that improvement of PTSD symptoms following TF-psychotherapy is associated with changes in affective rather than non-affective processes. These findings accord with prevailing models that TF-psychotherapy promotes engagement and mastery of affective stimuli.Clinical Trials Registration: Trial Registration: Prospectively registered at Australian and New Zealand Clinical Trials Registry, ACTRN12612000185864 and ACTRN12609000324213. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=83857., (© 2023. The Author(s).)

Post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) often co-occur in the context of threat to one's life. These conditions also have an overlapping symptomatology and include symptoms of anxiety, poor concentration and memory problems. A major challenge has been articulating the underlying neurobiology of these overlapping conditions. The primary aim of this study was to compare intrinsic functional connectivity between mTBI (without PTSD) and PTSD (without mTBI). The study included functional MRI data from 176 participants: 42 participants with mTBI, 67 with PTSD and a comparison group of 66 age and sex-matched healthy controls. We used network-based statistical analyses for connectome-wide comparisons of intrinsic functional connectivity between mTBI relative to PTSD and controls. Our results showed no connectivity differences between mTBI and PTSD groups. However, we did find that mTBI had significantly reduced connectivity relative to healthy controls within an extensive network of regions including default mode, executive control, visual and auditory networks. The mTBI group also displayed hyperconnectivity between dorsal and ventral attention networks and perceptual regions. The PTSD group also demonstrated abnormal connectivity within these networks relative to controls. Connectivity alterations were not associated with severity of PTSD or post-concussive symptoms in either clinical group. Taken together, the similar profiles of intrinsic connectivity alterations in these two conditions provide neural evidence that can explain, in part, the overlapping symptomatology between mTBI and PTSD., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Importance: More than 10% of children experience sexual, physical, or emotional abuse, and abuse experienced during sensitive neurodevelopmental periods is associated with a greater risk of psychiatric disorders., Objective: To investigate the extent to which a history of abuse is associated with alterations in the intrinsic functional connectome of the adult brain independent from the restriction of associated psychiatric conditions., Design, Setting, and Participants: This cohort study assessed data from 768 adult participants from the greater Sydney, Australia, area who were included in the study without diagnostic restrictions and categorized based on a history of childhood sexual, physical, and/or emotional abuse. Data were collected from January 1, 2009, to December 31, 2015; data analysis was performed from October 1, 2020, to March 31, 2022., Main Outcomes and Measures: Outcomes were structured psychiatric interview responses, self-report of the frequency and extent of various types of negative experiences in childhood and adolescence, and intrinsic functional connectivity derived from 5 functional magnetic resonance imaging tasks and estimated among 436 brain regions, comprising intranetwork and internetwork connectivity of 8 large-scale brain networks., Results: Among the 647 individuals with usable data (330 female [51.0%]; mean [SD] age, 33.3 [12.0] years; age range, 18.2-69.2 years), history of abuse was associated with greater likelihood of a current psychiatric illness (odds ratio, 4.55; 95% CI, 3.07-6.72; P < .001) and with greater depressive, anxiety, and stress symptoms (mean difference, 20.4; 95% CI, 16.1-24.7; P < .001). An altered connectome signature of higher connectivity within somatomotor, dorsal, and ventral attention networks and between these networks and executive control and default mode networks was observed in individuals with a history of abuse experienced during childhood (n = 127) vs those without a history of abuse (n = 442; mean difference, 0.07; 95% CI, 0.05-0.08; familywise, Bonferroni-corrected P = .01; Cohen d = 0.82) and compared with those who experienced abuse in adolescence (n = 78; mean difference, 0.06; 95% CI, 0.04-0.08]; familywise, Bonferroni-corrected P < .001; Cohen d = 0.68). Connectome alterations were not observed for those who experienced abuse in adolescence. Connectivity of this signature was transdiagnostic and independent of the nature and frequency of abuse, sex, or current symptomatic state., Conclusions and Relevance: Findings highlight the associations of exposure to abuse before and during adolescence with the whole-brain functional connectome. The experience of child abuse was found to be associated with physiologic changes in intrinsic connectivity, independent of psychopathology, in a way that may affect functioning of systems responsible for perceptual processing and attention.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LME INT ), (2) LME that models both site-specific random intercepts and age-related random slopes (LME INT+SLP ), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ 2 (3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ 2 (3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ 2 (3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects., Competing Interests: Conflicts of Interest Dr. Abdallah has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, Psilocybin Labs, Genentech and Janssen, and editor of Chronic Stress for Sage Publications, Inc.; he has filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr. Davidson is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. Dr. Jahanshad, Dr. Thompson and Dr. Ching received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. Dr. Krystal is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No. 5,447,948 (issued September 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued July 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); US application or Patent Cooperation Treaty international application No. 14/306,382 (filed on June 17, 2014); Filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). Dr. Schmahl is a consultant for Boehringer Ingelheim International GmbH. Dr. Stein has received research grants and/or consultancy honoraria from Lundbeck and Sun. Dr. Lebois reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD) and spousal license payment for Vanderbilt IP from Acadia Pharmaceuticals unrelated to the topic of this manuscript. All other authors have no conflicts of interest to declare., (Copyright © 2022. Published by Elsevier Inc.)

Neuroimaging studies have revealed neurobiological differences in ADHD, particularly studies examining connectivity disruption and anatomical network organization. However, the underlying pathophysiology of ADHD types remains elusive as it is unclear whether dysfunctional network connections characterize the underlying clinical symptoms distinguishing ADHD types. Here, we investigated intrinsic functional network connectivity to identify neural signatures that differentiate the combined (ADHD-C) and inattentive (ADHD-I) presentation types. Applying network-based statistical (NBS) and graph theoretical analysis to task-derived intrinsic connectivity data from completed fMRI scans, we evaluated default mode network (DMN) and whole-brain functional network topology in a cohort of 34 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as predominantly inattentive (ADHD-I) type ( n = 15) or combined (ADHD-C) type ( n = 19), and 39 age and gender-matched typically developing controls. ADHD-C were characterized from ADHD-I by reduced network connectivity differences within the DMN. Additionally, reduced connectivity within the DMN was negatively associated with ADHD-RS hyperactivity-impulsivity subscale score. Compared with controls, ADHD-C but not ADHD-I differed by reduced connectivity within the DMN; inter-network connectivity between the DMN and somatomotor networks; the DMN and limbic networks; and between the somatomotor and cingulo-frontoparietal, with ventral attention and dorsal attention networks. However, graph-theoretical measures did not significantly differ between groups. These findings provide insight into the intrinsic networks underlying phenotypic differences between ADHD types. Furthermore, these intrinsic functional connectomic signatures support neurobiological differences underlying clinical variations in ADHD presentations, specifically reduced within and between functional connectivity of the DMN in the ADHD-C type., Competing Interests: JFS, KG, MRK, and SC have received honoraria for educational seminars from Takeda (Shire – Australia). LW has received consultant fees from BlackThorn Therapeutics and scientific advisory board fees from Psyberguide of the One Mind Institute. MSK, KG, MRK, and SC have received commercial funding from Takeda for funded project grants. The remaining author 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 Saad, Griffiths, Kohn, Braund, Clarke, Williams and Korgaonkar.)

Background: A significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function - a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD., Methods: 35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons., Results: The TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation., Conclusions: This study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Previous studies with adults suggest that aberrant communication between neural networks underpins functional neurological disorder (FND). The current study adopts a data-driven approach to investigate the extent that functional resting-state networks are disrupted in a pediatric mixed-FND cohort., Methods: 31 children with mixed FND and 33 age- and sex-matched healthy controls completed resting-state fMRI scans. Whole-brain independent component analysis (pFWE < 0.05) was then used to identify group differences in resting-state connectivity. Self-report measures included the Depression, Anxiety and Stress Scale (DASS-21) and Early Life Stress Questionnaire (ELSQ). Resting-state heart rate (HR) and cortisol-awakening response (CAR) were available in a subset., Results: Children with FND showed wide-ranging connectivity changes in eight independent components corresponding to eight resting-state neural networks: language networks (IC6 and IC1), visual network, frontoparietal network, salience network, dorsal attention network, cerebellar network, and sensorimotor network. Children whose clinical presentation included functional seizures (vs children with other FND symptoms) showed greater connectivity decreases in the frontoparietal and dorsal attentional networks. Subjective distress (total DASS score), autonomic arousal (indexed by HR), and HPA dysregulation (attenuated/reversed CAR) contributed to changes in neural network connectivity. Children with FND (vs controls) reported more subjective distress (total DASS score) and more adverse childhood experiences (ACEs) across their lifespan., Conclusions: Children with FND demonstrate changes in resting-state connectivity. Identified network alterations underpin a broad range of functions typically disrupted in children with FND. This study complements the adult literature by suggesting that FND in children and adolescents emerges in the context of their lived experience and that it reflects aberrant communication across neural networks., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Bipolar disorder (BD) is commonly misdiagnosed as major depressive disorder (MDD). This is understandable, as depression often precedes mania and is otherwise indistinguishable in both. It is therefore imperative to identify neural mechanisms that can differentiate the two disorders. Interrogating resting brain neural activity may reveal core distinguishing abnormalities. We adopted an a priori approach, examining three key networks documented in previous mood disorder literature subserving executive function, salience and rumination that may differentiate euthymic BD and MDD patients. Thirty-eight patients with BD, 39 patients with MDD matched for depression severity, and 39 age-gender matched healthy controls, completed resting-state fMRI scans. Seed-based and data-driven Independent Component analyses (ICA) were implemented to examine group differences in resting-state connectivity (pFDR < 0.05). Seed analysis masks were target regions identified from the fronto-parietal (FPN), salience (SN) and default-mode (DMN) networks. Seed-based analyses identified significantly greater connectivity between the subgenual cingulate cortex (DMN) and right dorsolateral prefrontal cortex (FPN) in BD relative to MDD and controls. The ICA analyses also found greater connectivity between the DMN and inferior frontal gyrus, an FPN region in BD relative to MDD. There were also significant group differences across the three networks in both clinical groups relative to controls. Altered DMN-FPN functional connectivity is thought to underlie deficits in the processing, management and regulation of affective stimuli. Our results suggest that connectivity between these networks could potentially distinguish the two disorders and could be a possible trait mechanism in BD persisting even in the absence of symptoms., (© 2021. The Author(s).)

Evidence from functional neuroimaging studies support neural differences between the Attention Deficit Hyperactivity Disorder (ADHD) presentation types. It remains unclear if these neural deficits also manifest at the structural level. We have previously shown that the ADHD combined, and ADHD inattentive types demonstrate differences in graph properties of structural covariance suggesting an underlying difference in neuroanatomical organization. The goal of this study was to examine and validate white matter brain organization between the two subtypes using both scalar and connectivity measures of brain white matter. We used both tract-based spatial statistical (TBSS) and tractography analyses with network-based Statistics (NBS) and graph-theoretical analyses in a cohort of 35 ADHD participants (aged 8-17 years) defined using DSM-IV criteria as combined (ADHD-C) type (n = 19) or as predominantly inattentive (ADHD-I) type (n = 16), and 28 matched neurotypical controls. We performed TBSS analyses on scalar measures of fractional anisotropy (FA), mean (MD), radial (RD), and axial (AD) diffusivity to assess differences in WM between ADHD types and controls. NBS and graph theoretical analysis of whole brain inter-regional tractography examined connectomic differences and brain network organization, respectively. None of the scalar measures significantly differed between ADHD types or relative to controls. Similarly, there were no tractography connectivity differences between the two subtypes and relative to controls using NBS. Global and regional graph measures were also similar between the groups. A single significant finding was observed for nodal degree between the ADHD-C and controls, in the right insula (corrected p = .029). Our result of no white matter differences between the subtypes is consistent with most previous findings. These findings together might suggest that the white matter structural architecture is largely similar between the DSM-based ADHD presentations is similar to the extent of being undetectable with the current cohort size., Competing Interests: The authors have read the journal’s policy and have the following competing interests: The iSPOT-A trial was sponsored by Brain Resource Company Operations Pty Ltd. JFS, KRG, MRK, and SC have received honoraria for educational seminars from Takeda (Shire - Australia). LMW has received consultant fees from BlackThorn Therapeutics and scientific advisory board fees from Psyberguide of the One Mind Institute. MSK, KRG, MRK and SC have received commercial funding from Takeda for funded project grants. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Although trauma-focused cognitive behavioural therapy (TF-CBT) is the frontline treatment for posttraumatic stress disorder (PTSD), up to one half of patients do not respond optimally to this treatment. Inhibitory functions are important for successful management of PTSD, yet there is a dearth of knowledge regarding the extent to which neural mechanisms unpinning response inhibition are associated with TF-CBT response. Treatment-seeking PTSD patients (n = 40) were assessed during a response inhibition task (the Go/No-Go task) while undergoing functional magnetic imaging (fMRI) and event-related potentials (ERP) in separate sessions. PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale, before undergoing nine sessions of TF-CBT. They were then reassessed post-treatment to estimate reduction in fear and dysphoric symptoms of PTSD. Although neural responses during the inhibitory task did not predict overall symptom change, reduced activation in the left precuneus and the right superior parietal cortex predicted greater improvement in dysphoric symptoms. ERP responses during response inhibition indicated that lower P3 peak latency predicted greater reduction of dysphoric symptoms. There were no significant predictors of changes of fear symptoms. These findings indicate that neural activity associated with response inhibition can act as a predictive biomarker of TF-CBT response for PTSD symptoms. This pattern of findings underscores the importance of delineating the role of biomarkers to predict remission of subtypes of PTSD.

Background: Previous fMRI studies of posttraumatic stress disorder (PTSD) have investigated region-specific alterations in intrinsic connectivity but connectome-wide changes in connectivity are yet to be characterized. Understanding the neurobiology of this is important to develop novel treatment interventions for PTSD. This study aims to identify connectome-wide disruptions in PTSD to provide a more comprehensive analysis of nseural networks in this disorder., Methods: A functional MRI scan was completed by 138 individuals (67 PTSD and 71 non-trauma-exposed healthy controls [HC]). For every individual, inter-regional intrinsic functional connectivity was estimated between 436 brain regions, comprising intra and inter-network connectivity of eight large-scale brain networks. Group-wise differences between PTSD and HC were investigated using network-based statistics at a family-wise error rate of p < 0.05. Significant network differences were then further investigated in 27 individuals with trauma exposure but no PTSD [TC])., Results: Compared to HC, PTSD displayed lower intrinsic functional connectivity in a network of 203 connections between 420 regions within and between mid-posterior default mode, central executive, limbic, visual and somatomotor regions. Additionally, PTSD displayed higher connectivity across a network of 50 connections from thalamic and limbic to sensory and default-mode regions. Connectivity in TC in both these networks was intermediate and significantly different to PTSD and HC., Conclusion: A large-scale imbalance between hypoconnectivity of higher-order cortical networks and hyperconnectivity of emotional and arousal response systems seems to occur on a sliding scale from trauma exposure to clinical manifestation as PTSD. Novel interventions that target this systemic functional imbalance could provide potential mitigation of PTSD., Competing Interests: All authors report no conflict of interest., (© 2021 The Authors.)

Behavioural disturbances in attention deficit hyperactivity disorder (ADHD) are thought to be due to dysfunction of spatially distributed, interconnected neural systems. While there is a fast-growing literature on functional dysconnectivity in ADHD, far less is known about the structural architecture underpinning these disturbances and how it may contribute to ADHD symptomology and treatment prognosis. We applied graph theoretical analyses on diffusion MRI tractography data to produce quantitative measures of global network organisation and local efficiency of network nodes. Support vector machines (SVMs) were used for comparison of multivariate graph measures of 37 children and adolescents with ADHD relative to 26 age and gender matched typically developing children (TDC). We also explored associations between graph measures and functionally-relevant outcomes such as symptom severity and prediction of methylphenidate (MPH) treatment response. We found that multivariate patterns of reduced local efficiency, predominantly in subcortical regions (SC), were able to distinguish between ADHD and TDC groups with 76% accuracy. For treatment prognosis, higher global efficiency, higher local efficiency of the right supramarginal gyrus and multivariate patterns of increased local efficiency across multiple networks at baseline also predicted greater symptom reduction after 6 weeks of MPH treatment. Our findings demonstrate that graph measures of structural topology provide valuable diagnostic and prognostic markers of ADHD, which may aid in mechanistic understanding of this complex disorder.

Mild traumatic brain injury (mTBI) is often characterized by deficits in response inhibition, which can contribute to marked social and occupational dysfunction. mTBI often occurs in the context of psychologically traumatic events. This can cause posttraumatic stress disorder (PTSD), which also impedes response inhibition. The overlap or distinction in these inhibitory deficits in mTBI and PTSD is unclear. This study aimed to assess behavioral, neurophysiological, and neuroimaging indices of response inhibition in mTBI by also assessing these parameters in healthy controls (HC) and PTSD participants. Participants with mTBI (without PTSD) (n = 46), PTSD (without mTBI) (n = 41), and HC (n = 40) were assessed during a response inhibition task (the Go/NoGo task) during neuropsychological testing and separate functional magnetic imaging and event-related potentials sessions. PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale. Both mTBI and PTSD participants performed more omission errors on the Go/NoGo task and were associated with greater N2 amplitude, greater left inferior parietal activation and reduced connectivity of the left inferior parietal cluster and left angular gyrus compared to HC. There were no differences between mTBI and PTSD on any of these measures. These findings highlight that both mTBI and PTSD contribute to neural dysfunction during response inhibition, and arguably these occur due to distinct mechanisms. In the context of the common comorbidity between these two conditions, strategies to address response inhibition deficits in mTBI may need to consider causative factors underpinning neurological insult of mTBI and psychological effects associated with PTSD., Competing Interests: No authors are declaring a conflict of interest., (© 2021 The Authors.)

Trauma-focused cognitive behavior therapy (TF-CBT) is the gold standard treatment for posttraumatic stress disorder (PTSD), up to one-half of PTSD patients remain treatment non-responders. Although studies have used functional MRI to understand the neurobiology of treatment response, there is less understanding of the role of white matter brain structures in response to TF-CBT. Thirty-six treatment-seeking PTSD patients and 33 age-gender matched healthy controls completed diffusion-weighted imaging scans at baseline. Patients underwent nine sessions of TF-CBT treatment and PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale before and after completing treatment. Patients were assessed to estimate the reduction in overall symptoms and also specifically fear and dysphoric symptoms of PTSD. Tract-based spatial statistical analyses were performed for the PTSD group to evaluate whole-brain correlations of fractional anisotropy (FA) with improvement in overall, fear, and dysphoric symptoms using non-parametric permutation inference testing (p FWE  < 0.05). Next, we evaluated if these significant measures also characterized PTSD from controls. Greater improvement in dysphoric symptoms was found correlated with lower FA in white matter regions associated with the limbic system, frontal cortex, thalamic association and projection fibers, corpus callosum, and tracts related to the brainstem. White matter anisotropy was not found associated with either overall or fear symptoms. FA in the significant clusters was similar between PTSD and controls. White-matter related to key functional regions may also play an important role in response to TF-CBT. Our results underscore the heterogeneity of PTSD and the need to evaluate distinct symptom phenotypes in treatment studies.

Background: Deficits in emotional processing are conceptualized in prevailing models of anxiety to underpin key symptoms of panic disorder (PD). Neuroimaging studies show evidence of aberrant neural functioning in PD patients during emotional processing, however little is understood about how non-conscious emotional processing impacts neural processes., Method: We examined activation and functional connectivity differences in brain regions involved in emotional processing between PD and healthy controls (HC) during subliminal and supraliminal presentations of facial emotions. Twenty-two PD and 33 HC participants were shown happy, sad, neutral, fear, anger and disgust facial expressions during functional magnetic resonance imaging using a 3T MRI scanner. We performed voxelwise ROI analyses at FWE-corrected p < 0.05 for main effects of group and group*emotion interactions., Results: There was less pregenual anterior cingulate cortex (pgACC) activation to subliminal presentations of happy and sad faces in PD compared to HC participants (group*emotion). In addition, PD patients had less pgACC - right amygdala connectivity than HC participants during sad and fear subliminal processing (group*emotion). PD patients also exhibited lower right cerebellum activity across all supraliminal presentations of facial expressions compared to HC., Conclusion: These findings suggest that there is aberrant neural processing in PD patients during both conscious and preconscious processing of both positive and negative stimuli, suggesting impaired recruitment of implicit regulatory networks during affective processing. It appears that PD patients may experience deficits in key regulatory connections between inhibitory and emotional neural networks at very early stages of processing of negative affective states., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Although trauma-focused cognitive behavior therapy (TF-CBT) is the frontline treatment for post-traumatic stress disorder (PTSD), up to one-half of patients are treatment nonresponders. To understand treatment nonresponse, it is important to understand the neural mechanisms of TF-CBT. Here, we used whole-brain intrinsic functional connectivity analysis to identify neural connectomic signatures of treatment outcome. In total, 36 PTSD patients and 36 healthy individuals underwent functional MRI at pre-treatment baseline. Patients then underwent nine sessions of TF-CBT and completed clinical and follow-up MRIs. We used an established large-scale brain network atlas to parcellate the brain into 343 brain regions. Pairwise intrinsic task-free functional connectivity was calculated and used to identify pre-treatment connectomic features that were correlated with reduction of PTSD severity from pretreatment to post treatment. We formed a composite metric of intrinsic connections associated with therapeutic outcome, and then interrogated this composite metric to determine if it distinguished PTSD treatment responders and nonresponders from healthy control status and changed post treatment. Lower pre-treatment connectivity for the cingulo-opercular, salience, default mode, dorsal attention, and frontoparietal executive control brain networks was associated with treatment improvement. Treatment responders had lower while nonresponders had significantly greater connectivity than controls at pretreatment. With therapy, connectivity significantly increased for responders and decreased for nonresponders, while controls remain unchanged over this time period. We provide evidence that the intrinsic functional architecture of the brain, specifically connectivity within and between brain networks associated with external vigilance, self-awareness, and cognitive control, may characterize a positive response to TF-CBT for PTSD.

Reduced gray matter (GM) volume may represent a hallmark of major depressive disorder (MDD) neuropathology, typified by wide-ranging distribution of structural alteration. In the study, we aimed to replicate and extend our previous finding of profound and widespread GM loss in MDD, and evaluate the diagnostic accuracy of a structural biomarker derived from GM volume in an interconnected pattern across the brain. In a sub-study of the International Study to Predict Optimized Treatment in Depression (iSPOT-D), two cohorts of clinically defined MDD participants "Test" (n = 98) and "Replication" (n = 131) were assessed alongside healthy controls (n = 66). Using 3T MRI T1-weighted volumes, GM volume differences were evaluated using voxel-based morphometry. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to evaluate an MDD diagnostic biomarker based on a precise spatial pattern of GM loss constructed using principal component analysis. We demonstrated a highly conserved symmetric widespread pattern of reduced GM volume in MDD, replicating our previous findings. Three bilateral dominant clusters were observed: Cluster 1: midline/cingulate (GM reduction: Test: 6.4%, Replication: 5.3%), Cluster 2: medial temporal lobe (GM reduction: Test: 8.2%, Replication: 11.9%), Cluster 3: prefrontal cortex (GM reduction: Test: 12.1%, Replication: 23.2%). We developed a biomarker reflecting the global pattern of GM reduction, achieving good diagnostic classification performance (AUC: Test = 0.75, Replication = 0.84). This study establishes that a highly specific pattern of reduced GM volume is a feature of MDD, suggestive of a structural basis for this disease. We introduce and validate a novel diagnostic biomarker based on this pattern.

Background: The efficacy and safety of Lisdexamfetamine dimesylate (LDX) in the treatment of moderate to severe binge eating disorder (BED) has been demonstrated in multiple randomised clinical trials. Despite this, little is known about how LDX acts to improve binge eating symptoms. This study aims to provide a comprehensive understanding of the neural mechanisms by which LDX improves symptoms of BED. We hypothesise that LDX will act by normalising connectivity within neural circuits responsible for reward and impulse control, and that this normalisation will correlate with reduced binge eating episodes., Methods: This is an open-label Phase 4 clinical trial of LDX in adults with moderate to severe BED. Enrolment will include 40 adults with moderate to severe BED aged 18-40 years and Body Mass Index (BMI) of 20-45 kg/m 2 , and 22 healthy controls matched for age, gender and BMI. Clinical interview and validated scales are used to confirm diagnosis and screen for exclusion criteria, which include comorbid anorexia nervosa or bulimia nervosa, use of psychostimulants within the past 6 months, and current use of antipsychotics or noradrenaline reuptake inhibitors. Baseline assessments include clinical symptoms, multimodal neuroimaging, cognitive assessment of reward sensitivity and behavioural inhibition, and an (optional) genetic sample. A subset of these assessments are repeated after eight weeks of treatment with LDX titrated to either 50 or 70 mg. The primary outcome measures are resting-state intrinsic connectivity and the number of binge eating episodes. Analyses will be applied to resting-state fMRI data to characterise pharmacological effects across the functional connectome, and assess correlations with symptom measure changes. Comparison of neural measures between controls and those with BED post-treatment will also be performed to determine whether LDX normalises brain function., Discussion: First enrolment was in May 2018, and is ongoing. This study is the first comprehensive investigation of the neurobiological changes that occur with LDX treatment in adults with moderate to severe BED., Trial Registration: ACTRN12618000623291, Australian and New Zealand Clinical Trials Registry URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374913&isReview=true. Date of Registration: 20 April 2018., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: Major depressive disorder (MDD) is a chronic disease with a large global impact. There are currently no clinically useful predictors of treatment outcome, and the development of biomarkers to inform clinical treatment decisions is highly desirable., Methods: In this exploratory study we performed fixel-based analysis of diffusion MRI data from the International Study to Predict Optimized Treatment in Depression with the aim of identifying novel biomarkers at baseline that may relate to diagnosis and outcome to treatment with antidepressant medications. Analyses used MR data from individuals with MDD (n = 221) and healthy controls (n = 67)., Results: We show focal, gender-specific differences in the anterior limb of the internal capsule (males) and bilaterally in the genu of the corpus callosum (females) associated with diagnosis. Lower fibre cross-section in the tapetum, the conduit between the right and left hippocampi, were also associated with a decreased probability of remission. Analysis of conventional fractional anisotropy showed scattered abnormalities in the corona radiata, cerebral peduncles and mid-brain which were much lower in total volume compared to fixel-based analysis., Conclusions: Fixel-based analysis appeared to identify different underlying abnormalities than conventional tensor-based metrics, with almost no overlap between significant regions. We show that MDD is associated with gender specific abnormalities in the genu of the corpus callosum (females) and in the anterior limb of the internal capsule (males), as well as gender-independent differences in the tapetum that predict remission. Diffusion MRI may play a key role in future guidance of clinical decision-making for MDD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive control is one of the most important skills in day-to-day social and intellectual functioning but we are yet to understand the neural basis of the group of behaviors required to carry this out. Here, we probed changes over time in the brain network associated with cognitive control (the dorsolateral prefrontal cortex, the dorsal posterior parietal cortex, and the dorsal anterior cingulate cortex) using both behavioral assays and functional brain imaging during a selective working memory task in 69 healthy participants within the age range 18-38 years (mean: 25, SD: ±6), assessed twice, 2 years apart. We aimed to explore the relationship of changing network activation and connectivity with behavioral tasks associated with cognitive control in this otherwise neurodevelopmentally stable group. We found that increased connectivity between frontoparietal cognitive control network regions during the working memory task was associated with improved memory and executive functions over the 2-year period and that this association was not impacted by age, gender, or baseline performance. These results provide evidence that changes in the functional organization of the cognitive control brain network occur despite the absence of neurodevelopment, aging or targeted cognitive training effects, and could modulate cognitive performance in early to mid-adulthood. Understanding how and why this change is occurring could provide insights into the mechanisms through which cognitive control ability is cultivated over time. This could aid in the development of interventions in cases where cognitive control is impaired., (© 2018 Wiley Periodicals, Inc.)

Background: Associations between well-being, resilience to trauma and the volume of grey-matter regions involved in affective processing (e.g., threat/reward circuits) are largely unexplored, as are the roles of shared genetic and environmental factors derived from multivariate twin modelling., Methods: This study presents, to our knowledge, the first exploration of well-being and volumes of grey-matter regions involved in affective processing using a region-of-interest, voxel-based approach in 263 healthy adult twins (60% monozygotic pairs, 61% females, mean age 39.69 yr). To examine patterns for resilience (i.e., positive adaptation following adversity), we evaluated associations between the same brain regions and well-being in a trauma-exposed subgroup., Results: We found a correlated effect between increased well-being and reduced grey-matter volume of the pontine nuclei. This association was strongest for individuals with higher resilience to trauma. Multivariate twin modelling suggested that the common variance between the pons volume and well-being scores was due to environmental factors., Limitations: We used a cross-sectional sample; results need to be replicated longitudinally and in a larger sample., Conclusion: Associations with altered grey matter of the pontine nuclei suggest that basic sensory processes, such as arousal, startle, memory consolidation and/or emotional conditioning, may have a role in well-being and resilience., Competing Interests: J. Gatt has previously received consultancy fees from Brain Resource Ltd unrelated to this study and is a stockholder in MAP Corp. Pte Ltd. A. Harris has consulted for Lundbeck Australia and received fees for lectures from Janssen-Cilag and Lundbeck Australia. He has been an investigator on industry-sponsored trials by Janssen-Cilag and Brain Resource Ltd. C.R. Clark holds a small quantum of stock and has received fees from Brain Resource Ltd for consultancies unrelated to this study. L. Williams has received fees for consultancies unrelated to this study and previously held stock options from Brain Resource Ltd. No other authors declare competing interests., (© 2018 Joule Inc. or its licensors)