Anorexia nervosa (AN) is a serious psychiatric illness that remains difficult to treat. Elucidating the neural mechanisms of AN is necessary to identify novel treatment targets and improve outcomes. A growing body of literature points to a role for dorsal fronto-striatal circuitry in the pathophysiology of AN, with increasing evidence of abnormal task-based fMRI activation within this network among patients with AN. Whether these abnormalities are present at rest and reflect fundamental differences in brain organization is unclear.

The current study combined resting-state fMRI data from patients with AN (n = 89) and healthy controls (HC; n = 92) across four studies, removing site effects using ComBat harmonization. First, the a priori hypothesis that dorsal fronto-striatal connectivity strength – specifically between the anterior caudate and dlPFC – differed between patients and HC was tested using seed-based functional connectivity analysis with small-volume correction. To assess specificity of effects, exploratory analyses examined anterior caudate whole-brain connectivity, amplitude of low-frequency fluctuations (ALFF), and node centrality.

Compared to HC, patients showed significantly reduced right, but not left, anterior caudate-dlPFC connectivity (p = 0.002) in small-volume corrected analyses. Whole-brain analyses also identified reduced connectivity between the right anterior caudate and left superior frontal and middle frontal gyri (p = 0.028) and increased connectivity between the right anterior caudate and right occipital cortex (p = 0.038). No group differences were found in analyses of anterior caudate ALFF and node centrality.

Decreased coupling of dorsal fronto-striatal regions indicates that circuit-based abnormalities persist at rest and suggests this network may be a potential treatment target.

Despite increasing knowledge on the neuroimaging patterns of eating disorder (ED) symptoms in non-clinical populations, studies using whole-brain machine learning to identify connectome-based neuromarkers of ED symptomatology are absent. This study examined the association of connectivity within and between large-scale functional networks with specific symptomatic behaviors and cognitions using connectome-based predictive modeling (CPM).

CPM with ten-fold cross-validation was carried out to probe functional networks that were predictive of ED-associated symptomatology, including body image concerns, binge eating, and compensatory behaviors, within the discovery sample of 660 participants. The predictive ability of the identified networks was validated using an independent sample of 821 participants.

The connectivity predictive of body image concerns was identified within and between networks implicated in cognitive control (frontoparietal and medial frontal), reward sensitivity (subcortical), and visual perception (visual). Crucially, the set of connections in the positive network related to body image concerns identified in one sample was generalized to predict body image concerns in an independent sample, suggesting the replicability of this effect.

These findings point to the feasibility of using the functional connectome to predict ED symptomatology in the general population and provide the first evidence that functional interplay among distributed networks predicts body shape/weight concerns.

Treatment non-response and recurrence are the main sources of disease burden in major depressive disorder (MDD). However, little is known about its neurobiological mechanism concerning the brain network changes accompanying pharmacotherapy. The present study investigated the changes in the intrinsic brain networks during 6-month antidepressant treatment phase associated with the treatment response and recurrence in MDD.

Resting-state functional magnetic resonance imaging was acquired from untreated patients with MDD and healthy controls at baseline. The patients' depressive symptoms were monitored by using the Hamilton Rating Scale for Depression (HAMD). After 6 months of antidepressant treatment, patients were re-scanned and followed up every 6 months over 2 years. Traditional statistical analysis as well as machine learning approaches were conducted to investigate the longitudinal changes in macro-scale resting-state functional network connectivity (rsFNC) strength and micro-scale resting-state functional connectivity (rsFC) associated with long-term treatment outcome in MDD.

Repeated measures of the general linear model demonstrated a significant difference in the default mode network (DMN) rsFNC change before and after the 6-month antidepressant treatment between remitters and non-remitters. The difference in the rsFNC change over the 6-month antidepressant treatment between recurring and stable MDD was also specific to DMN. Machine learning analysis results revealed that only the DMN rsFC change successfully distinguished non-remitters from the remitters at 6 months and recurring from stable MDD during the 2-year follow-up.

Our findings demonstrated that the intrinsic DMN connectivity could be a unique and important target for treatment and recurrence prevention in MDD.

Adolescents with major depressive disorder (MDD) often show reduced prefrontal functional connectivity with the subcortical regions than healthy controls (HC) (Tang et al., 2018). However, relatively little is known about longitudinal effects of antidepressant (AD) treatment on resting state functional connectivity (RSFC) in the prefrontal cortex (PFC).

This study aimed to investigate abnormal PFC RSFC in MDD adolescents compared to HC and longitudinal effects of AD on PFC RSFC.

This study included 59 adolescents with MDD and 43 HC. MDD adolescents were treated with escitalopram in an 8 week, open-label trial. The treatment outcome was assessed by Children’s Depression Rating Scale (CDRS-R) and patients showing at least a 40% improvement in CDRS-R scores from baseline to week 8 were defined as “responders”. Functional and T1 images collected before and after treatment were processed using AFNI and Freesurfer. Our seed was the lateral PFC (LPFC, BA46). T-tests and repeated measures ANCOVAs, controlling for age and IQ, were conducted to examine abnormal PFC RSFC and longitudinal effects of AD on LPFC RSFC.

Relative to HC, MDD showed increased LPFC RSFC with the posterior middle temporal gyrus (pMTG) and superior frontal cortex (SFG) involved in attentional networks. Responders showed greater changes in LPFC RSFC with the MTG and SFG after AD treatment compared to non-responders and HC (Figure 1).

Our finding suggests that reduced LPFC RSFC with the pMTG and SFG reflecting decreased attentional network connectivity may serve as a biomarker to predict AD treatment outcome in adolescents with MDD.

No significant relationships.

Neuroimaging findings have reported aberrant functional connectivity in brain regions involved reward system in individuals with anorexia nervosa (AN) altering hedonic processing over food. Likewise, endocannabinoids such as Anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) have been involved in rewarding aspects of food intake.

To identify nucleus accumbens (NAcc) functional connectivity with whole-brain comparing between individuals with AN and controls. Furthermore, in a sub-study, to explore the interaction between NAcc functional connectivity and peripheral AEA and 2-AG levels.

A total of 60 adult women (18 to 56 years of age) took part in the present study. Twenty-six individuals belonged to the AN group (BMI<18) and 34 to the HC group (BMI=18-24.99). All participants underwent functional magnetic resonance in resting-state, and blood samples were obtained in fasting.

Negative functional connectivity was observed in the AN group compared with the control group between the NAcc and the cerebellum (pFWE<.001), between the NAcc and the insula (pFWE<.001), between the NAcc and the supramarginal gyrus (pFWE=.019), and between the NAcc and the postcentral gyrus (pFWE=.010). Analyses exploring the association between NAcc functional connectivity and peripheral endocannabinoids levels displayed altered NAcc-cerebellum functional connectivity was negatively associated with peripheral 2-AG levels in the AN group (r= -.553; p=.011).

Understanding the interaction between the reward system and peripheral endocannabinoids in patients with AN could contribute to better elucidate the pathophysiology of this disorder. Future studies will need to further investigate the clinical and therapeutic implications of these findings in patients with AN.

No significant relationships.

Emotional dysregulation (ED) is a common characteristic of both attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD), especially in adolescents. However, whether ADHD and MDD may share the specific ED-related neural networks remains unknown.

In total, 43 adolescents with clinical ED (22 adolescents with ADHD and 21 with MDD) were recruited; in addition, 29 sex- and age-matched healthy controls (HCs) were included. Resting-state functional connectivity (RSFC) analysis, voxel-based morphometry, and diffusion tensor imaging analysis were performed for each patient. In addition, we determined the significant regions of interest in patients with ED due to ADHD and MDD as compared with HCs and tested their correlations with clinical rating scale scores.

Compared with HCs, patients with ED had greater RSFC in the cerebellum and supramarginal gyrus (SMG), especially between vermis VI and the SMG in the attention networks, and lower RSFC between the right supplementary motor area and right lateral parietal area. Lower gray matter (GM) volume in the SMG was also found. RSFC was significantly correlated with clinical rating scale scores for all patients with ED due to ADHD or MDD. GM change was correlated with ED and MDD rating scale scores.

The cerebellum and attention networks might play major roles in ED pathophysiology in adolescents with ADHD and MDD. Increased connectivity of the vermis to the SMG serves as a possible underlying neural network.

Childhood maltreatment (CM) represents a potent risk factor for major depressive disorder (MDD), including poorer treatment response. Altered resting-state connectivity in the fronto-limbic system has been reported in maltreated individuals. However, previous results in smaller samples differ largely regarding localization and direction of effects.

We included healthy and depressed samples [n = 624 participants with MDD; n = 701 healthy control (HC) participants] that underwent resting-state functional MRI measurements and provided retrospective self-reports of maltreatment using the Childhood Trauma Questionnaire. A-priori defined regions of interest [ROI; amygdala, hippocampus, anterior cingulate cortex (ACC)] were used to calculate seed-to-voxel connectivities.

No significant associations between maltreatment and resting-state connectivity of any ROI were found across MDD and HC participants and no interaction effect with diagnosis became significant. Investigating MDD patients only yielded maltreatment-associated increased connectivity between the amygdala and dorsolateral frontal areas [pFDR < 0.001; η2partial = 0.050; 95%-CI (0.023–0.085)]. This effect was robust across various sensitivity analyses and was associated with concurrent and previous symptom severity. Particularly strong amygdala-frontal associations with maltreatment were observed in acutely depressed individuals [n = 264; pFDR < 0.001; η2partial = 0.091; 95%-CI (0.038–0.166)). Weaker evidence – not surviving correction for multiple ROI analyses – was found for altered supracallosal ACC connectivity in HC individuals associated with maltreatment.

The majority of previous resting-state connectivity correlates of CM could not be replicated in this large-scale study. The strongest evidence was found for clinically relevant maltreatment associations with altered adult amygdala-dorsolateral frontal connectivity in depression. Future studies should explore the relevance of this pathway for a maltreated subgroup of MDD patients.

Understanding the neurobiological underpinnings of childhood maltreatment is vital given consistent links with poor mental health. Dimensional models of adversity purport that different types of adversity likely have distinct neurobiological consequences. Adolescence is a key developmental period, during which deviations from normative neurodevelopment may have particular relevance for mental health. However, longitudinal work examining links between different forms of maltreatment, neurodevelopment, and mental health is limited.

In the present study, we explored associations between abuse, neglect, and longitudinal development of within-network functional connectivity of the salience (SN), default mode (DMN), and executive control network in 142 community residing adolescents. Resting-state fMRI data were acquired at age 16 (T1; M = 16.46 years, s.d. = 0.52, 66F) and 19 (T2; mean follow-up period: 2.35 years). Mental health data were also collected at T1 and T2. Childhood maltreatment history was assessed prior to T1.

Abuse and neglect were both found to be associated with increases in within-SN functional connectivity from age 16 to 19. Further, there were sex differences in the association between neglect and changes in within-DMN connectivity. Finally, increases in within-SN connectivity were found to mediate the association between abuse/neglect and lower problematic substance use and higher depressive symptoms at age 19.

Our findings suggest that childhood maltreatment is associated with altered neurodevelopmental trajectories, and that changes in salience processing may be linked with risk and resilience for the development of depression and substance use problems during adolescence, respectively. Further work is needed to understand the distinct neurodevelopmental and mental health outcomes of abuse and neglect.

Childhood trauma is a vulnerability factor for the development of obsessive–compulsive disorder (OCD). Empirical findings suggest that trauma-related alterations in brain networks, especially in thalamus-related regions, have been observed in OCD patients. However, the relationship between childhood trauma and thalamic connectivity in patients with OCD remains unclear. The present study aimed to examine the impact of childhood trauma on thalamic functional connectivity in OCD patients.

Magnetic resonance imaging resting-state scans were acquired in 79 patients with OCD, including 22 patients with a high level of childhood trauma (OCD_HCT), 57 patients with a low level of childhood trauma (OCD_LCT) and 47 healthy controls. Seven thalamic subdivisions were chosen as regions of interest (ROIs) to examine the group difference in thalamic ROIs and whole-brain resting-state functional connectivity (rsFC).

We found significantly decreased caudate-thalamic rsFC in OCD patients as a whole group and also in OCD_LCT patients, compared with healthy controls. However, OCD_HCT patients exhibited increased thalamic rsFC with the prefrontal cortex when compared with both OCD_LCT patients and healthy controls.

Taken together, OCD patients with high and low levels of childhood trauma exhibit different pathological alterations in thalamic rsFC, suggesting that childhood trauma may be a predisposing factor for some OCD patients.

Many emotional experiences such as anxiety and depression are influenced by negative affect (NA). NA has both trait and state features, which play different roles in physiological and mental health. Attending to NA common to various emotional experiences and their trait-state features might help deepen the understanding of the shared foundation of related emotional disorders.

The principal component of five measures was calculated to indicate individuals' NA level. Applying the connectivity-based correlation analysis, we first identified resting-state functional connectives (FCs) relating to NA in sample 1 (n = 367), which were validated through an independent sample (n = 232; sample 2). Next, based on the variability of FCs across large timescale, we further divided the NA-related FCs into high- and low-variability groups. Finally, FCs in different variability groups were separately applied to predict individuals' neuroticism level (which is assumed to be the core trait-related factor underlying NA), and the change of NA level (which represents the state-related fluctuation of NA).

The low-variability FCs were primarily within the default mode network (DMN) and between the DMN and dorsal attention network/sensory system and significantly predicted trait rather than state NA. The high-variability FCs were primarily between the DMN and ventral attention network, the fronto-parietal network and DMN/sensory system, and significantly predicted the change of NA level.

The trait and state NA can be separately predicted by stable and variable spontaneous FCs with different attentional processes and emotion regulatory mechanisms, which could deepen our understanding of NA.

Goldberg, the author of the “novelty-routinization” framework, suggested a new pair of cognitive styles for agent-centered decision-making (DM), context-dependency/independency (CD/CI), quantified by the Cognitive Bias Task (CBT) and supposedly reflecting functional brain hemispheric specialization. To date, there are only three lesion and activation neuroimaging studies on the CBT with the largest sample of 12 participants. The present study is the first to analyze whole-brain functional connectivity (FC) of the dorsolateral prefrontal cortex (DLPFC), involved in contextual agent-centered DM.

We compared whole-brain resting-state FC of the DLPFC between CD (n = 24) and CI (n = 22) healthy participants. Additionally, we investigated associations between CD/CI and different aspects of executive functions.

CD participants had stronger positive FC of the DLPFC with motor and visual regions; FC of the left DLPFC was more extensive. CI participants had stronger positive FC of the left DLPFC with right prefrontal and parietal-occipital areas and of the left and right DLPFC with ipsilateral cerebellar hemispheres. No sex differences were found. CD/CI had nonlinear associations with working memory.

The findings suggest that CD and CI are associated with different patterns of DLPFC FC. While CD is associated with FC between DLPFC and areas presumably involved in storing representations of current situation, CI is more likely to be associated with FC between DLPFC and right-lateralized associative regions, probably involved in the inhibition of the CD response and switching from processing of incoming perceptual information to creation of original response strategies.

Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions.

Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann’s area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity.

Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement.

rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis.

A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured.

Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs.

These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.

We hypothesize that the tumor necrosis factor-α (TNF-α) may play a role in disturbing the effect of selective serotonin reuptake inhibitor (SSRI) on the striatal connectivity in patients with major depressive disorder (MDD).

We performed a longitudinal observation by combining resting-state functional magnetic resonance imaging (rs-fMRI) and biochemical analyses to identify the abnormal striatal connectivity in MDD patients, and to evaluate the effect of TNF-α level on these abnormal connectivities during SSRI treatment. Eighty-five rs-fMRI scans were collected from 25 MDD patients and 35 healthy controls, and the scans were repeated for all the patients before and after a 6-week SSRI treatment. Whole-brain voxel-wise functional connectivity (FC) was calculated by correlating the rs-fMRI time courses between each voxel and the striatal seeds (i.e. spherical regions placed at the striatums). The level of TNF-α in serum was evaluated by Milliplex assay. Factorial analysis was performed to assess the interaction effects of ‘TNF-α × treatment’ in the regions with between-group FC difference.

Compared with controls, MDD patients showed significantly higher striatal FC in the medial prefrontal cortex (MPFC) and bilateral middle/superior temporal cortices before SSRI treatment (p < 0.001, uncorrected). Moreover, a significant interaction effect of ‘TNF-α × treatment’ was found in MPFC-striatum FC in MDD patients (p = 0.002), and the significance remained after adjusted for age, gender, head motion, and episode of disease.

These findings provide evidence that treatment-related brain connectivity change is dependent on the TNF-α level in MDD patients, and the MPFC-striatum connectivities possibly serve as an important target in the brain.

Exposure to threat-related early life stress (ELS) has been related to vulnerability for stress-related disorders in adulthood, putatively via disrupted corticolimbic circuits involved in stress response and regulation. However, previous research on ELS has not examined both the intrinsic strength and flexibility of corticolimbic circuits, which may be particularly important for adaptive stress responding, or associations between these dimensions of corticolimbic dysfunction and acute stress response in adulthood.

Seventy unmedicated women varying in history of threat-related ELS completed a functional magnetic resonance imaging scan to evaluate voxelwise static (overall) and dynamic (variability over a series of sliding windows) resting-state functional connectivity (RSFC) of bilateral amygdala. In a separate session and subset of participants (n = 42), measures of salivary cortisol and affect were collected during a social-evaluative stress challenge.

Higher severity of threat-related ELS was related to more strongly negative static RSFC between amygdala and left dorsolateral prefrontal cortex (DLPFC), and elevated dynamic RSFC between amygdala and rostral anterior cingulate cortex (rACC). Static amygdala-DLPFC antagonism mediated the relationship between higher severity of threat-related ELS and blunted cortisol response to stress, but increased dynamic amygdala-rACC connectivity weakened this mediated effect and was related to more positive post-stress mood.

Threat-related ELS was associated with RSFC within lateral corticolimbic circuits, which in turn was related to blunted physiological response to acute stress. Notably, increased flexibility between the amygdala and rACC compensated for this static disruption, suggesting that more dynamic medial corticolimbic circuits might be key to restoring healthy stress response.

As a disconnection syndrome, schizophrenia has shown impaired resting-state functional connectivity (rsFC) in the orbitofrontal cortex (OFC); however, the OFC is a rather heterogeneous region and the rsFC changes in the OFC subregions remain unknown.

A total of 98 schizophrenia patients and 102 healthy controls underwent resting-state functional MRI using a sensitivity-encoded spiral-in imaging sequence (SENSE-SPIRAL) to reduce susceptibility-induced signal loss and distortion. The OFC subregions were defined according to a previous parcellation study that divided the OFC into the anterior (OFCa), medial (OFCm), posterior (OFCp), intermediate (OFCi), and lateral (OFCl) subregions. The rsFC was compared using two-way repeated-measures ANOVA.

Whether or not global signal regression, compared with healthy controls, schizophrenia patients consistently exhibited decreased rsFC between the left OFCi and the left middle temporal gyrus and the right middle frontal gyrus (MFG), between the right OFCi and the right MFG and the left inferior frontal gyrus, between the right OFCm and the middle cingulate cortex and the left Rolandic operculum. These rsFC changes still remained significant even after cortical atrophy correction.

These findings suggest a selective functional disconnection of the OFC subregions in schizophrenia, and provide more precise information about the functional disconnections of the OFC in this disorder.

Childhood emotional maltreatment (CEM) has been associated with disturbances in emotional and behavioral functioning, and with changes in regional brain morphology. However, whether CEM has any effect on the intrinsic organization of the brain is not known. In this study, we investigated the effects of CEM on resting-state functional connectivity (RSFC) using seeds in the limbic network, the default-mode network (DMN) and the salience network, and the left dorsomedial prefrontal cortex (dmPFC).

Using 3-T magnetic resonance imaging (MRI), resting-state functional MRI (RS-fMRI) scans were obtained. We defined seeds in the bilateral amygdala, the dorsal anterior cingulate cortex (dACC), the posterior cingulate cortex (PCC) and the left dmPFC, and used these to examine whether individuals reporting CEM (n=44) differed from individuals reporting no CEM (n=44) in RSFC with other brain regions. The two groups were matched for age, gender, handedness and the presence of psychopathology.

CEM was associated with decreased RSFC between the right amygdala and the bilateral precuneus and a cluster extending from the left insula to the hippocampus and putamen. In addition, CEM was associated with decreased RSFC between the dACC and the precuneus and also frontal regions of the brain.

We found that CEM has a profound effect on RSFC in the limbic network and the salience network. Regions that show aberrant connectivity are related to episodic memory encoding, retrieval and self-processing operations.