Biomarkers predict the efficacy of closed-loop rTMS treatment for refractory depression.

Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients (i.e., less than 50%). Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders.

Increased entrainment and decreased excitability predict efficacious treatment of closed-loop phase-locked rTMS for treatment-resistant depression.

Transcranial magnetic stimulation (TMS) is an FDA-approved therapy for major depressive disorder (MDD), specifically for patients who have treatment-resistant depression (TRD). However, TMS produces response or remission in about 50% of patients but is ineffective for the other 50%. Limits on efficacy may be due to individual patient variability, but to date, there are no good biomarkers or measures of target engagement. In addition, TMS efficacy is typically not assessed until a six-week treatment ends, precluding the evaluation of intermediate improvements during the treatment duration. Here, we report on results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation informed by functional magnetic resonance imaging (fMRI). We find that, in responders, synchronized delivery of rTMS produces two systematic changes in brain dynamics. The first change is a decrease in global cortical excitability, and the second is an increase in the phase entrainment of cortical dynamics. These two effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly tracking of these biomarkers allows for efficacy prediction and potential of dynamic adjustments through a treatment course, improving the overall response rates.

Binge Eating (BE) and Obesity: Brain Activity and Psychological Measures before and after Roux-En-Y Gastric Bypass (RYGB).

Brain activity in response to food cues following Roux-En-Y Gastric Bypass (RYGB) in binge eating (BE) or non-binge eating (NB) individuals is understudied. Here, 15 RYGB (8 BE; 7 NB) and 13 no treatment (NT) (7 BE; 6 NB) women with obesity underwent fMRI imaging while viewing high and low energy density food (HEF and LEF, respectively) and non-food (NF) visual cues. A region of interest (ROI) analysis compared BE participants to NB participants in those undergoing RYGB surgery pre-surgery and 4 months post. Results were corrected for multiple comparisons using liberal (p < 0.006 uncorrected) and stringent (p < 0.05 FDR corrected) thresholds. Four months following RYGB (vs. no treatment (NT) control), both BE and NB participants showed greater reductions in blood oxygen level-dependent (BOLD) signals (a proxy of local brain activity) in the dorsomedial prefrontal cortex in response to HEF (vs. LEF) cues (p < 0.006). BE (vs. NB) participants showed greater increases in the precuneus (p < 0.006) and thalamic regions (p < 0.05 corrected) to food (vs. NF). For RYGB (vs. NT) participants, BE participants, but not NB participants, showed lower BOLD signal in the middle occipital gyrus (p < 0.006), whilst NB participants, but not BE participants, showed lower signal in inferior frontal gyrus (p < 0.006) in response to HEF (vs. LEF). Results suggest distinct neural mechanisms of RGYB in BE and may help lead to improved clinical treatments.

Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

BACKGROUND: Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. AIMS: We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). METHOD: Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. RESULTS: Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. CONCLUSIONS: These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

The timing of transcranial magnetic stimulation relative to the phase of prefrontal alpha EEG modulates downstream target engagement.

BACKGROUND: The communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited. METHODS: Here, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Six runs (276 total trials) were acquired in each participant. Phase at each TMS pulse was determined post-hoc using single-trial sorting. Results were examined in two independent datasets: healthy volunteers (HV) (n = 11) and patients with major depressive disorder (MDD) (n = 17) collected as part of an ongoing clinical trial. RESULTS: In both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC fMRI-derived effective connectivity (EC) was modulated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS pulses during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group. DISCUSSION: Results demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest potential clinical applications whereby TMS is synchronized to the brain's internal rhythms in order to more efficiently engage deep therapeutic targets.

Smaller cornu ammonis (CA3) as a potential risk factor for suicidal behavior in mood disorders.

Mood disorders and suicidal behavior have moderate heritability and familial transmission, and are associated with smaller hippocampal volumes. However, it is unclear whether hippocampal alterations reflect heritable risk or epigenetic effects of childhood adversity, compensatory mechanisms, illness-related changes, or treatment effects. We sought to separate the relationships of hippocampal substructure volumes to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed the age of greatest risk for psychopathology onset. Structural brain imaging and hippocampal substructure segmentation quantified Cornu Ammonis (CA1-4), dentate gyrus, and subiculum gray matter volumes in healthy volunteers (HV, N = 25) and three groups with one or more relatives reporting early-onset mood disorder and suicide attempt: 1. Unaffected HR (N = 20); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 25); and 3. HR with lifetime mood disorder and a previous suicide attempt (HR-MOOD + SA, N = 18). Findings were tested in an independent cohort not selected for family history (HV, N = 47; MOOD, N = 44; and MOOD + SA, N = 21). Lower CA3 volume was found in HR (vs. HV), consistent with the direction of previously published findings in MOOD+SA (vs. HV and MOOD), suggesting the finding reflects a familial biological risk marker, not illness or treatment-related sequelae, of suicidal behavior and mood disorder. Familial suicide risk may be mediated in part by smaller CA3 volume. The structure may serve as a risk indicator and therapeutic target for suicide prevention strategies in high-risk families.

In vivo serotonin transporter and 1A receptor binding potential and ecological momentary assessment (EMA) of stress in major depression and suicidal behavior.

We examined relationships between the serotonin system and stress in major depression and suicidal behavior. Twenty-five medication-free depressed participants (13 suicide attempters) underwent same-day [11C]DASB and [11C]CUMI-101 positron emission tomography (PET) imaging. Binding potential (BPND) to the serotonin transporter (5-HTT) and serotonin 1A (5-HT1A) receptor, respectively, was quantified using the NRU 5-HT atlas, reflecting distinct spatial distributions of multiple serotonin targets. Ecological momentary assessment (EMA) measured current stress over one week proximal to imaging. EMA stress did not differ between attempters and non-attempters. In all depressed participants, 5-HTT and 5-HT1A BPND were unrelated to EMA stress. There were region-specific effects of 5-HTT (p=0.002) and 5-HT1A BPND (p=0.03) in attempters vs. nonattempters. In attempters, region-specific associations between 5-HTT (p=0.03) and 5-HT1A (p=0.005) BPND and EMA stress emerged. While no post-hoc 5-HTT BPND correlations were significant, 5-HT1A BPND correlated positively with EMA stress in attempters in 9/10 regions (p-values<0.007), including the entire cortex except the largely occipital region 5. Brodmann-based regional analyses found diminished effects for 5-HTT and subcortically localized positive corrrelations between 5-HT1A and EMA stress, in attempters only. Given comparable depression severity and childhood and current stress between attempters and nonattempters, lower 5-HTT binding in attempters vs. nonattempters may suggest a biological risk marker. Localized lower 5-HTT and widespread higher 5-HT1A binding with stress among attempters specifically may suggest that a serotonergic phenotype might be a key determinant of risk or resiliency for suicidal behavior.

Volume of subcortical brain regions in social anxiety disorder: mega-analytic results from 37 samples in the ENIGMA-Anxiety Working Group.

There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE < 0.001; right: d = -0.158, pFWE < 0.001) and larger bilateral pallidum volumes (left: d = 0.129, pFWE = 0.006; right: d = 0.099, pFWE = 0.046) were detected in adult SAD patients relative to controls, but no volumetric differences were apparent in adolescent SAD patients relative to controls. Comorbid anxiety disorders and age of SAD onset were additional determinants of SAD-related volumetric differences in subcortical regions. To conclude, subtle volumetric alterations in subcortical regions in SAD were detected. Heterogeneity in age and clinical characteristics may partly explain inconsistencies in previous findings. The association between alterations in subcortical volumes and SAD illness progression deserves further investigation, especially from adolescence into adulthood.

Ventral prefrontal serotonin 1A receptor binding: a neural marker of vulnerability for mood disorder and suicidal behavior?

Mood disorders and suicidal behavior have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) brain binding. However, it is unclear whether this reflects genetic effects or epigenetic effects of childhood adversity, compensatory mechanisms, or illness stress-related changes. We sought to separate such effects on 5-HT1A binding by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset with and without developing mood disorder or suicidal behavior. PET imaging quantified 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV, N = 23) and three groups with one or more relatives manifesting early-onset mood disorder and suicide attempt: 1. unaffected HR (N = 23); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N = 26); and 3. HR-MOOD with previous suicide attempt (HR-MOOD + SA, N = 20). Findings were tested in an independent cohort not selected for family history (HV, MOOD, and MOOD + SA, total N = 185). We tested for regional BPND differences and whether brain-wide patterns distinguished between groups. Low ventral prefrontal 5-HT1A BPND was associated with lifetime mood disorder diagnosis and suicide attempt, but only in subjects with a family history of mood disorder and suicide attempt. Brain-wide 5-HT1A BPND patterns including low ventral prefrontal and mesiotemporal cortical binding distinguished HR-MOOD + SA from HV. A biological endophenotype associated with resilience was not observed. Low ventral prefrontal 5-HT1A BPND may reflect familial mood disorder and suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND confers resilience, reducing risk of suicidal behavior in the context of familial risk, and thereby offer a potential prevention target.

Resting State MRI Amplitude of Low Frequency Fluctuations Associated With Suicidal Ideation in Bipolar Depression.

Objective: Suicidal ideation (SI) is a risk factor for completed suicide. Our previous resting state functional magnetic resonance imaging (fMRI) study found that higher amplitude of low frequency fluctuation (ALFF) in right hippocampus and thalamus was associated with SI in major depressive disorder (MDD). The present study aimed to evaluate that association in participants with bipolar disorder (BD).Methods: Thirty depressed, adult participants with a DSM-IV diagnosis of BD had resting state fMRI scans. Region-of-interest (ROI) analyses used ALFF values within areas that were previously associated with SI in MDD. Spearman rank correlation and ordinal regression analyses were performed to assess associations between ALFF values and the SI item of the Montgomery-Asberg Depression Rating Scale. Exploratory whole-brain analyses identified regions where ALFF was associated with SI.Results: Within the right hippocampus region, SI was positively associated with ALFF (Spearman R = 0.490, P = .0060). Ordinal regression analysis indicated that for every 0.1-unit increase in ALFF in that region, the odds of having higher SI were increased by 35% (odds ratio = 1.35; 95% confidence interval, 1.08-1.73; P = .012). Within the previously identified thalamus cluster, SI was associated with ALFF only at a trend level (Spearman R = 0.310, P = .069). Whole-brain analyses identified 3 clusters of positive association between SI and ALFF, 1 of which was located in the right hippocampus.Conclusions: This study found that our previous finding of positive association between SI and ALFF in the right hippocampus extended to bipolar depression. Future studies should examine the clinical utility of this association, and the role of the hippocampus in SI.Trial Registration: Data used for this secondary analysis came from studies with ClinicalTrials.gov identifiers NCT02239094 (January 2015 through September 2016) and NCT02473250 (January 2015 through December 2019).

Serotonin 1A Receptor Binding of [11C]CUMI-101 in Bipolar Depression Quantified Using Positron Emission Tomography: Relationship to Psychopathology and Antidepressant Response.

BACKGROUND: The pathophysiology of bipolar disorder (BD) remains largely unknown despite it causing significant disability and suicide risk. Serotonin signaling may play a role in the pathophysiology, but direct evidence for this is lacking. Treatment of the depressed phase of the disorder is limited. Previous studies have indicated that positron emission tomography (PET) imaging of the serotonin 1A receptor (5HT1AR) may predict antidepressant response. METHODS: A total of 20 participants with BD in a current major depressive episode and 16 healthy volunteers had PET imaging with [11C]CUMI-101, employing a metabolite-corrected input function for quantification of binding potential to the 5HT1AR. Bipolar participants then received an open-labeled, 6-week clinical trial with a selective serotonin reuptake inhibitor (SSRI) in addition to their mood stabilizer. Clinical ratings were obtained at baseline and during SSRI treatment. RESULTS: Pretreatment binding potential (BPF) of [11C]CUMI-101 was associated with a number of pretreatment clinical variables within BD participants. Within the raphe nucleus, it was inversely associated with the baseline Montgomery Åsberg Rating Scale (P = .026), the Beck Depression Inventory score (P = .0023), and the Buss Durkee Hostility Index (P = .0058), a measure of lifetime aggression. A secondary analysis found [11C]CUMI-101 BPF was higher in bipolar participants compared with healthy volunteers (P = .00275). [11C]CUMI-101 BPF did not differ between SSRI responders and non-responders (P = .907) to treatment and did not predict antidepressant response (P = .580). Voxel-wise analyses confirmed the results obtained in regions of interest analyses. CONCLUSIONS: A disturbance of serotonin system function is associated with both the diagnosis of BD and its severity of depression. Pretreatment 5HT1AR binding did not predict SSRI antidepressant outcome.The study was listed on clinicaltrials.gov with identifier NCT02473250.

fMRI Food Cue Reactivity as a Predictor for BMI Change Following Roux-en-Y Gastric Bypass (RYGB) or Diet Intervention.

Prevalence of severe obesity continues to increase, with only bariatric surgery showing long-term efficacy for sustained weight loss. Individuals with severe obesity (vs normal weight) show greater fMRI responsivity to high energy dense (ED) vs low ED food cues and reduced responsivity post-surgery. We examined responsivity to high vs low ED cues pre-intervention in association with postsurgical (RYGB) or dietary weight-loss (dWL) change in BMI at 4 and 18 mo. Region of interest (ROI) analysis employed separate ANCOVA models; group as single factor with three levels and baseline activation and interaction with group covarying for age and gender as nuisance covariates. Significant results were identified at p < 0.1 false discovery rate (FDR) corrected, following multiple comparisons across ROIs. In the precentral gyrus (motor and motor readiness area), higher baseline activation was associated with greater %BMI reduction in RYGB at 4 and 18 mo and less %BMI reduction in dWL at 4 mo (p = 0.006 uncorrected, P < 0.1 FDR corrected). The findings show opposite directionality in predicting change in BMI for RYGB vs. dWL from responsivity to high vs low ED food cues in the precentral gyrus. Greater baseline motor planning to ingest high ED foods may be associated with reduced weight loss in dWL, and with greater weight loss in RYGB due to neuromodulatory effects of surgery.

Relationship between binge eating and associated eating behaviors with subcortical brain volumes and cortical thickness.

BACKGROUND: Binge eating disorder (BED) is the most prevalent eating disorder. We examined the presence of binge eating (BE) and three associated eating behaviors in relation to subcortical regional volumes and cortical thickness from brain scans. METHODS: We processed structural MRI brain scans for 466 individuals from the Nathan Kline Institute Rockland Sample using Freesurfer. We investigated subcortical volumes and cortical thicknesses among those with and without BE and in relation to the scores on dietary restraint, disinhibition, and hunger from the Three-Factor Eating Questionnaire (TFEQ). We conducted a whole-brain analysis and a region of analysis (ROI) using a priori regions associated with BE and with the three eating factors. We also compared scores on the three TFEQ factors for the BE and non-BE. RESULTS: The BE group had higher scores for dietary restraint (p = .013), disinhibition (p = 1.22E-07), and hunger (p = 5.88E-07). In the whole-brain analysis, no regions survived correction for multiple comparisons (FDR corrected p<0.01) for either BE group or interaction with TFEQ. However, disinhibition scores correlated positively with left nucleus accumbens (NAc) volume (p < 0.01 FDR corrected). In the ROI analysis, those with BE also had greater left NAc volume (p = 0.008, uncorrected) compared to non-BE. LIMITATIONS: Limitations include potential self-report bias on the EDE-Q and TFEQ. CONCLUSIONS: The findings show that BE and disinhibition scores were each associated with greater volumes in the left NAc, a reward area, consistent with a greater drive and pleasure for food.

Toward Establishing Internal Validity for Correlated Gene Expression Measures in Imaging Genomics of Functional Networks: Why Distance Corrections and External Face Validity Alone Fall Short. Reply to "Distance Is Not Everything in Imaging Genomics of Functional Networks: Reply to a Commentary on Correlated Gene Expression Supports Synchronous Activity in Brain Networks".

The primary claim of the Richiardi et al. (2015) Science article is that a measure of correlated gene expression, significant strength fraction (SSF), is related to resting state fMRI (rsfMRI) networks. However, there is still debate about this claim and whether spatial proximity, in the form of contiguous clusters, accounts entirely, or only partially, for SSF (Pantazatos and Li, 2017; Richiardi et al., 2017). Here, 13 distributed networks were simulated by combining 34 contiguous clusters randomly placed throughout cortex, with resulting edge distance distributions similar to rsfMRI networks. Cluster size was modulated (6-15 mm radius) to test its influence on SSF false positive rate (SSF-FPR) among the simulated "noise" networks. The contribution of rsfMRI networks on SSF-FPR was examined by comparing simulated networks whose clusters were sampled from: (1) all 1,777 cortical tissue samples, (2) all samples, but with non-rsfMRI cluster centers, and (3) only 1,276 non-rsfMRI samples. Results show that SSF-FPR is influenced only by cluster size (r > 0.9, p < 0.001), not by rsfMRI samples. Simulations using 14 mm radius clusters most resembled rsfMRI networks. When thresholding at p < 10-4, the SSF-FPR was 0.47. Genes that maximize SF have high global spatial autocorrelation. In conclusion, SSF is unrelated to rsfMRI networks. The main conclusion of Richiardi et al. (2015) is based on a finding that is ∼50% likely to be a false positive, not <0.01% as originally reported in the article (Richiardi et al., 2015). We discuss why distance corrections alone and external face validity are insufficient to establish a trustworthy relationship between correlated gene expression measures and rsfMRI networks, and propose more rigorous approaches to preclude common pitfalls in related studies.

Depression-related anterior cingulate prefrontal resting state connectivity normalizes following cognitive behavioral therapy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder.

Individuals with both post-traumatic stress disorder and major depressive disorder (PTSD+MDD) often show greater social and occupational impairment and poorer treatment response than individuals with PTSD alone. Increasing evidence reveals that the amygdala, a brain region implicated in the pathophysiology of both of these conditions, is a complex of structurally and functionally heterogeneous nuclei. Quantifying the functional connectivity of two key amygdala subregions, the basolateral (BLA) and centromedial (CMA), in PTSD+MDD and PTSD-alone could advance our understanding of the neurocircuitry of these conditions. 18 patients with PTSD+MDD, 28 with PTSD-alone, and 50 trauma exposed healthy controls (TEHC), all from a cohort who survived the same large earthquake in China, underwent resting-state functional magnetic resonance imaging. Bilateral BLA and CMA functional connectivity (FC) maps were created using a seed-based approach for each participant. The analysis of covariance of FC was used to determine between-group differences. A significant interaction between amygdala subregion and diagnostic group suggested that differences in connectivity patterns between the two seeds were mediated by diagnosis. Post-hoc analyses revealed that PTSD+MDD patients showed weaker connectivity between right BLA and (a) left anterior cingulate cortex/supplementary motor area, and (b) bilateral putamen/pallidum, compared with PTSD-alone patients. Higher CMA connectivities left ACC/SMA were also observed in PTSD+MDD compared with PTSD-alone. An inverse relationship between the connectivity of right BLA with right putamen/pallidum and MDD symptoms was found in PTSD+MDD. These findings indicate a relationship between the neural pathophysiology of PTSD+MDD compared with PTSD-alone and TEHC and may inform future clinical interventions.

Resting-state amplitude of low-frequency fluctuation is associated with suicidal ideation.

BACKGROUND: Identifying brain activity patterns that are associated with suicidal ideation (SI) may help to elucidate its pathogenesis and etiology. Suicide poses a significant public health problem, and SI is a risk factor for suicidal behavior. METHODS: Forty-one unmedicated adult participants in a major depressive episode (MDE), 26 with SI on the Beck Scale for Suicidal Ideation and 15 without SI, underwent resting-state functional magnetic resonance imaging scanning. Twenty-one healthy volunteers (HVs) were scanned for secondary analyses. Whole brain analysis of both amplitude of low-frequency fluctuations (ALFFs) and fractional ALFF was performed in MDE subjects to identify regions where activity was associated with SI. RESULTS: Subjects with SI had greater ALFF than those without SI in two clusters: one in the right hippocampus and one in the thalamus and caudate, bilaterally. Multi-voxel pattern analysis distinguished between those with and without SI. Post hoc analysis of the mean ALFF in the hippocampus cluster found it to be associated with a delayed recall on the Buschke memory task. Mean ALFF from the significant clusters was not associated with depression severity and did not differ between MDE and HV groups. DISCUSSION: These results indicate that SI is associated with altered resting-state brain activity. The pattern of elevated activity in the hippocampus may be related to how memories are processed.

Functional Magnetic Resonance Imaging (fMRI) of Neural Responses to Visual and Auditory Food Stimuli Pre and Post Roux-en-Y Gastric Bypass (RYGB) and Sleeve Gastrectomy (SG).

Of current obesity treatments, bariatric surgery induces the most weight loss. Given the marked increase in the number of bariatric surgeries performed, elucidating the mechanisms of action is a key research goal. We compared whole brain activation in response to high-energy dense (HED) vs. low-energy dense (LED) visual and auditory food cues before and approximately 4 months after Roux-en-Y Gastric Bypass (RYGB) (n = 16) and Sleeve Gastrectomy (SG) (n = 9). We included two control groups: a low-calorie diet weight loss group (WL) (n = 14) and a non-treatment group (NT) (n = 16). Relative to the control groups, the surgery groups showed increased dorsolateral prefrontal cortex (dlPFC) and decreased parahippocampal/fusiform gyrus (PHG/fusiform) activation in response to HED vs. LED, suggesting greater cognitive dietary inhibition and decreased rewarding effects and attention related to HED foods. dlPFC activation was significantly more increased in RYGB vs. SG. We also found that postprandial increases in GLP-1 concentrations (pre to postsurgery) correlated with postsurgical decreases in RYGB brain activity in the inferior temporal gyrus and the right middle occipital gyrus in addition to increases in the right medial prefrontal gyrus/paracingulate for HED > LED stimuli, suggesting involvement of these attention and inhibitory regions in satiety signaling postsurgery.