Mental health during the COVID-19 pandemic: the importance of social support in midlife women.

OBJECTIVE: This study aimed to examine sex differences in factors associated with mood and anxiety in midlife men and women during the COVID-19 pandemic. METHODS: During a remote visit, 312 adults aged 40-60 years (167 female; 23.6% perimenopausal) from the Human Connectome Project in Aging completed PROMIS measures of depression, anxiety and anger/irritability; perceived stress; and questions about social support, financial stress and menopause stage. Multivariate linear regression models assessed sex differences in mental health and the association of social support, financial stress and menopause stage with mental health. RESULTS: Anxiety was higher in women than in men (b = 2.39, p = 0.02). For women only, decreased social support was associated with increased anxiety (b = -2.26, p = 0.002), anger/irritability (b = -1.89, p = 0.02) and stress (b = -1.67, p = 0.002). For women only, not having close family was associated with increased depressive symptoms (b = -6.60, p = 0.01) and stress (b = -7.03, p < 0.001). For both sexes, having children was associated with lower depressive symptoms (b = -3.08, p = 0.002), anxiety (b = -1.93, p = 0.07), anger/irritability (b = -2.73, p = 0.02) and stress (b = -1.44, p = 0.07). Menopause stage was unrelated to mental health. CONCLUSION: Social support, but not financial stress, influenced mental health during the COVID-19 pandemic at midlife, particularly for women.

Ketamine treatment modulates habenular and nucleus accumbens static and dynamic functional connectivity in major depression.

Dysfunctional reward processing in major depressive disorder (MDD) involves functional circuitry of the habenula (Hb) and nucleus accumbens (NAc). Ketamine elicits rapid antidepressant and alleviates anhedonia in MDD. To clarify how ketamine perturbs reward circuitry in MDD, we examined how serial ketamine infusions (SKI) modulate static and dynamic functional connectivity (FC) in Hb and NAc networks. MDD participants (n=58, mean age=40.7 years, female=28) received four ketamine infusions (0.5mg/kg) 2-3 times weekly. Resting-state fMRI scans and clinical assessments were collected at baseline and 24 hours post-SKI completion. Static FC (sFC) and dynamic FC variability (dFCv) were calculated from left and right Hb and NAc seeds to all other brain regions. Paired t-tests examined changes in FC pre-to-post SKI, and correlations were used to determine relationships between FC changes with mood and anhedonia. Following SKI, significant increases in left Hb-bilateral visual cortex FC, decreases in left Hb-left inferior parietal cortex FC, and decreases in left NAc-right cerebellum FC occurred. Decreased dFCv between left Hb and right precuneus and visual cortex, and decreased dFCv between right NAc and right visual cortex both significantly correlated with improvements in Hamilton Depression Rating Scale. Decreased FC between left Hb and bilateral visual/parietal cortices as well as increased FC between left NAc and right visual/parietal cortices both significantly correlated with improvements in anhedonia. Subanesthetic ketamine modulates functional pathways linking the Hb and NAc with visual, parietal, and cerebellar regions. Overlapping effects between Hb and NAc functional systems were associated with ketamine's therapeutic response.

White matter microstructural perturbations after total sleep deprivation in depression.

Background: Total sleep deprivation (TSD) transiently reverses depressive symptoms in a majority of patients with depression. How TSD modulates diffusion tensor imaging (DTI) measures of white matter (WM) microstructure, which may be linked with TSD's rapid antidepressant effects, remains uncharacterized. Methods: Patients with depression (N = 48, mean age = 33, 26 women) completed diffusion-weighted imaging and Hamilton Depression Rating (HDRS) and rumination scales before and after >24 h of TSD. Healthy controls (HC) (N = 53, 23 women) completed the same assessments at baseline, and after receiving TSD in a subset of HCs (N = 15). Tract based spatial statistics (TBSS) investigated voxelwise changes in fractional anisotropy (FA) across major WM pathways pre-to-post TSD in patients and HCs and between patients and HCs at baseline. Post hoc analyses tested for TSD effects for other diffusion metrics, and the relationships between change in diffusion measures with change in mood and rumination symptoms. Results: Significant improvements in mood and rumination occurred in patients with depression (both p < 0.001), but not in HCs following TSD. Patients showed significant (p < 0.05, corrected) decreases in FA values in multiple WM tracts, including the body of the corpus callosum and anterior corona radiata post-TSD. Significant voxel-level changes in FA were not observed in HCs who received TSD (p > 0.05). However, differential effects of TSD between HCs and patients were found in the superior corona radiata, frontal WM and the posterior thalamic radiation (p < 0.05, corrected). A significant (p < 0.05) association between change in FA and axial diffusivity within the right superior corona radiata and improvement in rumination was found post-TSD in patients. Conclusion: Total sleep deprivation leads to rapid microstructural changes in WM pathways in patients with depression that are distinct from WM changes associated with TSD observed in HCs. WM tracts including the superior corona radiata and posterior thalamic radiation could be potential biomarkers of the rapid therapeutic effects of TSD. Changes in superior corona radiata FA, in particular, may relate to improvements in maladaptive rumination.

Maternal perinatal depression and child brain structure at 2-3 years in a South African birth cohort study.

Maternal perinatal depression is associated with risk of adverse child developmental outcomes and differences in offspring brain structure. Evidence from low- and middle-income countries is lacking as is an investigation of antenatal, postnatal, and persistent depression in the same sample. In a South African birth cohort, we investigated the effect of antenatal and postpartum maternal depressive symptoms on offspring brain structure at 2-3 years of age. Magnetic resonance imaging was performed, extracting cortical thickness and surface areas in frontal cortex regions of interest and subcortical volumes using FreeSurfer software. Maternal depressive symptoms were measured using the Edinburgh Postpartum Depression Scale and the Beck Depression Inventory II antenatally and at 6-10 weeks, 6 months, 12 months, and 18 months postpartum and analyzed dichotomously and continuously. Linear regressions were used controlling for child age, sex, intracranial volume, maternal education, age, smoking, alcohol use and HIV. 146 children were included with 38 (37%) exposed to depressive symptoms antenatally and 44 (35%) exposed postnatally. Of these, 16 (13%) were exposed to both. Postpartum, but not antenatal, depressive symptoms were associated with smaller amygdala volumes in children (B = -74.73, p = 0.01). Persistent maternal depressive symptoms across pregnancy and postpartum were also independently associated with smaller amygdala volumes (B = -78.61, p = 0.047). Differences in amygdala volumes among children exposed to postnatal as well as persistent maternal depressive symptomatology underscore the importance of identifying women at-risk for depression during the entire perinatal period.

Changes in white matter microstructure following serial ketamine infusions in treatment resistant depression.

Ketamine produces fast-acting antidepressant effects in treatment resistant depression (TRD). Though prior studies report ketamine-related changes in brain activity in TRD, understanding of ketamine's effect on white matter (WM) microstructure remains limited. We thus sought to examine WM neuroplasticity and associated clinical improvements following serial ketamine infusion (SKI) in TRD. TRD patients (N = 57, 49.12% female, mean age: 39.9) received four intravenous ketamine infusions (0.5 mg/kg) 2-3 days apart. Diffusion-weighted scans and clinical assessments (Hamilton Depression Rating Scale [HDRS-17]; Snaith Hamilton Pleasure Scale [SHAPS]) were collected at baseline and 24-h after SKI. WM measures including the neurite density index (NDI) and orientation dispersion index (ODI) from the neurite orientation dispersion and density imaging (NODDI) model, and fractional anisotropy (FA) from the diffusion tensor model were compared voxelwise pre- to post-SKI after using Tract-Based Spatial Statistics workflows to align WM tracts across subjects/time. Correlations between change in WM metrics and clinical measures were subsequently assessed. Following SKI, patients showed significant improvements in HDRS-17 (p-value = 1.8 E-17) and SHAPS (p-value = 1.97 E-10). NDI significantly decreased in occipitotemporal WM pathways (p < .05, FWER/TFCE corrected). ΔSHAPS significantly correlated with ΔNDI in the left internal capsule and left superior longitudinal fasciculus (r = -0.614, p-value = 6.24E-09). No significant changes in ODI or FA were observed. SKI leads to significant changes in the microstructural features of neurites within occipitotemporal tracts, and changes in neurite density within tracts connecting the basal ganglia, thalamus, and cortex relate to improvements in anhedonia. NODDI may be more sensitive for detecting ketamine-induced WM changes than DTI.

Subcortical brain volumes in young infants exposed to antenatal maternal depression: Findings from a South African birth cohort.

BACKGROUND: Several studies have reported enlarged amygdala and smaller hippocampus volumes in children and adolescents exposed to maternal depression. It is unclear whether similar volumetric differences are detectable in the infants' first weeks of life, following exposure in utero. We investigated subcortical volumes in 2-to-6 week old infants exposed to antenatal maternal depression (AMD) from a South African birth cohort. METHODS: AMD was measured with the Beck Depression Inventory 2nd edition (BDI-II) at 28-32 weeks gestation. T2-weighted structural images were acquired during natural sleep on a 3T Siemens Allegra scanner. Subcortical regions were segmented based on the University of North Carolina neonatal brain atlas. Volumetric estimates were compared between AMD-exposed (BDI-II ⩾ 20) and unexposed (BDI-II < 14) infants, adjusted for age, sex and total intracranial volume using analysis of covariance. RESULTS: Larger volumes were observed in AMD-exposed (N = 49) compared to unexposed infants (N = 75) for the right amygdala (1.93% difference, p = 0.039) and bilateral caudate nucleus (left: 5.79% difference, p = 0.001; right: 6.09% difference, p < 0.001). A significant AMD-by-sex interaction was found for the hippocampus (left: F(1,118) = 4.80, p = 0.030; right: F(1,118) = 5.16, p = 0.025), reflecting greater volume in AMD-exposed females (left: 5.09% difference, p = 0.001, right: 3.54% difference, p = 0.010), but not males. CONCLUSIONS: Volumetric differences in subcortical regions can be detected in AMD-exposed infants soon after birth, suggesting structural changes may occur in utero. Female infants might exhibit volumetric changes that are not observed in male infants. The potential mechanisms underlying these early volumetric differences, and their significance for long-term child mental health, require further investigation.

The impact of prenatal alcohol exposure on gray matter volume and cortical surface area of 2 to 3-year-old children in a South African birth cohort.

BACKGROUND: There is a growing literature that demonstrates the effects of prenatal alcohol exposure (PAE) on brain development in school-aged children. Less is known, however, on how PAE impacts the brain early in life. We investigated the effects of PAE and child sex on subcortical gray matter volume, cortical surface area (CSA), cortical volume (CV), and cortical thickness (CT) in children aged 2 to 3 years. METHODS: The sample was recruited as a nested cross-sectional substudy of the Drakenstein Child Health Study. Images from T1-weighted magnetic resonance imaging were acquired on 47 alcohol-exposed and 124 control children (i.e., with no or minimal alcohol exposure), aged 2 to 3 years, some of whom were scanned as neonates. Brain images were processed through automated processing pipelines using FreeSurfer version 6.0. Subcortical and a priori selected cortical regions of interest were compared. RESULTS: Subcortical volume analyses revealed a PAE by child sex interaction for bilateral putamen volumes (Left: p = 0.02; Right: p = 0.01). There was no PAE by child sex interaction effect on CSA, CV, and CT. Analyses revealed an impact of PAE on CSA (p = 0.04) and CV (p = 0.04), but not CT in this age group. Of note, the inferior parietal gyrus CSA was significantly smaller in children with PAE compared to control children. CONCLUSIONS: Findings from this subgroup scanned at age 2 to 3 years build on previously described subcortical volume differences in neonates from this cohort. Findings suggest that PAE persistently affects gray matter development through the critical early years of life. The detectable influence of PAE on brain structure at this early age further highlights the importance of brain imaging studies on the impact of PAE on the young developing brain.

Anterior default mode network and posterior insular connectivity is predictive of depressive symptom reduction following serial ketamine infusion.

BACKGROUND: Ketamine is a rapidly-acting antidepressant treatment with robust response rates. Previous studies have reported that serial ketamine therapy modulates resting state functional connectivity in several large-scale networks, though it remains unknown whether variations in brain structure, function, and connectivity impact subsequent treatment success. We used a data-driven approach to determine whether pretreatment multimodal neuroimaging measures predict changes along symptom dimensions of depression following serial ketamine infusion. METHODS: Patients with depression (n = 60) received structural, resting state functional, and diffusion MRI scans before treatment. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17), the Inventory of Depressive Symptomatology (IDS-C), and the Rumination Response Scale (RRS) before and 24 h after patients received four (0.5 mg/kg) infusions of racemic ketamine over 2 weeks. Nineteen unaffected controls were assessed at similar timepoints. Random forest regression models predicted symptom changes using pretreatment multimodal neuroimaging and demographic measures. RESULTS: Two HDRS-17 subscales, the HDRS-6 and core mood and anhedonia (CMA) symptoms, and the RRS: reflection (RRSR) scale were predicted significantly with 19, 27, and 1% variance explained, respectively. Increased right medial prefrontal cortex/anterior cingulate and posterior insula (PoI) and lower kurtosis of the superior longitudinal fasciculus predicted reduced HDRS-6 and CMA symptoms following treatment. RRSR change was predicted by global connectivity of the left posterior cingulate, left insula, and right superior parietal lobule. CONCLUSIONS: Our findings support that connectivity of the anterior default mode network and PoI may serve as potential biomarkers of antidepressant outcomes for core depressive symptoms.

Modulation of brain networks during MR-compatible transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) can influence performance on behavioral tasks and improve symptoms of brain conditions. Yet, it remains unclear precisely how tDCS affects brain function and connectivity. Here, we measured changes in functional connectivity (FC) metrics in blood-oxygenation-level-dependent (BOLD) fMRI data acquired during MR-compatible tDCS in a whole-brain analysis with corrections for false discovery rate. Volunteers (n = 64) received active tDCS, sham tDCS, and rest (no stimulation), using one of three previously established electrode tDCS montages targeting left dorsolateral prefrontal cortex (DLPFC, n = 37), lateral temporoparietal area (LTA, n = 16), or superior temporal cortex (STC, n = 11). In brain networks where simulated E field was highest in each montage, connectivity with remote nodes decreased during active tDCS. During active DLPFC-tDCS, connectivity decreased between a fronto-parietal network and subgenual ACC, while during LTA-tDCS connectivity decreased between an auditory-somatomotor network and frontal operculum. Active DLPFC-tDCS was also associated with increased connectivity within an orbitofrontal network overlapping subgenual ACC. Irrespective of montage, FC metrics increased in sensorimotor and attention regions during both active and sham tDCS, which may reflect the cognitive-perceptual demands of tDCS. Taken together, these results indicate that tDCS may have both intended and unintended effects on ongoing brain activity, stressing the importance of including sham, stimulation-absent, and active comparators in basic science and clinical trials of tDCS.

Prenatal depression exposure alters white matter integrity and neurodevelopment in early childhood.

Prenatal exposure to maternal depression increases the risk for onset of emotional and behavioral disorders in children. We investigated the effects of exposure to prenatal depression on white matter microstructural integrity at birth and at 2-3 years, and associated neurodevelopment. Diffusion-weighted images were acquired for children of the Drakenstein Child Health Study at 2-4 weeks postpartum (n=70, 47% boys) and at 2-3 years of age (n=60, 58% boys). Tract-Based Spatial Statistics was used to compare, using an ROI based approach, diffusion tensor metrics across groups defined by presence (>19 on Beck's Depression Inventory and/or >12 on the Edinburgh Postnatal Depression Scale) or absence (below depression thresholds) of depression, and associations with neurodevelopmental measures at age 2-3 years were determined. We did not detect group differences in white matter integrity at neonatal age, but at 2-3 years, children in the exposed group demonstrated higher fractional anisotropy, and lower mean and radial diffusivity in association tracts compared to controls. This was notable in the sagittal stratum (radial diffusivity: p<0.01). Altered white matter integrity metrics were also observed in projection tracts, including the corona radiata, which associated with cognitive and motor outcomes in exposed 2-3-year-olds (p<0.05). Our findings of widespread white matter alterations in 2-3-year-old children with prenatal exposure to depression are consistent with previous findings, as well as with neuroimaging findings in adults with major depression. Further, we identified novel associations of altered white matter integrity with cognitive development in depression-exposed children, suggesting that these neuroimaging findings may have early functional impact.

Modulation of the functional connectome in major depressive disorder by ketamine therapy.

BACKGROUND: Subanesthetic ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depression. How single and repeated ketamine treatment modulates the whole-brain functional connectome to affect clinical outcomes remains uncharacterized. METHODS: Data-driven whole brain functional connectivity (FC) analysis was used to identify the functional connections modified by ketamine treatment in patients with major depressive disorder (MDD). MDD patients (N = 61, mean age = 38, 19 women) completed baseline resting-state (RS) functional magnetic resonance imaging and depression symptom scales. Of these patients, n = 48 and n = 51, completed the same assessments 24 h after receiving one and four 0.5 mg/kg intravenous ketamine infusions. Healthy controls (HC) (n = 40, 24 women) completed baseline assessments with no intervention. Analysis of RS FC addressed effects of diagnosis, time, and remitter status. RESULTS: Significant differences (p < 0.05, corrected) in RS FC were observed between HC and MDD at baseline in the somatomotor network and between association and default mode networks. These disruptions in FC in MDD patients trended toward control patterns with ketamine treatment. Furthermore, following serial ketamine infusions, significant decreases in FC were observed between the cerebellum and salience network (SN) (p < 0.05, corrected). Patient remitters showed increased FC between the cerebellum and the striatum prior to treatment that decreased following treatment, whereas non-remitters showed the opposite pattern. CONCLUSION: Results support that ketamine treatment leads to neurofunctional plasticity between distinct neural networks that are shown as disrupted in MDD patients. Cortico-striatal-cerebellar loops that encompass the SN could be a potential biomarker for ketamine treatment.

Epigenetic clock and methylation studies in vervet monkeys.

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.

Ketamine's modulation of cerebro-cerebellar circuitry during response inhibition in major depression.

Patients with major depressive disorder (MDD) exhibit impaired control of cognitive and emotional systems, including deficient response selection and inhibition. Though these deficits are typically attributed to abnormal communication between macro-scale cortical networks, altered communication with the cerebellum also plays an important role. Yet, how the circuitry between the cerebellum and large-scale functional networks impact treatment outcome in MDD is not understood. We thus examined how ketamine, which elicits rapid therapeutic effects in MDD, modulates cerebro-cerebellar circuitry during response-inhibition using a functional imaging NoGo/Go task in MDD patients (N = 46, mean age: 39.2, 38.1% female) receiving four ketamine infusions, and healthy controls (N = 32, mean age:35.2, 71.4% female). We fitted psychophysiological-interaction (PPI) models for a functionally-derived cerebellar-seed and extracted average PPI in three target functional networks, frontoparietal (FPN), sensory-motor (SMN) and salience (SN) networks. Time and remission status were then evaluated for each of the networks and their network-nodes. Follow-up tests examined whether PPI-connectivity differed between patient remitter/non-remitters and controls. Results showed significant decreases in PPI-connectivity after ketamine between the cerebellum and FPN (p < 0.001) and SMN networks (p = 0.008) in remitters only (N = 20). However, ketamine-related changes in PPI-connectivity between the cerebellum and the SN (p = 0.003) did not vary with remitter status. Cerebellar-FPN, -SN PPI values at baseline were also associated with treatment outcome. Using novel methodology to quantify the functional coupling of cerebro-cerebellar circuitry during response-inhibition, our findings highlight that these loops play distinct roles in treatment response and could potentially serve as novel biomarkers for fast-acting antidepressant therapies in MDD.

Accounting for symptom heterogeneity can improve neuroimaging models of antidepressant response after electroconvulsive therapy.

Depression symptom heterogeneity limits the identifiability of treatment-response biomarkers. Whether improvement along dimensions of depressive symptoms relates to separable neural networks remains poorly understood. We build on work describing three latent symptom dimensions within the 17-item Hamilton Depression Rating Scale (HDRS) and use data-driven methods to relate multivariate patterns of patient clinical, demographic, and brain structural changes over electroconvulsive therapy (ECT) to dimensional changes in depressive symptoms. We included 110 ECT patients from Global ECT-MRI Research Collaboration (GEMRIC) sites who underwent structural MRI and HDRS assessments before and after treatment. Cross validated random forest regression models predicted change along symptom dimensions. HDRS symptoms clustered into dimensions of somatic disturbances (SoD), core mood and anhedonia (CMA), and insomnia. The coefficient of determination between predicted and actual changes were 22%, 39%, and 39% (all p < .01) for SoD, CMA, and insomnia, respectively. CMA and insomnia change were predicted more accurately than HDRS-6 and HDRS-17 changes (p < .05). Pretreatment symptoms, body-mass index, and age were important predictors. Important imaging predictors included the right transverse temporal gyrus and left frontal pole for the SoD dimension; right transverse temporal gyrus and right rostral middle frontal gyrus for the CMA dimension; and right superior parietal lobule and left accumbens for the insomnia dimension. Our findings support that recovery along depressive symptom dimensions is predicted more accurately than HDRS total scores and are related to unique and overlapping patterns of clinical and demographic data and volumetric changes in brain regions related to depression and near ECT electrodes.

Central white matter integrity alterations in 2-3-year-old children following prenatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure (PAE) remains a potentially preventable, but pervasive risk factor to neurodevelopment. Yet, evidence is lacking on the impact of alcohol on brain development in toddlers. This study aimed to investigate the impact of PAE on brain white matter integrity in 2-3-year-old children. METHODS: Children (n = 83, 30-37 months old) of the Drakenstein Child Health Study birth cohort, underwent diffusion MRI on a 3 T Siemens scanner during natural sleep. Parameters were extracted in children with PAE (n = 25, 56 % boys) and unexposed controls (n = 58, 62 % boys) using Tract-based Spatial Statistics, and compared by group. The contribution of maternal tobacco smoking to white matter differences was also explored. RESULTS: Children with PAE had altered fractional anisotropy, radial diffusivity and axial diffusivity in brain stem, limbic and association tracts compared to unexposed controls. Notably lower fractional anisotropy was found in the uncinate fasciculus, and lower mean and radial diffusivity were found in the fornix stria terminalis and corticospinal tract (FDR corrected p < 0.05). There was a significant interaction effect of PAE and prenatal tobacco exposure which lowered mean, radial and axial diffusivity in the corticospinal tract significantly in the PAE group but not controls. CONCLUSION: Widespread altered white matter microstructural integrity at 2-3 years of age is consistent with findings in neonates in the same and other cohorts, indicating persistence of effects of PAE through early life. Findings also highlight that prenatal tobacco exposure impacts the association of PAE on white matter alterations, amplifying effects in tracts underlying motor function.

In-vivo imaging of targeting and modulation of depression-relevant circuitry by transcranial direct current stimulation: a randomized clinical trial.

Recent clinical trials of transcranial direct current stimulation (tDCS) in depression have shown contrasting results. Consequently, we used in-vivo neuroimaging to confirm targeting and modulation of depression-relevant neural circuitry by tDCS. Depressed participants (N = 66, Baseline Hamilton Depression Rating Scale (HDRS) 17-item scores ≥14 and <24) were randomized into Active/Sham and High-definition (HD)/Conventional (Conv) tDCS groups using a double-blind, parallel design, and received tDCS individually targeted at the left dorsolateral prefrontal cortex (DLPFC). In accordance with Ampere's Law, tDCS currents were hypothesized to induce magnetic fields at the stimulation-target, measured in real-time using dual-echo echo-planar-imaging (DE-EPI) MRI. Additionally, the tDCS treatment trial (consisting of 12 daily 20-min sessions) was hypothesized to induce cerebral blood flow (CBF) changes post-treatment at the DLPFC target and in the reciprocally connected anterior cingulate cortex (ACC), measured using pseudo-continuous arterial spin labeling (pCASL) MRI. Significant tDCS current-induced magnetic fields were observed at the left DLPFC target for both active stimulation montages (Brodmann's area (BA) 46: pHD = 0.048, Cohen's dHD = 0.73; pConv = 0.018, dConv = 0.86; BA 9: pHD = 0.011, dHD = 0.92; pConv = 0.022, dConv = 0.83). Significant longitudinal CBF increases were observed (a) at the left DLPFC stimulation-target for both active montages (pHD = 3.5E-3, dHD = 0.98; pConv = 2.8E-3, dConv = 1.08), and (b) at ACC for the HD-montage only (pHD = 2.4E-3, dHD = 1.06; pConv = 0.075, dConv = 0.64). These results confirm that tDCS-treatment (a) engages the stimulation-target, and (b) modulates depression-relevant neural circuitry in depressed participants, with stronger network-modulations induced by the HD-montage. Although not primary outcomes, active HD-tDCS showed significant improvements of anhedonia relative to sham, though HDRS scores did not differ significantly between montages post-treatment.

Hippocampal subregions and networks linked with antidepressant response to electroconvulsive therapy.

Electroconvulsive therapy (ECT) has been repeatedly linked to hippocampal plasticity. However, it remains unclear what role hippocampal plasticity plays in the antidepressant response to ECT. This magnetic resonance imaging (MRI) study tracks changes in separate hippocampal subregions and hippocampal networks in patients with depression (n = 44, 23 female) to determine their relationship, if any, with improvement after ECT. Voxelwise analyses were restricted to the hippocampus, amygdala, and parahippocampal cortex, and applied separately for responders and nonresponders to ECT. In analyses of arterial spin-labeled (ASL) MRI, nonresponders exhibited increased cerebral blood flow (CBF) in bilateral anterior hippocampus, while responders showed CBF increases in right middle and left posterior hippocampus. In analyses of gray matter volume (GMV) using T1-weighted MRI, GMV increased throughout bilateral hippocampus and surrounding tissue in nonresponders, while responders showed increased GMV in right anterior hippocampus only. Using CBF loci as seed regions, BOLD-fMRI data from healthy controls (n = 36, 19 female) identified spatially separable neurofunctional networks comprised of different brain regions. In graph theory analyses of these networks, functional connectivity within a hippocampus-thalamus-striatum network decreased only in responders after two treatments and after index. In sum, our results suggest that the location of ECT-related plasticity within the hippocampus may differ according to antidepressant outcome, and that larger amounts of hippocampal plasticity may not be conducive to positive antidepressant response. More focused targeting of hippocampal subregions and/or circuits may be a way to improve ECT outcome.

Structural and functional brain network alterations in prenatal alcohol exposed neonates.

Prenatal alcohol exposure leads to alterations in cognition, behavior and underlying brain architecture. However, prior studies have not integrated structural and functional imaging data in children with prenatal alcohol exposure. The aim of this study was to characterize disruptions in both structural and functional brain network organization after prenatal alcohol exposure in very early life. A group of 11 neonates with prenatal alcohol exposure and 14 unexposed controls were investigated using diffusion weighted structural and resting state functional magnetic resonance imaging. Covariance networks were created using graph theoretical analyses for each data set, controlling for age and sex. Group differences in global hub arrangement and regional connectivity were determined using nonparametric permutation tests. Neonates with prenatal alcohol exposure and controls exhibited similar global structural network organization. However, global functional networks of neonates with prenatal alcohol exposure comprised of temporal and limbic hubs, while hubs were more distributed in controls representing an early default mode network. On a regional level, controls showed prominent structural and functional connectivity in parietal and occipital regions. Neonates with prenatal alcohol exposure showed regionally, predominant structural and functional connectivity in several subcortical regions and occipital regions. The findings suggest early functional disruption on a global and regional level after prenatal alcohol exposure and indicate suboptimal organization of functional networks. These differences likely underlie sensory dysregulation and behavioral difficulties in prenatal alcohol exposure.

BRAIN NETWORK CONNECTIVITY FROM MATCHING CORTICAL FEATURE DENSITIES.

We present a new method for constructing structural inference brain networks from functional measures of cortical features. Instead of averaging vertex-wise cortical features, we propose the use of full functions of spatial densities of measures such as thickness and use two dimensional pairwise correlations between regions to construct population networks. We show increased within group correlations for both healthy controls and toddlers with prenatal alcohol exposure compared to the existing mean-based correlation approach. Further, we also show significant differences in brain connectivity between the healthy controls and the exposed group.