A Pilot Study of High-Frequency Transcranial Magnetic Stimulation for Bipolar Depression.

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a standard treatment approach for major depressive disorder. There is growing clinical experience to support the use of high-frequency left-sided rTMS in bipolar depression. This study collected open-label safety and effectiveness data in a sample of patients with bipolar depression.Methods: Thirty-one adults (13 male/ 18 female; mean age: 42.2 [14.3] years) with bipolar (I or II) depression verified by DSM-5 criteria were recruited at Sheppard Pratt and Mayo Clinic between August 2017 and February 2020 for rTMS. Standardized treatment protocols employed 6 weeks of 10-Hz rTMS to the left dorsolateral prefrontal cortex at 120% of motor threshold with 3,000 pulses per session in 4-second trains with intertrain intervals of 26 seconds. All patients were treated concurrently with a mood stabilizer. The primary outcome measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Response and remission were defined as MADRS score reductions of ≥50% or score <10, respectively. We examined response, remission, and potential contributing factors with multivariate and logistic regression models.Results: The majority of patients with bipolar depression reached response (n = 27; 87.1%) and remission (n = 23; 74.2%). Older age and concurrent treatment with lithium were associated with higher MADRS scores throughout the treatment course (0.1 ± 0.05, P =.05; 4.05 ± 1.27, P = .003, respectively). Concurrent treatment with lamotrigine was associated with lower MADRS scores (-3.48 ± 1.26, P = .01). Treatment with rTMS was safe and well tolerated. There were no completed suicides, induced manic episodes, or other serious adverse events.Conclusion: Although preliminary, the present findings are encouraging regarding the safety and effectiveness of 10-Hz rTMS for bipolar depression.Trial Registration: ClinicalTrials.gov identifier: NCT02640950.

Age-Related Decline in Blood-Brain Barrier Function is More Pronounced in Males than Females in Parietal and Temporal Regions.

The blood-brain barrier (BBB) plays a pivotal role in protecting the central nervous system (CNS), shielding it from potential harmful entities. A natural decline of BBB function with aging has been reported in both animal and human studies, which may contribute to cognitive decline and neurodegenerative disorders. Limited data also suggest that being female may be associated with protective effects on BBB function. Here we investigated age and sex-dependent trajectories of perfusion and BBB water exchange rate (kw) across the lifespan in 186 cognitively normal participants spanning the ages of 8 to 92 years old, using a non-invasive diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) MRI technique. We found that the pattern of BBB kw decline with aging varies across brain regions. Moreover, results from our DP-pCASL technique revealed a remarkable decline in BBB kw beginning in the early 60s, which was more pronounced in males. In addition, we observed sex differences in parietal and temporal regions. Our findings provide in vivo results demonstrating sex differences in the decline of BBB function with aging, which may serve as a foundation for future investigations into perfusion and BBB function in neurodegenerative and other brain disorders.

Reciprocal relationships between stress and depressive symptoms: the essential role of the nucleus accumbens.

BACKGROUND: Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms. METHODS: In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006-2010, age = 55.0 ± 7.5 [40-70] years; second visit: 2014-2019; age = 62.7 ± 7.5 [44-80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes. RESULTS: Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = -0.032 to -0.023, p = 0.006-0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7-14.3%, p < 0.001-p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10-5) in participants with high v. no SLEs. CONCLUSIONS: The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms.

Effects of independent versus dependent stressful life events on major symptom domains of schizophrenia.

We evaluated two models to link stressful life events (SLEs) with the psychopathology of schizophrenia spectrum disorders (SSD). We separated SLEs into independent (iSLEs, unlikely influenced by one's behavior) and dependent (dSLEs, likely influenced by one's behavior). Stress-diathesis and stress generation models were evaluated for the relationship between total, i- and d- SLEs and the severity of positive, negative, and depressive symptoms in participants with SSD. Participants with SSD (n = 286; 196 males; age = 37.5 ± 13.5 years) and community controls (n = 121; 83 males; 35.4 ± 13.9 years) completed self-report of lifetime negative total, i- and d- SLEs. Participants with SSD reported a significantly higher number of total SLEs compared to controls (B = 1.11, p = 6.4 × 10-6). Positive symptom severity was positively associated with the total number of SLEs (ß = 0.20, p = 0.001). iSLEs (ß = 0.11, p = 0.09) and dSLEs (ß = 0.21, p = 0.0006) showed similar association with positive symptoms (p = 0.16) suggesting stress-diathesis effects. Negative symptom severity was negatively associated with the number of SLEs (ß = -0.19, p = 0.003) and dSLEs (ß = -0.20, p = 0.001) but not iSLEs (ß = -0.04, p = 0.52), suggesting stress generation effects. Depressive symptom severity was positively associated with SLEs (ß = 0.34, p = 1.0 × 10-8), and the association was not statistically stronger for dSLEs (ß = 0.33, p = 2.7 × 10-8) than iSLEs (ß = 0.21, p = 0.0006), p = 0.085, suggesting stress-diathesis effects. The SLE - symptom relationships in SSD may be attributed to stress generation or stress-diathesis, depending on symptom domain. Findings call for a domain-specific approach to clinical intervention for SLEs in SSD.

Evidence of Neurovascular Water Exchange and Endothelial Vascular Dysfunction in Schizophrenia: An Exploratory Study.

BACKGROUND AND HYPOTHESIS: Mounting evidence supports cerebrovascular contributions to schizophrenia spectrum disorder (SSD) but with unknown mechanisms. The blood-brain barrier (BBB) is at the nexus of neural-vascular exchanges, tasked with regulating cerebral homeostasis. BBB abnormalities in SSD, if any, are likely more subtle compared to typical neurological insults and imaging measures that assess large molecule BBB leakage in major neurological events may not be sensitive enough to directly examine BBB abnormalities in SSD. STUDY DESIGN: We tested the hypothesis that neurovascular water exchange (Kw) measured by non-invasive diffusion-prepared arterial spin label MRI (n = 27 healthy controls [HC], n = 32 SSD) is impaired in SSD and associated with clinical symptoms. Peripheral vascular endothelial health was examined by brachial artery flow-mediated dilation (n = 44 HC, n = 37 SSD) to examine whether centrally measured Kw is related to endothelial functions. STUDY RESULTS: Whole-brain average Kw was significantly reduced in SSD (P = .007). Exploratory analyses demonstrated neurovascular water exchange reductions in the right parietal lobe, including the supramarginal gyrus (P = .002) and postcentral gyrus (P = .008). Reduced right superior corona radiata (P = .001) and right angular gyrus Kw (P = .006) was associated with negative symptoms. Peripheral endothelial function was also significantly reduced in SSD (P = .0001). Kw in 94% of brain regions in HC positively associated with peripheral endothelial function, which was not observed in SSD, where the correlation was inversed in 52% of brain regions. CONCLUSIONS: This study provides initial evidence of neurovascular water exchange abnormalities, which appeared clinically associated, especially with negative symptoms, in schizophrenia.

Depression, stress and regional cerebral blood flow.

Decreased cerebral blood flow (CBF) may be an important mechanism associated with depression. In this study we aimed to determine if the association of CBF and depression is dependent on current level of depression or the tendency to experience depression over time (trait depression), and if CBF is influenced by depression-related factors such as stressful life experiences and antidepressant medication use. CBF was measured in 254 participants from the Amish Connectome Project (age 18-76, 99 men and 154 women) using arterial spin labeling. All participants underwent assessment of symptoms of depression measured with the Beck Depression Inventory and Maryland Trait and State Depression scales. Individuals diagnosed with a unipolar depressive disorder had significantly lower average gray matter CBF compared to individuals with no history of depression or to individuals with a history of depression that was in remission at time of study. Trait depression was significantly associated with lower CBF, with the associations strongest in cingulate gyrus and frontal white matter. Use of antidepressant medication and more stressful life experiences were also associated with significantly lower CBF. Resting CBF in specific brain regions is associated with trait depression, experience of stressful life events, and current antidepressant use, and may provide a valuable biomarker for further studies.

Association between brain similarity to severe mental illnesses and comorbid cerebral, physical, and cognitive impairments.

Severe mental illnesses (SMIs) are often associated with compromised brain health, physical comorbidities, and cognitive deficits, but it is incompletely understood whether these comorbidities are intrinsic to SMI pathophysiology or secondary to having SMIs. We tested the hypothesis that cerebral, cardiometabolic, and cognitive impairments commonly observed in SMIs can be observed in non-psychiatric individuals with SMI-like brain patterns of deviation as seen on magnetic resonance imaging. 22,883 participants free of common neuropsychiatric conditions from the UK Biobank (age = 63.4 ± 7.5 years, range = 45-82 years, 50.9% female) were split into discovery and replication samples. The regional vulnerability index (RVI) was used to quantify each participant's respective brain similarity to meta-analytical patterns of schizophrenia spectrum disorder, bipolar disorder, and major depressive disorder in gray matter thickness, subcortical gray matter volume, and white matter integrity. Cluster analysis revealed five clusters with distinct RVI profiles. Compared with a cluster with no RVI elevation, a cluster with RVI elevation across all SMIs and brain structures showed significantly higher volume of white matter hyperintensities (Cohen's d = 0.59, pFDR < 10-16), poorer cardiovascular (Cohen's d = 0.30, pFDR < 10-16) and metabolic (Cohen's d = 0.12, pFDR = 1.3 × 10-4) health, and slower speed of information processing (|Cohen's d| = 0.11-0.17, pFDR = 1.6 × 10-3-4.6 × 10-8). This cluster also had significantly higher level of C-reactive protein and alcohol use (Cohen's d = 0.11 and 0.28, pFDR = 4.1 × 10-3 and 1.1 × 10-11). Three other clusters with respective RVI elevation in gray matter thickness, subcortical gray matter volume, and white matter integrity showed intermediate level of white matter hyperintensities, cardiometabolic health, and alcohol use. Our results suggest that cerebral, physical, and cognitive impairments in SMIs may be partly intrinsic via shared pathophysiological pathways with SMI-related brain anatomical changes.

Frontal white matter association with sleep quality and the role of stress.

An important measure of brain health is the integrity of white matter connectivity structures that link brain regions. Studies have found an association between poorer sleep quality and decreased white matter integrity. Stress is among the strongest predictors of sleep quality. This study aimed to evaluate the association between sleep quality and white matter and to test if the relationship persisted after accounting for stress. White matter microstructures were measured by diffusion tensor imaging in a population of Old Order Amish/Mennonite (N = 240). Sleep quality was determined by the Pittsburgh Sleep Quality Index. Current stress levels were measured by the perceived stress scale. Exposure to lifetime stress was measured by the lifetime stressor inventory. Microstructures of four white matter tracts: left and right anterior limbs of internal capsule, left anterior corona radiata, and genu of corpus callosum were significantly correlated with sleep quality (all p ≤ 0.001). The current stress level was a significant predictor of sleep quality (p ≤ 0.001) while lifetime stress was not. PSQI remained significantly associated with white matter integrity in these frontal tracts (all p < 0.01) after accounting for current stress and lifetime stress, while current and lifetime stress were not significant predictors of white matter in any of the four models. Sleep quality did not have any substantial mediation role between stress and white matter integrity. Sleep quality was significantly associated with several frontal white matter tracts that connect brain structures important for sleep regulation regardless of current or past stress levels.

Neuroimaging Correlates of Post-Traumatic Stress Disorder in Traumatic Brain Injury: A Systematic Review of the Literature.

Neuroimaging is widely utilized in studying traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD). The risk for PTSD is greater after TBI than after non-TBI trauma, and PTSD is associated with worse outcomes after TBI. Studying the neuroimaging correlates of TBI-related PTSD may provide insights into the etiology of both conditions and help identify those TBI patients most at risk of developing persistent symptoms. The objectives of this systematic review were to examine the current literature on neuroimaging in TBI-related PTSD, summarize key findings, and highlight strengths and limitations to guide future research. A Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) compliant literature search was conducted in PubMed (MEDLINE®), PsycINFO, Embase, and Scopus databases prior to January 2022. The database query yielded 4486 articles, which were narrowed based on specified inclusion criteria to a final cohort of 16 studies, composed of 854 participants with TBI. There was no consensus regarding neuroimaging correlates of TBI-related PTSD among the included articles. A small number of studies suggest that TBI-related PTSD is associated with white matter tract changes, particularly in frontotemporal regions, as well as changes in whole-brain networks of resting-state connectivity. Future studies hoping to identify reliable neuroimaging correlates of TBI-related PTSD would benefit from ensuring consistent case definition, preferably with clinician-diagnosed TBI and PTSD, selection of comparable control groups, and attention to imaging timing post-injury. Prospective studies are needed and should aim to further differentiate predisposing factors from sequelae of TBI-related PTSD.

Erratum: Separating Clinical and Subclinical Depression by Big Data Informed Structural Vulnerability Index and Its impact on Cognition: ENIGMA Dot Product.

In the PSB article published in Biocomputing 2022: Proceedings of the Pacific Symposium, pp. 133-143; doi: 10.1142/9789811250477_0013 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8719281/), the following author name is missing: Si Gao MS

Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity.

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10-3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10-6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10-6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10-27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

Brain-wide versus genome-wide vulnerability biomarkers for severe mental illnesses.

Severe mental illnesses (SMI), including major depressive (MDD), bipolar (BD), and schizophrenia spectrum (SSD) disorders have multifactorial risk factors and capturing their complex etiopathophysiology in an individual remains challenging. Regional vulnerability index (RVI) was used to measure individual's brain-wide similarity to the expected SMI patterns derived from meta-analytical studies. It is analogous to polygenic risk scores (PRS) that measure individual's similarity to genome-wide patterns in SMI. We hypothesized that RVI is an intermediary phenotype between genome and symptoms and is sensitive to both genetic and environmental risks for SMI. UK Biobank sample of N = 17,053/19,265 M/F (age = 64.8 ± 7.4 years) and an independent sample of SSD patients and controls (N = 115/111 M/F, age = 35.2 ± 13.4) were used to test this hypothesis. UKBB participants with MDD had significantly higher RVI-MDD (Cohen's d = 0.20, p = 1 × 10-23 ) and PRS-MDD (d = 0.17, p = 1 × 10-15 ) than nonpsychiatric controls. UKBB participants with BD and SSD showed significant elevation in the respective RVIs (d = 0.65 and 0.60; p = 3 × 10-5 and .009, respectively) and PRS (d = 0.57 and 1.34; p = .002 and .002, respectively). Elevated RVI-SSD were replicated in an independent sample (d = 0.53, p = 5 × 10-5 ). RVI-MDD and RVI-SSD but not RVI-BD were associated with childhood adversity (p < .01). In nonpsychiatric controls, elevation in RVI and PRS were associated with lower cognitive performance (p < 10-5 ) in six out of seven domains and showed specificity with disorder-associated deficits. In summary, the RVI is a novel brain index for SMI and shows similar or better specificity for SMI than PRS, and together they may complement each other in the efforts to characterize the genomic to brain level risks for SMI.

Behavioral and Emotional Dyscontrol Following Traumatic Brain Injury: A Systematic Review of Neuroimaging and Electrophysiological Correlates.

BACKGROUND: Behavioral and emotional dyscontrol commonly occur following traumatic brain injury (TBI). Neuroimaging and electrophysiological correlates of dyscontrol have not been systematically summarized in the literature to date. OBJECTIVE: To complete a systematic review of the literature examining neuroimaging and electrophysiological findings related to behavioral and emotional dyscontrol due to TBI. METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search was conducted in PubMed (MEDLINE), PsycINFO, EMBASE, and Scopus databases prior to May 2019. The database query yielded 4392 unique articles. These articles were narrowed based on specific inclusion criteria (e.g., clear TBI definition, statistical analysis of the relationship between neuroimaging and dyscontrol). RESULTS: A final cohort of 24 articles resulted, comprising findings from 1552 patients with TBI. Studies included civilian (n = 12), military (n = 10), and sport (n = 2) samples with significant variation in the severity of TBI incorporated. Global and region-based structural imaging was more frequently used to study dyscontrol than functional imaging or diffusion tensor imaging. The prefrontal cortex was the most common neuroanatomical region associated with behavioral and emotional dyscontrol, followed by other frontal and temporal lobe findings. CONCLUSIONS: Frontal and temporal lesions are most strongly implicated in the development of postinjury dyscontrol symptoms although they are also the most frequently investigated regions of the brain for these symptom categories. Future studies can make valuable contributions to the field by (1) emphasizing consistent definitions of behavioral and emotional dyscontrol, (2) assessing premorbid dyscontrol symptoms in subjects, (3) utilizing functional or structural connectivity-based imaging techniques, or (4) restricting analyses to more focused brain regions.

A Preliminary Report: The Hippocampus and Surrounding Temporal Cortex of Patients With Schizophrenia Have Impaired Blood-Brain Barrier.

Though hippocampal volume reduction is a pathological hallmark of schizophrenia, the molecular pathway(s) responsible for this degeneration remains unknown. Recent reports have suggested the potential role of impaired blood-brain barrier (BBB) function in schizophrenia pathogenesis. However, direct evidence demonstrating an impaired BBB function is missing. In this preliminary study, we used immunohistochemistry and serum immunoglobulin G (IgG) antibodies to investigate the state of BBB function in formalin-fixed postmortem samples from the hippocampus and surrounding temporal cortex of patients with schizophrenia (n = 25) and controls without schizophrenia (n = 27) matched for age, sex, and race. Since a functional BBB prevents the extravasation of IgGs, detection of IgGs in the parenchyma is used as direct evidence of BBB breakdown. We also developed a semi-quantitative approach to quantify the extent of IgG leak and therein BBB breach. Analysis of our immunohistochemistry data demonstrated a significantly higher incidence of IgG leak in patients with schizophrenia compared to controls. Further, BBB permeability was significantly higher in advanced-age patients with schizophrenia than both advanced-age controls and middle-aged patients with schizophrenia. Male patients with schizophrenia also demonstrated a significant increase in IgG permeability compared to control males. Interestingly, the extravasated IgGs also demonstrated selective immunoreactivity for neurons. Based on these observations, we suggest that BBB dysfunction and IgG autoantibodies could be two key missing pathoetiological links underwriting schizophrenia hippocampal damage.

The additive impact of cardio-metabolic disorders and psychiatric illnesses on accelerated brain aging.

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio-metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning "BrainAge" index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD- (N = 964), SMI-/CMD+ (N = 3,765), SMI-/CMD- (N = 8,083). SMI (F = 40.47, p = 2.06 × 10-10 ) and CMD (F = 24.69, p = 6.82 × 10-7 ) significantly, independently impacted whole-brain QRI in SMI+. SSD had the largest effect (Cohen's d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI- (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole-brain QRI was significantly (p < 10-16 ) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10-16 ). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio-metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age-related cognitive decline.

Role of White Matter Microstructure in Impulsive Behavior.

OBJECTIVE: Increased impulsivity is a hallmark trait of some neuropsychiatric illnesses, including addiction, traumatic brain injury, and externalizing disorders. The authors hypothesized that altered cerebral white matter microstructure may also underwrite normal individual variability in impulsive behaviors and tested this among healthy individuals. METHODS: Impulsivity and diffusion tensor imaging (DTI) data were collected from 74 healthy adults (32 women; mean age=36.6 years [SD=13.6]). Impulsivity was evaluated using the Barratt Impulsiveness Scale-11, which provides a total score and scores for three subdomains: attentional, motor, and nonplanning impulsiveness. DTI was processed using the Enhancing Neuro Imaging Genetics Through Meta Analysis-DTI analysis pipeline to measure whole-brain and regional white matter fractional anisotropy (FA) values in 24 tracts. RESULTS: Whole-brain total average FA was inversely correlated with motor impulsiveness (r=-0.32, p=0.007) and positively correlated with nonplanning impulsiveness (r=0.29, p=0.02); these correlations were significant after correction for multiple comparisons. Additional significant correlations were observed for motor impulsiveness and regional FA values for the corticospinal tract (r=-0.29, p=0.01) and for nonplanning impulsiveness and regional FA values for the superior fronto-occipital fasciculus (r=0.32, p=0.008). CONCLUSIONS: These results provide initial evidence that the motor and nonplanning subdomains of impulsive behavior are linked to specific white matter microstructural connectivity, supporting the notion that impulsivity is in part a network-based construct involving white matter microstructural integrity among otherwise healthy populations.

Separating Clinical and Subclinical Depression by Big Data Informed Structural Vulnerability Index and Its impact on Cognition: ENIGMA Dot Product.

Big Data neuroimaging collaborations including Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) integrated worldwide data to identify regional brain deficits in major depressive disorder (MDD). We evaluated the sensitivity of translating ENIGMA-defined MDD deficit patterns to the individual level. We treated ENIGMA MDD deficit patterns as a vector to gauge the similarity between individual and MDD patterns by calculating ENIGMA dot product (EDP). We analyzed the sensitivity and specificity of EDP in separating subjects with (1) subclinical depressive symptoms without a diagnosis of MDD, (2) single episode MDD, (3) recurrent MDD, and (4) controls free of neuropsychiatric disorders. We compared EDP to the Quantile Regression Index (QRI; a linear alternative to the brain age metric) and the global gray matter thickness and subcortical volumes and fractional anisotropy (FA) of water diffusion. We performed this analysis in a large epidemiological sample of UK Biobank (UKBB) participants (N=17,053/19,265 M/F). Group-average increases in depressive symptoms from controls to recurrent MDD was mirrored by EDP (r2=0.85), followed by FA (r2=0.81) and QRI (r2=0.56). Subjects with MDD showed worse performance on cognitive tests than controls with deficits observed for 3 out of 9 cognitive tests administered by the UKBB. We calculated correlations of EDP and other brain indices with measures of cognitive performance in controls. The correlation pattern between EDP and cognition in controls was similar (r2=0.75) to the pattern of cognitive differences in MDD. This suggests that the elevation in EDP, even in controls, is associated with cognitive performance - specifically in the MDD-affected domains. That specificity was missing for QRI, FA or other brain imaging indices. In summary, translating anatomically informed meta-analytic indices of similarity using a linear vector approach led to better sensitivity to depressive symptoms and cognitive patterns than whole-brain imaging measurements or an index of accelerated aging.

Neuroimaging Correlates of Syndromal Anxiety Following Traumatic Brain Injury: A Systematic Review of the Literature.

BACKGROUND: Traumatic brain injury (TBI) can precipitate new-onset psychiatric symptoms or worsen existing psychiatric conditions. To elucidate specific mechanisms for this interaction, neuroimaging is often used to study both psychiatric conditions and TBI. This systematic review aims to synthesize the existing literature of neuroimaging findings among patients with anxiety after TBI. METHODS: We conducted a Preferred Reporting Items for Systematic Review and Meta-Analyses-compliant literature search via PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases before May, 2019. We included studies that clearly defined TBI, measured syndromal anxiety as a primary outcome, and statistically analyzed the relationship between neuroimaging findings and anxiety symptoms. RESULTS: A total of 5982 articles were retrieved from the systematic search, of which 65 studied anxiety and 13 met eligibility criteria. These studies were published between 2004 and 2017, collectively analyzing 764 participants comprised of 470 patients with TBI and 294 non-TBI controls. Imaging modalities used included magnetic resonance imaging, functional magnetic resonance imaging, diffusion tensor imaging, electroencephalogram, magnetic resonance spectrometry, and magnetoencephalography. Eight of 13 studies presented at least one significant finding and together reflect a complex set of changes that lead to anxiety in the setting of TBI. The left cingulate gyrus in particular was found to be significant in 2 studies using different imaging modalities. Two studies also revealed perturbances in functional connectivity within the default mode network. CONCLUSIONS: This is the first systemic review of neuroimaging changes associated with anxiety after TBI, which implicated multiple brain structures and circuits, such as the default mode network. Future research with consistent, rigorous measurements of TBI and syndromal anxiety, as well as attention to control groups, previous TBIs, and time interval between TBI and neuroimaging, are warranted. By understanding neuroimaging correlates of psychiatric symptoms, this work could inform future post-TBI screening and surveillance, preventative efforts, and early interventions to improve neuropsychiatric outcomes.

White matter in prolonged glucocorticoid response to psychological stress in schizophrenia.

Stress is implicated in psychosis etiology and exacerbation, but pathogenesis toward brain network alterations in schizophrenia remain unclear. White matter connects limbic and prefrontal regions responsible for stress response regulation, and white matter tissues are also vulnerable to glucocorticoid aberrancies. Using a novel psychological stressor task, we studied cortisol stress responses over time and white matter microstructural deficits in schizophrenia spectrum disorder (SSD). Cortisol was measured at baseline, 0-, 20-, and 40-min after distress induction by a psychological stressor task in 121 SSD patients and 117 healthy controls (HC). White matter microstructural integrity was measured by 64-direction diffusion tensor imaging. Fractional anisotropy (FA) in white matter tracts were related to cortisol responses and then compared to general patterns of white matter tract deficits in SSD identified by mega-analysis. Differences between 40-min post-stress and baseline, but not acute reactivity post-stress, was significantly elevated in SSD vs HC, time × diagnosis interaction F2.3,499.9 = 4.1, p = 0.013. All SSD white matter tracts were negatively associated with prolonged cortisol reactivity but all tracts were positively associated with prolonged cortisol reactivity in HC. Individual tracts most strongly associated with prolonged cortisol reactivity were also most impacted in schizophrenia in general as established by the largest schizophrenia white matter study (r = -0.56, p = 0.006). Challenged with psychological stress, SSD and HC mount similar cortisol responses, and impairments arise in the resolution timeframe. Prolonged cortisol elevations are associated with the white matter deficits in SSD, in a pattern previously associated with schizophrenia in general.

Aberrant anterior cingulate processing of anticipated threat as a mechanism for psychosis.

Stress and abnormal stress response are associated with schizophrenia spectrum disorder (SSD), but the brain mechanisms linking stress to symptomatology remain unclear. In this study, we used a stress-based functional neuroimaging task, reverse-translated from preclinical studies, to test the hypothesis that abnormal corticolimbic processing of stressful threat anticipation is associated with psychosis and affective symptoms in SSD. Participants underwent an MRI-compatible ankle-shock task (AST) in which the threat of mild electrical shock was anticipated. We compared functional brain activations during anticipatory threat periods from N = 18 participants with SSD (10 M/8F) to those from N = 12 community controls (9 M/3F). After family-wise error correction, only one region, the ventral anterior cingulate cortex (vACC), showed significantly reduced activation compared with controls. vACC activation significantly correlated with clinical symptoms measured by the Brief Psychiatric Rating Scale total score (r = 0.54) and the psychosis subscale (r = 0.71), and inversely correlated with trait depression measured by the Maryland Trait and State Depression scale (r=-0.48). Deficient activation in vACC under stress of anticipated threat may lead to aberrant interpretation of such threat, contributing to psychosis and mood symptoms in SSD. This experimental paradigm has translational potential and may identify circuitry-level mechanisms of stress-related mental illness, leading to more targeted treatment.