Distinctively different human neurobiological responses after trauma exposure and implications for posttraumatic stress disorder subtyping.

Trauma elicits various adaptive and maladaptive responses among all exposed people. There may be distinctively different patterns of adaptation/maladaptation or types according to neurobiological predisposition. The present study aims to dissect the heterogeneity of posttraumatic conditions in order to identify clinically meaningful subtypes in recently traumatized individuals and evaluate their neurobiological correlates and long-term prognosis. We implemented a data-driven classification approach in both discovery (n = 480) and replication (n = 220) datasets of trauma-exposed and trauma-unexposed individuals based on the clinical data across a wide range of assessments. Subtype-specific patterns of functional connectivity in higher-order cortical networks, longitudinal clinical outcomes, and changes in functional connectivity were also evaluated. We identified four distinct and replicable subtypes for trauma-exposed individuals according to posttraumatic stress symptoms. Each subtype was distinct in clinical characteristics, brain functional organization, and long-term trajectories for posttraumatic symptoms. These findings help enhance current understanding of mechanisms underlying the human-specific heterogeneous responses to trauma. Furthermore, this study contributes data towards the development of improved interventions, including targeting of subtype-specific characteristics, for trauma-exposed individuals and those with PTSD.

Genetic profile for dopamine signaling predicts brain functional reactivity to repetitive transcranial magnetic stimulation.

Research integrating molecular and imaging data provides important insights into how the genetic profile associated with dopamine signaling influences inter-individual differences in brain functions. However, the effects of genetic variations in dopamine signaling on the heterogeneity of brain changes induced by repetitive transcranial magnetic stimulation (rTMS) still remain unclear. The current study examined the composite effects of genetic variations in dopamine-related genes on rTMS-induced brain responses in terms of the functional network connectivity and working memory performance. Healthy individuals (n = 30) participated in a randomized, double-blind, sham-controlled study with a crossover design of five consecutive days where active rTMS or sham stimulation sessions were administered over the left dorsolateral prefrontal cortex (DLPFC) of the brain. Participants were mostly women (n = 29) and genotyped for polymorphisms in the catechol-O-methyltransferase and D2 dopamine receptor genes and categorized according to their genetic composite scores: high vs. low dopamine signaling groups. Pre- and post-intervention data of resting-state functional magnetic resonance imaging and working memory performance were obtained from 27 individuals with active rTMS and 30 with sham stimulation sessions. The mean functional connectivity within the resting-state networks centered on the DLPFC increased in the high dopamine signaling group. Working memory performance also improved with rTMS in the high dopamine signaling group compared to that in the low dopamine signaling group. The present results suggest that genetic predisposition to higher dopamine signaling may be a promising neurobiological predictor for rTMS effects on cognitive enhancement.Trial registration: ClinicalTrials.gov (NCT02932085).

Gray matter volume reduction in the emotional brain networks in adults with anosmia.

Loss of olfaction, or anosmia, frequently accompanies emotional dysfunctions, partly due to the overlapping brain regions between the olfactory and emotional processing centers. Here, we investigated whether anosmia was associated with gray matter volume alterations at a network level, and whether these alterations were related to the olfactory-specific quality of life (QOL) and depressive symptoms. Structural brain magnetic resonance imaging was acquired in 22 individuals with postinfectious or idiopathic anosmia (the anosmia group) and 30 age- and sex-matched controls (the control group). Using independent component analysis on the gray matter volumes, we identified 10 morphometric networks. The gray matter volumes of these networks were compared between the two groups. Olfactory-specific QOL and depressive symptoms were assessed by self-report questionnaires and clinician-administered interviews, respectively. The anosmia group showed lower gray matter volumes in the hippocampus-amygdala and the precuneus networks, relative to the control group. Lower gray matter volumes in the hippocampus-amygdala network were also linearly associated with lower olfactory-specific QOL and higher depressive symptom scores. These findings suggest a close relationship between anosmia and gray matter volume alterations in the emotional brain networks, albeit without determined causal relations.

Hippocampal subregional alterations and verbal fluency in the early stage of type 2 diabetes mellitus.

Growing evidence indicates that type 2 diabetes mellitus (T2DM)-related cognitive dysfunction may develop in the early stage of the disease and is often accompanied by hippocampal structural alterations. In the current study, we investigated volume and shape alterations of the hippocampus at a subregional level in patients with T2DM. With the use of high-resolution brain structural images that were obtained from 30 T2DM patients with less than 5 years of disease duration and 30 healthy individuals, volumetric and shape analyses were performed. We also assessed the relationship between T2DM-related hippocampal structural alterations and performance on verbal fluency. In volumetric analysis, total hippocampal volume was smaller in the T2DM group, relative to the control group. At a subregional level, T2DM patients showed significant inward deformation and volume reduction of the right dentate gyrus and cornu ammonis 2/3 subregions as compared with healthy individuals. In particular, T2DM patients with lower performance on verbal fluency had smaller right dentate gyrus volumes relative to those with higher performance. These findings suggest that the hippocampus may undergo atrophy at a subregional level even in the early stage of T2DM, and this subregion-specific atrophy may be associated with reduced performance on verbal fluency.

Effects of Korean red ginseng on human gray matter volume and cognitive function: A voxel-based morphometry study.

OBJECTIVE: We aimed to investigate the effects of Korean red ginseng (KRG) supplementation on gray matter volume of the human brain which could be related to cognitive enhancing effects of KRG. METHODS: In this randomized, double-blind, placebo-controlled study, 51 healthy individuals were assigned to receive either KRG (1000 mg/day, n = 26) or placebo (n = 25) for 8 weeks. Gray matter volume of the whole brain was measured using voxel-based morphometry based on high-resolution T1-weighted magnetic resonance images acquired at baseline and week 8. The standardized composite cognitive scores of executive function, attention, and memory were also evaluated at baseline and week 8. Changes in gray matter volume as well as the composite cognitive scores were compared between the KRG and placebo groups. RESULTS: Following 8 weeks of KRG supplementation, the gray matter volume of the left parahippocampal gyrus increased significantly in the KRG group, relative to the placebo group (p for interaction < 0.001). The KRG group also showed greater magnitude of enhancement in the composite cognitive scores relative to the placebo group (p for interaction = 0.03). CONCLUSIONS: Gray matter volume increase in the parahippocampus may be a key neural change as induced by KRG supplementation, which could be associated with cognitive enhancement.

Alterations in Brain Morphometric Networks and Their Relationship with Memory Dysfunction in Patients with Type 2 Diabetes Mellitus.

Cognitive dysfunction, a significant complication of type 2 diabetes mellitus (T2DM), can potentially manifest even from the early stages of the disease. Despite evidence of global brain atrophy and related cognitive dysfunction in early-stage T2DM patients, specific regions vulnerable to these changes have not yet been identified. The study enrolled patients with T2DM of less than five years' duration and without chronic complications (T2DM group, n=100) and demographically similar healthy controls (control group, n=50). High-resolution T1-weighted magnetic resonance imaging data were subjected to independent component analysis to identify structurally significant components indicative of morphometric networks. Within these networks, the groups' gray matter volumes were compared, and distinctions in memory performance were assessed. In the T2DM group, the relationship between changes in gray matter volume within these networks and declines in memory performance was examined. Among the identified morphometric networks, the T2DM group exhibited reduced gray matter volumes in both the precuneus (Bonferroni-corrected p=0.003) and insular-opercular (Bonferroni-corrected p=0.024) networks relative to the control group. Patients with T2DM demonstrated significantly lower memory performance than the control group (p=0.001). In the T2DM group, reductions in gray matter volume in both the precuneus (r=0.316, p=0.001) and insular-opercular (r=0.199, p=0.047) networks were correlated with diminished memory performance. Our findings indicate that structural alterations in the precuneus and insular-opercular networks, along with memory dysfunction, can manifest within the first 5 years following a diagnosis of T2DM.

Aberrant Resting-state Functional Connectivity in Complex Regional Pain Syndrome: A Network-based Statistics Analysis.

Complex regional pain syndrome (CRPS) is a chronic neuropathic pain disorder. Pain catastrophizing, characterized by magnification, rumination, and helplessness, increases perceived pain intensity and mental distress in CRPS patients. As functional connectivity patterns in CRPS remain largely unknown, we aimed to investigate functional connectivity alterations in CRPS patients and their association with pain catastrophizing using a whole-brain analysis approach. Twenty-one patients with CRPS and 49 healthy controls were included in the study for clinical assessment and resting-state functional magnetic resonance imaging. Between-group differences in whole-brain functional connectivity were examined through a Network-based Statistics analysis. Associations between altered functional connectivity and the extent of pain catastrophizing were also assessed in CRPS patients. Relative to healthy controls, CRPS patients showed higher levels of functional connectivity in the bilateral somatosensory subnetworks (components 1~2), but lower functional connectivity within the prefronto-posterior cingulate (component 3), prefrontal (component 4), prefronto-parietal (component 5), and thalamo-anterior cingulate (component 6) subnetworks (p<0.05, family-wise error corrected). Higher levels of functional connectivity in components 1~2 (ß=0.45, p=0.04) and lower levels of functional connectivity in components 3~6 (ß=-0.49, p=0.047) were significantly correlated with higher levels of pain catastrophizing in CRPS patients. Higher functional connectivity in the somatosensory subnetworks implicating exaggerated pain perception and lower functional connectivity in the prefronto-parieto-cingulo-thalamic subnetworks indicating impaired cognitive-affective pain processing may underlie pain catastrophizing in CRPS.

Severity of post-traumatic stress disorder and childhood abuse in adult crime victims as mediated by low resilience and dysfunctional coping strategies.

BACKGROUND: Experience of childhood abuse has been suggested to increase the severity of post-traumatic stress disorder (PTSD) in adulthood. We hypothesized that resilience and coping strategies, which could be altered by experiencing childhood abuse, may mediate the effects of childhood abuse on PTSD severity in adulthood. METHODS: Crime victims with PTSD (n = 212, 38 men, aged 20-65 years) were recruited from South Korea. PTSD severity, a history of childhood abuse, resilience level, and use of coping strategies were assessed using structured clinical interviews and self-report questionnaires. Upon identifying the key factors that were associated with childhood abuse and PTSD severity, mediating roles of these key factors were examined using structural equation modeling and bootstrapping in simple and multiple mediation analyses. RESULTS: Resilience and dysfunctional coping strategies mediated the association between childhood abuse and lifetime PTSD severity in the adulthood, after covarying for the number of repeated trauma exposure (total effect: ß = 0.44, P = 0.01, 95% CI [0.10, 0.77]; direct effect: ß = 0.02, P = 0.90, 95% CI [-0.34, 0.38]; indirect effect: ß = 0.42, P = 0.003, 95% CI [0.14, 0.69]). LIMITATIONS: Recall of childhood abuse experience and lifetime PTSD severity can be biased in crime victims. CONCLUSIONS: These findings may suggest that resilience and coping strategies mediate the detrimental effects of childhood abuse on lifetime PTSD severity. Targeted treatments that are designed to enhance resilience as well as deter the use of dysfunctional coping strategies may be of help in crime victims with a history of childhood abuse.

Changes in Prefrontal Gamma-Aminobutyric Acid and Perfusion After the Computerized Relaxation Training in Women With Psychological Distress: A Preliminary Report.

Computerized relaxation training has been suggested as an effective and easily accessible intervention for individuals with psychological distress. To better elucidate the neural mechanism that underpins the effects of relaxation training, we investigated whether a 10-session computerized relaxation training program changed prefrontal gamma-aminobutyric acid (GABA) levels and cerebral blood flow (CBF) in women with psychological distress. We specifically focused on women since they were reported to be more vulnerable to develop stress-related disorders than men. Nineteen women with psychological distress but without a diagnosis of psychiatric disorders received the 10-day computerized relaxation training program that consisted of 30-min cognitive-relaxation training and 10-min breathing-relaxation training per day. At baseline and post-intervention, perceived stress levels, anxiety, fatigue, and sleep quality were assessed by self-report questionnaires. Brain magnetic resonance spectroscopy and arterial spin labeling scans were also performed before and after the intervention to evaluate GABA levels and relative CBF in the prefrontal region. Levels of perceived stress (t = 4.02, P < 0.001), anxiety (z = 2.33, P = 0.02), fatigue (t = 3.35, P = 0.004), and sleep quality (t = 4.14, P < 0.001) improved following 10 sessions of computerized relaxation training, resulting in a significant relief in composite scores of stress-related symptoms (t = -5.25, P < 0.001). The prefrontal GABA levels decreased (t = 2.53, P = 0.02), while relative CBF increased (t = -3.32, P = 0.004) after the intervention. In addition, a greater increase in relative prefrontal CBF was associated with better composite scores of stress-related symptoms following the intervention (t = 2.22, P = 0.04). The current findings suggest that computerized relaxation training may improve stress-related symptoms through modulating the prefrontal GABA levels and CBF in women with psychological distress.

Firefighters Have Cerebral Blood Flow Reductions in the Orbitofrontal and Insular Cortices That are Associated with Poor Sleep Quality.

PURPOSE: To investigate the cerebral blood flow (CBF) alterations associated with poor sleep quality and memory performance in firefighters. PARTICIPANTS AND METHODS: Thirty-seven firefighters (the FF group) and 37 non-firefighter controls (the control group) with sleep complaints were enrolled in this study. We performed brain arterial spin labeling perfusion magnetic resonance imaging (MRI) and compared the CBF between the two groups using whole-brain voxel-wise analyses. Self-reported sleep problems and actigraphy-measured sleep parameters, including the sleep efficiency, wake after sleep onset (WASO), total sleep time, and sleep latency, were assessed. Spatial working memory and learning performances were evaluated on the day of the MRI scan. RESULTS: The FF group, relative to the control group, had lower CBF in the right hemispheric regions: Middle temporal/lateral occipital, orbitofrontal, and insular cortices. Lower CBF in the right orbitofrontal cortex was linearly associated with poor sleep quality, as indicated by lower sleep efficiency and longer WASO. The CBF of the right insular cortex was also associated with longer WASO. Despite comparable degrees of self-reported sleep problems between the two groups, the FF group had lower sleep efficiency and longer WASO in the actigraphy, and lower spatial working memory and learning performance, relative to the control group. Poor sleep efficiency was linearly associated with lower spatial working memory performance. CONCLUSION: These results demonstrated an association of poor sleep quality with decreased brain perfusion in the right orbitofrontal and insular cortices, as well as with reduced working memory performance.

Obesity May Connect Insulin Resistance to Decreased Neuronal Viability in Human Diabetic Brain.

OBJECTIVE: This study aimed to investigate the relationship between insulin resistance and markers of neuronal viability and energy metabolism, as well as the additive effects of overweight or obesity, in individuals with type 2 diabetes mellitus (T2DM). METHODS: Using 1 H-magnetic resonance spectroscopy, prefrontal N-acetyl aspartate (NAA) and creatine levels, markers for neuronal viability and energy metabolism, respectively, were measured in 50 adults with overweight or obesity and T2DM (T2DM-O; aged 49.0 ± 7.4 years; 50% female), 50 adults with normal weight and T2DM (T2DM-N), and 50 healthy adults with normal weight (healthy-control [HC] group) matched for age and sex. The homeostatic model assessment for insulin resistance levels were calculated to assess insulin resistance. RESULTS: Prefrontal NAA levels were lower in the T2DM-O group relative to the HC group (t = -2.51, P = 0.013). Higher insulin resistance was associated with lower prefrontal NAA levels in the T2DM-O group (t = -2.21, P = 0.032) but not in the T2DM-N group (t = -0.72, P = 0.48). Prefrontal creatine levels did not differ across the three groups. CONCLUSIONS: Overweight and obesity might contribute to T2DM-related neuronal viability deficits and could be the key links that connect insulin resistance to the decreased neuronal viability in the human diabetic brain.