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.

Changes in Structural Covariance among Olfactory-related Brain Regions in Anosmia Patients.

Anosmia, characterized by the loss of smell, is associated not only with dysfunction in the peripheral olfactory system but also with changes in several brain regions involved in olfactory processing. Specifically, the orbitofrontal cortex is recognized for its pivotal role in integrating olfactory information, engaging in bidirectional communication with the primary olfactory regions, including the olfactory cortex, amygdala, and entorhinal cortex. However, little is known about alterations in structural connections among these brain regions in patients with anosmia. In this study, high-resolution T1-weighted images were obtained from participants. Utilizing the volumes of key brain regions implicated in olfactory function, we employed a structural covariance approach to investigate brain reorganization patterns in patients with anosmia (n=22) compared to healthy individuals (n=30). Our structural covariance analysis demonstrated diminished connectivity between the amygdala and entorhinal cortex, components of the primary olfactory network, in patients with anosmia compared to healthy individuals (z=-2.22, FDR-corrected p=0.039). Conversely, connectivity between the orbitofrontal cortex-a major region in the extended olfactory network-and amygdala was found to be enhanced in the anosmia group compared to healthy individuals (z=2.32, FDR-corrected p=0.039). However, the structural connections between the orbitofrontal cortex and entorhinal cortex did not differ significantly between the groups (z=0.04, FDR-corrected p=0.968). These findings suggest a potential structural reorganization, particularly of higher-order cortical regions, possibly as a compensatory effort to interpret the limited olfactory information available in individuals with olfactory loss.

Cerebral cortical thinning in brain regions involved in emotional regulation relates to persistent symptoms in subjects with posttraumatic stress disorder.

A considerable proportion of individuals exposed to trauma experience chronic and persistent posttraumatic stress disorder (PTSD). However, the specific brain and clinical features that render trauma-exposed individuals more susceptible to enduring symptoms remain elusive. This study investigated 112 trauma-exposed participants who had been diagnosed with PTSD and 112 demographically-matched healthy controls. Trauma-exposed participants were classified into those with current PTSD (persistent PTSD, n = 78) and those without (remitted PTSD, n = 34). Cortical thickness analysis was performed to discern group-specific brain structural characteristics. Coping strategies and resilience levels, assessed as clinical attributes, were compared across the groups. The persistent PTSD group displayed cortical thinning in the superior frontal cortex (SFC), insula, superior temporal cortex, dorsolateral prefrontal cortex, superior parietal cortex, and precuneus, relative to the remitted PTSD and control groups. Cortical thinning in the SFC was associated with increased utilization of maladaptive coping strategies, while diminished thickness in the insula correlated with lower resilience levels among trauma-exposed individuals. These findings imply that cortical thinning in brain regions related to coping strategy and resilience plays a vital role in the persistence of PTSD symptoms.

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.

Disturbed insular functional connectivity and its clinical implication in patients with complex regional pain syndrome.

BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by continued amplification of pain intensity. Given the pivotal roles of the insula in the perception and interpretation of pain, we examined insular functional connectivity and its associations with clinical characteristics in patients with CRPS. METHODS: Twenty-one patients with CRPS and 49 healthy controls underwent resting-state functional magnetic resonance imaging. The seed-to-seed functional connectivity analysis was performed for the bilateral insulae and cognitive control regions including the dorsal anterior cingulate cortex (dACC) and bilateral dorsolateral prefrontal cortex (DLPFC) between the two groups. Correlations between altered functional connectivity and clinical characteristics were assessed in CRPS patients. RESULTS: CRPS patients exhibited lower functional connectivity within the bilateral anterior insulae, between the insular and cognitive control regions (the bilateral anterior/posterior insulae-dACC; the right posterior insula-left DLPFC), as compared with healthy controls at false discovery rate-corrected p < 0.05. In CRPS patients, pain severity was associated negatively with the left-right anterior insular functional connectivity (r = -0.49, p = 0.03), yet positively with the left anterior insula-dACC functional connectivity (r = 0.51, p = 0.02). CONCLUSIONS: CRPS patients showed lower functional connectivity both within the bilateral anterior insulae and between the insular and cognitive control regions. The current findings may suggest pivotal roles of the insula in dysfunctional pain processing of CRPS patients.

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).

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.

Hippocampal cerebral blood flow increased following low-pressure hyperbaric oxygenation in firefighters with mild traumatic brain injury and emotional distress.

BACKGROUND: Recent evidence suggests that hyperbaric oxygenation (HBO), which has been used as an effective treatment for certain types of tissue injury, may change neural activities in the human brain and subsequently improve symptoms of psychiatric disorders. To scrutinize the neural mechanism of HBO in the human brain, we investigated whether 20 sessions of HBO changed regional cerebral blood flow (rCBF) of the limbic system in firefighters with mild traumatic brain injury (mTBI) and subjective emotional distress. METHODS: Twenty firefighters with mTBI and mild emotional distress were treated with HBO at a relatively low pressure of 1.3 atmospheres absolute for 45 min a day for 20 consecutive days (the mild emotional distress group). The rCBF of the limbic system was measured using an arterial spin labeling perfusion magnetic resonance imaging before and after the HBO. Analyses were performed on the data from fourteen individuals who completed the study and 14 age- and sex-matched healthy firefighters (the comparison group). RESULTS: Firefighters in the mild emotional distress group showed increase rCBF following HBO in a cluster encompassing the right hippocampal and parahippocampal regions (peak t = 4.31; cluster size = 248 mm3)(post-hoc analysis, z = 5.92, p < 0.001) that had lower rCBF relative to the comparison group at baseline (post-hoc analysis, t = -2.20, p = 0.04). CONCLUSION: The current study demonstrated that low-pressure HBO might increase rCBF of the hippocampal and parahippocampal regions, suggesting a potential underpinning mechanism of HBO in the human brain.

A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms.

Growing evidence indicates a reciprocal relationship between low-grade systemic inflammation and stress exposure towards increased vulnerability to neuropsychiatric disorders, including posttraumatic stress disorder (PTSD). However, the neural correlates of this reciprocity and their influence on the subsequent development of PTSD are largely unknown. Here we investigated alterations in functional connectivity among brain networks related to low-grade inflammation and stress exposure using two large independent data sets. Functional couplings among the higher-order cognitive network system including the salience, default mode, and central executive networks were reduced in association with low-grade inflammation and stress exposure. This reduced functional coupling may also be related to subsequent posttraumatic stress symptom severity. The current findings propose functional couplings among the higher-order cognitive network system as neural correlates of low-grade inflammation and stress exposure, and suggest that low-grade inflammation, alongside with stress, may render individuals more vulnerable to PTSD.

Identification of Tendency to Alcohol Misuse From the Structural Brain Networks.

The propensity to engage in risky behaviors including excessive alcohol consumption may impose increased medical, emotional, and psychosocial burdens. Personality and behavioral traits of individuals may contribute in part to the involvement in risky behaviors, and therefore the classification of one's traits may help identify those who are at risk for future onset of the addictive disorder and related behavioral issues such as alcohol misuse. Personality and behavioral characteristics including impulsivity, anger, reward sensitivity, and avoidance were assessed in a large sample of healthy young adults (n = 475). Participants also underwent diffusion tensor imaging for the analysis of structural brain networks. A data-driven clustering using personality and behavioral traits of the participants identified four subtypes. As compared with individuals clustered into the neutral type, individuals with a high level of impulsivity (A subtype) and those with high levels of reward sensitivity, impulsivity, anger, and avoidance (B subtype) showed significant associations with problem drinking. In contrast, individuals with high levels of impulsivity, anger, and avoidance but not reward sensitivity (C subtype) showed a pattern of social drinking that was similar to those of the neutral subtype. Furthermore, logistic regression analysis with ridge estimators was applied to demonstrate the neurobiological relevance for the identified subtypes according to distinct patterns of structural brain connectivity within the addiction circuitry [neutral vs. A subtype, the area under the receiver operator characteristic curve (AUC) = 0.74, 95% CI = 0.67-0.81; neutral vs. B subtype, AUC = 0.74, 95% CI = 0.66-0.82; neutral vs. C subtype, AUC = 0.77, 95% CI = 0.70-0.84]. The current findings enable the characterization of individuals according to subtypes based on personality and behavioral traits that are also corroborated by neuroimaging data and may provide a platform to better predict individual risks for addictive disorders.

Diverging roles of the anterior insula in trauma-exposed individuals vulnerable or resilient to posttraumatic stress disorder.

Distinct brain alterations in response to traumatic events may render trauma-exposed individuals either resilient or vulnerable to posttraumatic stress disorder (PTSD). This study compared regional cerebral metabolic rate of glucose (rCMRglu) among trauma-exposed individuals with current PTSD (PTSD group, n = 61), those without current PTSD (Resilience/Recovery group, n = 26), and trauma-unexposed controls (Control group, n = 54). All participants underwent brain [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans. Voxel-wise group differences in rCMRglu among the three groups were evaluated. Associations between rCMRglu and both PTSD severity and resilience were examined. The rCMRglu in the right anterior insula and adjacent prefrontal and striatal areas was lower in the PTSD group, while higher in the Resilience/Recovery group, compared to the Control group. In addition, the lower glucose metabolism of these areas was associated with higher severity and less improvement in PTSD symptoms in the PTSD group, while the higher levels of rCMRglu were correlated with stronger resilience in the Resilience/Recovery group. This study suggests distinct roles of the anterior insula in response to trauma between the PTSD and Resilience/Recovery groups. Heightened rCMRglu in the anterior insular regions may reflect an underlying mechanism of resilience against traumatic stress, while reduced rCMRglu may indicate vulnerability to PTSD.

Efficacy of Polygonatum sibiricum on Mild Insomnia: A Randomized Placebo-Controlled Trial.

Polygonatum sibiricum (PS) rhizome, which contains glyceryl-1-monolinoleate as its primary active component, has been shown to improve insomnia in animal models. Based on these findings, we aimed to investigate the safety and efficacy of PS rhizome extract in improving sleep quality in individuals with mild insomnia. Eighty individuals with mild insomnia were enrolled in a four-week, randomized, double-blind, placebo-controlled trial of PS rhizome extract (500 mg/day, n = 40, PS group) or placebo (n = 40, placebo group). The primary outcome measure was change in total score on the Athens Insomnia Scale (AIS) to indicate sleep quality. The secondary outcome measures included change in actigraphy data and perfusion levels in the brain regions within the default mode network (DMN), which is known to play a key role in insomnia. The PS group showed greater improvement in the total AIS score with a significant increase in total sleep time, relative to the placebo group. In addition, significant group-by-visit interactions were observed in the perfusion level of the medial prefrontal cortex within the DMN. Findings of the current study provide first evidence that PS rhizome extract could be an effective natural ingredient for improving sleep in mild insomnia using a human model.

Low Prefrontal GABA Levels Are Associated With Poor Cognitive Functions in Professional Boxers.

Cognitive dysfunction has long been recognized as a frequently observed symptom in individuals with repetitive mild traumatic brain injury (rmTBI) such as professional boxers. The exact neurobiological mechanisms underlying this cognitive deficit have not yet been identified, but it is agreed upon that the prefrontal cortex (PFC) is one of the most commonly affected brain regions in professional boxers. Noting the pivotal role of the two major brain metabolites in human cognitive functions, γ-aminobutyric acid (GABA) and glutamate/glutamine (Glx), we hypothesized that alterations in levels of GABA and Glx in the PFC would be prominent and may correlate with cognitive deficits in professional boxers. Twenty male professional boxers (Boxers) and 14 age-matched healthy males who had never experienced any TBI (CON) were recruited. Using a 3T magnetic resonance imaging (MRI) scanner, single-voxel proton magnetic resonance spectroscopy with Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence was performed to evaluate the levels of GABA and Glx in the PFC. Cognitive function was assessed using the memory and attention domains from the Cambridge Neuropsychological Test Automated Battery. The Boxers showed lower GABA level in the PFC compared to the CON, while also showing lower performance in the attention and memory domains. There were no significant between-group differences in Glx levels. Furthermore, the GABA level correlated with memory performance in the Boxers, but not in attention performance. The current findings may suggest that alterations in GABA levels in the PFC may be a potential neurochemical correlate underlying memory dysfunction related to rmTBI.

Altered functional connectivity in the fear network of firefighters with repeated traumatic stress.

BACKGROUND: Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.AimsTo investigate how the human brain responds to or compensates for the repeated experience of traumatic stress. METHOD: We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale - Revised. RESULTS: The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula-amygdala connectivity was associated with greater severity of trauma-related symptoms (ß = 0.36, P = 0.005), whereas higher insula-vmPFC connectivity was related to milder symptoms in response to repeated trauma (ß = -0.28, P = 0.01). CONCLUSIONS: The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.Declaration of interestNone.