Atypical Integration of Sensory-to-Transmodal Functional Systems Mediates Symptom Severity in Autism.

A notable characteristic of autism spectrum disorder (ASD) is co-occurring deficits in low-level sensory processing and high-order social interaction. While there is evidence indicating detrimental cascading effects of sensory anomalies on the high-order cognitive functions in ASD, the exact pathological mechanism underlying their atypical functional interaction across the cortical hierarchy has not been systematically investigated. To address this gap, here we assessed the functional organisation of sensory and motor areas in ASD, and their relationship with subcortical and high-order trandmodal systems. In a resting-state fMRI data of 107 ASD and 113 neurotypical individuals, we applied advanced connectopic mapping to probe functional organization of primary sensory/motor areas, together with targeted seed-based intrinsic functional connectivity (iFC) analyses. In ASD, the connectopic mapping revealed topological anomalies (i.e., excessively more segregated iFC) in the motor and visual areas, the former of which patterns showed association with the symptom severity of restricted and repetitive behaviors. Moreover, the seed-based analysis found diverging patterns of ASD-related connectopathies: decreased iFCs within the sensory/motor areas but increased iFCs between sensory and subcortical structures. While decreased iFCs were also found within the higher-order functional systems, the overall proportion of this anomaly tends to increase along the level of cortical hierarchy, suggesting more dysconnectivity in the higher-order functional networks. Finally, we demonstrated that the association between low-level sensory/motor iFCs and clinical symptoms in ASD was mediated by the high-order transmodal systems, suggesting pathogenic functional interactions along the cortical hierarchy. Findings were largely replicated in the independent dataset. These results highlight that atypical integration of sensory-to-high-order systems contributes to the complex ASD symptomatology.

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.

Decreased functional connectivity within the salience network after two-week morning bright light exposure in individuals with sleep disturbances: a preliminary randomized controlled trial.

BACKGROUND: Bright light (BL) exposure is a safe non-pharmacological intervention for sleep disturbances. However, the functional brain correlates underlying the effects of bright light exposure need to be further clarified. As alterations in the salience network were reported in individuals with sleep disturbances, we have investigated whether bright light exposure may improve sleep quality by altering functional connectivity in this network. METHODS: In the current study, 30 individuals with sleep disturbances were randomly assigned to one of the two interventions for two weeks: (1) 1 h of bright light (10,000 lux) exposure (BL-exposed group) and (2) 1 h of dim light (<300 lux) exposure (DL-exposed group). Sleep characteristics and functional connectivity in the salience network were assessed by sleep diary and resting-state functional magnetic resonance imaging, respectively, as outcome measures at before and after the intervention. RESULTS: After two weeks of the intervention, the BL-exposed group showed greater improvement with respect to sleep efficiency (t = 2.27, p = 0.03) and sleep latency (t = -2.40, p = 0.03) as compared to the DL-exposed group. In addition, functional connectivity decreased in the cluster that encompasses the right anterior insular and the frontal opercular regions in the salience network (uncorrected p < 0.001, cluster size>100 mm3) in the BL-exposed group. Decreased functional connectivity in the cluster was associated with decreased sleep latency in the BL-exposed group (ß = 0.54, p = 0.01). CONCLUSIONS: Our results suggest that bright light exposure may improve sleep quality in individuals with sleep disturbances by modulating functional connectivity in the salience network. CLINICAL TRIAL REGISTRATION: https://cris.nih.go.kr/cris; KCT0002607.

Shorter sleep duration is associated with lower GABA levels in the anterior cingulate cortex.

BACKGROUND: Alterations in the levels of gamma-aminobutyric acid (GABA) and glutamate + glutamine (Glx), which are major inhibitory and excitatory neurotransmitters, respectively, are frequently associated with insomnia. Previous reports also suggested the involvement of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) in insomnia and shorter sleep duration. In the current study, we investigated whether the GABA and Glx levels were altered in the ACC/mPFC in subclinical insomnia while focusing on the sleep duration. METHODS: We examined levels of GABA and Glx in the ACC/mPFC of the brain with magnetic resonance spectroscopy in 166 individuals with subjective sleep complaints but without a diagnosis of insomnia. Participants were divided into two groups according to sleep duration (≥6 h/night: n = 79 vs. < 6 h/night: n = 74), which was measured using a wrist-worn actigraphy. Working memory function and overall subjective sleep quality were assessed with a computerized neuropsychological test and self-report questionnaire, respectively. RESULTS: GABA levels in the ACC/mPFC were lower in the shorter sleep duration group relative to the longer sleep duration group (t = -2.21, p = 0.03). Glx levels did not differ between the two groups (t = -0.20, p = 0.84). Lower GABA levels were associated with lower spatial working memory performance in the shorter sleep duration group (ß = -0.21, p = 0.03), but not the longer sleep duration group (ß = 0.04, p = 0.72). CONCLUSION: Shorter sleep duration was associated with lower GABA levels in the ACC/mPFC. These findings may provide insight into the underlying mechanisms of impaired working memory function related to insomnia and sleep loss.

FKBP5-associated miRNA signature as a putative biomarker for PTSD in recently traumatized individuals.

The epigenetic regulation of microRNA (miRNA) expression related to the FK506-binding protein 5 (FKBP5) gene may contribute to the risk of stress-related disorders such as posttraumatic stress disorder (PTSD). Here, we identified candidate miRNAs derived from FKBP5 knockout mice as a potential diagnostic biomarker of PTSD. Using a translational approach, candidate miRNAs found to alter in expression within the medial prefrontal cortex of FKBP5 knockout mice were selected. Each candidate miRNA was examined in the serum of 48 recently traumatized individuals with PTSD and 47 healthy individuals. Multimodal imaging was also conducted to identify the neural correlates for the expression of candidate exosomal miRNAs in response to trauma exposure. Differential miRNA expression was found according to PTSD diagnosis in two composite marker groups. The differential miRNA expression between the composite marker groups contributed to PTSD symptom severity, which may be explained by differential recruitment of prefrontolimbic activity in brain imaging. The present study reveals that a set of circulating exosomal miRNAs showing altered expression in FKBP5 knockout mice play a potential role as epigenetic markers of PTSD. The corroborative evidence from multiple levels including molecular, brain, and behavioral indicates that these epigenetic biomarkers may serve as complementary measures for the diagnosis and prognosis prediction of PTSD in recently traumatized individuals.

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.

Efficacy and Safety of Lactobacillus Plantarum C29-Fermented Soybean (DW2009) in Individuals with Mild Cognitive Impairment: A 12-Week, Multi-Center, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Early intervention using dietary supplements may be effective in alleviating cognitive impairment among individuals with mild cognitive impairment (MCI). This study investigated the efficacy and safety of Lactobacillus plantarum C29-fermented soybean (DW2009) as a nutritional supplement for cognitive enhancement. One hundred individuals with MCI were randomly assigned to take DW2009 (800 mg/day, n = 50) or placebo (800 mg/day, n = 50) for 12 weeks. The primary outcome measure was change in the composite score of cognitive functions related to memory and attention, measured by computerized neurocognitive function tests. Associations between changes in serum brain-derived neurotrophic factor (BDNF) levels and cognitive performance for each treatment group were evaluated. Compared to the placebo group, the DW2009 group showed greater improvements in the combined cognitive functions (z = 2.36, p for interaction = 0.02), especially in the attention domain (z = 2.34, p for interaction = 0.02). Cognitive improvement was associated with increased serum BDNF levels after consumption of DW2009 (t = 2.83, p = 0.007). The results of this clinical trial suggest that DW2009 can be safely administered to enhance cognitive function in individuals with MCI. Increased serum BDNF levels after administering DW2009 may provide preliminary insight into the underlying effects of cognitive improvement, which suggests the importance of the gut-brain axis in ameliorating cognitive deficits in MCI.

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.

Efficacy and Safety of Tremella fuciformis in Individuals with Subjective Cognitive Impairment: A Randomized Controlled Trial.

The efficacy and safety of Tremella fuciformis (TF) as a nutritional supplement were assessed in individuals with subjective cognitive impairment (SCI). Seventy-five individuals with SCI were enrolled in an 8-week, randomized, double-blind, placebo-controlled trial of TF (600 mg/day, n = 30 or 1200 mg/day, n = 30) or placebo (n = 15). The primary outcome measure was changes in total scores of the subjective memory complaint questionnaire. The secondary outcome measures were changes in performance on short-term memory and executive functions, which were assessed using standardized cognitive tests. In addition, voxel-based morphometry was performed to examine the effects of TF on changes in gray matter volume. The individuals in the TF group showed greater improvements in the total scores on the subjective memory complaint questionnaire compared with those in the placebo group. There were also significantly greater improvements in short-term memory and executive functions in the TF group relative to the placebo group. Exploratory analysis demonstrated that there were significant group-by-visit interactions on the left precuneus, right supramarginal gyrus, right middle frontal gyrus, and right postcentral gyrus at corrected P < .05. Overall frequency of adverse events did not differ among high-dose TF (40.4%), low-dose TF (35.1%), and placebo groups (41.4%). The current findings suggest that TF could be safely administered to relieve subjective memory complaints and enhance cognition in individuals with SCI.

Natural Products from Single Plants as Sleep Aids: A Systematic Review.

Insufficient sleep, insomnia, and sleep-related problems are important health issues, as their overall prevalence accounts for about 30% of the general population. The aim of this study was to systematically review previous studies investigating the effects of orally administered single plant-derived extracts on sleep-related outcomes in humans. Data sources were PubMed, Google Scholar, and Cochrane Library. The data search was conducted in two steps: step 1, names of plants which have been studied as sleep aids in humans were searched and retrieved; and step 2, each ingredient listed in step 1 was then added into the search term. Only original articles or reviews were applicable to the scope of this review. Studies on human subjects, with or without sleep-related disorders, were included. Sleep-related disorders refer to not only insomnia or sleep behavior disorders but also diseases with sleep-related symptoms. Studies were considered eligible for this review when the plant extracts were administered orally. Outcome measures relevant to sleep quality, duration, or other sleep-related problems were included. Twenty-one plants were listed in the first step of the search as potential candidates for natural sleep aids. Seventy-nine articles using these single plant-derived natural products were included in the final review. Although valerian was most frequently studied, conflicting results were reported, possibly due to the various outcome measures of each study. Other plants were not as rigorously tested in human studies. There was limited evidence with inconclusive results regarding the effects of single plant-derived natural products on sleep, warranting further studies.

Firefighters, posttraumatic stress disorder, and barriers to treatment: Results from a nationwide total population survey.

Repeated exposure to traumatic experiences may put professional firefighters at increased risk of developing posttraumatic stress disorder (PTSD). To date, however, the rate of PTSD symptoms, unmet need for mental health treatment, and barriers to treatment have only been investigated in subsamples rather than the total population of firefighters. We conducted a nationwide, total population-based survey of all currently employed South Korean firefighters (n = 39,562). The overall response rate was 93.8% (n = 37,093), with 68.0% (n = 26,887) complete responses for all variables. The rate of current probable PTSD was estimated as 5.4%. Among those with current probable PTSD (n = 1,995), only a small proportion (9.7%) had received mental health treatment during the past month. For those who had not received treatment, perceived barriers of accessibility to treatment (29.3%) and concerns about potential stigma (33.8%) were reasons for not receiving treatment. Although those with higher PTSD symptom severity and functional impairment were more likely to seek treatment, greater symptom severity and functional impairment were most strongly associated with increased concerns about potential stigma. This nationwide study points to the need for new approaches to promote access to mental health treatment in professional firefighters.

A performance comparison between the two language versions of the Affective Go/No-Go test: A randomised crossover study.

The purpose of this randomised crossover study is to validate the Korean version of the Affective Go/No-go (AGN) test. The Korean words for the AGN test were selected after careful evaluation of emotional valences, word length and frequency. Fifteen Korean advanced learners of English were administered both Korean and English versions, yielding 30 data points. The performance of both language versions was compared for each of the AGN test parameters (response latency, commission error and omission error) using two-way analysis of variance (ANOVA). Intraclass correlation coefficients (ICCs) were estimated to evaluate associations between the two versions. The ICCs were high for response latencies of all valences and commission errors of positive and neutral words, but not for that of negative words and omission errors of all valences. A similar pattern of test results, as revealed by the high ICCs and non-significant interaction effects between language and word valence, suggests that the psychometric properties of the AGN test may be comparable over different language versions.

Brain changes in overweight/obese and normal-weight adults with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Overweight and obesity may significantly worsen glycaemic and metabolic control in type 2 diabetes. However, little is known about the effects of overweight and obesity on the brains of people with type 2 diabetes. Here, we investigate whether the presence of overweight or obesity influences the brain and cognitive functions during early stage type 2 diabetes. METHODS: This study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in their brain structures and cognition during early stage type 2 diabetes compared with participants with normal weight. Relationships between each of these measures and disease duration were also examined. RESULTS: Global mean cortical thickness was lower in the overweight/obese type 2 diabetes group than in the normal-weight type 2 diabetes group (z = -2.96, p for group effect = 0.003). A negative correlation was observed between disease duration and global mean white matter integrity (z = 2.42, p for interaction = 0.02) in the overweight/obese type 2 diabetes group, but not in the normal-weight type 2 diabetes group. Overweight/obese individuals with type 2 diabetes showed a decrease in psychomotor speed performance related to disease duration (z = -2.12, p for interaction = 0.03), while normal-weight participants did not. CONCLUSIONS/INTERPRETATION: The current study attempted to uncouple the effects of overweight/obesity from those of type 2 diabetes on brain structures and cognition. Overweight/obese participants with type 2 diabetes had more severe and progressive abnormalities in brain structures and cognition during early stage type 2 diabetes compared with normal-weight participants.

Psychometric Properties of the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) in Public First Responders.

Problematic alcohol consumption is prevalent among first responders because alcohol is commonly used to cope with occupational stress and frequent exposure to traumatic incidents, making them an at-risk population for alcohol use disorders (AUD). This study investigated the psychometric properties of the Korean version of the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) among public first responders. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (SCID), AUDIT-C, AUDIT, and CAGE were administered to 222 public first responders, who were recruited by convenience sampling. One-week test-retest reliability was evaluated in a subsample (n = 24). Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic accuracy and estimate the optimal cut-off scores for any AUD and alcohol dependence. Three different analytic criteria were utilized to calculate the cut-off scores. The AUDIT-C demonstrated good test-retest reliability (intraclass correlation coefficient for test-retest reliability = 0.91) and satisfactory convergent validity. The areas under the ROC curves for any AUD and alcohol dependence of the AUDIT-C were 0.87 and 0.93, respectively. For any AUD, all three criteria suggested a cut-off score of 7.5 (sensitivity = 81.8%, specificity = 79.8%), whereas for alcohol dependence, a cut-off score of 8.5 (sensitivity = 85.7%, specificity = 86.1%) was derived from two criteria. In conclusion, the AUDIT-C demonstrated good reliability and validity and proved to be a brief and effective screening test for AUD among first responders.

Longitudinal Cerebral Perfusion Changes in Parkinson's Disease with Subjective Cognitive Impairment.

BACKGROUND AND PURPOSE: Although subjective cognitive impairment (SCI) is often accompanied by Parkinson's disease (PD) and may predict the development of mild cognitive impairment or dementia, longitudinal brain perfusion changes in PD patients with SCI remain to be elucidated. The current prospective study examined cerebral perfusion changes in PD patients with SCI using technetium-99m hexamethylpropylene amine oxime single photon emission computed tomography (SPECT). METHODS: Among 53 PD patients at baseline, 30 patients were classified into the PD with SCI group and 23 patients were assigned to the PD without SCI group. The mean follow-up interval was 2.3±0.9 years. The Mini-Mental State Examination, Clinical Dementia Rating, and Global Deterioration Scale were used to assess impairments in cognitive function. Brain SPECT images were acquired at baseline and follow-up. RESULTS: Significant differences between the two groups were not found for demographic variables, PD severity, or cognitive function at either baseline or follow-up. At baseline, the PD with SCI group showed decreased perfusion in the left angular gyrus compared to the PD without SCI group. Longitudinal analysis revealed widespread perfusion reductions primarily in the bilateral temporo-parieto-occipital areas and cerebellum in the PD with SCI group. Relative to the PD without SCI group, an excessive decrease of perfusion was found in the left middle frontal gyrus of the PD with SCI patients. CONCLUSIONS: Our findings suggest that perfusion deficits in the middle frontal area may play an important role in the pathophysiology of SCI in PD.