Digital therapeutics using virtual reality-based visual perceptual learning for visual field defects in stroke: A double-blind randomized trial.

INTRODUCTION: Visual field defects (VFDs) represent a debilitating poststroke complication, characterized by unseen parts of the visual field. Visual perceptual learning (VPL), involving repetitive visual training in blind visual fields, may effectively restore visual field sensitivity in cortical blindness. This current multicenter, double-blind, randomized, controlled clinical trial investigated the efficacy and safety of VPL-based digital therapeutics (Nunap Vision [NV]) for treating poststroke VFDs. METHODS: Stroke outpatients with VFDs (>6 months after stroke onset) were randomized into NV (defective field training) or Nunap Vision-Control (NV-C, central field training) groups. Both interventions provided visual perceptual training, consisting of orientation, rotation, and depth discrimination, through a virtual reality head-mounted display device 5 days a week for 12 weeks. The two groups received VFD assessments using Humphrey visual field (HVF) tests at baseline and 12-week follow-up. The final analysis included those completed the study (NV, n = 40; NV-C, n = 35). Efficacy measures included improved visual area (sensitivity ≥6 dB) and changes in the HVF scores during the 12-week period. RESULTS: With a high compliance rate, NV and NV-C training improved the visual areas in the defective hemifield (>72 degrees2) and the whole field (>108 degrees2), which are clinically meaningful improvements despite no significant between-group differences. According to within-group analyses, mean total deviation scores in the defective hemifield improved after NV training (p = .03) but not after NV-C training (p = .12). CONCLUSIONS: The current trial suggests that VPL-based digital therapeutics may induce clinically meaningful visual improvements in patients with poststroke VFDs. Yet, between-group differences in therapeutic efficacy were not found as NV-C training exhibited unexpected improvement comparable to NV training, possibly due to learning transfer effects.

Identifying unique subgroups in suicide risks among psychiatric outpatients.

BACKGROUND: The presence of psychiatric disorders is widely recognized as one of the primary risk factors for suicide. A significant proportion of individuals receiving outpatient psychiatric treatment exhibit varying degrees of suicidal behaviors, which may range from mild suicidal ideations to overt suicide attempts. This study aims to elucidate the transdiagnostic symptom dimensions and associated suicidal features among psychiatric outpatients. METHODS: The study enrolled patients who attended the psychiatry outpatient clinic at a tertiary hospital in South Korea (n = 1, 849, age range = 18-81; 61% women). A data-driven classification methodology was employed, incorporating a broad spectrum of clinical symptoms, to delineate distinctive subgroups among psychiatric outpatients exhibiting suicidality (n = 1189). A reference group of patients without suicidality (n = 660) was included for comparative purposes to ascertain cluster-specific sociodemographic, suicide-related, and psychiatric characteristics. RESULTS: Psychiatric outpatients with suicidality (n = 1189) were subdivided into three distinctive clusters: the low-suicide risk cluster (Cluster 1), the high-suicide risk externalizing cluster (Cluster 2), and the high-suicide risk internalizing cluster (Cluster 3). Relative to the reference group (n = 660), each cluster exhibited distinct attributes pertaining to suicide-related characteristics and clinical symptoms, covering domains such as anxiety, externalizing and internalizing behaviors, and feelings of hopelessness. Cluster 1, identified as the low-suicide risk group, exhibited less frequent suicidal ideation, planning, and multiple attempts. In the high-suicide risk groups, Cluster 2 displayed pronounced externalizing symptoms, whereas Cluster 3 was primarily defined by internalizing and hopelessness symptoms. Bipolar disorders were most common in Cluster 2, while depressive disorders were predominant in Cluster 3. DISCUSSION: Our findings suggest the possibility of differentiating psychiatric outpatients into distinct, clinically relevant subgroups predicated on their suicide risk. This research potentially paves the way for personalizing interventions and preventive strategies that address cluster-specific characteristics, thereby mitigating suicide-related mortality among psychiatric outpatients.

Functional connectivity interacts with visual perceptual learning for visual field recovery in chronic stroke.

A reciprocal relationship between perceptual learning and functional brain changes towards perceptual learning effectiveness has been demonstrated previously; however, the underlying neural correlates remain unclear. Further, visual perceptual learning (VPL) is implicated in visual field defect (VFD) recovery following chronic stroke. We investigated resting-state functional connectivity (RSFC) in the visual cortices associated with mean total deviation (MTD) scores for VPL-induced VFD recovery in chronic stroke. Patients with VFD due to chronic ischemic stroke in the visual cortex received 24 VPL training sessions over 2 months, which is a dual discrimination task of orientation and letters. At baseline and two months later, the RSFC in the ipsilesional, interhemispheric, and contralesional visual cortices and MTD scores in the affected hemi-field were assessed. Interhemispheric visual RSFC at baseline showed the strongest correlation with MTD scores post-2-month VPL training. Notably, only the subgroup with high baseline interhemispheric visual RSFC showed significant VFD improvement following the VPL training. The interactions between the interhemispheric visual RSFC at baseline and VPL led to improvement in MTD scores and largely influenced the degree of VFD recovery. The interhemispheric visual RSFC at baseline could be a promising brain biomarker for the effectiveness of VPL-induced VFD recovery.

Brain age prediction using combined deep convolutional neural network and multi-layer perceptron algorithms.

The clinical applications of brain age prediction have expanded, particularly in anticipating the onset and prognosis of various neurodegenerative diseases. In the current study, we proposed a deep learning algorithm that leverages brain structural imaging data and enhances prediction accuracy by integrating biological sex information. Our model for brain age prediction, built on deep neural networks, employed a dataset of 3004 healthy subjects aged 18 and above. The T1-weighted images were minimally preprocessed and analyzed using the convolutional neural network (CNN) algorithm. The categorical sex information was then incorporated using the multi-layer perceptron (MLP) algorithm. We trained and validated both a CNN-only algorithm (utilizing only brain structural imaging data), and a combined CNN-MLP algorithm (using both structural brain imaging data and sex information) for age prediction. By integrating sex information with T1-weighted imaging data, our proposed CNN-MLP algorithm outperformed not only the CNN-only algorithm but also established algorithms, such as brainageR, in prediction accuracy. Notably, this hybrid CNN-MLP algorithm effectively distinguished between mild cognitive impairment and Alzheimer's disease groups by identifying variances in brain age gaps between them, highlighting the algorithm's potential for clinical application. Overall, these results underscore the enhanced precision of the CNN-MLP algorithm in brain age prediction, achieved through the integration of sex information.

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.

Structural and Functional Correlates of Higher Cortical Brain Regions in Chronic Refractory Cough.

BACKGROUND: Chronic refractory cough significantly impairs the psychological and social aspects of quality of life. Loss of inhibitory control is suggested as a potential central neurobiological mechanism underlying chronic refractory cough. RESEARCH QUESTION: Do structural and functional changes related to chronic cough occur in higher cortical brain regions? STUDY DESIGN AND METHODS: The structural and resting-state functional alterations in the brains of 15 patients with chronic refractory cough and 15 age- and sex-matched healthy control participants were evaluated. Gray matter volumes of the whole brain were measured using voxel-based morphometry based on T1-weighted MRI. Intrinsic functional connectivity within large-scale brain networks was examined on resting-state functional MRI. Correlation analyses were performed to examine the relationships of these brain changes with duration, severity, and impact of cough. RESULTS: Compared with healthy control participants, patients with chronic refractory cough demonstrated a lower gray matter volume in the left frontal cluster and enhanced functional connectivity within the left frontoparietal network, which were associated with greater cough scores. Furthermore, enhanced functional connectivity within the left frontoparietal network was associated with a greater psychological and social impact of coughing. Lower left frontal gray matter volume was associated with longer cough duration. INTERPRETATION: Structural and functional alterations in the left frontal brain regions may be implicated in the psychological and social impact and disease duration of chronic refractory cough. Our findings provide new perspectives on developing interventional approaches targeting the cognitive modulation of chronic coughing.

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.

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.

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.

Repetitive transcranial magnetic stimulation in trauma-related conditions.

Some of trauma-exposed individuals develop posttraumatic stress disorder (PTSD), an incapacitating psychiatric disorder that is characterized by intrusion, avoidance, negative changes in mood and cognition, and hyperarousal. A number of other trauma-related conditions are very frequently found in individuals with PTSD. Traumatic brain injury (TBI) is one of the most frequently observed trauma-related conditions that trauma-exposed individuals with PTSD may experience. TBI refers to transient or permanent brain dysfunction that results in a wide range of neurological, cognitive, and psychiatric symptoms. These trauma-related conditions significantly affect one's quality of life, leading to substantial disability and socioeconomic burden. As the prevalence of PTSD with comorbid TBI is increasing in the general population along with the rates of crimes and accidents, effective prevention and intervention strategies are necessitated. However, a definitive treatment for PTSD with comorbid TBI is still lacking, resulting in high rates of treatment resistance and chronicity. It is essential to investigate the neurobiological mechanisms and potential therapeutics of PTSD with comorbid TBI. Yet, a few repetitive transcranial magnetic stimulation (rTMS) studies have recently investigated therapeutic efficacy in treatment-resistant patients with PTSD and/or TBI. Thus, this article reviews rTMS studies in trauma-related conditions, mainly focusing on PTSD and PTSD with TBI as one of the comorbidities. The review focuses on the applications of rTMS in reducing PTSD symptoms with and without comorbidities based on differential parameters and effects of rTMS as well as concomitant clinical conditions. The section on PTSD with comorbidities focuses on TBI with neurological, cognitive, and psychiatric symptoms. Although there were some inconsistencies in the clinical outcomes and optimized parameters of rTMS applied in PTSD and TBI, low frequency stimulation over the hyperactive frontal regions and/or high frequency stimulation over the hypoactive frontal regions generally improved the clinical symptoms of PTSD and TBI. Lastly, the limitations of the rTMS studies in PTSD and TBI as well as potential directions for future research are discussed.

Alterations in structural rich-club connectivity of the precuneus are associated with depressive symptoms among individuals with subjective memory complaints.

The association between subjective memory complaints (SMCs) and depressive symptoms has been widely reported and both have been regarded as risk factors for dementia, such as Alzheimer's disease (AD). Although SMCs arise as early as in middle age, the exact neural correlates of comorbid depressive symptoms among individuals who are middle-aged and with SMCs have not yet been well investigated. Because rich-club organization of the brain plays a key role in the pathophysiology of various neuropsychiatric disorders, the investigation of rich club organization may provide insight regarding the neurobiological mechanisms of depressive symptoms in SMCs. In the current study, we compared the rich-club organization in the structural brain connectivity between individuals who have SMCs along with depressive symptoms (SMCD) and individuals with SMCs but without depressive symptoms (SMCO). A total of 53 individuals with SMCD and 91 individuals with SMCO participated in the study. For all participants, high-resolution, T1-weighted images and diffusion tensor images were obtained, and the network analysis was performed. Individuals with SMCD had lower connectivity strength between the precuneus and other rich-club nodes than those with SMCO, which was significant after adjusting for potential confounders. Our findings suggest that disruptions of rich-club connectivity strength of the precuenus are associated with depressive symptoms in middle-aged individuals with SMCs. Given that the precuneus is one of the commonly affected regions in the early stages of AD, our findings may imply that the concomitant depressive symptoms in middle-aged individuals with SMCs could reflect structural alterations related to AD.

Altered attentional control over the salience network in complex regional pain syndrome.

The degree and salience of pain have been known to be constantly monitored and modulated by the brain. In the case of maladaptive neural responses as reported in centralized pain conditions such as complex regional pain syndrome (CRPS), the perception of pain is amplified and remains elevated even without sustained peripheral pain inputs. Given that the attentional state of the brain greatly influences the perception and interpretation of pain, we investigated the role of the attention network and its dynamic interactions with other pain-related networks of the brain in CRPS. We examined alterations in the intra- and inter-network functional connectivities in 21 individuals with CRPS and 49 controls. CRPS-related reduction in intra-network functional connectivity was found in the attention network. Individuals with CRPS had greater inter-network connectivities between the attention and salience networks as compared with healthy controls. Furthermore, individuals within the CRPS group with high levels of pain catastrophizing showed greater inter-network connectivities between the attention and salience networks. Taken together, the current findings suggest that these altered connectivities may be potentially associated with the maladaptive pain coping as found in CRPS patients.

Brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A longitudinal voxel-based morphometry and diffusion tensor imaging study.

In animal models of Parkinson's disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

Network attributes underlying intellectual giftedness in the developing brain.

Brain network is organized to maximize the efficiency of both segregated and integrated information processing that may be related to human intelligence. However, there have been surprisingly few studies that focus on the topological characteristics of brain network underlying extremely high intelligence that is intellectual giftedness, particularly in adolescents. Here, we examined the network topology in 25 adolescents with superior intelligence (SI-Adol), 25 adolescents with average intelligence (AI-Adol), and 27 young adults with AI (AI-Adult). We found that SI-Adol had network topological properties of high global efficiency as well as high clustering with a low wiring cost, relative to AI-Adol. However, contrary to the suggested role that brain hub regions play in general intelligence, the network efficiency of rich club connection matrix, which represents connections among brain hubs, was low in SI-Adol in comparison to AI-Adol. Rather, a higher level of local connection density was observed in SI-Adol than in AI-Adol. The highly intelligent brain may not follow this efficient yet somewhat stereotypical process of information integration entirely. Taken together, our results suggest that a highly intelligent brain may communicate more extensively, while being less dependent on rich club communications during adolescence.