In vivo gamma-aminobutyric acid-A/benzodiazepine receptor availability and genetic liability in asymptomatic individuals with high genetic loading of schizophrenia: A [11C]flumazenil positron emission tomography study.

OBJECTIVES: Whilst reduced signalling and gene expression related to gamma-aminobutyric acid (GABA) play a role in the presumed pathophysiology of schizophrenia, its origin is unclear. Studying asymptomatic individuals with high genetic liability to schizophrenia (AIs) would provide insights. Therefore, this study aimed to investigate the role of genetic liability in GABAergic dysfunction of schizophrenia by exploring in vivo GABA-A/benzodiazepine receptor (GABAR) availability in AIs. METHODS: A total of 10 AIs with multiple relatives diagnosed as schizophrenia and 11 healthy controls underwent [11C]flumazenil positron emission tomography and neurocognitive function tests. RESULTS: There was no significant difference in [11C]flumazenil availability based on the groups. GABAR availability in caudate nuclei had positive correlations with genetic liability of AIs. GABAR availability in caudate nuclei and verbal memory measures of AIs revealed positive correlations. Only the correlation between right caudate and short-term verbal memory survived multiple-comparison correction (p = 0.030). CONCLUSIONS: This study, for the first time, reports correlations between the genetic liability of schizophrenia and GABAR availability. Correlations between [11C]flumazenil binding in caudate of individuals with high genetic liability to schizophrenia suggests that the GABAergic dysfunction may arise from shared genetic factors and also that it may be responsible for cognitive impairment of AIs.

Functional and Structural Connectivity of the Cerebellar Nuclei With the Striatum and Cerebral Cortex in First-Episode Psychosis.

OBJECTIVE: Evidence suggests that the cortico-striatal-thalamo-cortical circuitry plays an important role in schizophrenia pathophysiology. Cerebellar contribution from deep cerebellar nuclei to the circuitry has not yet been examined. The authors investigated resting-state functional connectivity (RSFC) of cerebellar output nuclei with striatal-thalamic-cortical regions in relation to white-matter integrity and regional gray-matter volumes in first-episode psychosis (FEP). Methods: Forty FEP patients and 40 age- and gender-matched healthy control subjects (HCs) participated. RSFC between cerebellar nuclei and striatal-thalamic-cortical regions was examined. Diffusion tensor imaging and volumetric scans were examined for possible structural constraints on RSFC. The authors also examined relationships between neuroimaging variables and cognitive and clinical measures. Results: FEP patients, compared with HCs, exhibited decreased RSFC between the left fastigial nucleus and right putamen, which was associated with poor letter fluency performance and lower global assessment of functioning scores. By contrast, patients showed widespread increased accumbens network connectivity in the left nucleus. The authors further observed both hypo- and hyper-RSFC between the cerebellar nuclei and fronto-parietal areas in patients, independent of striatal activity. Finally, the authors found impaired integrity of the left superior cerebellar peduncle and decreased bilateral putamen volume in patients, whereas structural-functional relationships found in HCs were absent in patients. Conclusions: This study provides evidence of disordered RSFC of cerebellar output nuclei to the striatum and neocortex at the early stage of schizophrenia. Furthermore, dysfunctional cerebellar influences on fronto-parietal areas that are independent of striatal dysfunction in patients with FEP were observed. The results suggest that cortico-striatal abnormalities in patients with FEP are produced by abnormal cerebellar influences.

Disturbed thalamocortical connectivity in unaffected relatives of schizophrenia patients with a high genetic loading.

OBJECTIVES: Alterations in thalamocortical anatomical connectivity, specifically the connection between the orbitofrontal cortex and thalamus, have been frequently reported in schizophrenia and are suggested to contribute to the pathophysiology of schizophrenia. The connectivity of the thalamocortical white matter in unaffected relatives of schizophrenia patients was compared to that of healthy controls. METHODS: The unaffected relative group was defined as asymptomatic family members who had at least one first-degree relative with schizophrenia and one or more other affected first- to third-degree relatives. A total of 35 unaffected relatives and 34 healthy controls underwent diffusion-weighted and T1-weighted magnetic resonance imaging to examine the white matter connectivity between the thalamus and orbitofrontal cortex using probabilistic tractography. RESULTS: After controlling for age and sex, the unaffected relatives exhibited significantly reduced fractional anisotropy values for the left thalamo-orbitofrontal tract compared to that of healthy controls, F(1, 65) = 6.93, p = 0.011, effect size partial η2 = 0.10. However, there was no association between the Genetic Liability Score and fractional anisotropy in the left thalamo-orbitofrontal tracts. CONCLUSION: Our findings in the unaffected relatives of schizophrenia patients, which are in line with the alterations reported in schizophrenia, first-episode psychosis and clinical high risk for psychosis, highlight a possible genetic contribution to the proposed biomarker of altered thalamocortical connectivity.

Higher serotonin transporter availability in early-onset obsessive-compulsive disorder patients undergoing escitalopram treatment: A [11 C]DASB PET study.

OBJECTIVE: Early-onset obsessive-compulsive disorder (EOCD) and late-onset obsessive-compulsive disorder (LOCD) are distinct subtypes of obsessive-compulsive disorder (OCD). OCD patients are treated with serotonin reuptake inhibitors, but the difference in serotonin transporter (SERT) availability between medicated EOCD and LOCD is unexplored yet. METHODS: Six EOCD and 6 LOCD patients were enrolled. They underwent serial [11 C]DASB positron emission tomography scans during maintenance therapy with escitalopram, and their plasma concentration of escitalopram was measured simultaneously with the scan. Then, the drug-free binding potential of SERT was calculated by pharmacokinetic-pharmacodynamic modelling. RESULTS: In comparison with LOCD patients, SERT availability was significantly higher in the putamen of EOCD patients (U = 4, p = .026), but not in the caudate nucleus (U = 14, p = .589), thalamus (U = 16, p = .818), and dorsal raphe nucleus (U = 7, p = .093). Binding potential of putamen showed a negative correlation (r = -.580, p = .048) with age of onset of the disease, but not with the Yale-Brown Obsessive Compulsive Scale scores. CONCLUSIONS: These findings indicate that the earlier the age of onset of OCD, the less serotonergic pathology there is and that this difference remains even after long-term serotonin reuptake inhibitor treatment. Clinically, it might suggest that nonserotonergic treatments would be a better option for EOCD patients.

Developmental coupling of brain iron and intrinsic activity in infants during the first 150 days.

Brain iron is vital for core neurodevelopmental processes including myelination and neurotransmitter synthesis and, accordingly, iron accumulates in the brain with age. However, little is known about the association between brain iron and neural functioning and how they evolve with age in early infancy. This study investigated brain iron in 48 healthy infants (22 females) aged 64.00 ± 33.28 days by estimating R2 * relaxometry from multi-echo functional MRI (fMRI). Linked independent component analysis was performed to examine the association between iron deposition and spontaneous neural activity, as measured by the amplitude of low frequency fluctuations (ALFF) by interrogating shared component loadings across modalities. Further, findings were validated in an independent dataset (n = 45, 24 females, 77.93 ± 26.18 days). The analysis revealed developmental coupling between the global R2 * and ALFF within the default mode network (DMN). Furthermore, we observed that this coupling effect significantly increased with age (r = 0.78, p = 9.2e-11). Our results highlight the importance of iron-neural coupling during early development and suggest that the neural maturation of the DMN may correspond to growth in distributed brain iron.

Effect of tDCS on Aberrant Functional Network Connectivity in Refractory Hallucinatory Schizophrenia: A Pilot Study.

We aim to investigate the effect of fronto-temporal transcranial direct current stimulation (tDCS) on the interactions among functional networks and its association with psychotic symptoms. In this pilot study, we will determine possible candidate functional networks and an adequate sample size for future research. Seven schizophrenia patients with treatment-refractory auditory hallucinations underwent tDCS twice daily for 5 days. Resting-state fMRI data and measures of the severity of psychotic symptoms were acquired at baseline and after completion of the tDCS sessions. At baseline, decreased functional network interaction was negatively correlated with increased hallucinatory behavior. After tDCS, the previously reduced functional network connectivity significantly increased. Our results showed that fronto-temporal tDCS could possibly remediate aberrant hallucination-related functional network interactions in patients with schizophrenia.

Functional connectivity of the raphe nucleus as a predictor of the response to selective serotonin reuptake inhibitors in obsessive-compulsive disorder.

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological agents for treating obsessive-compulsive disorder (OCD). However, because nearly half of patients show insufficient SSRI responses, serotonergic dysfunction in heterogeneous OCD patients should be investigated for precision medicine. We aimed to determine whether functional connectivity (FC) of the raphe nucleus (RN), the major source of most serotonergic neurons, was altered in OCD patients and could predict the SSRI response. A total of 102 medication-free OCD patients and 101 matched healthy control (HC) subjects participated in resting-state functional magnetic resonance imaging. Among them, 54 OCD patients were treated with SSRIs for 16 weeks, resulting in 26 responders and 28 nonresponders. Seed-based whole brain FC with the RN as a seed region was compared between the OCD and HC groups, as well as between SSRI responders and nonresponders. FC cluster values showing significant group differences were used to investigate factors correlated with symptomatic severity before treatment and predictive of SSRI response. Compared to HCs, OCD patients exhibited significantly larger FC between the RN and temporal cortices including the middle temporal gyrus (MTG), paracingulate gyrus, amygdala, hippocampus, putamen, thalamus, and brain stem. Greater RN-left MTG FC was positively correlated with OC symptom severity at baseline. In addition, larger FC of the RN-left MTG was also found in SSRI nonresponders compared to responders, which was a significant predictor of SSRI response after 16 weeks. The FC of RN may reflect the neurobiological underpinning of OCD and could aid future precision medicine as a differential brain-based biomarker.

Predicting Remission in Subjects at Clinical High Risk for Psychosis Using Mismatch Negativity.

Background: The declining transition rate to psychotic disorder and the increasing rate of nonpsychotic poor outcomes among subjects at clinical high risk (CHR) for psychosis have increased the need for biomarkers to predict remission regardless of transition. This study investigated whether mismatch negativity (MMN) predicts the prognosis of CHR individuals during a 6-year follow-up period. Methods: A total of 47 healthy control (HC) subjects and 48 subjects at CHR for psychosis participated in the MMN assessment. The clinical statuses of the CHR subjects were examined at baseline and regularly for up to 6 years. The CHR subjects were divided into remitter and nonremitter groups, and the baseline MMN amplitudes and latencies were compared across the remitter, nonremitter, and HC groups. Regression analyses were performed to identify the predictive factors of remission, the improvement of attenuated positive symptoms, and functional recovery. Results: CHR nonremitters showed reduced MMN amplitudes at baseline compared to CHR remitters and HC subjects. A logistic regression analysis revealed that the baseline MMN amplitude at the frontal electrode site was the only significant predictor of remission. In a multiple regression analysis, the MMN amplitude, antipsychotic use, and years of education predicted an improvement in attenuated positive symptoms. The MMN amplitude at baseline predicted functional recovery. Conclusions: These results suggest that MMN is a putative predictor of prognosis regardless of the transition to psychotic disorder in subjects at CHR. Early prognosis prediction and the provision of appropriate interventions based on the initial CHR status might be aided using MMN.

Aberrant within- and between-network connectivity of the mirror neuron system network and the mentalizing network in first episode psychosis.

INTRODUCTION: It has been suggested that the mentalizing network and the mirror neuron system network support important social cognitive processes that are impaired in schizophrenia. However, the integrity and interaction of these two networks have not been sufficiently studied, and their effects on social cognition in schizophrenia remain unclear. METHODS: Our study included 26 first-episode psychosis (FEP) patients and 26 healthy controls. We utilized resting-state functional connectivity to examine the a priori-defined mirror neuron system network and the mentalizing network and to assess the within- and between-network connectivities of the networks in FEP patients. We also assessed the correlation between resting-state functional connectivity measures and theory of mind performance. RESULTS: FEP patients showed altered within-network connectivity of the mirror neuron system network, and aberrant between-network connectivity between the mirror neuron system network and the mentalizing network. The within-network connectivity of the mirror neuron system network was noticeably correlated with theory of mind task performance in FEP patients. CONCLUSION: The integrity and interaction of the mirror neuron system network and the mentalizing network may be altered during the early stages of psychosis. Additionally, this study suggests that alterations in the integrity of the mirror neuron system network are highly related to deficient theory of mind in schizophrenia, and this problem would be present from the early stage of psychosis.

Higher extrinsic and lower intrinsic connectivity in resting state networks for professional Baduk (Go) players.

Introduction: Dedication and training to a profession results in a certain level of expertise. This expertise, like any other skill obtained in our lifetime, is encoded in the brain and may be reflected in our brain's connectome. This property can be observed by mapping resting state connectivity. In this study, we examine the differences in resting state functional connectivity in four major networks between professional "Baduk" (Go) players and normal subjects. Methods: Resting state fMRI scans were acquired for professional "Baduk" (Go) players and normal controls. Major resting state networks were identified using independent component analysis and compared between the two groups. Networks which were compared include the default mode network, the left and right fronto-parietal network, and the salience network. Results: We found that normal subjects showed increased connectivity within certain areas of each target network. Professional players, however, showed higher connectivity to regions outside the traditional regions of each given network. Close examination of these regions revealed that regions shown to have higher connectivity in professional players have been revealed to be relevant in expertise for board games. Conclusion: The findings in this study suggest that continuous training results in greater integration between regions and networks, which are necessary for high-level performance. The differences observed in our study between normal controls and professional players also shed light on the difference in brain connectivity which can arise through lifestyle and specialization in a specific field.

Aberrant temporal behavior of mismatch negativity generators in schizophrenia patients and subjects at clinical high risk for psychosis.

OBJECTIVE: Although disconnection syndrome has been considered a core pathophysiologic mechanism of schizophrenia, little is known about the temporal behavior of mismatch negativity (MMN) generators in individuals with schizophrenia or clinical high risk (CHR) for psychosis. METHODS: MMN was assessed in 29 schizophrenia patients, 40 CHR subjects, and 47 healthy controls (HCs). Individual realistic head models and the minimum L2 norm algorithm were used to generate a current source density (CSD) model of MMN. The strength and time course of MMN CSD activity were calculated separately for the frontal and temporal cortices and were compared across brain regions and groups. RESULTS: Schizophrenia patients and CHR subjects displayed lower MMN CSD strength than HCs in both the temporal and frontal cortices. We found a significant time delay in MMN generator activity in the frontal cortex relative to that in the temporal cortex in HCs. However, the sequential temporo-frontal activities of MMN generators were disrupted in both the schizophrenia and CHR groups. CONCLUSIONS: Impairments and altered temporal behavior of MMN multiple generators were observed even in individuals at risk for psychosis. SIGNIFICANCE: These findings suggest that aberrant MMN generator activity might be helpful in revealing the pathophysiology of schizophrenia.

Brain Structural Networks Associated with Intelligence and Visuomotor Ability.

Increasing evidence indicates that multiple structures in the brain are associated with intelligence and cognitive function at the network level. The association between the grey matter (GM) structural network and intelligence and cognition is not well understood. We applied a multivariate approach to identify the pattern of GM and link the structural network to intelligence and cognitive functions. Structural magnetic resonance imaging was acquired from 92 healthy individuals. Source-based morphometry analysis was applied to the imaging data to extract GM structural covariance. We assessed the intelligence, verbal fluency, processing speed, and executive functioning of the participants and further investigated the correlations of the GM structural networks with intelligence and cognitive functions. Six GM structural networks were identified. The cerebello-parietal component and the frontal component were significantly associated with intelligence. The parietal and frontal regions were each distinctively associated with intelligence by maintaining structural networks with the cerebellum and the temporal region, respectively. The cerebellar component was associated with visuomotor ability. Our results support the parieto-frontal integration theory of intelligence by demonstrating how each core region for intelligence works in concert with other regions. In addition, we revealed how the cerebellum is associated with intelligence and cognitive functions.

Node Identification Using Inter-Regional Correlation Analysis for Mapping Detailed Connections in Resting State Networks.

Brain function is often characterized by the connections and interactions between highly interconnected brain regions. Pathological disruptions in these networks often result in brain dysfunction, which manifests as brain disease. Typical analysis investigates disruptions in network connectivity based correlations between large brain regions. To obtain a more detailed description of disruptions in network connectivity, we propose a new method where functional nodes are identified in each region based on their maximum connectivity to another brain region in a given network. Since this method provides a unique approach to identifying functionally relevant nodes in a given network, we can provide a more detailed map of brain connectivity and determine new measures of network connectivity. We applied this method to resting state fMRI of Alzheimer's disease patients to validate our method and found decreased connectivity within the default mode network. In addition, new measure of network connectivity revealed a more detailed description of how the network connections deteriorate with disease progression. This suggests that analysis using key relative network hub regions based on regional correlation can be used to detect detailed changes in resting state network connectivity.

Decreased neural response for facial emotion processing in subjects with high genetic load for schizophrenia.

BACKGROUND: Patients with schizophrenia show impairment in facial emotion processing which is essential for successful social cognition. Using a functional magnetic resonance imaging (fMRI), this study aimed to investigate the implicit facial emotion recognition processing in participants with high genetic load for schizophrenia (GHR) as a possible trait marker of developing schizophrenia. METHODS: Block design fMRI of implicit facial emotion processing was used in 20 participants with GHR aged 16-35, and 17 age, sex, and education year-matched healthy controls (HC). During the facial emotional processing for fearful, happy, and neutral face stimuli, participants were asked to explicitly determine the gender per stimuli. RESULTS: Occipito-temporo-limbic area in fearful face condition and involvement of broader region including prefrontal cortex in neutral face condition revealed significant attenuation of BOLD signal activation in GHR compared to HC. The GHR demonstrated less activity in right amygdala during fearful and neutral face condition. CONCLUSION: The study presented that GHR displayed abnormal brain activity in occipito-temporo-limbic-frontal network implicated in facial emotion processing. It indicates that abnormal facial emotion processing may be influenced by a genetic factor and could be a trait marker in schizophrenia.

Altered Fronto-Temporal Functional Connectivity in Individuals at Ultra-High-Risk of Developing Psychosis.

BACKGROUND: The superior temporal gyrus (STG) is one of the key regions implicated in psychosis, given that abnormalities in this region are associated with an increased risk of conversion from an at-risk mental state to psychosis. However, inconsistent results regarding the functional connectivity strength of the STG have been reported, and the regional heterogeneous characteristics of the STG should be considered. METHODS: To investigate the distinctive functional connection of each subregion in the STG, we parcellated the STG of each hemisphere into three regions: the planum temporale, Heschl's gyrus, and planum polare. Resting-state functional magnetic resonance imaging was obtained from 22 first-episode psychosis (FEP) patients, 41 individuals at ultra-high-risk for psychosis (UHR), and 47 demographically matched healthy controls. RESULTS: Significant group differences (in seed-based connectivity) were demonstrated in the left planum temporale and from both the right and left Heschl's gyrus seeds. From the left planum temporale seed, the FEP and UHR groups exhibited increased connectivity to the bilateral dorsolateral prefrontal cortex. In contrast, the FEP and UHR groups demonstrated decreased connectivity from the bilateral Heschl's gyrus seeds to the dorsal anterior cingulate cortex. The enhanced connectivity between the left planum temporale and right dorsolateral prefrontal cortex was positively correlated with positive symptom severity in individuals at UHR (r = .34, p = .03). CONCLUSIONS: These findings corroborate the fronto-temporal connectivity disruption hypothesis in schizophrenia by providing evidence supporting the altered fronto-temporal intrinsic functional connection at earlier stages of psychosis. Our data indicate that subregion-specific aberrant fronto-temporal interactions exist in the STG at the early stage of psychosis, thus suggesting that these aberrancies are the neural underpinning of proneness to psychosis.