HIGH PLOIDY2-mediated SUMOylation of transcription factor ARR1 controls two-component signaling in Arabidopsis.

Cytokinins regulate plant growth, development, and responses to environmental stresses such as cold via phosphorelay from cytokinin receptors to the ARABIDOPSIS RESPONSE REGULATORs (ARRs). However, the molecular mechanisms underlying the activation of type-B ARR transcriptional activity in Arabidopsis (Arabidopsis thaliana) remain unclear. Here, we show that the E3 SUMO ligase HIGH PLOIDY2 SUMOylates ARR1, a type-B ARR, at K236, triggering its activation. Cold- or cytokinin-induced phosphorylation of ARR1 at D89 is crucial for its interaction with HPY2. Lysine 236 is critical for ARR1's transactivation without compromising its DNA-binding ability, while D89 is crucial for ARR1's binding to target gene promoters. Cytokinin enhances ARR1's chromatin binding, but cold does not. ARR1 K236 plays a critical role in promoting histone H3 acetylation in response to both cytokinin and cold without affecting chromatin binding. The K236R mutation in ARR1 reduces target gene expression and alters cytokinin and cold response phenotypes. This study unveils a mechanism of ARR1 activation wherein phosphorylated ARR1 interacts with HPY2 and binds to chromatin in response to cytokinin. Cold triggers a phosphorelay targeting chromatin-bound ARR1. HPY2 then catalyzes ARR1 SUMOylation at K236, enhancing histone H3 acetylation and leading to transcriptional activation of ARR1 in response to both cold and cytokinin.

In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18-Labeled THK5351.

Importance: In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation. Objective: To investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)-binding fluorine 18 ([18F])-labeled THK5351 positron emission tomography (PET). Design, Setting, and Participants: In this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals. Main Outcomes and Measures: Standardized uptake value ratios (SUVrs) of [18F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores. Results: A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [18F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)-corrected P = .04]; right, F = 5.977 [FDR-corrected P = .04]) and left hippocampus (F = 4.834 [FDR-corrected P = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [P = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r = 0.423 [FDR-corrected P = .03]; right, r = 0.406 [FDR-corrected P = .03]) in patients with schizophrenia. Conclusions and Relevance: This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.

Neurocomputational model of compulsivity: Deviating from an uncertain goal-directed system.

Despite a theory that an imbalance in goal-directed versus habitual systems serve as building blocks of compulsions, research has yet to delineate how it occurs during an arbitration process between the two systems in obsessive-compulsive disorder. Inspired by a brain model that the inferior frontal cortex selectively gates the putamen to guide goal-directed or habitual actions, this study aimed to examine whether disruptions in the arbitration process via the fronto-striatal circuit would underlie the imbalanced decision-making and compulsions in patients. Thirty patients with obsessive-compulsive disorder (mean [SD] age = 26.93 [6.23] years, 12 females [40%]) and thirty healthy controls (mean [SD] age = 24.97 [4.72] years, 17 females [57%]) underwent functional MRI scans while performing the two-step Markov decision task, which was designed to dissociate goal-directed behavior from habitual behavior. We employed a neurocomputational model to account for an uncertainty-based arbitration process, in which a prefrontal arbitrator (i.e., inferior frontal gyrus) allocates behavioral control to a more reliable strategy by selectively gating the putamen. We analyzed group differences in the neural estimates of uncertainty of each strategy. We also compared the psychophysiological interaction effects of system preference (goal-directed vs. habitual) on fronto-striatal coupling between groups. We examined the correlation between compulsivity score and the neural activity and connectivity involved in the arbitration process. The computational model captured subjects' preference between the strategies. Compared to healthy controls, patients had a stronger preference for the habitual system (t = -2.88, P = 0.006), which was attributed to a more uncertain goal-directed system (t = 2.72, P = 0.009). Before the allocation of controls, patients exhibited hypoactivity in the inferior frontal gyrus compared to healthy controls when this region tracked the inverse of uncertainty (i.e., reliability) of goal-directed behavior (P = 0.001, family-wise error rate corrected). When reorienting behaviors to reach specific goals, patients exhibited weaker right ipsilateral ventrolateral prefronto-putamen coupling than healthy controls (P = 0.001, family-wise error rate corrected). This hypoconnectivity was correlated with more severe compulsivity (r = -0.57, P = 0.002). Our findings suggest that the attenuated top-down control of the putamen by the prefrontal arbitrator underlies compulsivity in obsessive-compulsive disorder. Enhancing fronto-striatal connectivity may be a potential neurotherapeutic approach for compulsivity and adaptive decision-making.

Alteration in left frontoparietal connectivity correlates with impaired cognitive reappraisal in early psychosis.

BACKGROUND: Impaired cognitive reappraisal is a notable symptom of early psychosis, but its neurobiological basis remains underexplored. We aimed to identify the underlying neurobiological mechanism of this impairment by using resting-state functional connectivity (FC) analyses focused on brain regions related to cognitive reappraisal. METHODS: Resting-state functional magnetic resonance images were collected from 36 first-episode psychosis (FEP) patients, 32 clinical high-risk (CHR) individuals, and 48 healthy controls (HCs). Whole-brain FC maps using seed regions associated with cognitive reappraisal were generated and compared across the FEP, CHR and HC groups. We assessed the correlation between resting-state FC, reappraisal success ratio, positive symptom severity and social functioning controlling for covariates. RESULTS: FEP patients showed higher FC between the left superior parietal lobe and left inferior frontal gyrus than HCs. Higher FC between the left superior parietal lobe and left inferior frontal gyrus negatively correlated with the reappraisal success ratio in the FEP group after controlling for covariates. Lower FC correlated with lower positive symptom severity and improved global functioning in the FEP group. CONCLUSIONS: Alteration in left frontoparietal connectivity reflects impaired cognitive reappraisal in early psychosis, and such alteration correlates with increased positive symptoms and decreased global functioning. These findings offer a potential path for interventions targeting newly emerging symptoms in the early stages of psychosis.

Pharmacotherapy for obsessive-compulsive disorder: Real-world evidence from a 10-year retrospective data analysis.

We investigated pharmacotherapy trends for obsessive-compulsive disorder (OCD) patients at a Korean tertiary hospital from 2008 to 2017. Out of 1894 patients, 82.9% received at least one psychotropic medication, with prescription rates increasing over time. The most frequently prescribed drug classes were selective serotonin reuptake inhibitors (SSRIs, 80.5%), anxiolytics (57.5%), antipsychotics (47.2%), other antidepressants (21.1%), and mood stabilizers (18.4%). Combination therapy was administered to 79.7% of medicated patients, with SSRIs, anxiolytics, and antipsychotics being the most common combination. Comorbidities significantly increased the prescription rates of all psychotropic classes (P < 0.001). Our study offers insights that may aid in bridging the gap between OCD treatment guidelines and real-world clinical practice.

Impact of long-acting injectable aripiprazole on the concomitant medication and antipsychotic polypharmacy: a retrospective, observational study of 127 patients with psychosis.

Antipsychotic polypharmacy (APP) has become prevalent over the years, but several concerns have been raised over APP. Accumulating evidence suggests that aripiprazole long-acting injectable (LAI) may reduce the rate of APP, but the association remains speculative. This retrospective observational study included 127 patients with psychosis and observed them for 1.8 ±â€…1.3 years, up to 4 years. Prescription data of antipsychotics (APs), mood stabilisers, benzodiazepines, and anti-extrapyramidal side effect medications were obtained at baseline and the last observation. Daily chlorpromazine equivalent (CPZ) dose of APs decreased from 124.40 ±â€…235.35 mg to 77.95 ±â€…210.36 mg (P = 0.027). The daily dose of anticholinergics and beta-blockers also significantly decreased after introducing aripiprazole LAI. Among the patients having APP, the number of concurrent APs along with daily CPZ dose of APs decreased after initiation of aripiprazole LAI from 1.28 ±â€…0.62 to 0.85 ±â€…0.73 (P < 0.001) and 298.33 ±â€…308.70 mg to 155.43 ±â€…280.53 mg (P = 0.004), respectively. Treatment with aripiprazole LAI for up to 4 years in patients with psychosis was associated with a reduced number of prescribed APs in patients having an APP and a reduced dose of APs and concurrent psychotropic medications.

Fronto-striato-thalamic circuit connectivity and neuromelanin in schizophrenia: an fMRI and neuromelanin-MRI study.

Changes in dopamine and fronto-striato-thalamic (FST) circuit functional connectivity are prominent in schizophrenia. Dopamine is thought to underlie connectivity changes, but experimental evidence for this hypothesis is lacking. Previous studies examined the association in some of the connections using positron emission tomography (PET) and functional MRI (fMRI); however, PET has disadvantages in scanning patients, such as invasiveness. Excessive dopamine induces neuromelanin (NM) accumulation, and NM-MRI is suggested as a noninvasive proxy measure of dopamine function. We aimed to investigate the association between NM and FST circuit connectivity at the network level in patients with schizophrenia. We analysed substantia nigra NM-MRI and resting-state fMRI data from 29 schizophrenia patients and 63 age- and sex-matched healthy controls (HCs). We identified the FST subnetwork with abnormal connectivity found in schizophrenia patients compared to that of HCs and investigated the relationship between constituting connectivity and NM-MRI signal. We found a higher NM signal (t = -2.12, p = 0.037) and a hypoconnected FST subnetwork (FWER-corrected p = 0.014) in schizophrenia patients than in HCs. In the hypoconnected subnetwork of schizophrenia patients, lower left supplementary motor area-left caudate connectivity was associated with a higher NM signal (ß = -0.38, p = 0.042). We demonstrated the association between NM and FST circuit connectivity. Considering that the NM-MRI signal reflects dopamine function, our results suggest that dopamine underlies changes in FST circuit connectivity, which supports the dopamine hypothesis. In addition, this study reveals implications for the future use of NM-MRI in investigations of the dopamine system.

Emerging Immune Checkpoint Molecules on Cancer Cells: CD24 and CD200.

Cancer immunotherapy strategies are based on the utilization of immune checkpoint inhibitors to instigate an antitumor immune response. The efficacy of immune checkpoint blockade, directed at adaptive immune checkpoints, has been demonstrated in select cancer types. However, only a limited subset of patients has exhibited definitive outcomes characterized by a sustained response after discontinuation of therapy. Recent investigations have highlighted the significance of immune checkpoint molecules that are overexpressed in cancer cells and inhibit myeloid lineage immune cells within a tumor microenvironment. These checkpoints are identified as potential targets for anticancer immune responses. Notably, the immune checkpoint molecules CD24 and CD200 have garnered attention owing to their involvement in tumor immune evasion. CD24 and CD200 are overexpressed across diverse cancer types and serve as signaling checkpoints by engaging their respective receptors, Siglec-10 and CD200 receptor, which are expressed on tumor-associated myeloid cells. In this review, we summarized and discussed the latest advancements and insights into CD24 and CD200 as emergent immune checkpoint moieties, further delving into their therapeutic potentials for cancer treatment.

Magnetic resonance texture analysis reveals stagewise nonlinear alterations of the frontal gray matter in patients with early psychosis.

Although gray matter (GM) abnormalities are present from the early stages of psychosis, subtle/miniscule changes may not be detected by conventional volumetry. Texture analysis (TA), which permits quantification of the complex interrelationship between contrasts at the individual voxel level, may capture subtle GM changes with more sensitivity than does volume or cortical thickness (CTh). We performed three-dimensional TA in nine GM regions of interest (ROIs) using T1 magnetic resonance images from 101 patients with first-episode psychosis (FEP), 85 patients at clinical high risk (CHR) for psychosis, and 147 controls. Via principal component analysis, three features of gray-level cooccurrence matrix - informational measure of correlation 1 (IMC1), autocorrelation (AC), and inverse difference (ID) - were selected to analyze cortical texture in the ROIs that showed a significant change in volume or CTh in the study groups. Significant reductions in GM volume and CTh of various frontotemporal regions were found in the FEP compared with the controls. Increased frontal AC was found in the FEP group compared to the controls after adjusting for volume and CTh changes. While volume and CTh were preserved in the CHR group, a stagewise nonlinear increase in frontal IMC1 was found, which exceeded both the controls and FEP group. Increased frontal IMC1 was also associated with a lesser severity of attenuated positive symptoms in the CHR group, while neither volume nor CTh was. The results of the current study suggest that frontal IMC1 may reflect subtle, dynamic GM changes and the symptomatology of the CHR stage with greater sensitivity, even in the absence of gross GM abnormalities. Some structural mechanisms that may contribute to texture changes (e.g., macrostructural cortical lamina, neuropil/myelination, cortical reorganization) and their possible implications are explored and discussed. Texture may be a useful tool to investigate subtle and dynamic GM abnormalities, especially during the CHR period.

Compromised Cerebello-Thalamic White Matter Integrity in Medication-Free Patients With Obsessive-Compulsive Disorder.

OBJECTIVE: The cerebello-thalamic tract is the only efferent white matter (WM) bundle of the cerebellum that connects the cerebellum to the thalamus and has recently attracted much attention in obsessive-compulsive disorder (OCD) with its integral role in higher order cognitive functions commonly impaired in OCD patients. Previous neuroimaging studies have shown that the cerebello-thalamic circuit is functionally impaired in OCD patients. However, the WM integrity of the cerebello-thalamic tract in OCD, which may underly functional abnormalities of the cerebello-thalamic circuit, is not yet sufficiently understood. Therefore, the current study aimed to elucidate whether compromised cerebello-thalamic WM integrity is observed in medication-free OCD patients. METHODS: In this study, diffusion tensor imaging was acquired from 106 medication-free OCD patients and 105 matched healthy controls (HCs). Probabilistic tractography was then used to reconstruct the cerebello-thalamic tract with accurate anatomical features. Three diffusion indices (fractional anisotropy, FA; mean diffusivity, MD; radial diffusivity, RD) were measured from the reconstructed bilateral cerebello-thalamic tract and then compared between groups. RESULTS: We found that patients with OCD showed significantly increased MD and RD in the right cerebello-thalamic tract compared to HCs, and there was no difference in FA between groups. CONCLUSION: Our findings may indicate the underlying structural abnormalities of the dysfunctional cerebello-thalamic circuit in OCD patients. Therefore, our findings are expected to provide novel insights into the pathophysiology of OCD on the cerebello-thalamic WM architecture, extending our knowledge from the existing functional neurobiological model of OCD.

Altered intrinsic cerebellar-cerebral functional connectivity is related to negative symptoms in patients with first-episode psychosis.

BACKGROUND: Negative symptoms in schizophrenia include cognitive and affective dysfunction, such as diminished expression and amotivation. Although the cerebellar posterior hemisphere and vermis are involved in cognitive and affective functioning, previous studies on the neural mechanism of negative symptoms have mostly been confined to the cerebral cortex. This study aimed to investigate whether resting-state cerebellar-cerebral functional connectivity (FC) is altered in first-episode psychosis (FEP) patients and whether this connectivity is related to negative symptoms. METHODS: Resting-state functional magnetic resonance images were obtained from 38 FEP patients and 100 healthy controls (HCs). Using the posterior hemisphere and vermis of the cerebellum as seeds, whole-brain FC was compared between FEP patients and HCs. As cerebellar-parietal cortex connectivity is associated with negative symptoms and sociocognitive dysfunctions in schizophrenia patients, its correlation with negative symptoms was explored in FEP patients. RESULTS: FEP patients showed hyperconnectivity between the cerebellum and bilateral frontal pole (FP), occipital pole, fusiform gyrus, right lingual gyrus, central opercular cortex, anterior middle temporal gyrus, precuneus, and subcallosal cortex. Hypoconnectivity was found between the cerebellum and left FP, right anterior supramarginal gyrus (aSMG), and cerebellum crus I. FC between the left crus II and right aSMG was negatively correlated with the severity of negative symptoms and diminished expression. CONCLUSIONS: Altered FC between the cerebellum and cerebral regions related to cognitive, affective, and sensory processing was found in FEP patients and was connected to negative symptoms. These results suggest that the cerebellum plays a role in the pathophysiology of negative symptoms in schizophrenia.

Forecasting prognostic trajectories with mismatch negativity in early psychosis.

BACKGROUND: Prognostic heterogeneity in early psychosis patients yields significant difficulties in determining the degree and duration of early intervention; this heterogeneity highlights the need for prognostic biomarkers. Although mismatch negativity (MMN) has been widely studied across early phases of psychotic disorders, its potential as a common prognostic biomarker in early periods, such as clinical high risk (CHR) for psychosis and first-episode psychosis (FEP), has not been fully studied. METHODS: A total of 104 FEP patients, 102 CHR individuals, and 107 healthy controls (HCs) participated in baseline MMN recording. Clinical outcomes were assessed; 17 FEP patients were treatment resistant, 73 FEP patients were nonresistant, 56 CHR individuals were nonremitters (15 transitioned to a psychotic disorder), and 22 CHR subjects were remitters. Baseline MMN amplitudes were compared across clinical outcome groups and tested for utility prognostic biomarkers using binary logistic regression. RESULTS: MMN amplitudes were greatest in HCs, intermediate in CHR subjects, and smallest in FEP patients. In the clinical outcome groups, MMN amplitudes were reduced from the baseline in both FEP and CHR patients with poor prognostic trajectories. Reduced baseline MMN amplitudes were a significant predictor of later treatment resistance in FEP patients [Exp(ß) = 2.100, 95% confidence interval (CI) 1.104-3.993, p = 0.024] and nonremission in CHR individuals [Exp(ß) = 1.898, 95% CI 1.065-3.374, p = 0.030]. CONCLUSIONS: These findings suggest that MMN could be used as a common prognostic biomarker across early psychosis periods, which will aid clinical decisions for early intervention.

Cortical gyrification differences between early- and late-onset obsessive-compulsive disorder: neurobiological evidence for neurodevelopmentally distinct subtypes.

BACKGROUND: Identifying more homogenous subtypes of patients with obsessive-compulsive disorder (OCD) using biological evidence is critical for understanding complexities of the disorder in this heterogeneous population. Age of onset serves as a useful subtyping scheme for distinguishing OCD into two subgroups that aligns with neurodevelopmental perspectives. The underlying neurobiological markers for these distinct neurodevelopmental differences can be identified by investigating gyrification changes to establish biological evidence-based homogeneous subtypes. METHODS: We compared whole-brain cortical gyrification in 84 patients with early-onset OCD, 84 patients with late-onset OCD, and 152 healthy controls (HCs) to identify potential markers for early neurodevelopmental deficits using the local gyrification index (lGI). Then, the relationships between lGI in clusters showing significant differences and performance in visuospatial memory and verbal fluency, which are considered trait-related neurocognitive impairments in OCD, were further examined in early-onset OCD patients. RESULTS: The early-onset OCD patients exhibited significantly greater gyrification than those with late-onset OCD patients and HCs in frontoparietal and cingulate regions, including the bilateral precentral, postcentral, precuneus, paracentral, posterior cingulate, superior frontal, and caudal anterior cingulate gyri. Moreover, impaired neurocognitive functions in early-onset OCD patients were correlated with increased gyrification. CONCLUSIONS: Our findings provide a neurobiological marker to distinguish the OCD population into more neurodevelopmentally homogeneous subtypes, which may contribute to the understanding of the neurodevelopmental underpinnings of an etiology in early-onset OCD consistent with the accumulated phenotypic evidence of greater neurodevelopmental deficits in early-onset OCD than in late-onset OCD.

Large-Scale Thalamocortical Triple Network Dysconnectivities in Patients With First-Episode Psychosis and Individuals at Risk for Psychosis.

BACKGROUND AND HYPOTHESIS: Aberrant thalamocortical connectivity and large-scale network interactions among the default mode network (DMN), salience network (SN), and executive control network (ECN) (ie, triple networks) have been regarded as critical in schizophrenia pathophysiology. Despite the importance of network properties and the role of the thalamus as an integrative hub, large-scale thalamocortical triple network functional connectivities (FCs) in different stages of the psychotic disorder have not yet been reported. STUDY DESIGN: Thirty-nine first-episode psychosis (FEP) patients, 75 individuals at clinical high risk (CHR) for psychosis, 46 unaffected relatives (URs) of schizophrenia patients with high genetic loading, and 110 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging (rs-fMRI). Modular community detection was used to identify cortical and thalamic resting-state networks, and thalamocortical network interactions were compared across the groups. STUDY RESULTS: Thalamic triple networks included higher-order thalamic nuclei. Thalamic SN-cortical ECN FC was greater in the FEP group than in the CHR, UR, and HC groups. Thalamic DMN-cortical DMN and thalamic SN-cortical DMN FCs were greater in FEP and CHR participants. Thalamic ECN-cortical DMN and thalamic ECN-cortical SN FCs were greater in FEP patients and URs. CONCLUSIONS: These results highlight critical modulatory functions of thalamic triple networks and the shared and distinct patterns of thalamocortical triple network dysconnectivities across different stages of psychotic disorders. The current study findings suggest that large-scale thalamocortical triple network dysconnectivities may be used as an integrative biomarker for extending our understanding of the psychosis pathophysiology and for targeting network-based neuromodulation therapeutics.

Inter-fractional entrance dose monitoring as quality assurance using Gafchromic EBT3 film.

Introduction: This study describes a simple method of inter-fractional photon beam monitoring to measure the entrance dose of radiation treatment using Gafchromic EBT3 film. Materials and Methods: The film was placed at the center of a 1-cm thick phantom shaped like a block tray and fixed on the accessory tray of the gantry. The entrance dose was measured following the placement of the film in the accessory tray. The dose distribution calculated with the treatment planning system was compared with the dose distribution on the irradiated EBT3 films. The effectiveness of this methodology, as determined by gamma passing rates, was evaluated for the 22 fields of eight three-dimensional conformal radiotherapy (3D-CRT) plans and the 41 fields of nine intensity-modulated radiotherapy (RT) plans. The plans for three-dimensional conformal RT included treatments of the rectum, liver, breast, and head and neck, whereas the plans for intensity-modulated RT included treatments of the liver, brain, and lung. Results: The gamma passing rates for 3D-CRT ranged from 96.4% to 99.5%, with the mean gamma passing rate for 22 fields being 98.0%. The gamma passing rate for intensity-modulated RT ranged from 96.1% to 98.9%, with the mean gamma passing rate for 41 fields being 97.7%. All gamma indices were over the 95% tolerance level. Conclusions: The methodology described in this study, based on Gafchromic EBT3 film, can be utilized for inter-fractional entrance dose monitoring as quality assurance during RT. Clinical application of this method to patients can verify the accuracy of beam delivery in the treatment room.

Aberrant cortico-striatal white matter connectivity and associated subregional microstructure of the striatum in obsessive-compulsive disorder.

The striatum and its cortical circuits play central roles in the pathophysiology of obsessive-compulsive disorder (OCD). The striatum is subdivided by cortical connections and functions; however, the anatomical aberrations in different cortico-striatal connections and coexisting microstructural anomalies in striatal subregions of OCD patients are poorly understood. Thus, we aimed to elucidate the aberrations in cortico-striatal white matter (WM) connectivity and the associated subregional microstructure of the striatum in patients with OCD. From diffusion tensor/kurtosis imaging of 107 unmedicated OCD patients and 110 matched healthy controls (HCs), we calculated the cortico-striatal WM connectivity and segmented the striatum using probabilistic tractography. For the segmented striatal subregions, we measured average diffusion kurtosis values, which represent microstructural complexity. Connectivity and mean kurtosis values in each cortical target and associated striatal subregions were compared between groups. We identified significantly reduced orbitofrontal WM connectivity with its associated striatal subregion in patients with OCD compared to that in HCs. However, OCD patients exhibited significantly increased caudal-motor and parietal connectivity with the associated striatal subregions. The mean kurtosis values of the striatal subregions connected to the caudal-motor and parietal cortex were significantly decreased in OCD patients. Our results highlighted contrasting patterns of striatal WM connections with the orbitofrontal and caudal-motor/parietal cortices, thus supporting the cortico-striatal circuitry imbalance model of OCD. We suggest that aberrations in WM connections and the microstructure of their downstream regions in the caudal-motor-/parietal-striatal circuits may underlie OCD pathophysiology and further provide potential neuromodulation targets for the treatment of OCD.

Unbalanced fronto-pallidal neurocircuit underlying set shifting in obsessive-compulsive disorder.

Maladaptive habitual behaviours of obsessive-compulsive disorder are characterized by cognitive inflexibility, which hypothetically arises from dysfunctions of a certain cortico-basal ganglia-thalamo-cortical circuit including the ventrolateral prefrontal region. Inside this neurocircuit, an imbalance between distinct striatal projections to basal ganglia output nuclei, either directly or indirectly via the external globus pallidus, is suggested to be relevant for impaired arbitration between facilitation and inhibition of cortically initiated activity. However, current evidence of individually altered cortico-striatal or thalamo-cortical connectivities is insufficient to understand how cortical dysconnections are linked to the imbalanced basal ganglia system in patients. In this study, we aimed to identify aberrant ventrolateral prefronto-basal ganglia-thalamic subnetworks representing direct-indirect imbalance and its association with cognitive inflexibility in patients. To increase network detection sensitivity, we constructed a cortico-basal ganglia-thalamo-cortical network model incorporating striatal, pallidal and thalamic subregions defined by unsupervised clustering in 105 medication-free patients with obsessive-compulsive disorder (age = 25.05 ± 6.55 years, male/female = 70/35) and 99 healthy controls (age = 23.93 ± 5.80 years, male/female = 64/35). By using the network-based statistic method, we analysed group differences in subnetworks formed by suprathreshold dysconnectivities. Using linear regression models, we tested subnetwork dysconnectivity effects on symptom severity and set-shifting performance assessed by well-validated clinical and cognitive tests. Compared with the healthy controls, patients were slower to track the Part B sequence of the Trail Making Test when the effects of psychomotor and visuospatial functions were adjusted (t = 3.89, P < 0.001) and made more extradimensional shift errors (t = 4.09, P < 0.001). In addition to reduced fronto-striatal and striato-external pallidal connectivities and hypoconnected striato-thalamic subnetwork [P = 0.001, family-wise error rate (FWER) corrected], patients had hyperconnected fronto-external pallidal (P = 0.012, FWER corrected) and intra-thalamic (P = 0.015, FWER corrected) subnetworks compared with the healthy controls. Among the patients, the fronto-pallidal subnetwork alteration, especially ventrolateral prefronto-external globus pallidal hyperconnectivity, was associated with relatively fewer extradimensional shifting errors (ß = -0.30, P = 0.001). Our findings suggest that the hyperconnected fronto-external pallidal subnetwork may have an opposite effect to the imbalance caused by the reduced indirect pathway (fronto-striato-external pallidal) connectivities in patients. This ventrolateral prefrontal hyperconnectivity may help the external globus pallidus disinhibit basal ganglia output nuclei, which results in behavioural inhibition, so as to compensate for the impaired set shifting. We suggest the ventrolateral prefrontal and external globus pallidus as neuromodulatory targets for inflexible habitual behaviours in obsessive-compulsive disorder.

Fraxinol Stimulates Melanogenesis in B16F10 Mouse Melanoma Cells through CREB/MITF Signaling.

Melanin pigment produced in melanocytes plays a protective role against ultraviolet radiation. Selective destruction of melanocytes causes chronic depigmentation conditions such as vitiligo, for which there are very few specific medical treatments. Here, we found that fraxinol, a natural coumarin from Fraxinus plants, effectively stimulated melanogenesis. Treatment of B16-F10 cells with fraxinol increased the melanin content and tyrosinase activity in a concentration-dependent manner without causing cytotoxicity. Additionally, fraxinol enhanced the mRNA expression of melanogenic enzymes such as tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2. Fraxinol also increased the expression of microphthalmia-associated transcription factor at both mRNA and protein levels. Fraxinol upregulated the phosphorylation of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB). Furthermore, H89, a cAMP-dependent protein kinase A inhibitor, decreased fraxinol-induced CREB phosphorylation and microphthalmia-associated transcription factor expression and significantly attenuated the fraxinol-induced melanin content and intracellular tyrosinase activity. These results suggest that fraxinol enhances melanogenesis via a protein kinase A-mediated mechanism, which may be useful for developing potent melanogenesis stimulators.

Volume deficits in hippocampal subfields in unaffected relatives of schizophrenia patients with high genetic loading but without any psychiatric symptoms.

BACKGROUND: Hippocampal volume changes have been reported in schizophrenia patients and their relatives and are proposed to contribute to the pathophysiology of schizophrenia. However, volume changes in the total hippocampus have not been consistently reported in relatives. The hippocampus consists of multiple subregions, and based on previous inconsistent results, subtle changes in specific subregions may occur in relatives. Here, we examined the subregion volumes in unaffected, high-functioning relatives (URs) without any psychiatric symptoms with high genetic loading with at least one first-degree relative diagnosed with schizophrenia and at least one or more other affected first- to third-degree relatives. METHODS: We acquired structural magnetic resonance imaging data from 50 URs, 101 first-episode psychosis (FEP) patients, and 101 healthy controls (HCs). The cornu ammonis (CA), dentate gyrus, and subiculum subfields were automatically segmented using FreeSurfer 7.1.0. Each subregion volume was compared across the groups. RESULTS: Compared with the HCs, the URs had a significant volume reduction in the left anterior CA (p = 0.039, Cohen's d = 0.480). In addition, the URs had a significantly larger right posterior subiculum (p = 0.001, Cohen's d = 0.541) than the FEP. CONCLUSIONS: The smaller left anterior CA in the URs may reflect their genetic vulnerability to schizophrenia and supports previous findings suggesting specific vulnerability in this region. The volume differences between the URs and FEP patients in the right posterior subiculum may suggest that a smaller volume in this region may reflect a risk for schizophrenia other than genetic vulnerability.

Triple-Network Dysconnectivity in Patients With First-Episode Psychosis and Individuals at Clinical High Risk for Psychosis.

OBJECTIVE: In the triple-network model, the salience network (SN) plays a crucial role in switching between the default-mode network (DMN) and the central executive network (CEN). Aberrant patterns of triple-network connectivity have been reported in schizophrenia patients, while findings have been less consistent for patients in the early stages of psychotic disorders. Thus, the present study examined the connectivity among the SN, DMN, and CEN in first-episode psychosis (FEP) patients and individuals at clinical high risk (CHR) for psychosis. METHODS: Thirty-nine patients with FEP, 78 patients with CHR for psychosis, and 110 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. We compared the SN, DMN, and CEN connectivity patterns of the three groups. The role of the SN in networks with significant connectivity differences was examined by mediation analysis. RESULTS: FEP patients showed lower SN-DMN and SN-CEN (cluster-level F=5.83, false discovery rate [FDR] corrected-p=0.001) connectivity than HCs. There was lower SN-DMN connectivity (cluster-level F=3.06, FDR corrected-p=0.053) at a trend level in CHR subjects compared to HCs. Between HCs and FEP patients, mediation analysis showed that SN-DMN connectivity was a mediator between group and SN-CEN connectivity. Additionally, SN-CEN connectivity functioned as a mediator between group and SN-DMN connectivity. CONCLUSION: Aberrant connectivity between the SN and DMN/CEN suggests disrupted network switching in FEP patients, although CHR subjects showed trend-level SN-DMN dysconnectivity. Our findings suggest that dysfunctional triple-network dynamics centered on the SN can appear in patients in the early stages of psychotic disorders.