Je-Yeon Yun

Effects of Oxytocin on Neural Response to Facial Expressions in Patients with Schizophrenia

Na Young Shin, Hye Yoon Park, Wi Hoon Jung, Jin Woo Park, Je-Yeon Yun, Joon Hwan Jang, Sung Nyun Kim, Hyun Jung Han, So-Yeon Kim, Do-Hyung Kang and Jun Soo Kwon Institute of Human Behavioral Medicine, SNU-MRC, Seoul, Republic of Korea; Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea

Symptomatic and functional remission of subjects at clinical high risk for psychosis: A 2-year naturalistic observational study

BACKGROUND The aim of this study was to assess the frequency and predictors of symptomatic and functional remission in individuals at clinical high risk (CHR) for psychosis at 1-2 years of follow-up. METHODS Help-seeking CHR individuals with symptomatic (Scale of Prodromal Symptoms (SOPS) positive scores <3) and functional (Global Assessment of Functioning (GAF) score >60) (CHR-R) remission at 12-24 months were compared to non-remitted individuals (CHR-NR) regarding baseline and treatment characteristics, symptom changes and predictors. Time to full remission was compared with that of symptomatic remission only. RESULTS Of 73 individuals, 29 (39.7%) achieved full remission; 44 (60.3%) did not. Compared to CHR-NR individuals, CHR-R individuals had lower baseline SOPS positive symptoms (p=0.017), antipsychotic use (p=0.004), antipsychotic chlorpromazine dose equivalents (p=0.001) and anxiolytic use (p=0.004). In survival analyses, the estimated full remission rate was 48.3% (95% confidence interval (CI)=36.2-61.9) and symptomatic remission rate was 67.5% (CI95=55.4-79.2). Time to full remission was longer than time to symptomatic remission (p=0.017). Linear mixed-effect models revealed significantly greater improvements from 6 months onward in CHR-R subjects compared to CHR-NR subjects regarding SOPS positive symptoms (p=0.003), highest SOPS positive symptom (p<0.001) and GAF scores (p=0.004). Examining baseline predictors, time to full remission was significantly longer in patients with higher SOPS positive scores (p=0.017). CONCLUSIONS More stringent remission criteria that include functional status in addition to attenuated positive symptom severity should be applied to CHR subjects. Furthermore, more attention should be given to CHR individuals with highly positive prodromal symptoms at baseline.

Impact of the BDNF Val66Met Polymorphism on Regional Brain Gray Matter Volumes: Relevance to the Stress Response

Objective Genetic imaging is used to investigate the mechanism by which genetic variants influence brain structure. In a previous study, a structural change of the dorsolateral prefrontal cortex was associated with symptom modulation in post-traumatic stress disorder patients. This study examined the effect of a polymorphism in the gene encoding brain-derived neurotrophic factor (BDNF) on regional gray matter (GM) volumes and the correlations between the dorsolateral prefrontal GM volume and the stress level in healthy volunteers. Methods Sixty-one volunteers underwent genotyping for the BDNF Val66Met single nucleotide polymorphism (SNP) and completed the Stress Response Inventory (SRI). Magnetic resonance images were also acquired, and the effect of each subjects BDNF genotype and SRI subscore on his or her dorsolateral prefrontal GM volume was evaluated. Results The Val/Val homozygotes had significantly larger GM volumes in the prefrontal cortex and the precuneus, the uncus, and the superior temporal and occipital cortices than Met carriers. The Met homozygotes demonstrated a higher stress response in depression domain than Val/Val and Val/Met groups. A negative correlation between the middle frontal cortex GM volume and the SRI depression subscore was found. Conclusion These findings indicate an interaction between genes and brain structure, and they suggest that differences in dorsolateral prefrontal GM volume related to the BDNF Val66Met SNP are associated with resilience to stressful life events, particularly in the dimension of emotion.

Dysfunctional role of parietal lobe during self-face recognition in schizophrenia

BACKGROUND Anomalous sense of self is central to schizophrenia yet difficult to demonstrate empirically. The present study examined the effective neural network connectivity underlying self-face recognition in patients with schizophrenia (SZ) using [15O]H2O Positron Emission Tomography (PET) and Structural Equation Modeling. METHODS Eight SZ and eight age-matched healthy controls (CO) underwent six consecutive [15O]H2O PET scans during self-face (SF) and famous face (FF) recognition blocks, each of which was repeated three times. RESULTS There were no behavioral performance differences between the SF and FF blocks in SZ. Moreover, voxel-based analyses of data from SZ revealed no significant differences in the regional cerebral blood flow (rCBF) levels between the SF and FF recognition conditions. Further effective connectivity analyses for SZ also showed a similar pattern of effective connectivity network across the SF and FF recognition. On the other hand, comparison of SF recognition effective connectivity network between SZ and CO demonstrated significantly attenuated effective connectivity strength not only between the right supramarginal gyrus and left inferior temporal gyrus, but also between the cuneus and right medial prefrontal cortex in SZ. CONCLUSION These findings support a conceptual model that posits a causal relationship between disrupted self-other discrimination and attenuated effective connectivity among the right supramarginal gyrus, cuneus, and prefronto-temporal brain areas involved in the SF recognition network of SZ.

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.

Neural Correlates of Response to Pharmacotherapy in Obsessive-Compulsive Disorder: Individualized Cortical Morphology-Based Structural Covariance.

BACKGROUND Primary pharmacotherapy regimen for obsessive-compulsive disorder (OCD) named Serotonin reuptake inhibitors (SRIs) does not attain sufficient symptom improvement in 40-60% of OCD. We aimed to decode the differential profile of OCD-related brain pathology per subject in the context of cortical surface area (CSA) or thickness (CT)-based individualized structural covariance (ISC) and to demonstrate the potential of which as a biomarker of treatment response to SRI-based pharmacotherapy in OCD using the support vector machine (SVM). METHODS T1-weighted magnetic resonance imaging was obtained at 3T from 56 unmedicated OCD subjects and 75 healthy controls (HCs) at baseline. After 4months of SRI-based pharmacotherapy, the OCD subjects were classified as responders (OCD-R,N=25; ≥35% improvement) or nonresponders (OCD-NR,N=31; <35% improvement) according to the percentage change in the Yale-Brown Obsessive Compulsive Scale total score. Cortical ISCs sustaining between-group difference (p<.001) for every run of leave-one-out group-comparison were packaged as feature set for group classification using the SVM. RESULTS An optimal feature set of the top 12 ISCs including a CT-ISC between the dorsolateral prefrontal cortex versus precuneus, a CSA-ISC between the anterior insula versus intraparietal sulcus, as well as perisylvian area-related ISCs predicted the initial prognosis of OCD as OCD-R or OCD-NR with an accuracy of 89.0% (sensitivity 88.4%, specificity 90.1%). Extended sets of ISCs distinguished the OCD subjects from the HCs with 90.7-95.6% accuracy (sensitivity 90.8-96.2%, specificity 91.1-95.0%). CONCLUSION We showed the potential of cortical morphology-based ISCs, which reflect dysfunctional cortical maturation process, as a possible biomarker that predicts the clinical treatment response to SRI-based pharmacotherapy in OCD.

The impact of genetic variation in comt and bdnf on resting-state functional connectivity

Genetic imaging techniques allow investigation of the mechanisms by which genetic variants influence brain structure and function. The default mode network (DMN) is characterized by a default state of neuronal activity in the brain that is linked to core processes of human cognition. This study examined the role of catechol‐O‐methyl transferase (COMT) and brain‐derived neurotrophic factor (BDNF) polymorphisms on functional connectivity between brain areas. Twenty‐three healthy volunteers underwent a resting‐state functional magnetic resonance imaging scan and genotyping of COMT and BDNF single nucleotide polymorphisms (SNPs). A resting‐state functional connectivity map was created using the posterior cingulate cortex (PCC) as a seed region. The Val/Val homozygote group of the COMT Val158Met SNP showed significantly greater DMN connectivity in the medial and superior frontal gyri and cerebellum compared with the Met allele carrier group. For the BDNF Val66Met SNP, connectivity between the PCC and precuneus was stronger in the Val/Val homozygote group than in the Met allele carrier group. Different patterns of DMN connectivity related to BDNF and COMT SNPs were observed in this study. These findings suggest interaction between genes and functional connectivity in the brain and indicate that altered functional connectivity may be an endophenotype of cognitive vulnerability.

Individualized covariance profile of cortical morphology for auditory hallucinations in first-episode psychosis

Neocortical phenotype of cortical surface area (CSA) and thickness (CT) are influenced by distinctive genetic factors and undergo differential developmental trajectories, which could be captured using the individualized cortical structural covariance (ISC). Disturbed patterns of neocortical development and maturation underlie the perceptual disturbance of psychosis including auditory hallucination (AH). To demonstrate the utility of selected ISC features as primal biomarker of AH in first‐episode psychosis (FEP) subjects experiencing AH (FEP‐AH), we employed herein a support vector machine (SVM). A total of 147 subjects (FEP‐AH, n = 27; FEP‐NAH, n = 24; HC, n = 96) underwent T1‐weighted magnetic resonance imaging at 3T. The FreeSurfer software suite was used for cortical parcellation, with the CSA‐ISC and CT‐ISC then calculated. The most informative ISCs showing statistical significance (P < 0.001) across every run of leave‐one‐out group‐comparison were aligned according to the absolute value of averaged t‐statistics and were packaged into candidate feature sets for classification analysis using the SVM. An optimal feature set comprising three CSA‐ISCs, including the intraparietal sulcus, Brocas complex, and the anterior insula, distinguished FEP‐AH from FEP‐NAH subjects with 83.6% accuracy (sensitivity = 82.8%; specificity = 85.7%). Furthermore, six CT‐ISCs encompassing the executive control network and Wernickes module classified FEP‐AH from FEP‐NAH subjects with 82.3% accuracy (sensitivity = 79.5%; specificity = 88.6%). Finally, extended sets of ISCs related to the default‐mode network distinguished FEP‐AH or FEP‐NAH from HC subjects with 89.0–93.0% accuracy (sensitivity = 88.4–93.4%; specificity = 89.0–94.1%). This study established a distinctive intermediate phenotype of biological proneness for AH in FEP using CSA‐ISCs as well as a state marker of disease progression using CT‐ISCs. Hum Brain Mapp 37:1051–1065, 2016.

Early referral and comorbidity as possible causes of the declining transition rate in subjects at clinical high risk for psychosis.

A clinical high risk (CHR) for psychosis is regarded as the state of being at risk of developing psychosis. However, the rate of transition to psychosis among CHR subjects has been declining over time. We aimed to investigate the effects of the possible causes of the declining transition rate.

Parental socioeconomic status and prognosis in individuals with ultra-high risk for psychosis: A 2-year follow-up study

A possible relationship between socioeconomic status (SES) and the development of mental illness has been continuously suggested. Still, less clear is whether the SES has a direct effect on the development of schizophrenia. In this longitudinal study, we test the hypothesis that parental SES is associated with the prognosis of individuals at ultra-high risk (UHR) for psychosis. One hundred and sixteen individuals who were determined as UHR using a Comprehensive Assessment of At-Risk Mental States (CAARMS) were classified into three groups based on the parental SES levels assessed by the Hollingshead-Redlich scale. There were no differences in the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS) at baseline. However, at the 1-year follow-up, the higher versus lower SES group showed significant differences in clinical measures including SAPS, SANS, PANSS positive and negative scales as well as BPRS scores. Most of these clinical differences were attenuated by the second year of follow-up with no sign of an increased rate of conversion to psychosis derived from a socioeconomically disadvantaged status. However, SAPS and PANSS positive scale still revealed sub-threshold positive symptoms within the low SES group at the 2-year follow-up. Moreover, especially for the subjects who continued the follow-ups for 1year and/or 2years, the changes of clinical symptoms between the baseline and follow-ups showed that there were significant symptom changes in higher and middle SES groups within the 1-year period already, but the lower SES group showed significant recovery at the second year. Our findings suggest that low parental SES can be detrimental to the prognosis phase of individuals at UHR. Limited supportive socioeconomic resources may slow the rate of symptom recovery in UHR subjects.