Sung Nyun Kim

Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder

OBJECTIVE Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables. METHOD A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects. RESULTS Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age). CONCLUSIONS These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

The Effects of Pharmacological Treatment on Functional Brain Connectome in Obsessive-Compulsive Disorder

BACKGROUND Previous neuroimaging studies of obsessive-compulsive disorder (OCD) have reported both baseline functional alterations and pharmacological changes in localized brain regions and connections; however, the effects of selective serotonin reuptake inhibitor (SSRI) treatment on the whole-brain functional network have not yet been elucidated. METHODS Twenty-five drug-free OCD patients underwent resting-state functional magnetic resonance imaging. After 16-weeks, seventeen patients who received SSRI treatment were rescanned. Twenty-three matched healthy control subjects were examined at baseline for comparison, and 21 of them were rescanned after 16 weeks. Topological properties of brain networks (including small-world, efficiency, modularity, and connectivity degree) were analyzed cross-sectionally and longitudinally with graph-theory approach. RESULTS At baseline, OCD patients relative to healthy control subjects showed decreased small-world efficiency (including local clustering coefficient, local efficiency, and small-worldness) and functional association between default-mode and frontoparietal modules as well as widespread altered connectivity degrees in many brain areas. We observed clinical improvement in OCD patients after 16 weeks of SSRI treatment, which was accompanied by significantly elevated small-world efficiency, modular organization, and connectivity degree. Improvement of obsessive-compulsive symptoms was significantly correlated with changes in connectivity degree in right ventral frontal cortex in OCD patients after treatment. CONCLUSIONS This is first study to use graph-theory approach for investigating valuable biomarkers for the effects of SSRI on neuronal circuitries of OCD patients. Our findings suggest that OCD phenomenology might be the outcome of disrupted optimal balance in the brain networks and that reinstating this balance after SSRI treatment accompanies significant symptom improvement.

Aberrant Auditory Processing in Schizophrenia and in Subjects at Ultra-High-Risk for Psychosis

The N1 and the mismatch negativity (MMN) responses observed in electroencephalographic and magnetoencephalographic (MEG) recordings reflect sensory processing, sensory memory, and adaptation and are usually abnormal in patients with schizophrenia. However, their differential sensitivity to ultra-high-risk (UHR) status is controversial. The current study evaluated the sensitivity of MEG N1m, N1m adaptation, and magnetic counterpart of MMN (MMNm) in 16 UHR subjects, 15 schizophrenia patients, and 18 healthy controls (HCs) during a passive auditory oddball task. N1m adaptation was assessed using the difference in N1m dipole moment between the first and last standard tones in a standard stimulus sequence. N1m adaptation occurred in HCs, whereas neither the UHR nor the schizophrenia groups showed adaptation to the standard tone on repeated presentations. The UHR group had values between those for HCs and schizophrenia patients. Additionally, MMNm dipole moment was reduced in both the UHR and patient groups compared with HCs, whereas the UHR and schizophrenia groups did not differ from each other. These findings indicated that both N1m adaptation and MMNm were altered in UHR subjects and in schizophrenia patients, despite unaffected N1m dipole moment to the first standard tones. Moreover, both UHR and schizophrenia groups failed to show adaptation of the N1m to repeated standard tones. This failure in adaptation was more severe in patients than UHR subjects, suggesting that auditory adaptation may be sensitive to the progression of the illness and be an early biomarker of UHR for psychosis. Deficits in auditory sensory memory, on the other hand, may be similarly impaired in both groups.

Association study of 27 annotated genes for clozapine pharmacogenetics: validation of preexisting studies and identification of a new candidate gene, ABCB1, for treatment response.

Objective Pharmacogenetic studies on clozapine (CLZ) have provided meaningful insights but have shown redundancies owing to wide interindividual variability and insufficient replication. The present study was designed to validate hitherto suggested candidate genes on CLZ pharmacokinetics and pharmacodynamics and explore new markers through an integrative study. Methods Based on a literature review, a total of 127 variations in 27 candidate genes were selected and analyzed. Ninety-six schizophrenic patients of Korean ethnicity with constant CLZ dosing were recruited, and information on body weight and smoking habits was gathered, as well as plasma drug levels and treatment responses. Results Among the pharmacokinetic-related single nucleotide polymorphisms, rs2069521 and rs2069522 in CYP1A2 for CLZ/(dose/weight) and norclozapine/(dose/weight) and rs1135840 in CYP2D6 for norclozapine/CLZ showed borderline associations that were insignificant after correction for multiple testing. Regarding treatment response, significant associations were exhibited in rs7787082 and rs10248420 of ABCB1 (P = 0.0005 and P = 0.0013, respectively) even after correction, and the rs7787082 G and rs10248420 A alleles in ABCB1 were more frequently observed in nonresponders. We also observed a trend in the associations of rs13064530 in HRH1 and rs4938013 in DRD2/ANKK1 with treatment response. Conclusions We could not convincingly replicate most of the previous studies, a result that is possibly due to modest association between the suggested genes. Rather, we found a new candidate gene, ABCB1, for treatment response, which may provide a hypothesis on the relationship between the blood-brain distribution of CLZ and its clinical efficacy.

Regional Brain Atrophy and Functional Disconnection in Broca’s Area in Individuals at Ultra-High Risk for Psychosis and Schizophrenia

Background Abnormalities in cognitive abilities such as verbal fluency and in cognitive-related brain regions, particularly Broca’s area, have been reported in patients with schizophrenia. Additionally, previous studies have demonstrated that structural and functional abnormalities in Broca’s area were associated with clinical symptoms and cognitive deficits in patients with schizophrenia, suggesting that deficits in this area may reflect the core pathology of schizophrenia. Thus, it is important to understand how the structural volume and functional connectivity in this area changes at rest according to the course of the illness. Methods/Principal Findings We used magnetic resonance imaging (MRI) to measure the structural volume of Broca’s area as a region of interest in 16 schizophrenia, 16 ultra-high risk (UHR), and 23 healthy matched controls. We also assessed verbal fluency and analyzed differences across groups in the functional connectivity patterns using resting-state functional MRI. The UHR group showed significantly reduced structural volume in Broca’s area and significantly reduced functional connectivity between Broca’s area and the lateral and medial frontal cortex as well as decreased cognitive performance. Altered functional connectivity in patients was correlated with their positive symptoms. Conclusions/Significance Our results suggest the existence of functional disconnections in Broca’s area, even during resting-states, among those with schizophrenia as well as those at UHR for this disorder. These alterations may contribute to their clinical symptoms, suggesting that this is one of the key regions involved in the pathophysiology of schizophrenia.

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.

Power spectral aspects of the default mode network in schizophrenia: an MEG study

BackgroundSymptoms of schizophrenia are related to deficits in self-monitoring function, which may be a consequence of irregularity in aspects of the default mode network (DMN). Schizophrenia can also be characterized by a functional abnormality of the brain activity that is reflected in the resting state. Oscillatory analysis provides an important understanding of resting brain activity. However, conventional methods using electroencephalography are restricted because of low spatial resolution, despite their excellent temporal resolution.The aim of this study was to investigate resting brain oscillation and the default mode network based on a source space in various frequency bands such as theta, alpha, beta, and gamma using magnetoencephalography. In addition, we investigated whether these resting and DMN activities could distinguish schizophrenia patients from normal controls. To do this, the power spectral density of each frequency band at rest was imaged and compared on a spatially normalized brain template in 20 patients and 20 controls.ResultsThe spatial distribution of DMN activity in the alpha band was similar to that found in previous fMRI studies. The posterior cingulate cortex (PCC) and lateral inferior parietal cortex were activated at rest, while the medial prefrontal cortex (MPFC) was deactivated at rest rather than during the task. Although the MPFC and PCC regions exhibited contrasting activation patterns, these two regions were significantly coherent at rest. The DMN and resting activities of the PCC were increased in schizophrenia patients, predominantly in the theta and alpha bands.ConclusionsBy using MEG to identify the DMN regions, predominantly in the alpha band, we found that both resting and DMN activities were augmented in the posterior cingulate in schizophrenia patients. Furthermore, schizophrenia patients exhibited decreased coherence between the PCC and MPFC in the gamma band at rest.

Pharmacotherapy and clinical characteristics of ultra-high-risk for psychosis according to conversion status: a naturalistic observational study

Aim: To explore the differences in pharmacotherapy and clinical characteristics of individuals at ultra‐high‐risk (UHR) for psychosis according to the conversion status, we analyzed the data for UHR patients seen at the Seoul Youth Clinic.

Impaired mismatch negativity is associated with current functional status rather than genetic vulnerability to schizophrenia

The aim of this study is to investigate whether mismatch negativity (MMN) is associated with functional status or is a state-independent trait for schizophrenia. We assessed MMN in 26 patients with schizophrenia, 20 healthy subjects with high genetic loading, and 48 healthy controls. Repeated measures analysis of variance and Pearson׳s correlations were used to test the hypothesis that MMN is not state-independent. We found a significant main effect of group, indicating differences in the peak amplitudes of the MMN among the three groups. Post-hoc analyses revealed that schizophrenia patients showed a significant reduction in the peak amplitude of MMN, but subjects at high genetic risk and healthy controls did not. Additionally, significant correlations between Global Assessment of Functioning scores and MMN peak amplitude at Fz and Cz were found in patients with schizophrenia. These findings suggest that MMN may reflect current functional status rather than a genetic risk for schizophrenia.