The Relationship Between Frontostriatal Connectivity and Striatal Dopamine Function in Schizophrenia: An 18F-DOPA PET and Diffusion Tensor Imaging Study in Treatment Responsive and Resistant Patients

Objective@#Striatal dopamine dysfunction caused by cortical abnormalities is a leading hypothesis of schizophrenia. Although prefrontal cortical pathology is negatively correlated with striatal dopamine synthesis, the relationship between structural frontostriatal connectivity and striatal dopamine synthesis has not been proved in patients with schizophrenia with different treatment response. We therefore investigated the relationship between frontostriatal connectivity and striatal dopamine synthesis in treatment-responsive schizophrenia (non-TRS) and compared them to treatment-resistant schizophrenia (TRS) and healthy controls (HC). @*Methods@#Twenty-four patients with schizophrenia and twelve HC underwent [18F] DOPA PET scans to measure dopamine synthesis capacity (the influx rate constant Kicer) and diffusion 3T MRI to measure structural connectivity (fractional anisotropy, FA). Connectivity was assessed in 2 major frontostriatal tracts. Associations between Kicer and FA in each group were evaluated using Spearman’s rho correlation coefficients. @*Results@#Non-TRS showed a negative correlation (r=-0.629, p=0.028) between connectivity of dorsolateral prefrontal cortex-associative striatum (DLPFC-AST) and dopamine synthesis capacity of associative striatum but this was not evident in TRS (r=-0.07, p=0.829) and HC (r=-0.277, p=0.384). @*Conclusion@#Our findings are consistent with the hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology localized to connectivity of DLPFC-AST in non-TRS, and also extend the hypothesis to suggest that different mechanisms underlie the pathophysiology of non-TRS and TRS.

Effects of Intranasal Oxytocin on Emotion Recognition in Korean Male: A Dose-Response Study

OBJECTIVE: Research has shown that intranasal oxytocin affects social cognition and behavior; however, its effects vary based on social context, individual characteristics and dose. The present study aimed to determine effective dose of oxytocin spray on emotion recognition in healthy Korean males. METHODS: The study followed a randomized, double-blind, placebo-controlled design. Thirty-seven Korean males underwent two experimental sessions, with one week in between. They received either 32 (n=19) or 40 (n=18) international units (IU) of oxytocin and placebo, and then completed a face emotion recognition task. The effect of oxytocin on emotion recognition was examined using repeated measures analysis of variance (ANOVA) for each dose condition. RESULTS: The higher dose (40 IU) was found to improve recognition of happy faces, while the lower dose (32 IU) had no effect. There were no statistical differences in age, education, attachment style or empathic ability between the two dose groups. CONCLUSION: The results suggest that oxytocin increases the ability of Korean males to recognize positive emotion, and this effect is dose-dependent. Additional studies evaluating the effect of higher doses of oxytocin on social cognition will help to determine the optimal dose for Korean populations.

Executive Dysfunction in Obsessive-Compulsive Disorder and Anterior Cingulate-Based Resting State Functional Connectivity

OBJECTIVE: Executive dysfunction might be an important determinant for response to pharmacotherapy in obsessive-compulsive disorder (OCD), and could be sustained independently of symptom relief. The anterior cingulate cortex (ACC) has been indicated as a potential neural correlate of executive functioning in OCD. The present study examined the brain-executive function relationships in OCD from the ACC-based resting state functional connectivity networks (rs-FCNs), which reflect information processing mechanisms during task performance. METHODS: For a total of 58 subjects [OCD, n=24; healthy controls (HCs), n=34], four subdomains of executive functioning were measured using the Rey-Osterrieth Complex Figure Test (RCFT), the Stroop Color-Word Test (SCWT), the Wisconsin Card Sorting Test (WCST), and the Trail Making Test part B (TMT-B). To probe for differential patterns of the brain-cognition relationship in OCD compared to HC, the ACC-centered rs-FCN were calculated using five seed regions systemically placed throughout the ACC. RESULTS: Significant differences between the OCD group and the HCs with respect to the WCST perseverative errors, SCWT interference scores, and TMT-B reaction times (p<0.05) were observed. Moreover, significant interactions between diagnosis×dorsal ACC [S3]-based rs-FCN strength in the right dorsolateral prefrontal cortex for RCFT organization summary scores as well as between diagnosis×perigenual ACC [S7]-based rs-FCN strength in the left frontal eye field for SCWT color-word interference scores were unveiled. CONCLUSION: These network-based neural foundations for executive dysfunction in OCD could become a potential target of future treatment, which could improve global domains of functioning broader than symptomatic relief.

The Psychological Characteristics and Functional Magnetic Resonance Imaging Findings in Firefighters with Partial Posttraumatic Stress Disorder and the Effect of Treatment by Using Eye Movement Desensitization and Reprocessing / 신경정신의학

OBJECTIVES: This study investigated the clinical characteristics and functional magnetic resonance imaging (fMRI) findings of firefighters suffering from partial posttraumatic stress disorder (partial PTSD). They were treated by eye movement desensitization and reprocessing (EMDR) and the treatment effect was evaluated. METHODS: A total of 116 firefighters were screened and 15 of them were diagnosed as partial PTSD. 1) We compared sociodemographic and psychological characteristics between the firefighter partial PTSD group and the firefighter control group. 2) Subjects in the firefighter partial PTSD group (n=10), firefighter control group (n=8), and general control group (n=12) underwent fMRI with traumatic, negative, positive, and neutral picture stimuli. We compared clinical characteristics and fMRI findings among these three groups. 3) Seven firefighters in the partial PTSD group were treated by EMDR and the treatment effect was evaluated according to psychological scales. RESULTS: In fMRI analysis, there was a left middle temporal/occipital activation in the order of the general control group, firefighter control group, than the firefighter partial PTSD group for the Traumatic-Baseline contrast. For the Negative-Baseline contrast, there was an increased left middle temporal/occipital activation in the general control group versus decreased activation in the firefighter control group and the firefighter partial PTSD group. All firefighters in the partial PTSD group treated by EMDR showed significant improvement of Clinician-Administered PTSD Scale scores. CONCLUSION: These results show high incidence rate of partial PTSD in firefighters. In addition, partial PTSD firefighters exhibited distinct clinical characteristics and fMRI findings and showed significant improvement by EMDR treatment.

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 subject's 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.

Changes in Effective Connectivity According to Working Memory Load: An fMRI Study of Face and Location Working Memory Tasks

OBJECTIVE: The functional strategic mechanisms in the brain during performing visuospatial working memory tasks, especially tasks with heavy load, are controversial. We conducted the functional magnetic resonance imaging (fMRI) while sixteen subjects were performing face- and location-matching n-back tasks to examine causal relations within the frontoparietal networks. METHODS: We applied a sophisticated method, the structural equation modeling (SEM), to the fMRI data. The imaging data were analyzed by extracting the task-related eigenseries using the principal component analysis (PCA) and then by applying a form of data-driven model called the automated search method. RESULTS: The SEM analyses revealed a functional shift of network connectivity from the right to the left hemisphere with increasing load in the face-matching n-back tasks while the location-matching tasks required bilateral activation. In the locating matching n-back tasks, a pattern of parallel processing was observed in the left phonological loop and the right inferior parietal regions. Furthermore, object working memory-related activities in the left hemisphere reliably contributed to performance of both the face- and location-matching 2-back tasks. CONCLUSION: Our results are consistent with previous reports in terms of demonstrating parallel and distributed information processing during performing working memory tasks with heavy loads. Our results additionally suggest a dynamic shift between the fast imagery circuit (right hemisphere) and the stable verbal circuit (left hemisphere), depending on task load.

Altered Brain Activation in Ventral Frontal-Striatal Regions Following a 16-week Pharmacotherapy in Unmedicated Obsessive-Compulsive Disorder

Recent studies have reported that cognitive inflexibility associated with impairments in a frontal-striatal circuit and parietal region is a core cognitive deficit of obsessive-compulsive disorder (OCD). However, few studies have examined progressive changes in these regions following clinical improvement in obsessive-compulsive symptoms. To determine if treatment changes the aberrant activation pattern associated with task switching in OCD, we examined the activation patterns in brain areas after treatment. The study was conducted on 10 unmedicated OCD patients and 20 matched controls using event-related functional magnetic resonance imaging. Treatment improved the clinical symptoms measured by the Yale-Brown Obsessive Compulsive Scale and behavioral flexibility indicated by the switching cost. At baseline, OCD showed significantly less activation in the dorsal and ventral frontal-striatal circuit and parietal regions under the task-switch minus task-repeat condition compared with controls. After treatment, the neural responses in the ventral frontal-striatal circuit in OCD were partially normalized, whereas the activation deficit in dorsal frontoparietal regions that mediate shifting attention or behavioral flexibility persisted. It is suggested that altered brain activation in ventral frontal-striatal regions in OCD patients is associated with their cognitive flexibility and changes in these regions may underlie the pathophysiology of OCD.

Structural Brain Alterations in Individuals at Ultra-high Risk for Psychosis: A Review of Magnetic Resonance Imaging Studies and Future Directions

Individuals at ultra-high-risk (UHR) for psychosis have become a major focus for research designed to explore markers for early detection of and clinical intervention in schizophrenia. In particular, structural magnetic resonance imaging studies in UHR individuals have provided important insight into the neurobiological basis of psychosis and have shown the brain changes associated with clinical risk factors. In this review, we describe the structural brain abnormalities in magnetic resonance images in UHR individuals. The current accumulated data demonstrate that abnormalities in the prefrontal and temporal cortex and anterior cingulate cortex occur before illness onset. These regions are compatible with the regions of structural deficits found in schizophrenia and first-episode patients. In addition, the burgeoning evidence suggests that such structural abnormalities are potential markers for the transition to psychosis. However, most findings to date are limited because they are from cross-sectional rather than longitudinal studies. Recently, researchers have emphasized neurodevelopmental considerations with respect to brain structural alterations in UHR individuals. Future studies should be conducted to characterize the differences in the brain developmental trajectory between UHR individuals and healthy controls using a longitudinal design. These new studies should contribute to early detection and management as well as provide more predictive markers of later psychosis.

Thalamic Volume in Schizophrenia Patients, Subjects at Ultra-High Risk for Psychosis and Controls / 신경정신의학

OBJECTIVES: To investigate the changes in thalamic volumes in subjects at ultra-high risk (UHR) for psychosis. Subjects manifest changes which are similar to but different from those found in subjects with schizophrenia, and thalamic structural changes were often reported in schizophrenic subjects. METHODS: Thalamic volumes of 29 UHR subjects, 31 subjects with schizophrenia and 29 healthy controls, were measured from their T1-weighted coronal magnetic resonance (MR) images using manual tracing. RESULTS: UHR subjects showed greater right (6.243+/-0.848 cm3) and total (12.254+/-1.532 cm3) thalamic volumes compared to healthy control subjects (right thalamic volume=5.527+/-0.715 cm3, total thalamic volume=11.058+/-1.490 cm3) or patients with schizophrenia (right thalamic volume=5.855+/-0.938 cm3, total thalamic volume=11.513+/-1.784 cm3). The difference was significant for right (F=5.837, p=0.004) and total (F=4.217, p=0.018) thalamic volumes after intracranial volume had been accounted for as a covariate in ANCOVA. However, thalamic volume of subjects with schizophrenia showed no significant difference from controls. This difference was not affected by the presence of major depressive disorder or the magnitude of psychotic symptoms. Those among the UHR subjects taking antipsychotic agents did not show enlarged thalamic volume compared to controls. CONCLUSION: Our findings suggest that the possibility of a volumetric alteration of the thalamus characteristic of the UHR state.

Depressive Symptoms and Brain Metabolite Alterations in Subjects at Ultra-high Risk for Psychosis: A Preliminary Study

OBJECTIVE: Recent neuroimaging studies have suggested that brain changes occur in subjects at ultra-high risk (UHR) for psychosis while experiencing prodromal symptoms, among which depression may increase the risk of developing a psychotic disorder. The goal of this study is to examine brain metabolite levels in the anterior cingulate cortex, the left dorsolateral prefrontal cortex and the left thalamus in subjects at UHR for psychosis and to compare brain metabolite levels between the UHR subjects with comorbid major depressive disorder and healthy controls. METHODS: Proton magnetic resonance spectroscopy was used to examine brain metabolite levels. Twenty UHR subjects and 20 age- and intelligence quotient (IQ)-matched healthy controls were included in this study. RESULTS: Overall, no significant differences were observed in any metabolite between the UHR and healthy control group. However, UHR subjects with major depressive disorder showed significantly higher myo-inositol (Ins) levels in the left thalamus, compared to the healthy control. CONCLUSION: Our results demonstrate that increased thalamic Ins level is associated with prodromal depressive symptoms. Further longitudinal follow-up studies with larger UHR sample sizes are required to investigate the function of Ins concentrations as a biomarker of vulnerability to psychosis.

Depressive Symptoms and Brain Metabolite Alterations in Subjects at Ultra-high Risk for Psychosis: A Preliminary Study

OBJECTIVE: Recent neuroimaging studies have suggested that brain changes occur in subjects at ultra-high risk (UHR) for psychosis while experiencing prodromal symptoms, among which depression may increase the risk of developing a psychotic disorder. The goal of this study is to examine brain metabolite levels in the anterior cingulate cortex, the left dorsolateral prefrontal cortex and the left thalamus in subjects at UHR for psychosis and to compare brain metabolite levels between the UHR subjects with comorbid major depressive disorder and healthy controls. METHODS: Proton magnetic resonance spectroscopy was used to examine brain metabolite levels. Twenty UHR subjects and 20 age- and intelligence quotient (IQ)-matched healthy controls were included in this study. RESULTS: Overall, no significant differences were observed in any metabolite between the UHR and healthy control group. However, UHR subjects with major depressive disorder showed significantly higher myo-inositol (Ins) levels in the left thalamus, compared to the healthy control. CONCLUSION: Our results demonstrate that increased thalamic Ins level is associated with prodromal depressive symptoms. Further longitudinal follow-up studies with larger UHR sample sizes are required to investigate the function of Ins concentrations as a biomarker of vulnerability to psychosis.

Gray Matter Changes in Patients with Pathological Gambling: A Preliminary Study Using Voxel-Based Morphometry Study

OBJECTIVES: The purpose of this study was to examine structural abnormalities of brain in patients with pathological gambling(PG) using voxel-based morphometry. METHODS: We compared gray matter(GM) volumes between 10 patients with PG and 14 age- and IQmatched healthy controls and examined the relationship of GM volumes with clinical variables in patients with PG. RESULTS: We found significant increase of GM volume in the superior, middle, and inferior frontal gyri, the midbrain, the middle temporal gyrus, the precuneus, and the fusiform gyrus of patients with PG. A significant decrease of GM volume was observed in the parahippocampal gyrus and the lingual gyrus of the patient group. In addition, GM volumes in some of these regions were positively associated with South Oaks Gambling Screen score and negatively with age of onset in patients with PG. CONCLUSION: Current findings indicate that structural abnormalities in the fronto-temporal cortex, the midbrain, and the precuneus might be involved in the pathophysiology of PG, and contribute to some of the behavioral changes observed in patients with PG.