Oguz Kelemen

Different trait markers for schizophrenia and bipolar disorder: A neurocognitive approach

BACKGROUND The aim of this study was to assess visual information processing and cognitive functions in unaffected siblings of patients with schizophrenia, bipolar disorder and control subjects with a negative family history. METHODS The siblings of patients with schizophrenia (N = 25), bipolar disorder (N = 20) and the controls subjects (N = 20) were matched for age, education, IQ, and psychosocial functioning, as indexed by the Global Assessment of Functioning scale. Visual information processing was measured using two visual backward masking (VBM) tests (target location and target identification). The evaluation of higher cognitive functions included spatial and verbal working memory, Wisconsin Card Sorting Test, letter fluency, short/long delay verbal recall and recognition. RESULTS The relatives of schizophrenia patients were impaired in the VBM procedure, more pronouncedly at short interstimulus intervals (14, 28, 42 ms) and in the target location task. Marked dysfunctions were also found in the spatial working memory task and in the long delay verbal recall test. In contrast, the siblings of patients with bipolar disorder exhibited spared performances with the exception of a deficit in the long delay recall task. CONCLUSIONS Dysfunctions of sensory-perceptual analysis (VBM) and working memory for spatial information distinguished the siblings of schizophrenia patients from the siblings of individuals with bipolar disorder. Verbal recall deficit was present in both groups, suggesting a common impairment of the fronto-hippocampal system.

Sharing secrets: Oxytocin and trust in schizophrenia

Abstract Previous studies indicated that oxytocin plays an important role in human trust, which is impaired in patients with severe mental disorders. In this study, we measured plasma oxytocin levels in patients with schizophrenia (n=50) and in healthy controls (n=50) after neutral and trust-related interpersonal interactions. Trust-related interactions were associated with increased oxytocin levels in controls. This effect was absent in patients with schizophrenia. Low oxytocin levels measured after trust-related interactions significantly predicted the negative symptoms of schizophrenia but were not related to positive symptoms, depression, anxiety, and neuropsychological functions. These results suggest that decreased trust-related oxytocin release is related to the negative symptoms and may be associated with social withdrawal, isolation, and flattened affect in schizophrenia.

Vernier threshold in patients with schizophrenia and in their unaffected siblings.

The aim of this study was to investigate magnocellular (M) and parvocellular (P) visual functions in nonmedicated patients with schizophrenia and in their unaffected siblings. Possible abnormalities in cortical integration of retinal receptive fields also were addressed. Twenty-two nonmedicated patients with schizophrenia, their unaffected siblings, and 20 age- and IQ-matched healthy control subjects received 4 vernier acuity tasks (blue-on-yellow, frequency-doubling, achromatic low and high contrast conditions) in which they were asked to detect the spatial alignment of dots and gratings. Results revealed that the patients with schizophrenia and their unaffected siblings showed selective dysfunctions in the frequency-doubling and achromatic low contrast conditions, which were devoted to investigate M pathways. In the isoluminant blue-on-yellow and high contrast achromatic conditions, there were no significant differences between the experimental groups. These results suggest that the deficit of M pathway is an endophenotype of schizophrenia.

Association among clinical response, hippocampal volume, and FKBP5 gene expression in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy.

BACKGROUND Posttraumatic stress disorder (PTSD) is characterized by a reduced expression of FKBP5, a key modulator of the glucocorticoid receptor. Smaller hippocampal volume has also been documented in PTSD. We explored possible changes in FKBP5 gene expression and brain structure in patients with PTSD after cognitive behavioral therapy (CBT). METHODS We measured peripheral FKBP5 RNA and volumes of the hippocampus, amygdala, and medial orbitofrontal cortex in 39 patients with PTSD before and after CBT. The control subjects were 31 trauma-exposed individuals without PTSD who were also assessed twice. Gene expression changes were screened with a microarray toolkit, which was followed by quantitative polymerase chain reaction for FKBP5 RNA. Brain volumes were measured using FreeSurfer. RESULTS At baseline, patients with PTSD showed lower FKBP5 gene expression and smaller hippocampal and medial orbitofrontal cortex, but not amygdala, volumes relative to control subjects. At follow-up, we found significantly increased FKBP5 expression and increased hippocampal volume in patients with PTSD. At follow-up, patients did not differ from control subjects in hippocampal volume. Improvement in PTSD symptoms was predicted by increased FKBP5 expression and increased hippocampal volume, but the primary predictor was FKBP5 expression. The most significantly altered gene expression in patients with PTSD relative to control subjects was found for ribosomal protein S6 kinase, which did not change after CBT and did not correlate with hippocampal volume. CONCLUSIONS Clinical improvement in individuals with PTSD was associated with increased expression of FKBP5 and increased hippocampal volume, which were positively correlated.

Theory of mind and motion perception in schizophrenia.

This study investigated the relationship between theory of mind (ToM) deficits and visual perception in patients with schizophrenia (N=52; 17 remitted and unmedicated) compared with healthy controls (N=30). ToM was assessed with the Eyes Test, which asked participants to choose which of 4 words best described the mental state of a person whose eyes were depicted in a photograph. Visual perception was evaluated with form and motion coherence threshold measurements. Results revealed that patients with schizophrenia (both remitted and nonremitted) showed deficits on the Eyes Test and the motion coherence task. ToM dysfunctions were associated with higher motion coherence thresholds and more severe negative symptoms. This suggests that ToM deficits are related to motion perception dysfunctions, which indicates a possible role of motion-sensitive areas in the pathophysiology of schizophrenia.

Anomalous visual experiences, negative symptoms, perceptual organization and the magnocellular pathway in schizophrenia: a shared construct?

BACKGROUND Schizophrenia is associated with impaired visual information processing. The aim of this study was to investigate the relationship between anomalous perceptual experiences, positive and negative symptoms, perceptual organization, rapid categorization of natural images and magnocellular (M) and parvocellular (P) visual pathway functioning. METHOD Thirty-five unmedicated patients with schizophrenia and 20 matched healthy control volunteers participated. Anomalous perceptual experiences were assessed with the Bonn Scale for the Assessment Basic Symptoms (BSABS). General intellectual functions were evaluated with the revised version of the Wechsler Adult Intelligence Scale. The 1-9 version of the Continuous Performance Test (CPT) was used to investigate sustained attention. The following psychophysical tests were used: detection of Gabor patches with collinear and orthogonal flankers (perceptual organization), categorization of briefly presented natural scenes (rapid visual processing), low-contrast and frequency-doubling vernier threshold (M pathway functioning), isoluminant colour vernier threshold and high spatial frequency discrimination (P pathway functioning). RESULTS The patients with schizophrenia were impaired on test of perceptual organization, rapid visual processing and M pathway functioning. There was a significant correlation between BSABS scores, negative symptoms, perceptual organization, rapid visual processing and M pathway functioning. Positive symptoms, IQ, CPT and P pathway measures did not correlate with these parameters. The best predictor of the BSABS score was the perceptual organization deficit. CONCLUSIONS These results raise the possibility that multiple facets of visual information processing deficits can be explained by M pathway dysfunctions in schizophrenia, resulting in impaired attentional modulation of perceptual organization and of natural image categorization.

Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia

The purpose of this study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated. Volunteers received the Rutgers acquired equivalence task (face-fish task) by [Myers, C.E., Shohamy, D., Gluck, M.A. et al., 2003. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J. Cogn. Neurosci. 15, 185-193.], the California Verbal Learning Test (CVLT), and the n-back working memory test. The Rutgers acquired equivalence task investigates BG-dependent processes (stimulus-response learning) and MTL-dependent processes (stimulus generalization) with a single test. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was spared. The stimulus generalization deficit correlated with the CVLT performance (total scores from trials 1-5 and long-delay recall), but not with the n-back test performance. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, this is the first study to show that patients with schizophrenia exhibit deficits during MTL-dependent learning, but not during BG-dependent learning within a single task. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-stiratal system.

Habit learning and the genetics of the dopamine D3 receptor : Evidence from patients with schizophrenia and healthy controls

In this study, the authors investigated the relationship between the Ser9Gly (SG) polymorphism of the dopamine D3 receptor (DRD3) and striatal habit learning in healthy controls and patients with schizophrenia. Participants were given the weather prediction task, during which probabilistic cue-response associations were learned for tarot cards and weather outcomes (rain or sunshine). In both healthy controls and patients with schizophrenia, participants with Ser9Ser (SS) genotype did not learn during the early phase of the task (1-50 trials), whereas participants with SG genotype did so. During the late phase of the task (51-100 trials), both participants with SS and SG genotype exhibited significant learning. Learning rate was normal in patients with schizophrenia. These results suggest that the DRD3 variant containing glycine is associated with more efficient striatal habit learning in healthy controls and patients with schizophrenia.

Lateral interactions in the visual cortex of patients with schizophrenia and bipolar disorder.

BACKGROUND Schizophrenia is associated with perceptual organization deficits and abnormal neuronal connectivity has been described in early visual areas. The purpose of this study was to investigate the functional integrity of lateral connections in early visual areas of patients with schizophrenia and type I bipolar disorder with a history of psychosis. METHOD Twenty-four out-patients with schizophrenia, 22 out-patients with bipolar disorder, and 20 healthy control subjects participated in the study. Using a computer-assisted psychophysical test, contrast thresholds were measured for centrally presented target stimuli (Gabor patches), which were surrounded by two collinear flankers. Target-to-flanker distances were 0, 1, 2, 3, 4, 6, 9 and 122. Psychophysical measures were contrast threshold changes at each target-to-flanker distance compared with baseline thresholds determined for isolated targets with no flankers. Clinical measures included IQ, positive, negative, and depressive symptoms. Results. In patients with schizophrenia, flankers did not facilitate contrast detection for target stimuli at 2-6 lambda distances compared to controls [effect size (Cohens d): 1.25-1.42]. The inhibitory effect of flankers (0 and 1lambda) and contrast thresholds in the absence of flankers were spared. Patients with bipolar disorder did not differ from the controls. Medicated and non-medicated patients displayed similar performances. Positive and negative symptoms and depression did not correlate with contrast threshold values. CONCLUSIONS Excitatory lateral connections in early visual cortex are specifically impaired in patients with schizophrenia, which may contribute to perceptual disorders such as unclear seeing, partial or skewed sight, disrupted rectilinearity, and abnormal figure-ground segregation.

Visual-perceptual dysfunctions are possible endophenotypes of schizophrenia: Evidence from the psychophysical investigation of magnocellular and parvocellular pathways

Visual information processing is impaired in schizophrenia patients and their biological relatives. The authors measured vernier thresholds in 72 schizophrenia patients, their 86 siblings, and 60 healthy control subjects. Subjects were asked to detect the direction of the horizontal displacement of 2 stimuli (left or right). During magnocellular (M) pathway tests, stimuli were dots with low contrast (5%) or counterphase-modulated gratings (25 Hz). For parvocellular (P) pathway tests, isoluminant blue-red dots with yellow-green background were used. Results revealed that patients with schizophrenia and their siblings were more impaired in M pathway conditions than in P pathway conditions. There was no color-specific impairment. The patients and their siblings displayed lower performances on tests of executive functions, psychomotor speed, and verbal memory compared with the controls. Visual-perceptual and neuropsychological data did not correlate. In conclusion, M pathway dysfunction is a potential endophenotype of schizophrenia.