Dual-modality impairment of implicit learning of letter-strings versus color-patterns in patients with schizophrenia

BACKGROUND: Implicit learning was reported to be intact in schizophrenia using artificial grammar learning. However, emerging evidence indicates that artificial grammar learning is not a unitary process. The authors used dual coding stimuli and schizophrenia clinical symptom dimensions to re-evaluate the effect of schizophrenia on various components of artificial grammar learning. METHODS: Letter string and color pattern artificial grammar learning performances were compared between 63 schizophrenic patients and 27 comparison subjects. Four symptom dimensions derived from a Chinese Positive and Negative Symptom Scale ratings were correlated with patients' artificial grammar implicit learning performances along the two stimulus dimensions. Patients' explicit memory performances were assessed by verbal paired associates and visual reproduction subtests of the Wechsler Memory Scales Revised Version to provide a contrast to their implicit memory function. RESULTS: Schizophrenia severely hindered color pattern artificial grammar learning while the disease affected lexical string artificial grammar learning to a lesser degree after correcting the influences from age, education and the performance of explicit memory function of both verbal and visual modalities. Both learning performances correlated significantly with the severity of patients' schizophrenic clinical symptom dimensions that reflect poor abstract thinking, disorganized thinking, and stereotyped thinking. CONCLUSION: The results of this study suggested that schizophrenia affects various mechanisms of artificial grammar learning differently. Implicit learning, knowledge acquisition in the absence of conscious awareness, is not entirely intact in patients with schizophrenia. Schizophrenia affects implicit learning through an impairment of the ability of making abstractions from rules and at least in part decreasing the capacity for perceptual learning

Aldehyde dehydrogenase deficiency, flush patterns and prevalence of alcoholism: an interethnic comparison.

A study was performed to verify that the prevalence of alcohol abuse and dependence in Formosan aborigines differs from that of Taiwanese (Chinese Han people), using analysis of aldehyde dehydrogenase (ALDH) isozymes and flush patterns on randomly sampled 70 Atayal, 66 Paiwan, 61 Yami and 94 Taiwanese subjects were studied. The activity of an isomer of ALDH having a low Km (ALDH-I) in hair roots was analysed by isoelectric focusing assay. The subjective experience of flushing response after alcohol ingestion was assessed. Results showed that the rate of ALDH-I deficiency in Taiwanese (51.1%) was significantly higher than in aborigines, i.e., 6.4%, 3.9%, and 0% in Atayal, Paiwan, and Yami subjects, respectively. The percentage occurrence of ALDH-I deficiency and prevalence of alcohol dependence in Taiwanese and aborigines were negatively correlated. The predominant pattern of self-reported flush response after alcohol use among aborigines was of slow onset. The flush response to alcohol ingestion was examined in relation to aldehyde metabolizing enzyme. Since alcohol sensitivity is an important factor in the development and maintenance of the alcohol ingestion habit in humans, our results support the hypothesis that there is a biological basis in the different rates of alcohol abuse and dependence among different ethnic groups.</p

Genetic copy number variants in sib pairs both affected with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is a complex disorder with involvement of multiple genes.</p> <p>Methods</p> <p>In this study, genome-wide screening for DNA copy-number variations (CNVs) was conducted for ten pairs, a total of 20 cases, of affected siblings using oligonucleotide array-based CGH.</p> <p>Results</p> <p>We found negative symptoms were significantly more severe (p < 0.05) in the subgroup that harbored more genetic imbalance (n ≧ 13, n = number of CNV-disrupted genes) as compared with the subgroup with fewer CNVs (n ≦ 6), indicating that the degree of genetic imbalance may influence the severity of the negative symptoms of schizophrenia. Four central nervous system (CNS) related genes including CCAAT/enhancer binding protein, delta (<it>CEBPD</it>, 8q11.21), retinoid × receptor, alpha (<it>RXRA</it>, 9q34.2), LIM homeobox protein 5 (<it>LHX5</it>, 12q24.13) and serine/threonine kinase 11 (<it>STK11</it>, 19p13.3) are recurrently (incidence ≧ 16.7%) disrupted by CNVs. Two genes, <it>PVR </it>(poliovirus receptor) and <it>BU678720</it>, are concordantly deleted in one and two, respectively, pairs of co-affected siblings. However, we did not find a significant association of this <it>BU678720 </it>deletion and schizophrenia in a large case-control sample.</p> <p>Conclusions</p> <p>We conclude that the high genetic loading of CNVs may be the underlying cause of negative symptoms of schizophrenia, and the CNS-related genes revealed by this study warrant further investigation.</p

Dosage and duration of antipsychotic treatment in demented outpatients with agitation or psychosis

Background/PurposeThe USA Food and Drug Administration (FDA) issued warnings regarding the use of antipsychotics in patients with dementia in 2003 and 2005. We aimed to study the dose and duration of antipsychotic treatment in dementia, and to examine whether physicians' prescription behaviors changed after the FDA warnings.MethodsMedical charts of outpatients who had Alzheimer's disease, vascular dementia, or mixed dementia were reviewed. Patients must have achieved a clinically stable state for at least 4 weeks after receiving antipsychotic treatment for agitation or psychosis. Demographics, clinical correlates, and duration of antipsychotic treatment were compared among different antipsychotic groups. Because the quetiapine group had the largest sample size, the optimal dose and duration of quetiapine treatment were compared among three time periods (before 2003, 2003–2005, after 2005).ResultsStable state was achieved in 215 patients (80 had Alzheimer's disease, 117 vascular dementia, and 18 mixed dementia). Most patients (177) took quetiapine, 25 took risperidone, and 13 took sulpiride. The whole sample had a long total duration of antipsychotic treatment (median 525 days, mean 707 days). The median dose and total duration of antipsychotic treatment were 1.0mg/day and 238 days for risperidone, 100mg/day and 390 days for sulpiride, and 25mg/day and 611 days for quetiapine, respectively. The optimal dose and total duration of quetiapine treatment decreased significantly after FDA warning in 2005, although the duration remained long.ConclusionThe optimal doses of antipsychotics were not higher than those of western reports, but the total duration of antipsychotic treatment was quite long. Although our study suggests the prescription dosage and duration of antipsychotic treatment decreased significantly after FDA warning in 2005, the duration of treatment was still long. Given the serious safety concerns, more effort should be made to avoid unnecessary and prolonged prescription

A protein interaction based model for schizophrenia study

<p>Abstract</p> <p>Background</p> <p>Schizophrenia is a complex disease with multiple factors contributing to its pathogenesis. In addition to environmental factors, genetic factors may also increase susceptibility. In other words, schizophrenia is a highly heritable disease. Some candidate genes have been deduced on the basis of their known function with others found on the basis of chromosomal location. Individuals with multiple candidate genes may have increased risk. However it is not clear what kind of gene combinations may produce the disease phenotype. Their collective effect remains to be studied.</p> <p>Results</p> <p>Most pathways except metabolic pathways are rich in protein-protein interactions (PPIs). Thus, the PPI network contains pathway information, even though the upstream-downstream relation of PPI is yet to be explored. Here we have constructed a PPI sub-network by extracting the nearest neighbour of the 36 reported candidate genes described in the literature. Although these candidate genes were discovered by different approaches, most of the proteins formed a cluster. Two major protein interaction modules were identified on the basis of the pairwise distance among the proteins in this sub-network. The large and small clusters might play roles in synaptic transmission and signal transduction, respectively, based on gene ontology annotation. The protein interactions in the synaptic transmission cluster were used to explain the interaction between the NRG1 and CACNG2 genes, which was found by both linkage and association studies. This working hypothesis is supported by the co-expression analysis based on public microarray gene expression.</p> <p>Conclusion</p> <p>On the basis of the protein interaction network, it appears that the NRG1-triggered NMDAR protein internalization and the CACNG2 mediated AMPA receptor recruiting may act together in the glutamatergic signalling process. Since both the NMDA and AMPA receptors are calcium channels, this process may regulate the influx of Ca²⁺. Reducing the cation influx might be one of the disease mechanisms for schizophrenia. This PPI network analysis approach combined with the support from co-expression analysis may provide an efficient way to propose pathogenetic mechanisms for various highly heritable diseases.</p

Auditory Event-Related Potentials in Antipsychotic-Free Subjects With Ultra-High-Risk State and First-Episode Psychosis

Background: Auditory event-related potentials (ERPs) have been utilized to study defective information processing of patients with schizophrenia. To delineate the pathophysiological processes from pre-psychotic state to first-episode psychosis, a study on subjects from ultra-high-risk (UHR) state to first-episode psychosis, ideally in an antipsychotic-free condition, can add important information to our understanding.Methods: Patients with UHR state or at their first-episode psychosis (FEP) who were drug-naive or only have been temporarily treated with antipsychotics were assessed by auditory ERPs measurement, including P50/N100 (sensory gating) and duration mismatch negativity (MMN; deviance detection). A group of age-matched healthy subjects served as their controls.Results: A total of 42 patients (23 UHR and 19 FEP) and 120 control subjects were recruited, including 21 pure drug-naive and 21 with very short exposure to antipsychotics. Collapsing FEP and UHR as a patient group, they exhibited significant sensory deficits manifested as larger P50 S2 amplitude, larger N100 ratio, and smaller N100 difference, and significantly less deviance detection response revealed by MMN. Such differences were less significant when treating FEP and UHR separately for comparisons. Comparisons of ERP results between drug-naive subjects and antipsychotic-short-exposure subjects revealed no significant difference in any P50/N100 and MMN parameter.Conclusion: Our study is one of the few studies focused on drug-naive or minimally treated patients at pre- or early-psychotic states. Our results exhibited impaired performance in sensory gating and deviance detection shown by certain parameters. A longitudinal study with larger sample sizes will be helpful to provide more evidence to elucidate the role of antipsychotics on an individual’s neurophysiological performance at different stages of psychosis

Frequency Dependent Alterations in Regional Homogeneity of Baseline Brain Activity in Schizophrenia

Low frequency oscillations are essential in cognitive function impairment in schizophrenia. While functional connectivity can reveal the synchronization between distant brain regions, the regional abnormalities in task-independent baseline brain activity are less clear, especially in specific frequency bands. Here, we used a regional homogeneity (ReHo) method combined with resting-state functional magnetic resonance imaging to investigate low frequency spontaneous neural activity in the three different frequency bands (slow-5:0.01–0.027 Hz; slow-4:0.027–0.08 Hz; and typical band: 0.01–0.08 Hz) in 69 patients with schizophrenia and 62 healthy controls. Compared with controls, schizophrenia patients exhibited decreased ReHo in the precentral gyrus, middle occipital gyrus, and posterior insula, whereas increased ReHo in the medial prefrontal cortex and anterior insula. Significant differences in ReHo between the two bands were found in fusiform gyrus and superior frontal gyrus (slow-4> slow-5), and in basal ganglia, parahippocampus, and dorsal middle prefrontal gyrus (slow-5> slow-4). Importantly, we identified significant interaction between frequency bands and groups in the inferior occipital gyrus and caudate body. This study demonstrates that ReHo changes in schizophrenia are widespread and frequency dependent

Impaired Flush Response to Niacin Skin Patch Among Schizophrenia Patients and Their Nonpsychotic Relatives: The Effect of Genetic Loading

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia

Genome-Wide Gene Expression Analysis Implicates the Immune Response and Lymphangiogenesis in the Pathogenesis of Fetal Chylothorax

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease