Ming H. Hsieh

Frequency-specific alternations in the amplitude of low-frequency fluctuations in schizophrenia

Schizophrenia has been associated with abnormal task‐related brain activation in sensory and motor regions as well as social cognition network. Recently, two studies investigated temporal correlation between resting‐state functional magnetic resonance imaging (R‐fMRI) low‐frequency oscillations (LFOs) in schizophrenia but reported mixed results. This may be due to the different frequency bands used in these studies. Here we utilized R‐fMRI to measure the amplitude of low‐frequency fluctuations (ALFF) and fractional ALFF (fALFF) in 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. We showed that there were significant differences in ALFF/fALFF between the two bands (slow‐5 and slow‐4) in regions including basal ganglia, midbrain, and ventromedial prefrontal cortex. Importantly, we also identified significant interaction between frequency bands and groups in inferior occipital gyrus, precunus, and thalamus. The results suggest that the abnormalities of LFOs in schizophrenia is dependent on the frequency band and suggest that future studies should take the different frequency bands into account when measure intrinsic brain activity. Hum Brain Mapp 35:627–637, 2014.

A single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1 : Association with impairment of sustained attention

BACKGROUND The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia. METHODS We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia. RESULTS Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test. CONCLUSIONS Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.

No association of G72 and d-amino acid oxidase genes with schizophrenia

The genes of D-amino acid oxidase (DAAO) activator (DAOA or G72; 13q34) and DAAO (12q24) have been suggested as candidate genes and involved in the N-methyl-D-aspartate receptor regulation pathway for schizophrenia. In order to evaluate the potential association of these two genes with schizophrenia in a Taiwanese sample, three single nucleotide polymorphisms (SNPs) for DAAO (rs2111902, rs3918346, rs3741775) and eleven SNPs for G72 (rs3916965, rs3916966, rs3916967, rs2391191, rs3916968, rs947267, rs778294, rs3916970, rs3916971, rs778293, rs3918342) were genotyped by the MALDI-TOF mass spectrometry method in 218 families (864 individuals) containing at least two siblings affected with schizophrenia. In SNP-based single locus association analyses, neither G72 nor DAAO showed significant association with schizophrenia. Additionally, a three-SNP haplotype in DAAO, and a four-SNP as well as a two-SNP haplotype in G72, showed no significant associations with schizophrenia. These results suggest that the DAAO and G72 genes are not susceptibility genes for schizophrenia in a Taiwanese sample.

Memory impairment and auditory evoked potential gating deficit in schizophrenia

Impaired sensory gating and memory function were reported in a study of 10 schizophrenic patients and 10 age- and sex-matched normal subjects. The P50 component of the auditory evoked potential was used as an index of gating. Explicit memory was tested with the Wechsler Memory Scale and implicit memory by artificial grammar learning. The schizophrenic patients showed deficits in both verbal paired associate and visual reproduction tasks. They demonstrated impaired implicit learning in color patterns but not letter strings. They also showed impaired P50 sensory gating. Three-dimensional brain mapping revealed a differential distribution of brain potentials in the processing of S1 and S2 at either P50 or N100 in both groups. However, the group difference was not statistically confirmed. In the controls, both implicit letter-string learning and explicit verbal paired associates were positively correlated with N100 gating, suggesting an association of the early attentive component with lexicons. In the schizophrenic patients, color-pattern implicit learning was positively correlated with P50 gating. The modality-specific impairment of implicit learning in schizophrenia may reflect a failure of adaptive filtering on the flooding input from color patterns.

RASD2, MYH9, and CACNG2 Genes at Chromosome 22q12 Associated with the Subgroup of Schizophrenia with Non-Deficit in Sustained Attention and Executive Function

BACKGROUND In a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p = .001). METHODS We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 Mb of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST). RESULTS Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p = .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p = .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p = .0163 with haplotype analysis). CONCLUSIONS The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.

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.

Auditory event-related potential of subjects with suspected pre-psychotic state and first‐episode psychosis

BACKGROUND Recent schizophrenia research exploring the complicated pathogenesis of schizophrenia has focused on the subjects with at-risk mental states in order to exclude the influence of confounding factors. This study explores 3 sets of auditory-related event potentials in subjects with different risk levels of psychosis. METHODS Subjects were recruited from the SOPRES study in Taiwan. P50 and N100 using an auditory paired-click paradigm and duration MMN were assessed on 32 first-episode psychosis (FEP), 30 ultra-high risk (UHR), 37 E-BARS (early/broad at-risk mental states) participants and 56 controls. RESULTS MMN was correlated with neither P50 nor N100, whereas many parameters of the latter two were intercorrelated with each other. Compared to healthy controls, MMNs were significantly lower in all 3 clinical groups (E-BARS, UHR and FEP). A gradient of sensory-gating deficits, manifested by increased P50 ratios (S2/S1) and decreased N100 differences, across different levels of clinical severity was suggested by a linear trend. For the UHR subjects, P50 gating ratio, N100 gating ratio, N100 difference, and N100S2 amplitude might be potential indicators to discriminate converters from non-converters. CONCLUSIONS By including subjects with E-BARS, our results provide new insight regarding pre-attentive auditory event-related potential in subjects across different risk levels of psychotic disorders. Impaired deviance detection shown by MMNs already exists in people at a pre-psychotic state regardless of clinical severity, while sensory-gating deficits shown by P50/N100 varies depending on the risk levels in prodromal period. Further longitudinal research exploring the relationship between ERPs and subjects with a suspected pre-psychotic state is needed.

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.

Differentiation of Schizophrenia Patients from Healthy Subjects by Mismatch Negativity and Neuropsychological Tests

Background Schizophrenia is a heterogeneous disorder with diverse presentations. The current and the proposed DSM-V diagnostic system remains phenomenologically based, despite the fact that several neurobiological and neuropsychological markers have been identified. A multivariate approach has better diagnostic utility than a single marker method. In this study, the mismatch negativity (MMN) deficit of schizophrenia was first replicated in a Han Chinese population, and then the MMN was combined with several neuropsychological measurements to differentiate schizophrenia patients from healthy subjects. Methodology/Principal Findings 120 schizophrenia patients and 76 healthy controls were recruited. Each subject received examinations for duration MMN, Continuous Performance Test, Wisconsin Card Sorting Test, and Wechsler Adult Intelligence Scale Third Edition (WAIS-III). The MMN was compared between cases and controls, and important covariates were investigated. Schizophrenia patients had significantly reduced MMN amplitudes, and MMN decreased with increasing age in both patient and control groups. None of the neuropsychological indices correlated with MMN. Predictive multivariate logistic regression models using the MMN and neuropsychological measurements as predictors were developed. Four predictors, including MMN at electrode FCz and three scores from the WAIS-III (Arithmetic, Block Design, and Performance IQ) were retained in the final predictive model. The model performed well in differentiating patients from healthy subjects (percentage of concordant pairs: 90.5%). Conclusions/Significance MMN deficits were found in Han Chinese schizophrenia patients. The multivariate approach combining biomarkers from different modalities such as electrophysiology and neuropsychology had a better diagnostic utility.

Facial and Prosodic Emotion Recognition Deficits Associate with Specific Clusters of Psychotic Symptoms in Schizophrenia

Background Patients with schizophrenia perform significantly worse on emotion recognition tasks than healthy participants across several sensory modalities. Emotion recognition abilities are correlated with the severity of clinical symptoms, particularly negative symptoms. However, the relationships between specific deficits of emotion recognition across sensory modalities and the presentation of psychotic symptoms remain unclear. The current study aims to explore how emotion recognition ability across modalities and neurocognitive function correlate with clusters of psychotic symptoms in patients with schizophrenia. Methods 111 participants who met the DSM-IV diagnostic criteria for schizophrenia and 70 healthy participants performed on a dual-modality emotion recognition task, the Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW), and selected subscales of WAIS-III. Of all, 92 patients received neurocognitive evaluations, including CPT and WCST. These patients also received the PANSS for clinical evaluation of symptomatology. Results The emotion recognition ability of patients with schizophrenia was significantly worse than healthy participants in both facial and vocal modalities, particularly fearful emotion. An inverse correlation was noted between PANSS total score and recognition accuracy for happy emotion. The difficulty of happy emotion recognition and earlier age of onset, together with the perseveration error in WCST predicted total PANSS score. Furthermore, accuracy of happy emotion and the age of onset were the only two significant predictors of delusion/hallucination. All the associations with happy emotion recognition primarily concerned happy prosody. Discussion Deficits in emotional processing in specific categories, i.e. in happy emotion, together with deficit in executive function, may reflect dysfunction of brain systems underlying severity of psychotic symptoms, in particular the positive dimension.