Junmei Hu

Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change

Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.

Neurocognitive deficits in first-episode schizophrenic patients and their first-degree relatives

Some neuropsychological abilities, particularly those affecting memory, attention and executive function, are impaired amongst both schizophrenic patients and their unaffected relatives, implying that these deficits are at least partly genetic in origin. However neuropsychological performance can be altered by medication, and has rarely been examined in first onset, drug naive patients. The objective of this study was to determine whether selected neurocognitive abilities are impaired in first‐onset schizophrenic patients and their relatives compared to controls. We examined attention and speed of information processing, memory and learning, verbal function, visuoconstructive abilities and executive function in 207 first‐episode schizophrenic patients (163 of whom were drug naïve), 322 of their first‐degree relatives and 133 unrelated normal controls. The data were subjected to multilevel modeling to compare neurocognitive performance between schizophrenic probands, relatives and controls while taking into account potential correlations among members of the same family; age, gender, and years of education were included as covariates. Of the three groups, schizophrenic patients performed poorest at all neuropsychological tests, suggestive of a broad range of neurocognitive deficits. Their first‐degree relatives showed a narrower pattern of poor performance at Digit Symbol, Digit Span, Trail Making, Verbal Fluency test, Tower of Hanoi, and WCST‐M tests. Our findings show that selected neurocognitive deficits especially attention and executive function are impaired in the families of schizophrenic patients. These patterns of neurocognitive deficits may represent “endophenotypes” denoting varying degrees of vulnerability to schizophrenia and may be of value in future molecular genetic studies.

Altered Cortical Thickness Related to Clinical Severity But Not the Untreated Disease Duration in Schizophrenia

Although previous studies have reported deficits in the gray matter volume of schizophrenic patients, it remains unclear whether these deficits occur at the onset of the disease, before treatment, and whether they are progressive over the duration of untreated disease. Furthermore, the gray matter volume represents the combinations of cortical thickness and surface area; these features are believed to be influenced by different genetic factors. However, cortical thickness and surface area in antipsychotic-naive first-episode schizophrenic patients have seldom been investigated. Here, the cortical thicknesses and surface areas of 128 antipsychotic-naive first-episode schizophrenic patients were compared with 128 healthy controls. The patients exhibited significantly lower cortical thickness, primarily in the bilateral prefrontal and parietal cortex, and increased thickness in the bilateral anterior temporal lobes, left medial orbitofrontal cortex, and left cuneus. Furthermore, decreased cortical thickness was related to positive schizophrenia symptoms but not to the severity of negative symptoms and the untreated disease duration. No significant difference of surface area was observed between the 2 groups. Thus, without the confounding factors of medication and illness progression, this study provides further evidence to support anatomical deficits in the prefrontal and parietal cortex early in course of the illness. The increased thicknesses of the bilateral anterior temporal lobes may represent a compensatory factor or may be an early-course neuronal pathology caused by preapoptotic osmotic changes or hypertrophy. Furthermore, these anatomical deficits are crucial to the pathogenesis of positive symptoms and relatively stable instead of progressing during the early stages of the disease.

Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis.

IMPORTANCEnAccumulating evidence supports the hypothesis that cerebral white matter abnormalities are involved in the pathophysiology of schizophrenia; however, findings from in vivo neuroimaging studies have been inconsistent. Besides confounding factors, including age, illness duration, and medication effects, an additional cause for the inconsistent results may be heterogeneity in the nature of white matter alterations associated with the disorder.nnnOBJECTIVEnTo investigate whether different patterns of white matter abnormalities exist in a large cohort of medication-naive patients with first-episode schizophrenia and the relationship between such patterns and clinical parameters.nnnDESIGN, SETTING, AND PARTICIPANTSnA cross-sectional diffusion tensor imaging study of 113 medication-naive patients with first-episode schizophrenia and 110 demographically matched healthy control individuals. The study was conducted in the mental health center of West China Hospital, Sichuan University, Chengdu, China, from January 2006 to June 2014.nnnMAIN OUTCOMES AND MEASURESnThe patterns of white matter abnormalities revealed by tract-specific analysis in conjunction with hierarchical clustering.nnnRESULTSnWith diffusion features extracted from 18 fiber tracts, cluster analysis revealed 2 patterns of abnormalities. One pattern (42.5% of patient sample) showed widespread white matter abnormalities compared with matched healthy control individuals, while another pattern (57.5% of patient sample) only showed circumscribed regional white matter abnormalities, mainly in the left superior longitudinal fasciculus. Patients in these subgroups did not differ in demographic features; however, negative symptoms were more severe in patients with widespread white matter abnormalities.nnnCONCLUSIONS AND RELEVANCEnTwo distinct patterns of white matter abnormalities exist at the early phase of schizophrenia, with those having global abnormalities experiencing more severe negative symptoms. The finding that distinct subgroups of patients with schizophrenia have different forms of white matter pathology may reflect qualitatively distinct genetic influences or neurodevelopmental alterations and thus represents a promising strategy for resolving neurobiological heterogeneity in the schizophrenia syndrome.

Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression

BACKGROUNDnStudies on treatment resistant depression (TRD) using advanced magnetic resonance imaging techniques are very limited.nnnMETHODSnA group of 15 patients with clinically defined TRD and 15 matched healthy controls underwent magnetization transfer imaging (MTI) and T1-weighted (T1W) imaging. MTI data were processed and analyzed voxel-wised in SPM2. A voxel based morphometric (VBM) analysis was performed using T1W images.nnnRESULTSnReduced magnetization transfer ratio was observed in the TRD group relative to normal controls in the anterior cingulate, insula, caudate tail and amygdala-parahippocampal areas. All these regions were identified within the right hemisphere. VBM revealed no morphological abnormalities in the TRD group compared to the control group. Negative correlations were found between MRI and clinical measures in the inferior temporal gyrus.nnnLIMITATIONSnThe cross-sectional design and small sample size.nnnCONCLUSIONSnThe findings suggest that MTI is capable of identifying subtle brain abnormalities which underlie TRD and in general more sensitive than morphological measures.

Longitudinal Changes in Resting-State Cerebral Activity in Patients with First-Episode Schizophrenia: A 1-Year Follow-up Functional MR Imaging Study

Purpose To determine whether the brain functional abnormalities of drug-naive first-episode schizophrenia are reduced after 1 year of undergoing antipsychotic treatment and whether pretreatment resting-state functional magnetic resonance (MR) imaging parameters are associated with longitudinal changes in clinical symptoms. Materials and Methods This prospective study was approved by the local ethical committee, and written informed consent was obtained from all participants. Twenty antipsychotic-naive first-episode patients with schizophrenia and 16 healthy individuals were recruited and underwent resting-state functional MR imaging at baseline and again at 1-year follow-up, by which time significant clinical improvement was seen. The amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) were analyzed with analysis of covariance. Results The amount of ALFF in the right inferior parietal lobule (IPL) and orbitofrontal cortex (OFC) and the amount of FC between the bilateral IPLs significantly increased over the follow-up period, and the amount of ALFF in the right occipital gyrus was reduced (P < .050, AlphaSim corrected [ http://afni.nimh.nih.gov/pub/dist/doc/manual/AlphaSim.pdf ]), returning toward normal levels. Furthermore, the degree of alteration in ALFF values in the right OFC (P = .037) and occipital gyrus (P = .002) at baseline was significantly correlated with the magnitude of the normalization in those regions at 1-year follow-up. In contrast, abnormalities of ALFF in the bilateral thalamus, ventral medial prefrontal cortex, precuneus, and right amygdala and of FC between the right OFC and the dorsal medial prefrontal cortex at baseline did not improve in patients at 1-year follow-up. Conclusion These findings show that some, but not all, neurophysiologic alterations that occur during the acute phase of schizophrenia are normalized in the context of clinical improvement and suggest therapeutic implications for exploration of which alterations in regional and network-level brain function evolve over time in patients with schizophrenia and which reflect persistent pathologic traits. Online supplemental material is available for this article.

Prediction of post-earthquake depressive and anxiety symptoms: a longitudinal resting-state fMRI study

Neurobiological markers of stress symptom progression for healthy survivors from a disaster (e.g., an earthquake) would greatly help with early intervention to prevent the development of stress-related disorders. However, the relationship between the neurobiological alterations and the symptom progression over time is unclear. Here, we examined 44 healthy survivors of the Wenchuan earthquake in China in a longitudinal resting-state fMRI study to observe the alterations of brain functions related to depressive or anxiety symptom progression. Using multi-variate pattern analysis to the fMRI data, we successfully predicted the depressive or anxiety symptom severity for these survivors in short- (25 days) and long-term (2 years) and the symptom severity changes over time. Several brain areas (e.g., the frontolimbic and striatal areas) and the functional connectivities located within the fronto-striato-thalamic and default-mode networks were found to be correlated with the symptom progression and might play important roles in the adaptation to trauma.

Forensic psychiatry assessments in Sichuan Province, People's Republic of China, 1997–2006

Forensic psychiatry is a growing sub-specialty in the Peoples Republic of China (PRC). This article describes 3016 persons assessed by a service in Sichuan Province, over 10 years (1997–2006). Most assessments were referred by the police for courts in criminal cases to determine fitness to stand trial and degree of criminal responsibility. Those not responsible were more likely to be older, farmers, with poor education, schizophrenia, facing charges of serious violence. The largest increase in referrals over the study period was for civil assessments. Forensic psychiatrists also provided assessments of competency of alleged female victims of sexual violence to consent to sexual intercourse. Forensic psychiatry in Sichuan showed many similarities to clinical practice in western countries.

The androgen receptor gene polyglycine repeat polymorphism is associated with memory performance in healthy Chinese individuals.

Cognitive functions such as memory are quantitative traits in human, and have both genetic and environmental influences. Testosterone has been implicated in the modulation of memory function. Therefore, genetic variation which influences testosterone signaling may modulate memory function. The principal receptor for testosterone is the androgen receptor, the gene for which maps to the X chromosome. In the present study, we hypothesized that common variation in two functional polymorphisms in the androgen receptor gene, the polyglutamine (CAG) and/or polyglycine (GGN) repeats, would influence memory function in healthy subjects. Variation in length of either repeat modulates the function of the AR gene, either by changing the amount of protein produced, by altering transactivation of the receptor or by producing toxic polyglycine or polyglutamine fragments. In order to test this hypothesis, we analyzed 449 healthy Chinese individuals. CAG repeats were not associated with memory performance. However we observed a significant association between GGN repeats and Immediate Logical Memory (chi(2)=23.6, d.f.=7, p=0.001) and Delayed Logical Memory (chi(2)=16.3, d.f.=7, p=0.022). The association of GGN repeats with Immediate Logical Memory remained significant after 6000 permutation corrections (p=0.013). There was also a sex difference, as association between GGN repeats and memory was observed only in females (p=0.002 for Immediate and p=0.014 for Delayed Logical Memory), but not in males (p=0.31 and 0.83, respectively). We conclude that functional variation of the androgen receptor gene is able to modulate memory function in women.

Urban Birth, Urban Living, and Work Migrancy: Differential Effects on Psychotic Experiences Among Young Chinese Men

Abstract Background Urban birth and urban living are associated with increased risk of schizophrenia but less is known about effects on more common psychotic experiences (PEs). China has undergone the most rapid urbanization of any country which may have affected the population-level expression of psychosis. We therefore investigated effects of urbanicity, work migrancy, and residential stability on prevalence and severity of PEs. Methods Population-based, 2-wave household survey of psychiatric morbidity and health-related behavior among 4132 men, 18–34 years of age living in urban and rural Greater Chengdu, Sichuan Province, China. PEs were measured using the Psychosis Screening Questionnaire. Results 1261 (31%) of young men experienced at least 1 PE. Lower levels of PEs were not associated with urbanicity, work migrancy or residential stability. Urban birth was associated with reporting 3 or more PEs (OR: 1.63; 95% CI: 1.25–2.11), after multivariable adjustment, with further evidence (P = .01) this effect was restricted to those currently living in urban environments (OR: 1.78; 95% CI: 1.16–2.72). Men experiencing a maximum of 5 PEs were over 8 times more likely to have been born in an urban area (adjusted odds ratio [AOR] 8.81; 95% CI 1.50–51.79). Conclusions Men in Chengdu, China, experience a high prevalence of PEs. This may be explained by rapid urbanization and residential instability. Urban birth was specifically associated with high, but not lower, severity levels of PEs, particularly amongst those currently living in urban environments. This suggests that early and sustained environmental exposures may be associated with more severe phenotypes.