Raymond C.K. Chan

Short-term Effects of Antipsychotic Treatment on Cerebral Function in Drug-Naive First-Episode Schizophrenia Revealed by “Resting State” Functional Magnetic Resonance Imaging

CONTEXT Most of what we know about antipsychotic drug effects is at the receptor level, distal from the neural system effects that mediate their clinical efficacy. Studying cerebral function in antipsychotic-naive patients with schizophrenia before and after pharmacotherapy can enhance understanding of the therapeutic mechanisms of these clinically effective treatments. OBJECTIVE To examine alterations of regional and neural network function in antipsychotic-naive patients with first-episode schizophrenia before and after treatment with second-generation antipsychotic medication. DESIGN Case-control study. SETTING Huaxi MR Research Center and Mental Health Centre of the West China Hospital. PARTICIPANTS Thirty-four antipsychotic-naive patients with first-episode schizophrenia were scanned using gradient-echo echo-planar imaging while in a resting state. After 6 weeks of antipsychotic treatment, patients were rescanned. Thirty-four matched healthy control subjects were studied at baseline for comparison purposes. MAIN OUTCOME MEASURES The amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent signals, believed to reflect spontaneous neural activity, was used to characterize regional cerebral function. Functional connectivity across brain regions was evaluated using a seed voxel correlation approach and an independent component analysis. Changes in these measures after treatment were examined to characterize effects of antipsychotic drugs on regional function and functional integration. RESULTS After short-term treatment with second-generation antipsychotic medications, patients showed increased ALFF, particularly in the bilateral prefrontal and parietal cortex, left superior temporal cortex, and right caudate nucleus. Increased regional ALFF was associated with a reduction of clinical symptoms, and a widespread attenuation in functional connectivity was observed that was correlated with increased regional ALFF. CONCLUSIONS We demonstrate for the first time, to our knowledge, that widespread increased regional synchronous neural activity occurs after antipsychotic therapy, accompanied by decreased integration of function across widely distributed neural networks. These findings contribute to the understanding of the complex systems-level effects of antipsychotic drugs.

Brain Anatomical Abnormalities in High-Risk Individuals, First-Episode, and Chronic Schizophrenia: An Activation Likelihood Estimation Meta-analysis of Illness Progression

OBJECTIVE The present study reviewed voxel-based morphometry (VBM) studies on high-risk individuals with schizophrenia, patients experiencing their first-episode schizophrenia (FES), and those with chronic schizophrenia. We predicted that gray matter abnormalities would show progressive changes, with most extensive abnormalities in the chronic group relative to FES and least in the high-risk group. METHOD Forty-one VBM studies were reviewed. Eight high-risk studies, 14 FES studies, and 19 chronic studies were analyzed using anatomical likelihood estimation meta-analysis. RESULTS Less gray matter in the high-risk group relative to controls was observed in anterior cingulate regions, left amygdala, and right insula. Lower gray matter volumes in FES compared with controls were also found in the anterior cingulate and right insula but not the amygdala. Lower gray matter volumes in the chronic group were most extensive, incorporating similar regions to those found in FES and high-risk groups but extending to superior temporal gyri, thalamus, posterior cingulate, and parahippocampal gryus. Subtraction analysis revealed less frontotemporal, striatal, and cerebellar gray matter in FES than the high-risk group; the high-risk group had less gray matter in left subcallosal gyrus, left amygdala, and left inferior frontal gyrus compared with FES. Subtraction analysis confirmed lower gray matter volumes through ventral-dorsal anterior cingulate, right insula, left amygdala and thalamus in chronic schizophrenia relative to FES. CONCLUSIONS Frontotemporal brain structural abnormalities are evident in nonpsychotic individuals at high risk of developing schizophrenia. The present meta-analysis indicates that these gray matter abnormalities become more extensive through first-episode and chronic illness. Thus, schizophrenia appears to be a progressive cortico-striato-thalamic loop disorder.

Resting-State Functional Connectivity in treatment-Resistant Depression

OBJECTIVE The authors used resting-state functional connectivity MRI to evaluate brain networks in patients with refractory and nonrefractory major depressive disorder. METHOD In a cross-sectional study, 28 patients with refractory major depression, 32 patients with nonrefractory major depression, and 48 healthy comparison subjects underwent scanning using a gradient-echo echo-planar imaging sequence on a 3-T MR system. Thirteen regions of interest that have been identified in the literature as relevant to mood regulation were selected as seed areas. A reference time series was extracted for each seed and used for voxel-wise correlation analysis with the rest of the brain. Voxel-based comparisons of z-value maps among the three groups were performed using one-way analysis of variance followed by post hoc t tests with age and duration of illness as covariates of no interest. RESULTS Relative to healthy comparison subjects, both patient groups showed significantly reduced connectivity in prefrontal-limbic-thalamic areas bilaterally. However, the nonrefractory group showed a more distributed decrease in connectivity than the refractory group, especially in the anterior cingulate cortex and in the amygdala, hippocampus, and insula bilaterally; in contrast, the refractory group showed disrupted functional connectivity mainly in prefrontal areas and in thalamus areas bilaterally. CONCLUSIONS Refractory depression is associated with disrupted functional connectivity mainly in thalamo-cortical circuits, while nonrefractory depression is associated with more distributed decreased connectivity in the limbic-striatal-pallidal-thalamic circuit. These results suggest that nonrefractory and refractory depression are characterized by distinct functional deficits in distributed brain networks.

A meta-analysis of association studies between the 10-repeat allele of a VNTR polymorphism in the 3'-UTR of dopamine transporter gene and attention deficit hyperactivity disorder.

The association between the 10‐repeat allele of the dopamine transporter gene (DAT) and attention deficit hyperactivity disorder (ADHD) is uncertain. This study aimed to conduct a meta‐analysis of the association between the 10‐repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3′‐untranslated region (UTR) of the DAT1 gene and ADHD. We pooled up 18 published transmission disequilibrium test (TDT) studies between the 40‐base pair VNTR polymorphism in the3′‐UTR of the DAT1 gene and ADHD. It included a total of 1,373 informative meioses, 7 haplotype‐based haplotype relative risk (HHRR) studies, and 6 case‐control‐based association studies. There were statistically significant evidences for heterogeneity of the odds ratio in TDT and HHRR studies (P < 0.10), but not in case‐control studies. The results of random effects model showed small but significant association between ADHD and the DAT1 gene in TDT studies (OR = 1.17, 95% CI = 1.05–1.30, chi‐square = 8.11, df = 1, P = 0.004), but not in HHRR and case‐control studies. The 10‐repeat allele of a VNTR polymorphism in the 3′‐UTR the DAT1 gene has a small but significant role in the genetic susceptibility of ADHD. These meta‐analysis findings support the involvement of the dopamine system genes in ADHD liability variation. However, more work is required to further identify the functional allelic variants/mutations that are responsible for this association.

Voxelwise meta-analysis of gray matter reduction in major depressive disorder

BACKGROUND Voxel-based morphometry (VBM) has been widely used in studies of major depressive disorder (MDD) and has provided cumulative evidence of gray matter abnormalities in patients relative to controls. Thus we performed a meta-analysis to integrate the reported studies to determine the consistent gray matter alterations in MDD. METHODS A systematic search was conducted to identify VBM studies which contrasted MDD patients against a comparison group. The coordinates of gray matter change across studies were meta-analyzed using the activation likelihood estimation (ALE) method hybridized with the rank-based Genome Scan Meta-Analysis (GSMA) to quantitatively estimate regional gray matter reductions in MDD. RESULTS A total of 20 VBM studies comparing 543 major depressive patients with 750 healthy control subjects were included. Consistent gray matter reductions in all MDD patients relative to healthy controls were identified in the bilateral anterior cingulate cortex (ACC), right middle and inferior frontal gyrus, right hippocampus and left thalamus. CONCLUSIONS Meta-analysis of all primary VBM studies indicates that significant gray matter reductions in MDD are localized in a distributed neural network which includes frontal, limbic and thalamic regions. Future studies will benefit from the use of a longitudinal approach to examine anatomical and functional abnormalities within this network and their relationship to clinical profile, particularly in first-episode and drug-naive MDD patients.

Neurological Soft Signs in Schizophrenia: A Meta-analysis

BACKGROUND Neurological soft signs (NSS) are hypothesized as candidate endophenotypes for schizophrenia, but their prevalence and relations with clinical and demographic data are unknown. The authors undertook a quantification (meta-analysis) of the published literature on NSS in patients with schizophrenia and healthy controls. A systematic search was conducted for published articles reporting NSS and related data using standard measures in schizophrenia and healthy comparison groups. METHOD A systematic search was conducted for published articles reporting data on the prevalence of NSS in schizophrenia using standard clinical rating scales and healthy comparison groups. Meta-analyses were performed using the Comprehensive Meta-analysis software package. Effect sizes (Cohen d) indexing the difference between schizophrenic patients and the healthy controls were calculated on the basis of reported statistics. Potential moderator variables evaluated included age of patient samples, level of education, sample sex proportions, medication doses, and negative and positive symptoms. RESULTS A total of 33 articles met inclusion criteria for the meta-analysis. A large and reliable group difference (Cohen d) indicated that, on average, a majority of patients (73%) perform outside the range of healthy subjects on aggregate NSS measures. Cognitive performance and positive and negative symptoms share 2%-10% of their variance with NSS. CONCLUSIONS NSS occur in a majority of the schizophrenia patient population and are largely distinct from symptomatic and cognitive features of the illness.

Abnormal regional spontaneous neural activity in treatment-refractory depression revealed by resting-state fMRI

Treatment‐refractory depression (TRD) represents a large proportion of the depressive population, yet has seldom been investigated using advanced imaging techniques. To characterize brain dysfunction in TRD, we performed resting‐state functional MRI (rs‐fMRI) on 22 TRD patients, along with 26 matched healthy subjects and 22 patients who were depressed but not treatment‐refractory (NDD) as comparison groups. Results were analyzed using a data‐driven approach known as Regional Homogeneity (ReHo) analysis which measures the synchronization of spontaneous fMRI signal oscillations within spatially neighboring voxels. Relative to healthy controls, both depressed groups showed high ReHo primarily within temporo‐limbic structures, and more widespread low ReHo in frontal, parietal, posterior fusiform cortices, and caudate. TRD patients showed more cerebral regions with altered ReHo than did NDD. Moderate but significant correlations between the altered regional ReHo and measures of clinical severity were observed in some identified clusters. These findings shed light on the pathophysiological mechanisms underlying TRD and demonstrate the feasibility of using ReHo as a research and clinical tool to monitor persistent cerebral dysfunction in depression, although further work is necessary to compare different measures of brain function to elucidate the neural substrates of these ReHo abnormalities. Hum Brain Mapp, 2011.

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Besides the enormous medical and economic consequences, national disasters, such as the Wenchuan 8.0 earthquake, also pose a risk to the mental health of survivors. In this context, a better understanding is needed of how functional brain systems adapt to severe emotional stress. Previous animal studies have demonstrated the importance of limbic, paralimbic, striatal, and prefrontal structures in stress and fear responses. Human studies, which have focused primarily on patients with clinically established posttraumatic stress disorders, have reported abnormalities in similar brain structures. At present, little is known about potential alterations of brain function in trauma survivors shortly after traumatic events. Here, we show alteration of brain function in a cohort of healthy survivors within 25 days after the Wenchuan earthquake by a recently discovered method known as “resting-state” functional MRI. The current investigation demonstrates that regional activity in frontolimbic and striatal areas increased significantly and connectivity among limbic and striatal networks was attenuated in our participants who had recently experienced severe emotional trauma. Trauma victims also had a reduced temporal synchronization within the “default mode” of resting-state brain function, which has been characterized in humans and other species. Taken together, our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in posttraumatic stress disorders, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors.

Impaired facial emotion perception in schizophrenia: a meta-analysis.

Research into facial emotion perception in schizophrenia has burgeoned over the past several decades. The evidence is mixed regarding whether patients with schizophrenia have a general facial emotion perception deficit (a deficit in facial emotion perception plus a more basic deficit in facial processing) or specific facial emotion perception deficits (deficits only in facial emotion perception tasks). A meta-analysis is conducted of 28 facial emotion perception studies that include control tasks. These studies use differential deficit designs to examine whether patients with schizophrenia demonstrate a general deficit or specific deficit in facial emotion perception. A significant mean effect size is found for total facial emotion perception (d=-0.85). Patients with schizophrenia demonstrate impaired ability to perform corresponding control tasks, and the mean effect size is -0.70. The current findings suggest that patients with schizophrenia have moderately to severely impaired perception of facial emotion.

Base rate of post-concussion symptoms among normal people and its neuropsychological correlates

Objective: To explore the base rate of symptoms similar to those of post-concussion symptoms (PCS) among a group of participants without head injury. The effect of subjective complaints upon cognitive functioning was also examined. Design: A cross-sectional study. Participants: A total of 85 participants without head injury, other identifiable neurological diseases or psychiatric diseases were recruited. Outcome measures: These included Rivermead Post-concussion Symptoms Checklist, Cognitive Failures Questionnaire, Colour Trails Test, Stroop Word-Colour Test, Paced Auditory Serial Addition Test, Symbol Digits Modality Test, Word Fluency Test, Design Fluency Test, Digits Forward and Backward Span Test, and Modified Six Elements Test. Results: A relatively high proportion of the participants reported symptoms similar to those of patients with PCS. These included longer time to think (65.9%), forgetfulness (58.9%), poor concentration (58.9%), fatigue easily (53.5%), and sleep disturbances (50.6%). Gender effect was not significant for either the individual item or the total score of the Rivermead Post-concussion Symptoms Checklist. Moreover, there was no difference found between low symptom reporters and high symptom reporters in terms of attention, working memory, mental fluency, and strategy allocation. Conclusion: The base rates of symptoms were consistent with previous studies among the nonclinical groups. However, persons reporting a high score of concussion-like symptoms did not perform less well than those reporting a low score of symptoms in attention, working memory, mental fluency and strategy allocation.