Maps of Group Differences in Cortical Thickness in Persons with Schizophrenia Compared with Healthy Controls.

<p>Statistical effects are color-encoded as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a>. Cortical thickness was rescaled for whole brain size. Results are GRF-corrected. Patients were divided in two subgroups: neuropsychologically near normal patients (NPNN; n = 21) (<i>Lower Left</i>) and neuropsychologically impaired (NPI; n = 50) (<i>Lower Right</i>) patients based on performance scores on the SPT. AC, anterior cingulate; IP, inferior parietal lobule; MFG, middle frontal gyrus; MTG, middle temporal gyrus; PC posterior cingulate; PoC, postcentral gyrus; PreC, precentral gyrus; SFG, superior frontal gyrus; SMG, supramarginal gyrus; SPG, superior parietal gyrus; STG, superior temporal gyrus. Other labels are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a>. (<i>Upper</i>) Entire patient group compared with healthy controls. (<i>Lower Left</i>) NPNN subgroup (n = 21) compared with healthy controls (n = 57). (<i>Lower Right</i>) NPI subgroup (n = 50) compared with healthy controls. Patients exhibited greater cortical thickness in the perisylvian cortices in both hemispheres, as well as thinner cortices in the superior frontal, superior parietal and cingulate gyri. We did not observe any differences in the degree of cortical thickness when we compared neuropsychological groups directly to each other. These findings were preserved in unscaled data.</p

Correlations of Memory Scores with Local Volumes along the Surface of the Brain and of the Underlying WM.

<p>Statistical effects are color-encoded as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a>. (<i>Left Half of the Figure</i>) GRF-corrected results for the Brain Surface (Left Column) and for the WM Surface (Right Column). (<i>Right Half of the Figure</i>) Uncorrected results for the Brain Surface (Left Column) and for the WM Surface (Right Column). These figures demonstrate that increasing memory scores are associated with relatively greater local volumes along the WM surface. These correlations are within-group and they suggest that patients with better memory scores have a smaller degree of WM deficits. However, patients as a whole still have reductions in WM when compared with healthy controls, as shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a>. Therefore the greater local volumes shown in this figure are not to be interpreted in the sense of an actual increase of WM in the patient group.</p

Correlations of Cortical Thickness with Severity of Negative Symptoms.

<p>Statistical effects are color-encoded as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a>. This figure shows correlations of cortical thickness measures with negative symptoms scores from the PANSS. All correlations are GRF-corrected. Increased symptom burden was associated with greater thickness in perisylvian cortices but only minimal thinning in the left superior and left precentral gyrus (compare with <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g002" target="_blank">Fig. 2</a>). We did not find any association of WM surface morphology with symptom scores.</p

Maps of Group Differences in Local Volumes along the Surface of the Brain and of the Underlying WM in Persons with Schizophrenia Compared with Healthy Controls.

<p>At each point on the brain or on the WM surface, the statistical significance of differences in local volumes between patients (n = 76) and healthy controls (n = 57) is color-coded. Warm colors (yellow, orange and red) represent significantly greater local volumes of brain tissue along the surface of the brain or of WM tissue along the underlying WM surface in the schizophrenia group. Cooler colors (blue and purple) represent reduced local volumes of brain tissue along the surface of the brain or of WM tissue along the underlying WM surface in that group. The color bar indicates the color-coding of p values for testing of statistical significance at each point. Brain and WM surfaces were rescaled for whole brain size and the statistical models accounted for age, age² and the gender of all participants. P values are thresholded at P<0.05 with corrections for multiple statistical comparisons using the theory of Gaussian Random Fields (GRF) on a 2D manifold. P values are displayed onto the ICBM brain surface of the template brain (in green) and onto the WM surface of the reference subject. More specifically, abnormalities in WM surface, brain surface, and cortical thickness are overlaid on the same reference brain. However, while brain surface and cortical thickness results can be displayed on a brain surface, WM results must be displayed on the WM surface of the reference brain after its cortical mantle has been removed. This figure shows that reduced local volumes of brain tissue along the surface of the brain are distributed in perisylvian regions and they closely reflect underlying reductions in local volumes along the WM surface. AC, anterior cingulate; IFG, inferior frontal; LG, lingual gyrus; MFG, middle frontal gyrus; MTG, middle temporal gyrus; PreC, precentral gyrus; PC posterior cingulate; PoC, postcentral gyrus; SFG, superior frontal gyrus; SMG, supramarginal gyrus; STG, superior temporal gyrus.</p

Maps of Group Differences in Local Volumes along the Surface of the Brain and of the Underlying WM Across Cognitive Subgroups.

<p>Statistical effects are color-encoded as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g001" target="_blank">Fig. 1</a> and subgroup definitions are the same as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055783#pone-0055783-g002" target="_blank">Fig. 2</a>. Results are GRF-corrected. Reductions in local volumes of brain tissue along the surface of the brain and of the WM in perisylvian regions are more prominent and more extensive in the NPI group. (<i>Upper Left</i>) Comparisons of the brain surface of NPNN patients with that of healthy controls. (<i>Lower Left</i>) Comparisons of the brain surface of NPI patients with that of healthy controls. (<i>Upper Right</i>) Comparisons of the WM surface of NPNN patients with that of healthy controls. (<i>Lower Right</i>) Comparisons of the WM surface of NPI patients with that of healthy controls. Neuropsychologically impaired patients show a higher burden of anatomical abnormalities than neuropsychologically near-normal patients. Reductions of local volumes of brain tissue along the surface of the brain corresponded to reductions in local volumes along the surface of the underlying WM.</p

Anatomical Abnormalities in Gray and White Matter of the Cortical Surface in Persons with Schizophrenia

<div><h3>Background</h3><p>Although schizophrenia has been associated with abnormalities in brain anatomy, imaging studies have not fully determined the nature and relative contributions of gray matter (GM) and white matter (WM) disturbances underlying these findings. We sought to determine the pattern and distribution of these GM and WM abnormalities. Furthermore, we aimed to clarify the contribution of abnormalities in cortical thickness and cortical surface area to the reduced GM volumes reported in schizophrenia.</p> <h3>Methods</h3><p>We recruited 76 persons with schizophrenia and 57 healthy controls from the community and obtained measures of cortical and WM surface areas, of local volumes along the brain and WM surfaces, and of cortical thickness.</p> <h3>Results</h3><p>We detected reduced local volumes in patients along corresponding locations of the brain and WM surfaces in addition to bilateral greater thickness of perisylvian cortices and thinner cortex in the superior frontal and cingulate gyri. Total cortical and WM surface areas were reduced. Patients with worse performance on the serial-position task, a measure of working memory, had a higher burden of WM abnormalities.</p> <h3>Conclusions</h3><p>Reduced local volumes along the surface of the brain mirrored the locations of abnormalities along the surface of the underlying WM, rather than of abnormalities of cortical thickness. Moreover, anatomical features of white matter, but not cortical thickness, correlated with measures of working memory. We propose that reductions in WM and smaller total cortical surface area could be central anatomical abnormalities in schizophrenia, driving, at least partially, the reduced regional GM volumes often observed in this illness.</p> </div

Demographic and Clinical Characteristics of Study Participants.

<p>Data are reported as mean (SD). F and T values are reported for independent T tests for means and chi-square values (χ²) for nominal data. An asterisk denotes significant p values. N = number.</p

Association of orexin receptor polymorphisms with antipsychotic-induced weight gain

<p><i>Objectives</i>: Antipsychotic-induced weight gain (AIWG) is a common side effect of treatment with antipsychotics such as clozapine and olanzapine. The orexin gene and its receptors are expressed in the hypothalamus and have been associated with maintenance of energy homeostasis. In this study, we have analysed tagging single nucleotide polymorphisms (SNPs) in orexin receptors 1 and 2 (HCRTR1 and HCRTR2) for association with AIWG. <i>Methods</i>: Schizophrenia or schizoaffective disorder subjects (<i>n</i> = 218), treated mostly with clozapine and olanzapine for up to 14 weeks, were included. Replication was conducted in a subset of CATIE samples (<i>n</i> = 122) treated with either olanzapine or risperidone for up to 190 days. Association between SNPs and AIWG was assessed using analysis of covariance (ANCOVA) with baseline weight and duration of treatment as covariates. <i>Results</i>: Several SNPs in HCRTR2 were nominally associated with AIWG in patients of European ancestry treated with either clozapine or olanzapine (<i>P</i><0.05). In the replication analysis two SNPs rs3134701 (<i>P</i> = 0.043) and rs12662510 (<i>P</i> = 0.012) were nominally associated with AIWG. None of the SNPs in HCRTR1 were associated with AIWG. <i>Conclusion</i>: This study provides preliminary evidence supporting the role of HCRTR2 in AIWG. However, these results need to be confirmed in large study samples.</p

Impact of histamine receptors H1 and H3 polymorphisms on antipsychotic-induced weight gain

<p><b>Objectives:</b> A positive correlation between antipsychotic-induced weight gain (AIWG) and the antagonist effect of antipsychotic drugs at the histamine H1 receptor (HRH1) as well as the agonist effect at the histamine H3 receptor (HRH3) in the brain has been consistently demonstrated. We investigated the potential impact of single-nucleotide polymorphisms (SNPs) in HRH1 and HRH3 genes on AIWG.</p> <p><b>Methods:</b> We analysed 40 tagSNPs in HRH1 (<i>n</i> = 34) and HRH3 (<i>n</i> = 6) in schizophrenia/schizoaffective disorder patients (<i>n</i> = 193) primarily treated with clozapine or olanzapine for up to 14 weeks. Linear regression was used to evaluate the association between SNPs and AIWG, with baseline weight and treatment duration as covariates.</p> <p><b>Results:</b> In HRH1, a nominal association of rs7639145 with AIWG was observed in patients of European ancestry treated with either clozapine or olanzapine (<i>P</i>= 0.043; β = 1.658; <i>n</i> = 77). We observed nominal association for two HRH1 SNPs rs346074 (<i>P = </i>0.002; β = –5.024) and rs13064530 (<i>P</i>= 0.004; β = –5.158) in patients of African ancestry treated with either clozapine or olanzapine (<i>n</i> = 37). However, the above associations are not significant after correcting for multiple testing. In HRH3, we did not observe association in either ancestry.</p> <p><b>Conclusions:</b> The current study suggests that SNPs in HRH1 and HRH3 may not have a major role in AIWG.</p