White Matter Integrity In Schizophrenia Research Articles

Association between enhanced carbonyl stress and decreased apparent axonal density in schizophrenia by multimodal white matter imaging

Carbonyl stress is a condition featuring increased rich reactive carbonyl compounds, which facilitate the formation of advanced glycation end products including pentosidine. We previously reported the relationship between enhanced carbonyl stress and disrupted white matter integrity in schizophrenia, although which microstructural component is disrupted remained unclear. In this study, 32 patients with schizophrenia (SCZ) and 45 age- and gender-matched healthy volunteers (HC) were recruited. We obtained blood samples for carbonyl stress markers (plasma pentosidine and serum pyridoxal) and multi-modal magnetic resonance imaging measures of white matter microstructures including apparent axonal density (intra-cellular volume fraction (ICVF)) and orientation (orientation dispersion index (ODI)), and inflammation (free water (FW)). In SCZ, the plasma pentosidine level was significantly increased. Group comparison revealed that mean white matter values were decreased for ICVF, and increased for FW. We found a significant negative correlation between the plasma pentosidine level and mean ICVF values in SCZ, and a significant negative correlation between the serum pyridoxal level and mean ODI value in HC, regardless of age. Our results suggest an association between enhanced carbonyl stress and axonal abnormality in SCZ.

The relationship between TLR4/NF-κB/IL-1β signaling, cognitive impairment, and white-matter integrity in patients with stable chronic schizophrenia.

ObjectivePrevious studies have implicated intricate interactions between innate immunity and the brain in schizophrenia. Monocytic Toll-like receptor (TLR) 4 signaling, a crucial “sensor” of innate immunity, was reported to be over-activated in link with cognitive impairment in schizophrenia. As TLR4 is predominantly expressed on gliocytes prior to expression in neurons, we hypothesized that higher TLR4 levels may contribute to cognitive deterioration by affecting white matter microstructure.MethodsForty-four patients with stable chronic schizophrenia (SCS) and 59 healthy controls (HCs) were recruited in this study. The monocytic function was detected with lipopolysaccharide (LPS) stimulation to simulate bacterial infection. Basal and LPS- stimulated levels of TLR4, nuclear factor-kappa B (NF-κB), and interleukin (IL)-1β were quantified with flow cytometry. Cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB) and psychopathological symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS). We employed diffusion tensor imaging with a 3-T scanner and evaluated white-matter integrity with fractional anisotropy (FA). Subcortical volume and cortical thickness were also assessed.ResultsThe TLR4/NF-κB/IL-1β signaling pathway was activated in patients with SCS, but responded sluggishly to LPS stimulation when compared with HCs. Furthermore, monocytic TLR4 expressions were inversely correlated with cognitive function and white matter FA, but not with cortical thickness or subcortical gray matter volume in schizophrenia.ConclusionOur findings support altered TLR4 signaling pathway activity in association with deficits in cognition and white matter integrity in schizophrenia.

Enhanced carbonyl stress and disrupted white matter integrity in schizophrenia

Carbonyl stress is a state caused by an increase in rich reactive carbonyl compounds (RCOs); RCOs facilitate the formation of advanced glycation end products (AGEs), which are associated with various age-related illnesses. Recently, enhanced carbonyl stress and lower levels of pyridoxal, a kind of vitamin B6 that scavenges RCOs, have been shown to be associated with schizophrenia. Meanwhile, lower levels of pyridoxal have been reported to decrease myelination through the biochemical process of carbonyl stress. Despite a number of reports on white matter disruption in schizophrenia, it is unclear whether this disruption is related to enhanced carbonyl stress. Therefore, we investigated the relationship between carbonyl stress and white matter integrity in schizophrenia using diffusion tensor imaging. A total of 53 patients with schizophrenia and 83 age- and gender-matched healthy controls were recruited. We used plasma pentosidine, an AGE, and serum pyridoxal as carbonyl stress markers. Between-group differences in these carbonyl stress markers and their relationships with white matter integrity were investigated using Tract-Based Spatial Statistics. In the schizophrenia group, plasma pentosidine level was significantly higher and serum pyridoxal level was lower than those of controls. There was a significant negative correlation between plasma pentosidine and white matter integrity in the schizophrenia group, but not in the control group. Our findings suggest that enhanced carbonyl stress is a possible underlying mechanism of white matter microstructural disruption in schizophrenia.

Altered structural connectivity and cytokine levels in Schizophrenia and Genetic high-risk individuals: Associations with disease states and vulnerability

BackgroundAlterations of white matter (WM) integrity have been observed in both schizophrenia (SZ) and individuals at genetic high risk for SZ (GHR-SZ); however, the molecular mechanisms underlying WM disruption remain unclear. Cytokines are chemical messengers of the immune system that are closely related to inflammation and neurogenesis in the brain. This study aimed to identify abnormalities in WM integrity, cytokine levels, and their association in SZ and GHR-SZ. MethodsA total of 355 participants (126 with SZ, 99 GHR-SZ, and 130 healthy controls [HCs]) were recruited. All participants underwent diffusion tensor imaging and blood samples were obtained from 113 participants within 24 h of imaging. ResultsIn SZ, there was decreased fractional anisotropy(FA) in the genu and body of the corpus callosum (GCC/BCC), anterior corona radiata, anterior and posterior limbs of the internal capsule (ALIC/PLIC), superior fronto-occipital fasciculus, external capsule, and fornix, and elevated IL-6 levels. In both SZ and GHR-SZ, decreased FA in the splenium of the corpus callosum (SCC), posterior corona radiate (PCR), and posterior thalamic radiation (PTR) was observed, and elevated leptin levels were present. Additionally, the IL-6 levels were negatively correlated with FA in the GCC and ALIC in SZ, and leptin levels were negatively correlated with the SCC, PCR, and PTR in SZ and GHR-SZ. ConclusionsAbnormal WM integrity in SZ may reflect the state of disease and is associated with increased IL-6 levels. In addition, these leptin-associated WM integrity abnormalities in both SZ and GHR-SZ may reflect a genetic vulnerability to SZ.

Galantamine-Memantine Combination as an Antioxidant Treatment for Schizophrenia.

The objective of this article is to highlight the potential role of the galantamine-memantine combination as a novel antioxidant treatment for schizophrenia. In addition to the well-known mechanisms of action of galantamine and memantine, these medications also have antioxidant activity. Furthermore, an interplay exists between oxidative stress, inflammation (redox-inflammatory hypothesis), and kynurenine pathway metabolites. Also, there is an interaction between brain-derived neurotrophic factor and oxidative stress in schizophrenia. Oxidative stress may be associated with positive, cognitive, and negative symptoms and impairments in white matter integrity in schizophrenia. The antipsychotic-galantamine-memantine combination may provide a novel strategy in schizophrenia to treat positive, cognitive, and negative symptoms. A "single antioxidant" may be inadequate to counteract the complex cascade of oxidative stress. The galantamine-memantine combination as "double antioxidants" is promising. Hence, randomized controlled trials are warranted with the antipsychotic-galantamine-memantine combination with oxidative stress and antioxidant biomarkers in schizophrenia.

Increased Peripheral Interleukin 10 Relate to White Matter Integrity in Schizophrenia.

Background: Schizophrenia is characterized by the disruption of microstructural white matter (WM) integrity, while the pathogenesis remains unclear. Inflammation has been associated with the WM pathology in schizophrenia. Interleukin 10 (IL-10) has been proven to be related to schizophrenia in both animal and human models. The aim of this study was to explore whether peripheral IL-10 was associated with microstructural WM integrity in schizophrenia.Methods: A total of 47 patients with schizophrenia (SZ) and 49 healthy controls (HC) underwent diffusion tensor imaging and venous blood sampling. Tract-based spatial statistics was conducted to explore the differences in fractional anisotropy (FA), radial diffusivity (RD), mean diffusivity (MD), and axial diffusivity (AD) between patients and controls. A quantitative chemiluminescence assay was performed to measure peripheral IL-10 levels. General linear regression analysis using a stepwise method was applied to examine the relationship between peripheral IL-10 and diffusion measures.Results: Compared with the HC, peripheral IL-10 levels were higher and a significant reduction of FA and AD, and increase of RD and MD were observed in SZ (corrected p < 0.05). A regression analysis revealed that peripheral IL-10 was negatively correlated with FA in the right posterior thalamic radiation and left inferior fronto-occipital fasciculus, in SZ (β = -0.51, p = 0.01; β = -0.47, p = 0.02, respectively) but not in HC (β = -0.01, p = 0.95; β = -0.003, p = 0.98, respectively), and the differences in regression curves were significant (z = 2.50, p = 0.01; z = 2.37, p = 0.02, respectively). IL-10 was negatively connected with MD in the right parietal arcuate fasciculus (β = -0.40, p = 0.048) and body of the corpus callosum (β = -0.43, p = 0.03) in SZ, while not in HC. The magnitude of correlation in the patient and control group was different (z = 2.48, p = 0.01 and z = 2.61, p < 0.01, respectively). In addition, IL-10 was positively correlated with RD in the right parietal arcuate fasciculus in patients (β = 0.45, p = 0.04) but not in HC (β = 0.26, p = 0.94), but the correlation coefficients were not significant (z = 0.98, p = 0.32).Conclusion: Our findings demonstrated that elevated peripheral IL-10 levels were associated with the disruption of microstructural WM integrity in schizophrenia, supporting the notion that inflammation plays a regulatory role in the pathology of microstructural WM and is associated with schizophrenia.

White matter integrity in schizophrenia and bipolar disorder: Tract- and voxel-based analyses of diffusion data from the Connectom scanner.

BackgroundDiffusion imaging abnormalities have been associated with schizophrenia (SZ) and bipolar disorder (BD), indicating impaired structural connectivity. Newer methods permit the automated reconstruction of major white matter tracts from diffusion-weighted MR images in each individual's native space. Using high-definition diffusion data from SZ and BP subjects, we investigated brain white matter integrity using both an automated tract-based and voxel-based methods.MethodsUsing a protocol matched to the NIH (Young-Adult) Human Connectome Project (and collected on the same customized ‘Connectom’ scanner), diffusion scans were acquired from 87 total participants (aged 18–30), grouped as SZ (n = 24), BD (n = 33) and healthy controls (n = 30). Fractional anisotropy (FA) of eighteen white matter tracks were analyzed using the TRACULA software. Voxel-wise statistical analyses of diffusion data was carried out using the tract-based spatial statistics (TBSS) software. TRACULA group effects and clinical correlations were investigated using analyses of variance and multiple regression.ResultsTRACULA analysis identified a trend towards lower tract FA in SZ patients, most significantly in the left anterior thalamic radiation (ATR; p = .04). TBSS results showed significantly lower FA voxels bilaterally within the cerebellum and unilaterally within the left ATR, posterior thalamic radiation, corticospinal tract, and superior longitudinal fasciculus in SZ patients compared to controls (FDR corrected p < .05). FA in BD patients did not significantly differ from controls using either TRACULA or TBSS. Multiple regression showed FA of the ATR as predicting chronic mania (p = .0005) and the cingulum-angular bundle as predicting recent mania (p = .02) in patients. TBSS showed chronic mania correlating with FA voxels within the left ATR and corpus callosum.ConclusionsWhite matter abnormality in SZ varies in severity across different white matter tract regions. Our results indicate that voxel-based analysis of diffusion data is more sensitive than tract-based analysis in identifying such abnormalities. Absence of white matter abnormality in BD may be related to medication effects and age.

Obesity influences white matter integrity in schizophrenia

BackgroundWhite matter (WM) alterations have been consistently described in patients with schizophrenia and correlated with the severity of psychotic symptoms and cognitive impairment.Obesity has been reported in over 40% of patients with schizophrenia and has been associated with cognitive deficits, cardiovascular diseases, metabolic alterations, and overall mortality. Moreover, studies among healthy subjects and subjects at risk for psychosis reported an influence of Body Mass Index (BMI) on structural connectivity. We therefore hypothesized that obesity and overweight could further disrupt WM integrity of patients affected by schizophrenia. MethodsEighty-eight schizophrenia patients were evaluated for BMI. We divided the sample in overweight/obese and normal weight groups. We then performed whole brain tract-based spatial statistics in the WM skeleton with threshold-free cluster enhancement of DTI measures of WM microstructure: axial (AD), radial (RD), and mean diffusivity (MD), and fractional anisotropy (FA). ResultsA significant difference between the two groups was observed: normal weight patients showed higher AD and a higher FA trend compared to obese patients in several fibers’ tracts including longitudinal fasciculus, uncinate fasciculus, corona radiata, thalamic radiation, fronto-occipital fasciculus, cingulum and corpus callosum. ConclusionsElevated BMI might contribute to WM disruption of schizophrenia by hampering structural connectivity in critical cortico-limbic networks, known to play a crucial role in neurocognitive functioning, emotional processing and psychopathology whose dysfunction are prominent features of the disorder.

Shared abnormality of white matter integrity in schizophrenia and bipolar disorder: A comparative voxel-based meta-analysis

Patients with schizophrenia and bipolar disorder (BD) shared a significant overlap in genetic susceptibility, pharmacological treatment responses, neuropsychological deficits, and epidemiological features. However, it remains unknown whether these clinical overlaps are mediated by shared or disorder-specific abnormalities of white matter integrity. In this voxel-based meta-analytic comparison of whole-brain white matter integrity, we aimed to identify the shared or disorder-specific structural abnormalities between schizophrenia and BD. A comprehensive literature search was conducted up to February 2016 to identify studies that compared between patients and healthy controls (HC) by using whole-brain diffusion approach (schizophrenia: 24 datasets with 754 patients vs. 775 HC; BD: 23 datasets with 705 patients vs. 679 HC). Voxel-wise meta-analyses were conducted and restricted to unified template using seed-based d-Mapping. Abnormal white matter integrity was calculated within each condition and a direct comparison of effect size was performed of alterations between two conditions. Two regions with significant reductions of fractional anisotropy (FA) characterized abnormal water diffusion in both disorders: the genu of the corpus callosum (CC) and posterior cingulum fibers. There was no significant difference found between the two disorders. Our results highlighted shared impairments of FA at genu of the CC and left posterior cingulum fibers, which suggests that, phenotypic overlap between schizophrenia and BD could be related to common brain circuit dysfunction.

Tryptophan Metabolism and White Matter Integrity in Schizophrenia.

Schizophrenia is associated with abnormalities in the structure and functioning of white matter, but the underlying neuropathology is unclear. We hypothesized that increased tryptophan degradation in the kynurenine pathway could be associated with white matter microstructure and biochemistry, potentially contributing to white matter abnormalities in schizophrenia. To test this, fasting plasma samples were obtained from 37 schizophrenia patients and 38 healthy controls and levels of total tryptophan and its metabolite kynurenine were assessed. The ratio of kynurenine to tryptophan was used as an index of tryptophan catabolic activity in this pathway. White matter structure and function were assessed by diffusion tensor imaging (DTI) and (1)H magnetic resonance spectroscopy (MRS). Tryptophan levels were significantly lower (p<0.001), and kynurenine/tryptophan ratios were correspondingly higher (p=0.018) in patients compared with controls. In patients, lower plasma tryptophan levels corresponded to lower structural integrity (DTI fractional anisotropy) (r=0.347, p=0.038). In both patients and controls, the kynurenine/tryptophan ratio was inversely correlated with frontal white matter glutamate level (r=-0.391 and -0.350 respectively, p=0.024 and 0.036). These results provide initial evidence implicating abnormal tryptophan/kynurenine pathway activity in changes to white matter integrity and white matter glutamate in schizophrenia.

Structural Brain Connectivity as a Genetic Marker for Schizophrenia.

Schizophrenia is accompanied by a loss of integrity of white matter connections that compose the structural brain network, which is believed to diminish the efficiency of information transfer among brain regions. However, it is unclear to what extent these abnormalities are influenced by the genetic liability for developing the disease. To determine whether white matter integrity is associated with the genetic liability for developing schizophrenia. In 70 individual twins discordant for schizophrenia and 130 matched individual healthy control twins, structural equation modeling was applied to quantify unique contributions of genetic and environmental factors on brain connectivity and disease liability. The data for this study were collected from October 1, 2008, to September 30, 2013. The data analysis was performed between November 1, 2013, and March 30, 2015. Structural connectivity and network efficiency were assessed through diffusion-weighted imaging, measuring fractional anisotropy (FA) and streamlines. The sample included 30 monozygotic twins matched to 72 control participants and 40 dizygotic twins matched to 58 control participants. Lower global FA was significantly correlated with increased schizophrenia liability (phenotypic correlation, -0.25; 95% CI, -0.38 to -0.10; P = .001), with 83.4% explained by common genes. In total, 8.1% of genetic variation in global FA was shared with genetic variance in schizophrenia liability. Local reductions in network connectivity (as defined by FA-weighted local efficiency) of frontal, striatal, and thalamic regions encompassed 85.7% of genetically affected areas. Multivariate genetic modeling revealed that global FA contributed independently of other genetic markers, such as white matter volume and cortical thickness, to schizophrenia liability. Global reductions in white matter integrity in schizophrenia are largely explained by the genetic risk of developing the disease. Network analysis revealed that genetic liability for schizophrenia is primarily associated with reductions in connectivity of frontal and subcortical regions, indicating a loss of integrity along the white matter fibers in these regions. The reported reductions in white matter integrity likely represent a separate and novel genetic vulnerability marker for schizophrenia.

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia.

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient-control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination.

Myelination-related genes are associated with decreased white matter integrity in schizophrenia

Disruptions in white matter (WM) tract structures have been implicated consistently in the pathophysiology of schizophrenia. Global WM integrity--as measured by fractional anisotropy (FA)--is highly heritable and may provide a good endophenotype for genetic studies of schizophrenia. WM abnormalities in schizophrenia are not localized to one specific brain region but instead reflect global low-level decreases in FA coupled with focal abnormalities. In this study, we sought to investigate whether functional gene sets associated with schizophrenia are also associated with WM integrity. We analyzed FA and genetic data from the Mind Research Network Clinical Imaging Consortium to study the effect of multiple oligodendrocyte gene sets on schizophrenia and WM integrity using a functional gene set analysis in 77 subjects with schizophrenia and 104 healthy controls. We found that a gene set involved in myelination was significantly associated with schizophrenia and FA. This gene set includes 17 genes that are expressed in oligodendrocytes and one neuronal gene (NRG1) that is known to regulate myelination. None of the genes within the gene set were associated with schizophrenia or FA individually, suggesting that no single gene was driving the association of the gene set. Our findings support the hypothesis that multiple genetic variants in myelination-related genes contribute to the observed correlation between schizophrenia and decreased WM integrity as measured by FA.

Genetic markers of white matter integrity in schizophrenia revealed by parallel ICA.

It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = −0.37, p = 1.25 × 10−6) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10−4. The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development.

The myelinated fiber loss in the corpus callosum of mouse model of schizophrenia induced by MK-801

Previous magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) investigations have shown that the white matter volume and fractional anisotropy (FA) were decreased in schizophrenia (SZ), which indicated impaired white matter integrity in SZ. However, the mechanism underlying these abnormalities has been less studied. The current study was designed to investigate the possible reasons for white matter abnormalities in the mouse model of SZ induced by NMDA receptor antagonist using the unbiased stereological methods and transmission electron microscope technique. We found that the mice treated with MK-801 demonstrated a series of schizophrenia-like behaviors including hyperlocomotor activity and more anxiety. The myelinated fibers in the corpus callosum (CC) of the mice treated with MK-801 were impaired with splitting lamellae of myelin sheaths and segmental demyelination. The CC volume and the total length of the myelinated fibers in the CC of the mice treated with MK-801 were significantly decreased by 9.4% and 16.8% when compared to those of the mice treated with saline. We further found that the loss of the myelinated fibers length was mainly due to the marked loss of the myelinated nerve fibers with the diameter of 0.4–0.5 μm. These results indicated that the splitting myelin sheaths, demyelination and the loss of myelinated fibers with small diameter might provide one of the structural bases for impaired white matter integrity of CC in the mouse model of SZ. These results might also provide a baseline for further studies searching for the treatment of SZ through targeting white matter.

CACNA1C genomewide supported psychosis genetic variation affects cortical brain white matter integrity in Chinese patients with schizophrenia.

Recent genomewide association studies have implicated the calcium channel, voltage-dependent, L type, alpha 1C subunit (CACNA1C) genetic variant in schizophrenia, which is associated with functional brain changes and cognitive deficits in healthy individuals. However, the impact of CACNA1C on brain white matter integrity in schizophrenia remains unclear. On the basis of prior evidence of CACNA1C-mediated changes involving cortical brain regions, we hypothesize that CACNA1C risk variant rs1006737 is associated with reductions of white matter integrity in the frontal, parietal, and temporal regions and cingulate gyrus. A total of 160 Chinese participants (96 DSM-IV-diagnosed patients with schizophrenia and 64 healthy controls) were genotyped by using blood samples and underwent structural magnetic resonance imaging and diffusion tensor imaging scans from 2008 to 2012. Two-way analysis of covariance was employed to examine CACNA1C-related genotype effects, diagnosis effects, and genotype × diagnosis interaction effects on fractional anisotropy (FA) of relevant brain regions. Significant diagnosis-genotype interactions were observed (left frontal lobe mean FA: F₁,₁₅₆ = 6.22, P = .014; left parietal lobe mean FA: F₁,₁₅₆ = 7.14, P = .008; left temporal lobe mean FA: F₁,₁₅₆ = 8.37, P = .004). Compared with patients who were A carriers, patients who were G homozygotes had lower mean FA in the left frontal lobe (F₁,₉₃ = 2.504, P = .014), left parietal lobe (F₁,₉₃ = 2.37, P = .020), and left temporal lobe (F₁,₉₃ = 3.01, P = .003), with standardized effect sizes of -1.43, -1.3, and -1.0, respectively. CACNA1C risk variant rs1006737 affects cortical white matter integrity in schizophrenia. Further imaging genetic investigations on the mediating effect of CACNA1C in schizophrenia can uncover brain circuitries involved in schizophrenia and suggest potential novel targets for intervention.

Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes.

Clozapine displays stronger systemic metabolic side effects than haloperidol and it has been hypothesized that therapeutic antipsychotic and adverse metabolic effects of these drugs are related. Considering that cerebral disconnectivity through oligodendrocyte dysfunction has been implicated in schizophrenia, it is important to determine the effect of these drugs on oligodendrocyte energy metabolism and myelin lipid production. Effects of clozapine and haloperidol on glucose and myelin lipid metabolism were evaluated and compared in cultured OLN-93 oligodendrocytes. First, glycolytic activity was assessed by measurement of extra- and intracellular glucose and lactate levels. Next, the expression of glucose (GLUT) and monocarboxylate (MCT) transporters was determined after 6 and 24 h. And finally mitochondrial respiration, acetyl-CoA carboxylase, free fatty acids, and expression of the myelin lipid galactocerebroside were analyzed. Both drugs altered oligodendrocyte glucose metabolism, but in opposite directions. Clozapine improved the glucose uptake, production and release of lactate, without altering GLUT and MCT. In contrast, haloperidol led to higher extracellular levels of glucose and lower levels of lactate, suggesting reduced glycolysis. Antipsychotics did not alter significantly the number of functionally intact mitochondria, but clozapine enhanced the efficacy of oxidative phosphorylation and expression of galactocerebroside. Our findings support the superior impact of clozapine on white matter integrity in schizophrenia as previously observed, suggesting that this drug improves the energy supply and myelin lipid synthesis in oligodendrocytes. Characterizing the underlying signal transduction pathways may pave the way for novel oligodendrocyte-directed schizophrenia therapies.

Association of GRM3 polymorphism with white matter integrity in schizophrenia

While the functional disconnectivity hypothesis of schizophrenia has received considerable attention, fewer studies have investigated the contribution of genotype to structural connectivity between brain regions either in schizophrenia patients or in healthy controls. In this study, we obtained diffusion tensor imaging (DTI) data and genome-wide single nucleotide polymorphism (SNP) data from 74 cases and 87 age- and gender-matched controls. We used independent component analysis (ICA) to analyze fractional anisotropy (FA) values and correlated FA values with 121 SNPs in genes associated with myelination and/or schizophrenia risk. Using ICA, we identified 6 maximally independent components in which the majority of the voxels corresponded to known white matter (WM) tracts. Among these WM-enriched components, two had FA values that were significantly decreased in patients. In addition, we examined the relationship between FA values and genotype and found that a SNP located in the intronic region of the metabotropic glutamate receptor 3 gene, GRM3, shows a significant correlation with FA values in a component containing tracts from the cortico-cerebellar-thalamic-cortical circuit of patients but not controls. Our findings strengthen the evidence for an association between GRM3 genotype and schizophrenia and suggest a role for glutamate neurotransmission in the establishment and maintenance of myelinated fibers.

Accelerated white matter aging in schizophrenia: role of white matter blood perfusion

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18–63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia.

Impaired empathic abilities and reduced white matter integrity in schizophrenia

Empathic abilities are impaired in schizophrenia. Although the pathology of schizophrenia is thought to involve disrupted white matter integrity, the relationship between empathic disabilities and altered white matter in the disorder remains unclear. The present study tested associations between empathic disabilities and white matter integrity in order to investigate the neural basis of impaired empathy in schizophrenia. Sixty-nine patients with schizophrenia and 69 age-, gender-, handedness-, education- and IQ level-matched healthy controls underwent diffusion-weighted imaging. Empathic abilities were assessed using the Interpersonal Reactivity Index (IRI). Using tract-based spatial statistics (TBSS), the associations between empathic abilities and white matter fractional anisotropy (FA), a measure of white matter integrity, were examined in the patient group within brain areas that showed a significant FA reduction compared with the controls. The patients with schizophrenia reported lower perspective taking and higher personal distress according to the IRI. The patients showed a significant FA reduction in bilateral deep white matter in the frontal, temporal, parietal and occipital lobes, a large portion of the corpus callosum, and the corona radiata. In schizophrenia patients, fantasy subscales positively correlated with FA in the left inferior fronto-occipital fasciculi and anterior thalamic radiation, and personal distress subscales negatively correlated with FA in the splenium of the corpus callosum. These results suggest that disrupted white matter integrity in these regions constitutes a pathology underpinning specific components of empathic disabilities in schizophrenia, highlighting that different aspects of empathic impairments in the disorder would have, at least partially, distinct neuropathological bases.