Abnormal white matter connections between medial frontal regions predict symptoms in patients with first episode schizophrenia

Abstract

Introduction The medial orbitofrontal cortex (mOFC) and rostral part of anterior cingulate cortex (rACC) have been suggested to be involved in the neural network of salience and emotional processing, and associated with specific clinical symptoms in schizophrenia. Considering the schizophrenia dysconnectivity hypothesis, the connectivity abnormalities between mOFC and rACC might be associated with clinical characteristics in first episode schizophrenia patients (FESZ). Methods After parcellating mOFC into the anterior and posterior part, diffusion properties of the mOFC-rACC white matter connections for 21 patients with FESZ and 21 healthy controls (HCs) were examined using stochastic tractography, one of the most effective Diffusion Tensor Imaging methods for examining tracts between adjacent gray matter regions. Results Fractional anisotropy (FA) reductions were observed in bilateral posterior, but not anterior mOFC-rACC connections (left: p<0.0001; right: p<0.0001) in FESZ compared to HCs. In addition, reduced FA in the left posterior mOFC-rACC connection was associated with more severe anhedonia-asociality (rho=−0.633, p=0.006) and total score (rho=−0.520, p=0.032) in the Scale for the Assessment of Negative Symptoms (SANS); reduced FA in the right posterior mOFC-rACC connection was associated with more severe affective flattening (rho=−0.644, p=0.005), total score (rho=−0.535, p=0.027) in SANS, hallucinations (rho=−0.551, p=0.018), delusions (rho=−0.632, p=0.005) and total score (rho=−0.721, p=0.001) in the Scale for the Assessment of Positive Symptoms (SAPS) in FESZ. Conclusions The observed white matter abnormalities within the connections between mOFC and rACC might be associated with the psychopathology of the early stage of schizophrenia.

Cerebral white matter structure is associated with DSM-5 schizophrenia symptom dimensions

“…Several studies found associations between delusions or hallucinations and WM microstructure in the arcuate fasciculus, cingulate bundle, corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and the connection between the amygdala and the nucleus accumbens ( Bracht et al, 2014 , Hubl et al, 2004 , Seok et al, 2007 , Szeszko et al, 2008 ). In addition, recent studies found associations of hallucination and delusion severity with WM microstructure in the right inferior longitudinal fasciculus and the connection between the right posterior middle orbitofrontal cortex and the rostral part of the anterior cingulate cortex ( Ohtani et al, 2015 , Seitz et al, 2016 ). Only for delusions researchers found associations with WM properties in the cingulum bundle ( Whitford et al, 2015 ), fornix and external capsule ( Arnedo et al, 2015 ).…”

“…Furthermore, WM microstructure in the splenium of the corpus callosum, the retrolenticular limb and posterior limb of the internal capsule have previously been associated with negative symptoms ( Arnedo et al, 2015 ). Additionally, fibertracking studies revealed correlations of negative symptoms with WM connections between the ventral tegmental area and the amygdala, the nucleus accumbens and the orbitofrontal cortex and between the anterior cingulate cortex and the orbitofrontal cortex ( Bracht et al, 2014 , Ohtani et al, 2014 , Ohtani et al, 2015 ). Contrary, there is one study of never-medicated first episode schizophrenia patients, which found no correlations between FA and negative symptoms ( Cheung et al, 2011 ).…”

“…A number of studies provide evidence of WM abnormalities in schizophrenia, predominantly in the prefrontal and temporal lobe, using most often fractional anisotropy (FA) as an indicator of the integrity of WM ( Federspiel et al, 2006 , Kubicki et al, 2007 ). Altered white matter microstructure has been reported across the course of schizophrenia, in subjects at risk for psychosis and in healthy first-degree relatives of schizophrenia patients, suggesting that these alterations are associated both with the biological risk of schizophrenia and with symptom progression ( Federspiel et al, 2006 , Fitzsimmons et al, 2013 , Ohtani et al, 2015 ).…”

Epigenetics in Schizophrenia: A Pilot Study of Global DNA Methylation in Different Brain Regions Associated with Higher Cognitive Functions

“…Even more, anatomical changes of these structures are related to mental disorders. For instance, schizophrenic patients showed reduced levels of gray matter volume in anterior cingulate cortex (ACC; Yamasue et al, 2004 ) and the connectivity of this structure with other brain regions could also play a role in first-episode schizophrenia development (Ohtani et al, 2015 ) and might be related to negative symptoms in schizophrenia (Ohtani et al, 2014 ).…”

Supplementation of Antipsychotic Treatment with the Amino Acid Sarcosine Influences Proton Magnetic Resonance Spectroscopy Parameters in Left Frontal White Matter in Patients with Schizophrenia

“…These receptors might have an excitotoxic effect on neurons, becoming a target for therapeutic agents [ 30 ]. Magnetic resonance imaging has revealed many disturbances in the function and density of glial cells, particularly the oligodendrocytes forming myelin, in the prefrontal WM of patients with schizophrenia [ 31 , 32 , 33 , 34 ]: decreased regional and global WM volumes [ 35 , 36 , 37 , 38 ], decreased ratios of magnetization transfer [ 39 , 40 ] and anisotropy of diffusion tensor imaging [ 41 , 42 , 43 , 44 , 45 ], all of which may indicate a possible pathology of myelin and WM in general [ 46 , 47 ].…”