Abnormalities in hemispheric specialization of caudate nucleus connectivity in schizophrenia

Abstract

Importance: Hemispheric specialization of the human brain is a marker of successful neurodevelopment. Altered brain asymmetry that has been repeatedly reported in schizophrenia may represent consequences of disrupted neurodevelopment in the disorder. However, a complete picture of functional specialization in the schizophrenic brain and its connectional substrates is yet to be unveiled.

Objectives: To quantify intrinsic hemispheric specialization at cortical and subcortical levels and to reveal potential disease effects in schizophrenia.

Design, setting, and participants: Resting-state functional connectivity magnetic resonance imaging has been previously used to quantitatively measure hemispheric specialization in healthy individuals in a reliable manner. We quantified the intrinsic hemispheric specialization at the whole brain level in 31 patients with schizophrenia and 37 demographically matched healthy controls from November 28, 2007, through June 29, 2010, using resting-state functional magnetic resonance imaging.

Results: The caudate nucleus and cortical regions with connections to the caudate nucleus had markedly abnormal hemispheric specialization in schizophrenia. Compared with healthy controls, patients exhibited weaker specialization in the left, but the opposite pattern in the right, caudate nucleus (P < .001). Patients with schizophrenia also had a disruption of the interhemispheric coordination among the cortical regions with connections to the caudate nucleus. A linear classifier based on the specialization of the caudate nucleus distinguished patients from controls with a classification accuracy of 74% (with a sensitivity of 68% and a specificity of 78%).

Conclusions and relevance: These data suggest that hemispheric specialization could serve as a potential imaging biomarker of schizophrenia that, compared with task-based functional magnetic resonance imaging measures, is less prone to the confounding effects of variation in task compliance, cognitive ability, and command of language.

Figure 1. Hemispheric specialization in specific cortical regions is altered in schizophrenia

A. Hemispheric specialization in the healthy control group (n=37). Strong hemispheric specialization was observed in the association cortices including the lateral prefrontal, inferior parietal and temporal regions. Visual, somatosensory and motor cortices exhibited minimal autonomy. In the left hemisphere, strong specialization was observed in inferior prefrontal and temporal regions overlapping the default network and areas involved in language processing. In the right hemisphere, strong specialization was observed in the insula, angular gyrus and supramarginal gyrus that are engaged in attention control. B. Hemispheric specialization in the patient group (n=31). The patterns of hemispheric specialization largely replicate between the patient and the control sample. However, subtle differences seem to emerge in the frontal and the midline regions. C. Cortical regions showing patient/control difference in specialization. For each voxel, the mean AI value in the patient group was subtracted from the mean AI value in the control group. The maps show uncorrected mean difference between the two groups. Schizophrenia patients showed decreased AI values in the left anterior cingulated cortex (ACC), left medial prefrontal cortex (mPFC), left inferior frontal gyrus (IFG) and in right frontal and parietal midline regions. Increased AI values in schizophrenia patients could be detected in the right ACC and mPFC.

Figure 2. Schizophrenia patients show decreased left-hemispheric and increased right-hemispheric specialization of the caudate nucleus

AI values were averaged within five subcortical regions, including two striatal structures (caudate nucleus and putamen), two limbic structures (hippocampus and amygdala), and the thalamus. Bars represent the mean AI value across subjects with the respective subcortical structure. Error bars indicate two standard errors. In the healthy control group (white bars) AI values were generally higher in the left than in the right hemisphere. In the patient group (gray bars) this overall pattern was generally less pronounced. Specifically, schizophrenia patients exhibited significantly decreased left- but increased right- hemispheric specialization of the caudate nucleus as compared to the healthy controls (p<0.005, respectively).

Figure 3. Schizophrenia patients show segregated left-hemispheric and right-hemispheric networks connected to the caudate nucleus and the putamen

According to the mathematical definition of the autonomy index, for a specific network spanning across two hemispheres, a negative correlation between left and right hemispheric AI values should be expected. All subcortical structures of interest showed this strong negative correlation in the healthy control group (solid line, white circles). In schizophrenia patients, this characteristic anti-correlation was reduced in the caudate nucleus and the putamen as compared to their healthy controls (dotted line, gray triangles), indicating a disruption of interconnection and coordination between the two hemispheres.

Figure 4. Hemispheric specialization is altered in subcortical and cortical networks associated with the caudate nucleus

A. Due to the decreased left- and increased right-hemispheric caudate specialization, the difference between left and right AI values was significantly diminished in schizophrenia patients (gray bar) as compared to healthy controls (white bar) (p<0.0005). B. This diminished difference between left- and right- hemispheric AI values could be replicated in caudate-connected cortical regions (p<0.01). The cortical mask was derived from a correlation analysis in 1000 healthy subjects, in which the caudate nucleus served as the seed region. Cortical AI values were averaged within the boundaries of this mask for each individual subject, and the individual mean values were averaged within each of the two groups.