Decreased interhemispheric coordination in schizophrenia: A resting state fMRI study

Abstract

Schizophrenia has been increasingly conceptualized as a disorder of brain connectivity, in large part due to findings emerging from white matter and functional connectivity (FC) studies. This work has focused primarily on within-hemispheric connectivity, however some evidence has suggested abnormalities in callosal structure and interhemispheric interaction. Here we examined functional connectivity between homotopic points in the brain using a technique called voxel-mirrored homotopic connectivity (VMHC). We performed VMHC analyses on resting state fMRI data from 23 healthy controls and 25 patients with schizophrenia or schizoaffective disorder. We found highly significant reductions in VMHC in patients for a number of regions, particularly the occipital lobe, the thalamus, and the cerebellum. No regions of increased VMHC were detected in patients. VMHC in the postcentral gyrus extending into the precentral gyrus was correlated with PANSS Total scores. These results show substantial impairment of interhemispheric coordination in schizophrenia.

Introduction

Interhemispheric interaction is primarily mediated by the brain's commissural system, including the corpus callosum, anterior commissure, posterior commissure, interthalamic adhesions, and cerebellar commissures (Hoptman and Davidson, 1994). Most callosal fibers connect homotopic regions across the two hemispheres (LaMantia and Rakic, 1990). Resting state fMRI (rsfMRI) is a technique that permits assessment of inter- as well as intrahemispheric functional connectivity (FC). The present study uses rsfMRI to assess the integrity of interhemispheric interaction in schizophrenia.

Since the early 1960s, it has been known that humans who have had forebrain commissures sectioned, including the corpus callosum, show disconnection phenomena on divided sensory spatial field tasks (Gazzaniga et al., 1962, Geschwind and Kaplan, 1962, Nebes, 1972). Deficits in sustained attention (Dimond, 1979a, Dimond, 1979b) and other cognitive processes have also been observed in split brain patients. The bulk of studies on laterally presented cognitive tasks in healthy individuals suggest that there is advantage to bihemispheric processing (Banich and Belger, 1990, Belger and Banich, 1992), provided that each hemisphere has competence at the given task. Moreover, interhemispheric interaction may be particularly important in the strategic deployment of attentional resources in response to task demands (Levy and Trevarthen, 1976).

Within sensory regions, Sergent and Bindra (1981) proposed that the left visual hemisphere is biased towards processing of high spatial frequencies, whereas the right hemisphere is more specialized for low spatial frequencies. This distinction has been mapped onto a local/global dimension (Ivry and Robertson, 1998, Robertson and Ivry, 2000). The right hemisphere also appears to be specialized for line orientation (Umilta et al., 1974), line bisection (Bowers and Heilman, 1980, Foxe et al., 2003), and mental rotation (Robertson et al., 1987). Given the advantages for interhemispheric interaction and the dysconnectivity processes implicated in schizophrenia, it would not be surprising if interhemispheric interaction deficits played an important role in the cognitive deficits, psychiatric symptoms, and sensory abnormalities seen in the disorder. Thus, deficits in interhemispheric interaction may contribute to sensory/cognitive impairments in schizophrenia.

The evidence for interhemispheric interaction deficits in schizophrenia predates recent conceptualizations of schizophrenia as a disorder of dysconnectivity (Friston and Frith, 1995, Bullmore et al., 1997, Stephan et al., 2009) and is fairly consistent, despite the fact that it has been underemphasized. Early postmortem studies found increased callosal thickness (Bigelow and Rosenthal, 1972), but more recent postmortem studies (Casanova et al., 1990), and the vast majority of in vivo imaging studies have found reduced callosal thickness or length, and/or altered shape in schizophrenia (Woodruff et al., 1995, Arnone et al., 2008). White matter density abnormalities in the corpus callosum also have been observed (Hulshoff Pol et al., 2004). Moreover, Highley et al. (1999) found reduced fiber density in the anterior commissure in women, but not men, with schizophrenia.

A number of diffusion tensor imaging (DTI) studies have found reduced fractional anisotropy (FA) in the corpus callosum in schizophrenia (Ardekani et al., 2003, Kubicki et al., 2008). It is likely that DTI studies understate the extent of callosal deficits in schizophrenia, in part because they are typically plagued by low image resolution. Many DTI sequences are obtained in the axial plane, which compounds this problem because it maximizes partial volume effects in the callosum. Indeed, in voxelwise studies, Dougherty noted that FA effect sizes are smallest in the corpus callosum (Dougherty et al., 2005), most likely because its thin dorsoventral extent is particularly susceptible to intersubject registration errors and partial volume effects. Nonetheless, recent DTI work has suggested interhemispheric hypoconnectivity in patients with schizophrenia and their relatives (Whitford et al., 2010, Knochel et al., 2012), which in turn predict interhemispheric transfer time (Whitford et al., 2011) and psychotic symptoms (Whitford et al., 2010).

Relatively few behavioral studies have investigated functional interhemispheric interaction in schizophrenia. The Poffenberger (1912) paradigm has long been used to measure interhemispheric dynamics. In this task, simple stimuli are presented either ipsilateral or contralateral to the response hand. The contralateral − ipsilateral difference in reaction time is taken as an estimate of interhemispheric transfer time, and is typically greater than 0. Patients with schizophrenia showed a prolongation of the ipsilateral advantage (Shelton and Knight, 1984), suggesting impaired interhemispheric transfer efficiency. Another early study showed that patients with schizophrenia are impaired on cross-localization tasks on which patients with callosal agenesis are also impaired (Craft et al., 1987). Patients also show deficits consistent with the callosum's role in optimizing processing under computationally complex situations. Under such conditions, healthy individuals show an advantage to processing information presented bilaterally compared to the same amount of information presented initially to one hemisphere alone (Belger and Banich, 1992). This bilateral advantage suggests that it can be more efficient for the two hemispheres to interact than for one hemisphere to perform all of the processing. The bilateral advantage is absent in patients with schizophrenia (Barnett et al., 2007), suggesting a deficit in interhemispheric interaction in schizophrenia.

Psychophysiological measures of interhemispheric functional interaction also have been observed to be abnormal in schizophrenia. For example, in a word task, healthy controls show increased event related potential (ERP) amplitudes to bilateral (and identical) stimulation compared to unilateral stimulation. Patients showed a reduction in this “bilateral redundancy gain” (Mohr et al., 2008). In addition, deficits in electroencephalographic (EEG) measures of interhemispheric alpha band coherence have been found in patients with schizophrenia (Morrison-Stewart et al., 1996) and in individuals at genetic risk for schizophrenia (Winterer et al., 2001). Another longitudinal study found that reduced symptom severity in schizophrenia was associated with higher EEG interhemispheric beta coherence (Higashima et al., 2006), although some studies have found higher interhemispheric coherence in both never-medicated patients with schizophrenia (Wada et al., 1998) and in siblings of patients with schizophrenia (Mann et al., 1997).

Despite the evidence of interhemispheric interaction deficits in schizophrenia, there are no studies examining FC between homotopic brain sites, which are the gray matter regions that are connected by commissural fibers. Here we evaluated interhemispheric resting state FC in patients with schizophrenia. We used a measure, voxel-mirrored homotopic connectivity (VMHC; (Zuo et al., 2010)), in which the time series for each voxel in one hemisphere was correlated with that of its homotopic voxel (i.e., from the other hemisphere). Similar methodologies have shown deficits in interhemispheric functional connectivity in autism (Anderson et al., 2011), showing that the method is sensitive to abnormal interhemispheric FC in psychopathology. Given the extensive evidence of both structural and functional disconnections in schizophrenia, we expected to observe reductions in homotopic connectivity in schizophrenia.