The role of white matter microstructure in inhibitory deficits in patients with schizophrenia

Abstract

Background Inhibitory-excitatory (I-E) imbalance has increasingly been proposed as a fundamental mechanism giving rise to many schizophrenia-related pathophysiology. The integrity of I-E functions should require precise and rapid electrical signal transmission. Objective/Hypothesis We hypothesized that part of the I-E abnormality in schizophrenia may originate from their known abnormal white matter connectivity that may interfere the I-E functions. Methods We test this using short-interval intracortical inhibition (SICI) vs. intracortical facilitation (ICF) which is a non-invasive measurement of I-E signaling. SICI-ICF from left motor cortex and white matter microstructure were assessed in schizophrenia patients and healthy controls. Results Schizophrenia patients showed significantly reduced SICI but not ICF. White matter microstructure as measured by fraction anisotropy (FA) in diffusion tensor imaging had a significant effect on SICI in patients, such that weaker SICI was associated with lower FA in several white matter tracts, most strongly with left corona radiata (r=−0.68, p=0.0002) that contains the fibers connecting with left motor cortex. Left corticospinal tract, which carries the motor fibers to peripheral muscular output, also showed significant correlation with SICI (r=−0.54, p=0.005). Mediation analysis revealed that much of the schizophrenia disease effect on SICI can be accounted for by mediation through left corona radiata. SICI was also significantly associated with the performance of processing speed in patients. Conclusion This study demonstrated the importance of structural circuitry integrity in inhibitory signaling in schizophrenia, and encouraged modeling the I-E dysfunction in schizophrenia from a circuitry perspective.

Aberrant Middle Prefrontal-Motor Cortex Connectivity Mediates Motor Inhibitory Biomarker in Schizophrenia

“…Therefore, we included only left CR in the study(Figure 3A). Some of the SICI and DTI data were reported in our previous work(35,38). None of the resting-state fMRI data were previously reported.…”

“…The white matter directly under the left motor cortex and connecting motor cortex to the frontal area is the left corona radiata(CR). In our previous research, by exploring SICI-related white matter tracts (25 tracts), we found left CR was also the only tract whose association with SICI in schizophrenia survived Bonferroni correction(35). Therefore, we included only left CR in the study(Figure 3A).…”

“…Previous studies suggested that SICI is a marker reflecting motor cortex GABAA-receptor function(34). Besides the neurochemical explanation of SICI, our previous research hinted another important mechanism: by exploring the association between SICI and all major white matter tracts, we found corticospinal tract, internal capsule, and corona radiata was associated with SICI in schizophrenia patients(35). Corona radiata in particular connects the frontal and other cortical areas to motor cortex, implying a possible cortico-cortical fronto-motor modulation in schizophrenia.…”

“…Paired-pulse TMS(ppTMS) with 1 and 3 ms ISIs(35,39) were used to induce short-interval intracortical inhibition(SICI). For each SICI trial, a subthreshold conditioning stimulus (80% RMT) was followed by a suprathreshold stimulation (120% RMT).…”

“…The details of DTI data preprocessing were described in Supplementary Material and our previous studies(35, 43). Based on a tract-based spatial statistics method(44), fractional anisotropy(FA) images were obtained, spatially normalized to the JHU atlas(45) which separated white matter into different tracts.…”