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.

Keywords: Corona radiata; Diffusion tensor imaging; Intracortical inhibition; Schizophrenia; Stimulation; White matter.

Figure 1

Illustration of TMS site and major motor related white matter tracts to generate SICI and ICF. Green coil represents the TMS site over the left motor cortex. Upper limb related motor cortex was marked in red.

Figure 2

Inhibition and facilitation of ppTMS. ppTMS effects were represented as ratios to TS alone. Therefore, ratios below (above) 1 indicates inhibition (facilitation). Both healthy controls (HC; blue, circle) and patients with schizophrenia (SCZ; red, triangle) showed inhibition at 1 and 3 ms ISIs and facilitationat 9 and 12 ms interstimulus intervals (ISIs) (covered by gray bars). Further, as in previous literature, ppTMS effects were merged at 1 and 3 ms ISIs to indicate inhibitory effect and at 9 and 12 ms ISIs to indicate facilitatory effect. Patients with schizophrenia showed deficit of inhibition but not facilitation as compared with healthy controls.SICI: short-interval intracortical inhibition; ICF: intracortical facilitation. Error bar indicates S.E.. *p<0.05. n.s., non-significant.

Figure 3

Relationship between short-interval intracortical inhibition (SICI)and the fractional anistropy (FA) of white matter tracts in patients. X-axis are partial correlations after controlling for age. *p<0.05; **significant after Bonferroni correction for multiple comparisons.

Figure 4

The relationship between short-interval intracortical inhibition (SICI) and fractional anisotropy (FA) of anterior corona radiata (CR) and processing speed (PS), controlling for age. For schizophrenia patients (SCZ, red dot and red line), but not healthy controls (HC, blue dot and blue line), less left corona radiata microstructure was associated with less intracortical inhibition (A). SCZ patients with slow processing speed showed less inhibition (B). Mediation of white matter microstructure of left corona radiata (CR) on the relationship between diagnosis and SICI (C). The significant effects (path C) of diagnosis on SICI was largely removed with left CR as a mediator (path C’). Specifically, the effects of disgnosis on FA of left CR (path A) and left CR on SICI (path B) were significant. T scores were shown on each path. *p<0.05.