Increased Thalamocortical Connectivity in Schizophrenia Correlates With Sleep Spindle Deficits: Evidence for a Common Pathophysiology

Abstract

Background: Converging evidence implicates abnormal thalamocortical interactions in the pathophysiology of schizophrenia. This evidence includes consistent findings of increased resting-state functional connectivity of the thalamus with somatosensory and motor cortex during wake and reduced spindle activity during sleep. We hypothesized that these abnormalities would be correlated, reflecting a common mechanism: reduced inhibition of thalamocortical neurons by the thalamic reticular nucleus (TRN). The TRN is the major inhibitory nucleus of the thalamus and is abnormal in schizophrenia. Reduced TRN inhibition would be expected to lead to increased and less filtered thalamic relay of sensory and motor information to the cortex during wake and reduced burst firing necessary for spindle initiation during sleep.

Methods: Overnight polysomnography and resting-state functional connectivity magnetic resonance imaging were performed in 26 outpatients with schizophrenia and 30 demographically matched healthy individuals. We examined the relations of sleep spindle density during stage 2 non-rapid eye movement sleep with connectivity of the thalamus to the cortex during wakeful rest.

Results: As in prior studies, patients with schizophrenia exhibited increased functional connectivity of the thalamus with bilateral somatosensory and motor cortex and reduced sleep spindle density. Spindle density inversely correlated with thalamocortical connectivity, including in somotosensory and motor cortex, regardless of diagnosis.

Conclusions: These findings link two biomarkers of schizophrenia-the sleep spindle density deficit and abnormally increased thalamocortical functional connectivity-and point to deficient TRN inhibition as a plausible mechanism. If TRN-mediated thalamocortical dysfunction increases risk for schizophrenia and contributes to its manifestations, understanding its mechanism could guide the development of targeted interventions.

Keywords: Functional connectivity; Schizophrenia; Sleep; Sleep spindles; Thalamic reticular nucleus; Thalamus.

Figure 1:

Group differences. (A) Statistical map of group differences in thalamocortical functional connectivity displayed on the cortical surface of the template brain at p_corrected≤05. Greater connectivity in schizophrenia (SZ) is depicted in blue. There were no regions of significantly greater connectivity in healthy controls (HC). (B) Dot plot of averaged thalamocortical connectivity in the group difference mask. Black bars represent group means. (C) Topographical map of group differences in sleep spindle density, warm colors represent higher spindle density in healthy controls. The electrodes circled in white form a significant cluster. (D) Dot plot of averaged sleep spindle density in the cluster of electrodes with significantly reduced spindle density. Black bars represent group means.

Figure 2:

Relations of sleep spindle density with thalamocortical connectivity. (A) Group differences in thalamocortical connectivity (blue), regions showing significant (p_corrected≤.05) inverse correlations of average spindle density with thalamocortical connectivity (yellow) and their overlap (green) displayed on the cortical surface of the template brain. No regions showed significant positive correlations. (B) Thalamocortical connectivity in regions showing a significant inverse correlation (yellow and green in 2A) is plotted against average spindle density.

Figure 3.

Relations of thalamocortical connectivity with cortical connectivity. (A) Dot plot of the averaged cortico-cortical connectivity in the regions that show thalamocortical hyperconnectivity in schizophrenia. Black bars represent group means. (B) Thalamocortical connectivity is plotted against cortico-cortical connectivity within the same mask. The slopes of the relations differ significantly between groups.