>Background: Cognitive deficits, a highly disabling feature of schizophrenia (SZ), are the strongest predictor of functional outcome. Recent evidence points to thalamocortical circuitry as the culprit in SZ risk and cognitive deficits. Patients with SZ have reduced sleep spindles (bursts of 12–15 Hz electroencephalogram activity during non-rapid eye movement sleep), which are initiated by the thalamic reticular nucleus and propagated to and synchronized in the cortex via thalamocortical feedback loops. Sleep spindles mediate memory consolidation and are associated with impaired sleep-dependent memory consolidation and symptom severity in SZ. Here we used resting state functional magnetic resonance imaging (fMRI) to investigate whether spindle deficits in SZ are associated with changes in the connectivity of thalamocortical networks. >Methods: Participants were chronic, medicated SZ patients (n = 26) and demographically matched healthy controls (HC, n = 29). The scanning protocol included resting-state fMRI (two 6-minute scans) and diffusion-weighted imaging on a 3T Siemens Trio scanner. We performed a seed-based functional connectivity analysis based on the FSL-Oxford thalamic connectivity atlas (7 thalamic seeds: prefrontal, premotor, primary motor, sensory, temporal, posterior parietal, and occipital). Following standard preprocessing, motion artifacts and physiological noise were regressed out, and functional connectivity was computed. All reported clusters survived a multiple comparison correction of pFDR <.05. Nocturnal sleep was monitored with polysomnography in a separate session. Sleep was scored according to standard criteria, and sleep spindles during N2 were identified using an automated wavelet spindle detector. >Results: Connectivity between the thalamus and prefrontal cortices was reduced in SZ (MNI coordinates: x = 22, y = 46, z = −6; cluster size: 442 voxels; pFDR = .04). In contrast, connectivity between the thalamus and sensory motor cortices was increased in SZ (−38, −14, 48; cluster size: 4989 voxels; pFDR = .001). Patients showed consistent, widespread reductions in sleep spindle density that reached significance in a centroparietal cluster (pFDR = .042). Reduced spindle density predicted abnormal hyperconnectivity of the thalamus with sensory motor cortex in SZ (−32, −34, 52; cluster size: 257 voxels; pFDR = .007). >Conclusion: This is the first demonstration that a prominent biomarker of SZ, sleep spindles, correlates with a regionally specific abnormality in sensory motor thalamocortical functional connectivity suggesting TRN-mediated thalamocortical circuit dysfunction. This relationship between spindle density and sensory motor thalamocortical connectivity is in line with recent animal work showing that the firing of sensory projecting TRN neurons correlate with sleep spindles (Halassa et al., 2014). Future plans include complementing functional connectivity analysis with measurements of thalamocortical white matter integrity.
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