Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging

Abstract

Context Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method. Objective Test the hypothesis that direct physiological stimulation of cortex will produce an abnormal thalamic response in individuals with schizophrenia. Design We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically-connected regions (thalamus, medial superior frontal cortex [mSFG], insula) using concurrent functional magnetic resonance imaging (fMRI). The mean hemodynamic response from these regions was fit with the sum of two gamma functions and response parameters were compared across groups. Setting Academic research laboratory. Participants Patients with schizophrenia and sex- and age- matched psychiatrically healthy subjects were recruited from the community. Main Outcome Measures Peak amplitude of the thalamic hemodynamic response to spTMS of precentral gyrus. Results spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared to healthy subjects, schizophrenia patients showed a reduced response to spTMS in the thalamus (P=1.86 × 10−9) and mSFG (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-mSFG and thalamus-insula connectivity in schizophrenia patients compared to control subjects. Conclusions Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

Brain-Wide Analysis of Functional Connectivity in First-Episode and Chronic Stages of Schizophrenia

“…The thalamus is connected to all cortical areas and conveys information to the neocortex, including information from the basal ganglia. Though a number of other studies have identified thalamic connectivity changes in the chronic stage of schizophrenia, 17,19,[22][23][24] such studies provide little information about early illness pathophysiology. In contrast, studies of FE schizophrenia have the advantage to specify brain changes at illness onset, thus providing crucial information about the pathogenesis of schizophrenia.…”

“…[17][18][19][20][21][22][23][24] Despite numerous leads, the reported findings are somewhat inconsistent and the core regions associated with the pathogenesis of schizophrenia still remain controversial.…”

Schizophrenia as a disturbance of cortical sensory maps

“…Schizophrenia is in the recent literature increasingly being recognized as a disorder of internal brain dynamics [6][7][8][9][10]. Accordingly, in the following sections, thalamic abnormalities in schizophrenia will be reviewed followed by a discussion of how sleep brain rhythms are affected in this illness.…”

Is Neuroscience Compatible with a Belief in God? A Perspective from the Thalamus

“…Namely, this illness is associated with thalamic abnormalities that affect the HO thalamic relays, which are tasked with relaying information between cortical areas. In an interesting study that combined functional neuroimaging and transcranial magnetic stimulation (TMS), Guller et al (2012) found that TMS stimulation of the precentral gyrus in individuals with schizophreArch Neurosci. 2017; 4(3):e57105.nia resulted in reduced thalamic activation, which was correlated with the severity of positive symptoms in those individuals (8).…”

“…In an interesting study that combined functional neuroimaging and transcranial magnetic stimulation (TMS), Guller et al (2012) found that TMS stimulation of the precentral gyrus in individuals with schizophreArch Neurosci. 2017; 4(3):e57105.nia resulted in reduced thalamic activation, which was correlated with the severity of positive symptoms in those individuals (8). They also reported reduced secondary cortical activation, which was statistically related to the reduced thalamic activation.…”