20 March 2012. Despite the current emphasis on identifying genetic lesions in schizophrenia, there are still researchers asking, Where in the brain is schizophrenia? A University of Wisconsin-Madison study, published online March 5 in the Archives of General Psychiatry, presents evidence that the reticular nucleus of the thalamus is one site that exhibits abnormal activity in people with schizophrenia.
As with other brain regions involved directly or indirectly in higher cognitive functions, the thalamus has periodically come under scrutiny in schizophrenia research. However, most findings that thalamic nuclei are structurally different or functionally abnormal in schizophrenia have been inconclusive or indirectly assessed.
In their new study, Yelena Guller and colleagues circumvent the methodological limitations of these earlier studies. Healthy controls and schizophrenia subjects received single-pulse transcranial magnetic stimulation (spTMS) to the precentral gyrus and concurrent functional magnetic resonance imaging (fMRI) to measure the response in the thalamus, medial superior frontal cortex, and insula. Subjects with schizophrenia showed reduced response in the thalamus and the cortical regions compared with controls. The functional anatomy of the thalamus suggests that the source of the abnormal response is the thalamic reticular nucleus, write the authors.
Troubled sleep in the inner chamber
The thalamus (Greek for "inner chamber" or "bedroom") acts as a relay center between subcortical areas and the cortex, plays a role in sleep regulation, arousal, and attention, and may act as a “filter” of salient and non-salient information. There is some support from disparate fields for a role of the thalamus and thalamus-related networks in the neurobiology of schizophrenia (see, e.g., Lisman, 2011). For example, Guller and colleagues note that some neuroimaging studies have reported both structural and functional differences in the thalamus between groups of people with schizophrenia and controls. Also, some studies of sensory gating, thought to involve the thalamus, find aberrant responses in people with schizophrenia.
The current research grows out of studies by coauthor Giulio Tononi, who has found that people with schizophrenia have fewer and smaller sleep spindles, waxing and waning oscillations on EEG that are initiated by the thalamic reticular nucleus (TRN) and regulated by TRN-thalamus and thalamocortical circuits (see Ferrarelli et al., 2010 and comments by Lisman, Zhang, and Otmakhova and Gottesmann). However, Guller and colleagues acknowledge that these studies, as with the imaging and sensory gating research, are limited by their inferential nature—they either do not directly assess thalamic function (or dysfunction), or they assume that the brains of people with schizophrenia perform behavioral tasks in the same way as control subjects.
Simple and direct brings results
To get around these limitations, Guller and colleagues designed an experiment in which they stimulated the cortex directly using spTMS during concurrent fMRI to measure any resulting effect on thalamus and downstream cortical areas. Unlike repetitive TMS, the authors write, spTMS “transiently excites discrete cortical patches without producing prolonged changes in cortical excitability or function.”
Although they are measuring the activity of multiple thalamic regions with fMRI, Guller and colleagues argue that one can presume to be measuring, to a great extent, TRN activity when stimulating cortex and recording in thalamus. TRN synaptic excitation makes up a very large portion of overall excitatory activity in thalamus in response to cortical stimulation.
Guller and colleagues tested 14 psychiatrically healthy subjects and 14 sex- and age-matched subjects with chronic, stable schizophrenia. As for choice of TMS stimulation target, the researchers selected the precentral gyrus, which is not known to be dysfunctional in schizophrenia.
Responses of schizophrenia subjects and healthy controls to spTMS at the cortical stimulation site (precentral gyrus) did not differ. However, thalamic responses were smaller (F1,26 = 80.79; P = 1.86 x 10-9; π2 = 0.762) and earlier peaking (F1,26 = 4.39; P = 0.05; π2 = 0.14) for schizophrenia subjects compared with healthy controls. Likewise, schizophrenia subjects showed a smaller magnitude of responses in a cortical region that was activated by the precentral gyrus stimulation, the medial superior frontal gyrus (mSFG; F1,26 = 6.56; P = 0.02; π2 = 0.20). Guller and colleagues explored possible factors underlying this difference and found schizophrenia subjects to have reduced functional connectivity between the thalamus and mSFG ((F1,26 = 32.00; P = 6.0 x 10-5; π2 = 0.55) relative to control subjects. The researchers found similar results in another activated cortical area, the insula.
According to the researchers, discriminant analysis showed that spTMS correctly identified members of the two groups (Χ2 = 36.0; P = 1.95 x 10-9; sensitivity = 85.7 percent; specificity = 100 percent; overall classification accuracy = 92.9 percent). Sham TMS showed the results could not be attributed to TMS coil discharge, and control analyses using chronicity, medication, and education factors did not predict any of the results.
The possibility that physiological abnormality of the stimulated cortical tissue accounted for the results was dismissed by Guller and colleagues, because there was no response difference between the groups at the placement of the spTMS. They also note that deficient corticothalamic signal propagation was unlikely because thalamus-precentral gyrus connectivity did not differ between the groups. “The most likely interpretation, therefore," the researchers write, "is that our results reflect aberrant functioning of the thalamus itself….”, and they suggest that future studies should examine whether this deficit more specifically stems from TRN dysfunction.—J. Meggin Hollister and Hakon Heimer.
Guller Y, Ferrarelli F, Shackman AJ, Sarasso S, Peterson MJ, Langheim FJ, Meyerand ME, Tononi G, Postle BR. Probing Thalamic Integrity in Schizophrenia Using Concurrent Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging. Arch Gen Psychiatry . 2012 Mar 5. Abstract