The Thalamus and the Schizophrenia Phenotype: Failure to Replicate Reduced Volume David Arciniegas, Donald C. Rojas, Peter Teale, Jeanelle Sheeder, Elliot Sandberg, and Martin Reite Background: Thalamic abnormalities resulting in im- paired attention and information processing may form a foundation for cognitive and perceptual disturbances in schizophrenia. Measurements of the thalamus in patients with schizophrenia have shown reductions relative to normal comparison subjects. Methods: In the current project, magnetic resonance images of the brain were obtained in 10 male and 11 female subjects with paranoid-type schizophrenia, and 15 male and 12 female normal comparison subjects. Total brain and bilateral thalamic volumes were calculated. Results: There were no significant diagnosis, hemisphere, or gender differences in thalamic volumes. Conclusions: Structural thalamic abnormalities are not likely to universally and parsimoniously explain the schizophrenia phenotype. Abnormal thalamic size in pa- tients with schizophrenia should be understood as reflect- ing one of several possible structural abnormalities con- tributing to production of the schizophrenia phenotype, but must be regarded with caution unless paired with functional studies. Biol Psychiatry 1999;45:1329 –1335 © 1999 Society of Biological Psychiatry Key Words: Schizophrenia, thalamus, magnetic reso- nance imaging, volume, structure, function Introduction R ecent neuroimaging investigations in schizophrenia have suggested the thalamus may play an important role in the development of perceptual and cognitive disturbances in this disorder (Siegel et al 993; Carlsson 1988; Buchsbaum et al 1996; Flaum et al 1995 Andreasen et al 1994). The thalamus is a composite of multiple nuclei that relay and filter sensory inputs, a function which involves multiple corticostriatothalamic loops modulated by the cerebral cortex (Buchsbaum et al 1996; Carlsson 1988). Defects in sensory stimulus filtering, or gating, may play an important role in symptom formation in schizo- phrenia (Nagamoto et al 1989; Adler et al 1993; Carlsson and Carlsson 1990). Similarly, cognitive disturbances in schizophrenia may be attributable to thalamic dysfunction. Activity of the cerebral cortex, particularly frontal regions, is felt to be modulated by the thalamus (particularly the mediodorsal thalamus), in concert with the striatum and basal ganglia (Mega and Cummings 1994; Carlsson 1988). Disturbances of this system may underlie cognitive symptoms in schizo- phrenia, and have been suggested to contribute to the hypofrontally of the schizophrenia phenotype (Weinberger et al 1994; Buchsbaum et al 1996). The reductionistic hypothesis, unifying a disparate set of symptoms to defects in a central subcortical structure or circuit, has been supported by recent studies reporting structural abnormalities of the thalamus in patients with schizophrenia (Andreasen et al 1994; Flaum et al 1995). In the first clear exposition of this hypothesis, Andreasen et al (1994) reported reduction of thalamic size (predomi- nantly in its lateral aspects, where it interdigitates with the internal capsule) in a group of individuals with schizo- phrenia, using a novel method of image averaging and subtraction. Subsequent detailed segmentation of the thal- amus in coronal orientation proved difficult, with an intraclass correlation of .4 (Flaum et al 1995). The present study was undertaken to replicate these findings through determination of the best orientation for thalamic segmen- tation, detailed definition of the thalamus and its bound- aries, and quantification of thalamic volumes. Methods and Materials Subjects Patients were volunteers recruited from outpatient clinics in the Denver metropolitan area. Comparison subjects were recruited from the Denver metropolitan area and our laboratory. Forty- eight subjects participated in this study. Twenty-one were diag- From the Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado (DA, DCR, PT, JS, MR); Department of Psychiatry, Denver Veterans Affairs Medical Center, Denver, Colorado (DA, MR); Department of Radiology, University of Colorado Health Sciences Center, Denver, Colorado (ES); and Department of Radiology, Denver Veterans Affairs Medical Center, Denver, Colorado (ES). Address reprint requests to David Arciniegas, MD, Department of Psychiatry C268-68, University of Colorado Health Sciences Center, 4200 E. 9th Avenue, Denver, CO 80262, USA. Received April 8, 1997; revised August 18, 1997; accepted September 4, 1997. © 1999 Society of Biological Psychiatry 0006-3223/99/$20.00 PII S0006-3223(97)00459-9