Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia

D. F. Salisbury, N. Kuroki, K. Kasai, M. E. Shenton, R. W. McCarley
Arch Gen Psychiatry
Volume 64, Pages 521-529

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Context:Progressive brain abnormalities in schizophrenia remain controversial. Evidence of interrelated progressive functional impairment would buttress the case for structural progression. Mismatch negativity (MMN) is reduced in chronic but not first-hospitalized schizophrenia and may index progressive structural changes.

Objective: To determine whether MMN shows associations with underlying auditory cortex gray matter at first hospitalization and progressive reduction longitudinally.

Design: Cross-sectional (first hospitalization) and longitudinal (1.5-year follow-up).

Setting: A private psychiatric hospital.

Participants: Protocol entrance:MMNand magnetic resonance imaging at first hospitalization in 20 subjects with schizophrenia, 21 subjects with bipolar disorder with psychosis, and 32 control subjects. Longitudinal electrophysiologic testing:MMNin 16 subjects with schizophrenia, 17 subjects with bipolar disorder, and 20 control subjects. Longitudinal electrophysiologic testing and magnetic resonance imaging:MMNand magnetic resonance imaging in 11 subjects with schizophrenia, 13 subjects with bipolar disorder, and 13 control subjects. At each time point, reported samples were group matched for age, handedness, and parental socioeconomic status.

Interventions: Electrophysiologic testing and highresolution structural magnetic resonance imaging.

Main Outcome Measures: Mismatch negativity amplitude and Heschl gyrus and planum temporale gray matter volumes.

Results: Initially, groups did not differ in MMN amplitude. Subjects with schizophrenia showed associations between MMN and Heschl gyrus (r=0.52; P=.02) not present in the other groups. At longitudinal MMN testing, schizophrenia showed MMN reduction (P=.004). Only schizophrenia evinced longitudinal left hemisphere Heschl gyrus reduction (P=.003), highly correlated with MMN reduction (r=0.6; P=.04).>

Conclusions: At first hospitalization for schizophrenia, MMNindexed left hemisphere Heschl gyrus gray matter volume, consistent with variable progression of prehospitalization cortical reduction. Longitudinally, the interrelated progressive reduction of functional and structural measures suggests progressive pathologic processes early in schizophrenia. An active process of progressive cortical reduction presents a potential therapeutic target. Mismatch negativity may be a simple, sensitive, and inexpensive index not only of this progressive pathologic process but also of successful intervention.


Salisbury DF, Kuroki N, Kasai K, Shenton ME, McCarley RW. Progressive and interrelated functional and structural evidence of post-onset brain reduction in schizophrenia. Arch Gen Psychiatry 2007;64:521-529.


REAP, VA Merit Award(MES) 2000-2008, MIND Foundation, Middleton Award, VA Merit Award(RWM) 1998-2009, NIH/NIMH 2RO1 MH40799, NIH/NIMH 2K02 MH01110, Young Investigator NARSAD (DFS), NIH/NIMH RO1 58704, NIH RO1 MH50747, NIH RO1 052807

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