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Schizophrenia and Neurodegeneration—Case Bolstered by MRI, Electrophysiology

22 May 2007. Shortly after the initial diagnosis of schizophrenia, auditory brain regions suffer both functional and structural decline, according to results of a longitudinal study published in this month’s Archives of General Psychiatry. Dean Salisbury and colleagues at Harvard Medical School, Boston, found that deficits in mismatch negativity, an electrophysiological phenomenon linked to the processing of sound, parallels volume reductions in the Heschl gyrus, a region of the cerebral cortex housing the auditory center. The data suggest that structural and functional changes are interrelated, and bolsters the case that schizophrenia is, to some extent, a degenerative disease.

That neurodegeneration may help explain schizophrenia is not a new idea: Kraepelin's original conception of the disease, influenced by the work of his contemporary, Alzheimer, included the concept of neurodegeneration. More recently, many studies have documented losses in white and gray matter volume and enlargement of the brain ventricles in patients with the illness (see, for example, Ho et al., 2003; Mathalon et al., 2001), especially around the time of onset (see Molina et al., 2004 and Sporn et al., 2003). But many of these studies have been small and/or complicated by confounding factors, such as prescription medication, and the alternative (and perhaps complementary) neurodevelopmental hypothesis of schizophrenia, which suggests that the illness reflects aberrant development of neural networks prior to onset, continues to receive strong support (see Weinberger, 1987; Murray and Lewis, 1987). "Whether schizophrenia involves progressive brain change is more than an esoteric issue," write Salisbury and colleagues. "Progressive change presupposes an active process that can be targeted pharmacologically before it has completed its insidious attack, whereas static brain lesions reflect the end stage of completed deterioration."

If gray matter losses do underlie this illness, then “the longitudinal testing of first-episode patients should reveal not only progressive reductions in brain structure, but also progressive worsening of functional measures of the integrity of the shrinking cortical areas,” write the authors. Their findings may satisfy those criteria.

Salisbury and colleagues measured mismatch negativity (MMN; see SRF related news story) and took MRI brain scans of 20 people with schizophrenia soon after their first hospitalization for psychosis. Normal individuals (n = 31) and people with bipolar disorder (n = 21) were also tested for comparison. Some subjects were retested after approximately 18 months. Salisbury and colleagues found that at initial testing, the left Heschl gyrus (HG) was significantly smaller in the schizophrenia group than in the control or bipolar groups, and that the MMN amplitude in the schizophrenia group correlated with the left HG volume. On follow-up, only the people with schizophrenia as a group showed significant losses in MMN amplitude, though some normal and bipolar subjects did also show lower MMN values. But the MMN losses in the schizophrenia subjects were also accompanied by significant and highly correlated reductions in the volume of the left HG. “These interrelated functional and structural measures support the presence of a late progressive lesion in schizophrenia,” write the authors, and they suggest that MMN may be a useful measure of successful intervention in peri-onset schizophrenia.

The authors caution that MRI volumetric data is sensitive to a variety of factors including hydration and medication, which can cause cortical volume changes—both increases and decreases. In particular, atypical antipsychotics have been shown to protect against gray matter loss (see Lieberman et al., 2005), but the authors found no significant differences in MMN and HG decline between patients taking these drugs at follow-up and those who were not, suggesting that the medication may not prevent the structural and related functional decline. This finding speaks to a major dilemma facing clinicians—how early to treat patients suspected of having schizophrenia. There are indications that early treatment can lead to improved clinical outcomes, but whether that benefit extends to the prodromal phase of the disease is still under debate (see SRF related news story and SRF news story).—Tom Fagan.

Reference:
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 May;64(5):521-9. Abstract

 
Comments on News and Primary Papers
Comment by:  Dan Javitt, SRF Advisor
Submitted 29 May 2007 Posted 29 May 2007

Salisbury et al., in the May 2007 issue of Archives of General Psychiatry, demonstrate associated progressive reductions in mismatch negativity (MMN) amplitude and Heschl’s gyrus reduction in schizophrenia. These findings provide strong support for involvement of auditory cortex in the pathogenesis of schizophrenia, and demonstrate that pathological changes in the illness are not confined to specific brain regions, such as prefrontal cortex, that receive the preponderance of attention.

Further, the manuscript helps resolve an important current controversy in the MMN literature. Deficits in MMN generation have been among the most consistent findings in chronic schizophrenia, with a recent meta-analysis showing large (~1 sd unit) effect size MMN reductions across studies (Umbricht et al., 2005). As noted by Salisbury et al., however, deficits have not been observed in first-episode patients (Salisbury et al., 2002; Umbricht et al., 2006)....  Read more


View all comments by Dan Javitt

Comment by:  Lei Wang
Submitted 5 June 2007 Posted 5 June 2007

The authors reported a cross-sectional (first hospitalization or within 1 year of first hospitalization) and longitudinal (1.5-year follow-up) study of electrophysiologic testing (mismatch negativity, or MMN, amplitude) and high-resolution structural magnetic resonance imaging of Heschl gyrus and planum temporale gray matter volumes. Schizophrenia subjects showed longitudinal volume reduction of left hemisphere Heschl gyrus (P = .003), which was highly correlated with MMN reduction (r = 0.6; P = .04). The interrelated progressive reduction of functional and structural measures suggests progressive pathologic processes early in schizophrenia. The design of the study helped minimize the effect of medication, the authors commented, therefore allowing the interpretation that brain change is due to disease progression.

From an imaging perspective, this is a straightforward longitudinal study of brain structure following previously published image processing and measuring protocols (Kasai et al., 2003). T1- and T2-weighted MR scans...  Read more


View all comments by Lei Wang

Comment by:  Robert McClure (Disclosure)
Submitted 10 June 2007 Posted 10 June 2007

Longitudinal increases in volume of the lateral ventricles and decreases in brain volume—progressive changes—are often observed over time early in the course of schizophrenia. There is not uniform agreement over the proper interpretation of these changes, prompting vigorous, healthy debate among investigators. A major point of contention appears to be whether these volume changes actually constitute evidence of active disease progression.

In the current study, the authors seek to bolster the case for structural progression by demonstrating evidence of interrelated progressive functional impairment. They buttress the case for structural progression by demonstrating a relationship between worsening deficit in mismatch negativity and auditory cortex volume decreases.

Identification of a direct causal relationship between the underlying pathophysiology of schizophrenia and volume losses observed early in the illness would conclusively demonstrate structural progression. Such a direct link has not yet been established, so the results of this study constitute...  Read more


View all comments by Robert McClure
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