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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 1 ; 64(5):521-9. Pubmed 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). An unknown issue was whether the discrepancy between first-episode and chronic patients was due to within-subject change (the “degeneration” hypothesis), or whether those patients with small MMN at entry tended to be retained disproportionately in chronic samples because of the relationship between MMN generation and global outcome (e.g., Light and Braff, 2005) (the “distillation” hypothesis).

The present study suggests that at least some patients show reductions of both MMN amplitude and left HG volumes over time, lending at least partial support for the degeneration hypothesis. This finding is important in that it shows that the pathological process contributing to cognitive impairment in schizophrenia continues beyond first episode, and may be a target for pro-cognitive interventions. It should be noted that the degeneration continued despite treatment with atypical, as well as typical, antipsychotic medication.

As noted by Salisbury et al., the change in MR volume in schizophrenia is best conceived as atrophy of neurons, rather than degeneration. On a histological level, the volume reductions noted on MR correspond with reduced pyramidal cell size in postmortem tissue (e.g., Sweet et al., 2004). Interestingly, postmortem studies have yet to show volumetric reductions in HG despite the change in some compartments, suggesting that MR may be detecting changes in tissue parameters that are not apparent in postmortem histological examination. This study also complements a recent diffusion tensor imaging (DTI) study that showed correlations between white matter changes in auditory projection pathways and auditory processing deficits in schizophrenia (Leitman et al., 2007). The relationship between white matter and grey matter pathology requires further investigation.

There are additional lessons hidden in the Salisbury et al. study. Given the relationship between reduced MMN generation (a functional measure) and cortical volume (a structural measure), there is a strong tendency to assume that structural changes are the cause of functional changes. The findings by Salisbury et al., as well as the extrapolation to postmortem histological studies, argue strongly against such an interpretation. For example, in the Salisbury et al. study, the change in left HG volume from time 1 to time 2 was only 6 percent, whereas MMN declined by 33 percent over the same period of time. At time 2, HG volumes were only 2 percent smaller in schizophrenia patients vs. controls, whereas MMN was 35 percent smaller. These findings suggest that simple volume loss does not cause the reduction in MMN. Further, even though MMN reduction seems to stabilize following the first 1.5 years (e.g., Umbricht et al., 2006; Javitt et al., 1995), this may not be the case with volumetric deficits. Thus, in a prior sample of chronic patients, this same group reported reductions of 13 percent in HG volume (Hirayasu et al., 2000), as opposed to the 2 percent reduction observed in patients following 1.5-year follow-up. Rather than suggesting a primary role of degeneration, this suggests a “use it or lose it” relationship within auditory cortex, wherein persistent reduction of activity may lead over time to structural involution. Even in postmortem studies (e.g., Sweet et al., 2004), pyramidal cell volumes are reduced by only 10 percent, whereas MMN in chronic schizophrenia may be reduced by 40 percent or more (e.g., Salisbury et al., 2002; Umbricht et al., 2006).

As noted by Salisbury et al., acute treatment with NMDA antagonists leads to reduced MMN amplitude in both human (Umbricht et al., 2000) and animal (Javitt et al., 1996) models. NMDA receptors also play a critical role in synaptic spine development and maintenance (Matsuzaki et al., 2004). A possible explanation, therefore, is that reduced NMDA activity in auditory cortex leads to both MMN reductions and reductions in spine density. Alternatively, primary alteration in subpopulations of cortical glutamatergic cells could trigger the sequence of events leading to reduced MMN generation.

There are several other intriguing features to the dataset. For example, at baseline, there were several controls who had larger than median HG volumes, but nevertheless failed to generate MMN (i.e., <1 μV). In schizophrenia patients, this sector of the plot was entirely empty and the only subjects who failed to generate MMN were those with small HG volumes. This suggests that there may be fundamental differences in structure/function relationships. It is almost as interesting to know why some controls fail to generate MMN despite having adequate HG size, as it is to know why HG is reduced in schizophrenia.

The finding that the relationships hold only for left, not right, HG, also is worthy of further investigation, as is the finding that right HG volumes are reduced even at first episode and do not decline further. Finally, the correlation on reduced MMN amplitude at Fz with reduced HG volume reiterates once again the role of auditory, rather than frontal, cortices in mediating MMN generation deficits in schizophrenia.

View all comments by Dan JavittComment 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 were acquired using the same sequence and on the same scanner for all subjects and at all time points. All baseline and follow-up MR scans were bias-field corrected and used in a fully automated segmentation algorithm for tissue classification, and then realigned to standard coordinate space and re-sampled to isotropic voxel resolution for application of standard manual segmentation protocols. Intracranial content was also estimated. Inter-rater and intra-rater reliability for segmentation of the Heschl gyrus and planum temporale was very high (volume ICC ranging from 0.95 to 0.99) (Kasai et al., 2003).

The authors showed in their earlier paper (Kasai et al., 2003) that using this approach, the time-dependent change in the volume of intracranial content did not correlate with time-dependent volume changes of brain structures. While this is reassuring, a trend-level decrease of intracranial content in time (p = 0.065), however, does raise the possibility of some systematic bias such as scanner drift resulting in global scaling, especially considering the subjects’ ages of 21-24 years. Some solutions such as scaling the follow-up scans with respect to the baseline scans could be evaluated (Freeborough and Fox, 1997).

This well-designed and well-presented study adds to a growing body of evidence that longitudinal structural neuroimaging is an effective way to detect progressive changes in specific brain structure in patients with schizophrenia. The results of this study contribute to the debate over whether the pathogenesis of schizophrenia includes a neurodegenerative as well as neurodevelopmental component.

View all comments by Lei WangComment 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 only indirect evidence that structural progression is tied to the emergence of functional impairment. Results of longitudinal MRI studies are useful for identify factors potentially associated with these volume changes, including altered neurodevelopment, disease progression, mismatch negativity, antipsychotic medications, and yet unidentified factors. Until the underlying etiology of schizophrenia is known, what underlies longitudinal volume change in schizophrenia is unlikely to be determined.

Future research should focus on specifying the neurodevelopmental mechanisms that contribute to the cortical pathology central to schizophrenia.

View all comments by Robert McClure