Several results support the presence of an active period of peri-onset cortical reduction in schizophrenia. At first hospitalization, only subjects with schizophrenia showed an abnormal brain volume–brain activity correlation between left hemisphere Heschl gyrus gray matter cortical volume and MMN amplitude, despite normal group mean amplitude and gray matter volume. This is consistent with a similar association between MMN and Heschl gyrus volume in chronic schizophrenia.46
Subjects with psychotic bipolar disorder and control subjects likely had substantially more cortex than necessary to generate MMN and, hence, no statistical relationship between the size of their cortex and the size of their electrical response. The abnormal brain structure-function relationship at first hospitalization is consistent with progressive cortical reduction before the emergence of psychotic symptoms and cannot be explained by medication effects because most subjects were only acutely medicated after hospitalization. However, subjects with abnormally small MMN and Heschl gyrus volumes may well have had those abnormalities from birth, and only longitudinal testing can prove progressive reductions.
Longitudinal testing of MMN showed that nearly all subjects with schizophrenia showed MMN amplitude reduction and left hemisphere Heschl gyrus gray matter volume reduction. Of primary importance was a tight relationship between MMN reduction and gray matter loss. Highly related progressive abnormalities of functional and structural measures are present in schizophrenia after the first hospitalization. Therefore, MMN at initial hospitalization may serve as an index of the course of prehospitalization brain reduction in schizophrenia, and MMN subsequently may index continued cortical volume reduction.
Our ideas about the causes and course of schizophrenia need be readdressed. In the static lesion model of schizophrenia, which has been highly influential, prenatal or perinatal developmental abnormalities or insults form a primary static lesion with emergence of symptoms in young adulthood due to dysfunction of brain areas maturing later in life.8
Alternative theories of combined early static and late progressive lesions have been proposed (eg, see Waddington et al47
and Pantelis et al48
), wherein the prenatal or perinatal neurodevelopmental abnormality interacts with some form of late-adolescent cortical gray matter reduction synergistically to cause psychosis. The MRI and MMN data from this study support the presence of a late progressive lesion.
The underlying biological mechanism of this late lesion is unknown. The schizophrenic brain as revealed through postmortem histologic examination is characterized by increased cell density,49
smaller somal size,50
reductions in the dendritic spines51
in the tertiary frontal cortex, and smaller somal size52
in the temporal cortices. These data indicate that schizophrenia is not characterized by classic neural degeneration but rather by a process of neuronal volume reduction that primarily involves dendrites.53,54
Several candidate mechanisms for this reduction in dendrites have been suggested, including glutamatergic excitotoxicity55–57
and synaptogenesis abnormalities.56,58
If glutamate plays a role in the late progressive lesion, there may be good reason why MMN seems to be a sensitive index of this process. Mismatch negativity reflects current inflow in N
-methyl-D-aspartate glutamate receptors59
and is reduced in healthy individuals after N
The relationship among MMN, N
-methyl-D-aspartate glutamate receptors, and dendrite physiology may be especially important for understanding the brain abnormalities of schizophrenia. The association between MMN and progressive gray matter volume reduction has novel clinical implications; early pharmacologic intervention to prevent progressive cortical gray matter reduction may be tracked via the relatively noninvasive measurement of MMN amplitude.
Several caveats should be considered. Retest MRI may be confounded by changes in hydration and perfusion between images,29
and medication may be associated with changes in cortical volumes, equivocally both increases30
Subjects in this study were generally taking atypical medications, recently related to less cortical gray matter reduction.31
Comparison of subjects with schizophrenia who were taking atypical medications at follow-up with those who were not revealed no significant differences in Heschl gyrus volume loss (effect size d
= 0.23) or MMN reduction (effect size d
=0.37). Subjects who were taking atypical antipsychotics and those who were not showed cortical gray matter and MMN reduction, with relatively small effect sizes for increased loss if not medicated at all. In addition, testing of subjects with psychotic bipolar disorder who were receiving antipsychotic medications served as a natural control for medication effects, and those subjects showed no evidence of MMN or Heschl gyrus reductions. Furthermore, medication effects would be expected to be observed across the whole brain, yet the left, but not the right, Heschl gyrus was reduced in these subjects. These data weigh against any global hydration, perfusion, or medication effects. Second, subjects with schizophrenia lost to follow-up may differ significantly in terms of course from those who returned. There were moderately lower IQ and worse Global Assessment of Functioning scale scores in the lost subjects. However, both groups were relatively bright and significantly impaired. Third, other brain areas may show progressive reductions that correlate with MMN. We note that MMN generators are not distributed throughout the brain, and the temporal lobe accounts for much, if not all, MMN activity. Fourth, the single-rater intraclass correlations for Heschl gyrus volumes were high in all groups (subjects with schizophrenia, 0.96; subjects with bipolar disorder, 0.97; and control subjects, 0.93), but MMN reliabilities were lower (schizophrenic subjects, 0.74; bipolar subjects, 0.22; and control subjects, 0.52). We note that the schizophrenia group, where the main finding is present, was acceptably reliable. State effects might account for the low MMN reliability in subjects with bipolar disorder. Never re-hospitalized subjects with bipolar disorder (n=11) showed an increase in MMN amplitudes (~27%), and those ever rehospitalized (n=9) showed a reduction (~20%). Finally, there were no associations between negative symptoms and MMN amplitudes at either time 1 or time 2, as has been reported in chronic schizophrenia.61
Likewise, we did not detect any associations between MMN amplitudes and social functioning.62
We suspect that the changing clinical picture of first-episode patients likely plays a role in this lack of associations. First-hospitalized patients have not settled into a characteristic pattern or typical constellation of symptoms and present with extreme anxiety and turmoil in a state of symptom flux and evolution. Thus, the clinical and social functioning measures may have a relative emphasis on state rather than trait. We note that significant associations in the first-hospitalized schizophrenic subjects between anxiety at time 1 and subsequent MMN change (r
=.06) and Heschl change (r
=.005) highlight the unique clinical picture at protocol entrance. Furthermore, there was no association between anxiety at retest and MMN or Heschl gyrus change. At retesting a significant association between paranoia and MMN reductions emerged. Subjects with schizophrenia with the most paranoia at retest had the greatest MMN amplitude reductions (r
=.03), although the association with Heschl gyrus volume reduction did not attain significance (r
In summary, these interrelated functional and structural measures support the presence of a late progressive lesion in schizophrenia. Mismatch negativity amplitude in schizophrenia, even when within the normal range, is tightly coupled to the volume of the underlying left temporal auditory cortex, shows progressive reductions coupled with ongoing cortical gray matter reduction of the left temporal auditory cortex, and, thus, may serve as a metric of successful interventions in halting such peri-onset progressive abnormalities.