CLINICAL HANDBOOK OF SCHIZOPHRENIA

52 I. CORE SCIENCE AND BACKGROUND INFORMATIONmatter underlying the DLPFC and anterior cingulate. This evidence is buttressed by a findingof globally reduced fractional anisotropy (FA)—the output measure of the sum of vectorsin a given brain region—in the brains of patients with schizophrenia. Relationships betweensymptoms of schizophrenia and decreased FA have been demonstrated as well. Forexample, decreased FA in the medial temporal lobe has been associated with increasingsymptom severity, as has a relationship between decreasing FA in frontal white matter in patientswith schizophrenia and the ability to live independently. Other associations betweendecreased FA in the cingulum bundle and executive function have been recently demonstratedin patients with schizophrenia, whereas decreased FA in the uncinate fasciculus hasbeen associated with deficits in declarative–episodic memory. Interestingly, increased FAhas been demonstrated in the arcuate fasciculus in patients with auditory hallucinations.These findings, which continue to accumulate, strongly support the idea of white matter involvementand dysconnectivity in schizophrenia, although the exact nature of the role whitematter plays in the disease is still under investigation.IS SCHIZOPHRENIA PROGRESSIVE?Although debate about whether schizophrenia is a progressive disease still continues,there appears to be increasing evidence that, at least in some populations and in someneuroanatomical measures, schizophrenia is progressive. For example, increase in ventricularsize has been shown to progress over time as patients with schizophrenia furtherdiverge from controls as time with the disease lengthens, and patients with the largestventricles have been demonstrated to have both the worst premorbid levels of functioning,and the worst prognoses and most severe symptoms. Temporal lobe and frontal lobevolume changes have been reported to progress with time as well. Further supporting theidea of schizophrenia as a progressive disease, in childhood-onset schizophrenia (COS), arare but fairly well-characterized presentation, ventricles are enlarged and temporal volumesare decreased. But more importantly, patients with COS have a progression of brainpathology, with severe reductions in frontal and temporal lobes that by age 18 begin toresemble those of adult schizophrenia. Finally, patients with schizophrenia have beendemonstrated to have a quickly progressing decline in cognitive function, beginning nearage 65, despite years of stable cognitive performance over the course of their disease,highlighting the fact that cross-sectional evidence that argues for the static nature of thedisease may require longitudinal confirmation.LIMITATIONS ON NEUROPATHOLOGICALINVESTIGATIONS IN SCHIZOPHRENIAThere are several problems with neuropathological investigations of schizophrenia (summarizedin Table 5.2 on page 46). First, in postmortem investigations, the postmortem index(PMI) is a profound determinant of tissue integrity and, consequently, of the validityand generalizability of findings. The PMI is essentially a measure of the integrity of braintissue at the time of fixation, and it includes numerous variables, including the time fromdeath to fixation, the pH of brain tissue at the time of death, the exact nature of death(i.e., suicide vs. “natural causes”), and the presence of agonal events that could alterbrain tissue. Second, the variable attention to stereological methods in sampling or sectioningbrain tissue is comparable to different methods of regional differentiation in imagingstudies. The lack of reliable methods in either instance can lead to inaccurate