The primary findings of this study were that, corrected for age and head size, smaller OFC volumes were associated with better neuropsychological performance and lower levels of aggression. This pattern was obtained for neurocognitive function and aggressive behavior. In addition, comorbid alcohol use disorders were associated with larger left than right white matter volumes. Although the relationships between OFC volumes and our functional measures appear counterintuitive, it should be noted that larger volumes do not necessarily reflect better neural function.
Increased volumes could reflect reduced neural density, increased neuronal size, or could reflect edema or other pathophysiological processes. Treatment with typical APDs appears to increase caudate volumes. The effects of long-term treatment with typical APDs on other brain regions are not well studied. However, one might speculate that the current results could be explained if such treatment has a similar effect on OFC volumes. It should be pointed out that we have obtained similar effects to the ones reported here in our examination of caudate volumes (Hoptman et al., submitted). In this light, it should be noted that although Chakos et al. (Chakos et al., 1994
) did not find a significant increase in cortical volume in their study, the cortical volume did increase by 3.2% in their patients, suggesting that the increased striatal volume associated with typical APD treatment may not be specific to that region.
The mean duration of illness, and, presumably, treatment with APDs, of patients in our sample was 18.6 years. The fact that these patients did not, by definition, respond well to such treatment, suggests that the deleterious effects of such treatments may be pronounced in our sample. It is thus relevant that higher levels of akathisia were associated with larger left OFC WM volumes. As noted in the Introduction, the duration of typical APD treatment may be related to increases in volume of the basal ganglia (Lang et al., 2001
), suggesting that the effects of such treatment may be cumulative. On the other hand, duration of illness did not account for the relationships between orbitofrontal volumes and either neuropsychological function or aggression. It is possible that long-term treatment with typical APDs had a nonlinear relationship with OFC volumes. The effects may plateau after a certain period of exposure. In other words, after a certain period of exposure to typical neuroleptics, a level of iatrogenic effects may be reached that does not progress further. As discussed by Jeste et al. (Jeste et al., 1998
), most studies of the effects of typical APDs do not find a correlation between changes in volume and duration of illness. Chakos et al. (Chakos et al., 1994
) suggested that this lack of correlation in the caudate may reflect reduced neuronal plasticity in older patients.
In this context, the patterns of relationships between OFC volumes, neuropsychological function, and aggression, are consistent with literature indicating a key role for that region in certain aspects of psychiatric symptomatology, neurocognitive function, and aggression.
With respect to the neurocognitive data, only the Attentional and Processing Speed Factor was related to OFC volumes. Of the specific tests administered, only the percentage of perseverative errors on the WCST, the number of errors on Trails B, and the span for the Letter Number span task were significantly related to OFC volumes. This pattern of findings suggests that variations in OFC volumes have relevance only for tasks that require cognitive abilities in which this region plays an important role. The performance of each of these tasks has in the past been shown to be dependent on the integrity of prefrontal regions. Similarly, the relationships between OFC volumes and aggression are consistent with a key role of the OFC in the modulation of such behavior (Grafman et al., 1996
; Hoptman, 2003
The current findings have implications for the interpretation of studies in which the relationship between neuropsychological and behavioral function and brain volumes are studied. Thus, for volumetric studies of schizophrenia, it is important to know the patients’ treatment history. Unfortunately, the participants in our study have a long duration of illness with many hospitalizations, but also many periods in which they were out of the hospital. As a result, their complete medical records were not available to us. Nonetheless, the issue is worthy of further attention.
The mechanism underlying the relationship between increased volume and poor neuropsychological and behavioral function is unclear. Although the basal ganglia volumetric data could possibly reflect a change in MRI signal properties with typical APD treatment that would artifactually affect results, this explanation seems highly unlikely given that the same effects have been found in post mortem tissue (Heckers et al., 1991
Typical APDs are potent D2 receptor blockers. It has been hypothesized that the increased caudate volumes seen with typical APD treatment are the result of compensatory neural mechanisms related to blockade of the D2 receptors. This hypothesis is consistent with the observation that haloperidol increased the size of axon terminals in the striatum (Benes et al., 1985b
) and increased the mean neuronal size in the medial prefrontal cortex (Benes et al., 1985a
) of rats with no change in neuronal density. The argument has been raised that D2 blockade cannot completely explain haloperidol-related increases in striatal size because such effects are not seen, with equivalent D2 blockade, following RIS treatment (Lang et al., 2001
). However, RIS’s effects on 5-HT2 receptors may partially compensate for its effects on D2 receptors.
It is also possible that these volumetric effects may be unrelated to treatment. The notion has been advanced that hyperactivity in the OFC may induce hypertrophy. Still another possibility is that aberrant cortical pruning might account for these effects (Swayze et al., 1992
A recent study (Molina et al., 2004
) using atlas based regions of interest has found that atrophy in the OFC region is associated with greater improvement in positive symptoms in patients with schizophrenia after 20–24 weeks of treatment with olanzapine. The authors suggested several possible mechanisms for this finding, including the speculation that N-methyl-D-aspartate (NMDA) receptor hypofunction may contribute both to regional atrophy and to positive symptoms. This suggestion was based on findings that the NMDA antagonist ketamine increases frontal metabolic activity (Vollenweider et al., 1997
) and that a positive correlation between positive symptoms and orbital metabolism has been observed (Silbersweig et al., 1995
). In addition, NMDA function plays a role in neuronal migration (Komuro and Rakic, 1993
). If the receptors are hypofunctional, Molina et al. (2004)
suggest, this might lead to gray matter deficits. Molina et al.’s interpretation cannot be ruled out from the present data. It should be noted that the patients in this study had a far lower duration of illness than the patients in the current study. It is therefore likely that their exposure to typical antipsychotics was considerable lower than the patients in our study.
The study has some important limitations. Firstly, a large number of tests were conducted, and we did not correct for multiplicity. We think that this is justified in light of the consistency of results across different domains and because of the exploratory nature of the analyses. Second, the subjects who received the MRI may not be representative of treatment-resistant schizophrenia patients, or even of the small sample from which they were selected. There were too few females to permit analyses of possible gender effects. We also were unable to evaluate the full medication history of the participants in the study. Finally, because we did not have a control group, we are unable to evaluate the specificity of these findings to schizophrenia. It is possible, for instance, that similar relationships to those we obtained here might be found in healthy controls.
In conclusion, in this sample of patients with treatment-resistant schizophrenia, larger OFC volumes were associated with poorer neuropsychological performance and aggression. Moreover, larger left than right OFC volumes were associated with comorbid substance use disorders. It seems possible that these results may be attributed to the iatrogenic effects of long-term ineffective treatment with typical APDs in this population, although it is also possible that they may related to the pathophysiology of schizophrenia.