To our knowledge, the findings in our study represent the first report on the quantitative assessment of shape in the caudate nucleus in SPD or in schizophrenia. There were two major findings. First, in neuroleptic, never-medicated SPD subjects we found a significantly higher head of the caudate nucleus SI for SPD subjects, lateralized to the right side. Second, we found lateralized significant correlations between higher (more abnormal) head of the caudate SI scores in SPD subjects and poorer performance on neuropsychological measures assessing cognitive but not noncognitive, motor functioning. That is, right and left head of the caudate SI scores in SPD subjects correlated with reduced performance in visuospatial and verbal cognitive domains, respectively. We found significant correlations between more abnormal right head of the caudate SI scores and poorer declarative/episodic memory for visual material. Specifically, we showed that higher right head of the caudate SI scores correlated with reduced immediate and delayed recall of complex figures (Rey-Osterreith Complex Figure Test), but not with figure copying itself. In addition, higher right head of the caudate scores correlated with reduced scores on a measure sensitive to working memory executive division operations of response inhibition, shifting attention, and ignoring of irrelevant spatial cues (object alternation delayed response task). We also found that left head of the caudate SI scores inversely correlated with impaired auditory/verbal working memory performance on the Serial Digit Learning Test. Specifically, we found that higher left head of the caudate SI scores inversely correlated with poorer performance on the Serial Digit Learning Test and positively correlated with number of trials required for learning. By contrast, as expected, noncognitive measures of motor speed and dexterity and copying of the Rey-Osterreith figure itself failed to correlate with caudate SI.
These data confirm the value of measuring the shape, as well as the volume, of cognitively relevant brain regions of interest (ROIs) mediating higher cognitive functions in neuropsychiatric conditions and offer further support for intrinsic pathology in the caudate nucleus in the schizophrenia spectrum. Our failure to correlate our measures of shape with clinical measures, despite showing neuropsychological correlations, is consistent with our prior correlative findings for caudate nucleus volumetric measures (Levitt et al 2002
). We believe that abulia, the difficulty in initiating thought and action described in clinical reports of isolated caudate stroke (Bhatia and Marsden 1994
), might not be sufficiently quantitatively captured by our clinical measures (e.g., negative symptoms), making such correlations difficult to achieve in studies with relatively small samples. Again, similar to our SPD caudate volumetric data (Levitt et al 2002
), no correlations with motor performance and caudate SI were found, offering additional support that caudate nucleus abnormalities reflect cognitive and not merely motor dysfunction.
Recently, greater interest in the field of neuroimaging has emerged in the quantitative measurement of shape of specific brain structures (Csernansky et al 1998
; Frumin et al 2002
; Shenton et al 2002
; Thompson et al 2000
; Wang et al 2001
). Shape has been described as a sensitive index of developmental disturbance. For example, tension effects during neural development and growth might distort the shape of midline and medial structures, such as the cavum septum pellucidum, the hippocampus, and the corpus callosum (Csernansky et al 1998
; Frumin et al 2002
; Kwon et al 1998
; Nopoulos et al 1996
; Shenton et al 2002
; Van Essen 1997
). We believe our results highlight the potential usefulness of the quantitative assessment of shape with MRI in the study of neuropsychiatric disorders. As indicated by our data, shape and volume can be thought of as independent structural parameters that might yield complementary information. For example, in our previous study of these same subjects (Levitt et al 2002
), our volumetric data revealed a bilateral decrease in volume of the caudate nucleus for our SPD sample, whereas the SI scores in this report yielded a group difference, which lateralized to the right.
Two important advantages of our shape analysis, in comparison both with volumetric and with other shape analyses, are these: first, it automatically normalizes for head size because it is independent of the radius or size of a given shape; second, it does not require realignment or coregistration of brains. Hence, our shape analysis method avoids the difficult problem in structural MRI studies of head size correction; and it avoids the additional step, with attendant potential errors, of coregistration of brains into normalized space, as required in other more complex shape analyses. A third advantage is that our shape measure is based on a single scalar value that has an intuitive geometric interpretation.
A potential limitation of our method is that it is a global measure of shape. Hence, we are also developing and using other shape measures, with greater localization capabilities (Levitt et al, unpublished data), and believe it will be of interest to complement and compare our results for the caudate nucleus with the results of these alternative shape measures. A further limitation of our SI measure is that a number of different shapes that deviate from a sphere might have the same SI score. This, however, can also be said of volumetric measures because diminished volume can be achieved in a number of different ways (e.g., a given ROI could be equally smaller because of reductions in different subcomponents of the overall ROI). Furthermore, although it is true that a number of different shapes might have the same SI scores, if an SI score is different for a given shape, this implies that the shape differs; thus in a group sense, our SPD subjects, whose SI scores were different form normal control subjects on the right side, clearly had different caudate shapes compared with normal control subjects. Hence, we believe that our SI retains value as a discriminator between groups.
Our findings are important because they support our previous report (Levitt et al 2002
) of abnormalities in the caudate nucleus in neuroleptic-naive schizophrenia spectrum subjects, further suggesting that these abnormalities might be intrinsic to the disorder itself, rather than being secondary to the effects of neuroleptic medications. In any study of basal ganglia structures, neuroleptic medication is an important confound, which makes neuroletic-naive SPD subjects such an appealing sample for such studies. Numerous prior postmortem, animal, and MRI studies have supported the effects of neuroleptic medications on the size of the caudate nucleus (Beckmann and Lauer 1997
; Benes et al 1985
; Chakos et al 1994
; Corson et al 1999
; Heckers et al 1991
; Hokama et al 1995
; Keshavan et al 1994
; Konradi and Heckers 2001
; Lauer and Beckmann 1997
). In our view, quantitative shape analysis provides an additional approach to volumetric analysis for studying the effect of neuroleptic medication on basal ganglia structures. We are currently following first-episode psychotic subjects longitudinally and will measure both the shape and volume of the caudate nucleus in these subjects.
Additionally, not only does our shape analysis reveal a group difference between SPD and control subjects, but we also found that our SI scores yielded meaningful correlations with cognitive functioning. We are encouraged that our neuropsychological correlates support that a shape abnormality in the head of the caudate nucleus in SPD predicts poorer neuropsychological functioning. Furthermore, our data support that right and left head of the caudate shape abnormalities predict visuospatial and verbal impairments, respectively, corresponding to material specific patterns of neuropsychological lateralization. This is consistent with the primarily ipsilateral anatomic connection between prefrontal cortex and the basal ganglia. Our data also are consistent with a recent review of positron emission tomography and functional MRI studies that suggests that prefrontal activation tends to be right lateralized during episodic memory retrieval, in contrast to left lateralized prefrontal activation during semantic memory retrieval (Cabeza and Nyberg 2000
). In addition, SI scores correlated strongly in the expected direction with two of our measures (the object alternation delayed response task and Serial Digits Learning) that are thought to be highly sensitive to prefrontally mediated working memory executive functions. This fits well with current conceptualizations that frontal–striatal circuits help mediate working memory. As pointed out in the Introduction, there is a heavy afferent input to the striatum from the DLPFC, and functional neuroimaging studies in humans and nonhuman primates support that frontal–striatal circuits are involved in mediating working memory (Levy et al 1997
; Manoach et al 2000
). Our data offer strong support for this view.
A limitation of this study is that our sample size is relatively small and, hence, the conclusions need to be considered preliminary, and the findings will require replication in a larger sample of SPD subjects.
A further potential methodologic limitation of our study again relates to the small sample size and the number of correlations with psychopathologic measures that we have performed. We have attempted to address this issue by basing our correlations on a priori hypotheses. We hypothesized that basal ganglia abnormalities in shape would be associated with impairment in performance of working memory and other frontally mediated neuropsychological traits, as suggested by our previous study (Levitt et al 2002
). We believe that our neuropsychological correlates do help to validate the finding of abnormality in shape that we report here. Future studies, however, involving larger samples of subjects, would be needed to confirm the findings in this report.
In sum, our finding of an abnormal shape of the caudate nucleus, lateralized to the right, and its associated neuropsychological correlates in neuroleptic-naive SPD subjects offers further support for an intrinsic abnormality in the striatum in schizophrenia spectrum conditions. Our findings also support that the caudate nucleus, as part of the frontal–striatal circuitry, helps to mediate cognitive functioning and that abnormalities in frontal–basal ganglia circuits might yield important insights into the pathophysiology of disorders of cognition and behavior, such as SPD. Lastly, our findings suggest that the quantitative assessment of shape with the use of advanced MRI techniques offers an important complement to quantitative volumetric MRI studies in neuropsychiatric disorders.