Female SPD subjects compared with comparison subjects exhibited bilaterally smaller hippocampal volumes, and an increase in the extent of CSP. There also was a trend toward an increase in frequency of abnormally large CSP in SPD when measured by a threshold of >6 mm. Of note, the CSP finding for female SPD subjects is similar to what was previously reported in our laboratory for male SPD subjects (Kwon et al., 1998
); with neither SPD group showing a correlation between hippocampus and CSP (Kwon et al., 1998
In addition, smaller left hippocampal volumes in female SPD subjects correlated with deficits on the Delayed Alternation task, a measure of spatial working memory and executive functioning. Specifically, on the Delayed Alternation test, errors, perseverations, and a trend toward failure to maintain set correlated negatively with the left hippocampal volumes. Although the Delayed Alternation task has been studied little in schizophrenia (Seidman et al., 1995
; Pantelis and Brewer, 1995
), it nonetheless may serve as a useful tool in measuring perseveration (Koenen et al., 2001
), a common deficit in the schizophrenia spectrum, including SPD (Levitt et al., 2002
). Poor spatial working memory has been shown in subjects who are at “ultra high risk” for developing schizophrenia (Wood et al., 2003
); and even normal subjects with features of SPD(Raine et al., 1992
; Gooding and Tallent, 2003
). Finally, data from animals with early hippocampal lesions demonstrate poor performance on Delayed Alternation tasks (Lipska et al., 2002
) and aberrant adolescent behavior in animals, and thus is one model implicating the hippocampus in schizophrenia (Lipska et al., 2002
; Weinberger, 1999
In contrast, there was no difference between groups in WMS-R logical memory, verbal encoding as measured by CVLT words learned trials 1–5, nor semantic clustering. Moreover, there was no correlation between any of these verbally-mediated tasks and hippocampal volumes. This is consistent with previous reports from our laboratory of females SPD subjects performing better than male SPD subjects on verbal learning (Voglmaier et al., 2005
) and relatively preserved logical memory (Voglmaier et al., 1997
). The validation of the null-hypothesis on these measures in the setting of impaired spatial working memory suggests that this finding is specific to spatial working memory for female SPD subjects.
In female SPD subjects, impairment due to odd appearance/behavior correlated negatively with right hippocampal volumes, and impairment due to odd speech correlated with the extent of CSP. Thus, smaller hippocampi and larger CSP in female SPD subjects had notable associations with clinical manifestations of the disorder, which may have implications for social functioning in SPD subjects (Dickey et al., 2005
). Less clear, however, is the positive association between suspiciousness/paranoia and larger right hippocampal volumes. As noted in the Results section, however, these exploratory correlations would not have withstood Bonferrroni correction. However, as this is the first study to examine the hippocampus in a female sample of neuroleptic-naïve SPD subjects, these correlations are included to guide future studies. In schizophrenia, many, but not all researchers (Flaum et al., 1995
), have reported clinical/ size correlations. For example, in schizophrenia, shorter hippocampi bilaterally correlated with bizarre behavior (Fukuzako et al., 1996
) and smaller hippocampal volumes with negative symptoms (Rajarethiam et al., 2001
). Abnormal hippocampal volumes may be involved in the manifestation of such behavior across the spectrum.
Why SPD subjects, or female SPD subjects specifically, should have smaller hippocampus volumes is speculative. Evidence from animal studies that suggest that repeated stress can result in dendritic atrophy in the CA3 region of the hippocampus (Magarinos and McEwen, 1995
), specifically, a reduction of apical length and branch points of pyramidal cells (Wood et al., 2004
) (reviewed in (McEwen, 2004
)). Although SPD subjects are not psychotic, SPD does result in significant impairment cognitively, occupationally, and socially (Dickey et al., 2005
), the cumulative effect of which may be stressful for these individuals.
Unlike the hippocampus, which recent work has shown can be affected by stress and depression (McEwen, 2005
; Bianchi et al., 2005
) (reviewed in Charney and Manji, 2004
) large CSP reflects potential abnormalities in neonatal development. Therefore, the increased prevalence of large CSP in male schizophrenics (Nopoulos et al., 1997
), male SPD subjects (Kwon et al., 1998
) and now females with SPD, suggests that the pathogenesis of schizophrenia spectrum disorders begins early in neurodevelopment.
Speculatively, anatomic abnormalities in SPD may be driven in part by neurodevelopment, with additional effects of co-morbid diagnoses and stress, whereas in the much more clinically severe schizophrenia, the overwhelming effects of abnormal development and genetic factors may obscure additional effects of co-morbid disorders. Such developmental and genetic factors may help explain why there were negative correlations between large CSP and hippocampal volumes (Kwon et al., 1998
) and parahippocampal volumes (Kasai et al., 2004
) in schizophrenia, but not in SPD. Nonetheless, the neurodevelopmental abnormalities which are manifest by having a larger CSP may be clinically important for SPD subjects, as suggested by the correlation between the clinical criteria of impairment due to odd speech and number of MRI slices containing a CSP in SPD subjects. Indeed, in schizophrenia, a larger CSP was correlated with thinking disturbances (Kasai et al., 2004
), similar to what was shown here.
There were several limitations to this study. One such limitation is that we can not rule out the effects of co-morbidity differences, which commonly fall along gender lines. Specifically, perhaps the higher incidence of histories of co-morbid Axis I disorders in this female sample (17/20 subjects or 85%) compared to our male sample (25%) (Dickey et al., 1999
) may account for the current finding of reduced hippocampi in SPD females while not in male SPD subjects. Additionally, small hippocampal volumes have been noted in several psychiatric disorders (Heckers, 2001
), including major depression,(Caetano et al., 2004
), with the total number of episodes correlating with reduced right hippcampal volumes (Videbech and Ravnkilde, 2004a
) and the longer duration of untreated depression the smaller hippocampal volumes (Sheline et al., 2003
). Given the high co-morbidity of depression in this female SPD sample, the hypothesis of major depression contributing to the small hippocampal volumes must be considered, but the small number of female SPD subjects without co-morbid disorders (N
=3) prohibited a direct test of this hypothesis. The lack of correlation between Beck Depression scores and hippocampal volumes is some-what reassuring, but the Beck Depression scores reflect a cross-sectional view of mood, not mood over time, which is more likely to affect hippocampal morphology. The degree of chronic stress was not evaluated in these subjects and may have contributed to the current findings. However, the lack of hippocampal volume findings in male SPD subjects, who generally have a more serious disorder (Dickey et al., 2005
), argues against this possibility. Neuroanatomic boundaries for defining ROI are critical for evaluating possible measurement differences among MRI studies. The original male study (Kwon et al., 1998
) had a different anterior boundary for the hippocampus, the mammillary body, which has been used in other reports (Shenton et al., 1992
). Moreover, it was the anterior boundary which differed between the two protocols, and the head or anterior portion of the hippocampus is more likely affected in schizophrenics (Csernansky et al., 2002
; Lee et al., 2004
) and their unaffected relatives (Tepest et al., 2003
) in terms of shape and volume (Heckers, 2001
) (compare images 1d and 1e). Perhaps, differing methodology in delineating that region could affect MRI volume measurements, particularly in a small ROI. Indeed it may be that the anterior portion of the hippcampus, that region which interdigitates with the amygdala, is most affected by schizophrenia spectrum disorders (Szeszko et al., 2003
). Future hippocampal shape analyses along with the inclusion of a second control group of subjects with major depression may help to differentiate these potential confounds. Finally, the correlations in the current report were exploratory, not Bonferroni corrected, necessitating further confirmation and limiting the interpretation of the findings. They are included in the current report to encourage future exploration of the clinical/anatomic relationships in this understudied disorder.
In conclusion, female SPD subjects display smaller hippocampi bilaterally compared with comparison subjects, a finding not previously demonstrated in male subjects (Dickey et al., 1999
). Hippocampal volume reduction on the left also correlated with deficits in spatial working memory, whereas reduction on the right correlated with odd appearance and behavior. Moreover, female SPD subjects like their male counter-parts, showed an increased incidence of large CSP, likely due to abnormalities of neurodevelopment. Moreover, the larger the CSP, the more odd the speech in SPD females. The interrelationship between neuro-development and lifelong stressors and their effects on the brains of individuals suffering from schizophrenia spectrum disorders warrants further investigation.