Abnormalities of hippocampal development may also have the secondary effect of lessening the degree of fusion of the two leaflets of the septum pellucidum, which separates the two lateral ventricles (Galarza et al., 2004). During normal development the growth of hippocampus and corpus callosum exert pressure on the two leaflets, facilitating fusion. Incomplete fusion is termed cavum septi pellucidi (CSP). CSP can be visualized by ultrasound at 16 weeks gestation and continues to expand throughout pregnancy to approximately 34 weeks, at which point the CSP begins to decline in size (Serhatlioglu et al., 2003), with 2/3 of CSP closed at birth, all part of normal development (Mott et al., 1992). Although a persistently large CSP can be normal (10.3%in (Kwon et al., 1998)), it is generally associated with a range of neuropsychiatric, anatomic, and genetic abnormalities (Serhatlioglu et al., 2003), including schizophrenia (0.15–58.8%) (Kwon et al., 1998; Nopoulos et al., 1997). Even within schizophrenics, however, the increased presence of CSP could be secondary to other developmental defects in other regions, including corpus callosum (Galarza et al., 2004).

One major complication in interpreting structural MRI data from patients diagnosed with schizophrenia, however, is the potential effects of neuroleptics (Chakos et al., 1994), other medications (Sassi et al., 2002), and the extreme stress (Sapolsky et al., 1986) of having a serious and chronic illness on various brain regions of interest (ROI), including the hippocampus (Sapolsky et al., 1986; Wood et al., 2004). To avoid these potential confounds, the study of subjects with schizotypal personality disorder (SPD), who share the same genetic diathesis as schizophrenia (Kendler et al., 1993), offers an opportunity to examine subjects in the schizophrenia spectrum who are relatively free of such confounds.

Previously we examined the hippocampus and CSP in males recruited from the community who were neuroleptic-naive and who met DSM-IV criteria for SPD. Male SPD subjects demonstrated an elevated rate of large CSP (18.8%) (Kwon et al., 1998). This finding suggested that the brains of SPD subjects, similar to the brains of patients diagnosed with schizophrenia, might have neurodevelopmental abnormalities. The hippocampus in male SPD subjects, however, was shown to have volumes comparable to age-matched male comparison subjects (Dickey et al., 1999). The brain structure of female SPD subjects, including the hippocampus and CSP, has, unfortunately, been a neglected area of research. As the hippocampus is rich in estrogen and androgen receptors during development (Goldstein et al., 2001), this might be expected to affect its development (Romeo et al., 2005), although two studies failed to find an effect of gender on hippocampal volume in schizophrenia (Bryant et al., 1999; Goldstein et al., 2002). Gender may, however, play a role in terms of the effect of co-morbid disorders on hippocampal volumes. Specifically, hippocampal volumes have been shown to be abnormal in major depression (e.g. Neumeister et al., 2005), including in a meta-analysis of 12 studies (Videbech and Ravnkilde, 2004b), with the duration of the untreated depression correlating with smaller volumes (Sheline et al., 2003).

Moreover, cognitive deficits in the schizophrenia spectrum, including SPD, attributable to impaired hippocampal function have been demonstrated. These include poor encoding (Voglmaier et al., 2000a; Jessen et al., 2003), poor working memory (Mitropoulou et al., 2005; Farmer et al., 2000; Barch et al., 2004; Trestman et al., 1995; Buchsbaum et al., 2002; Siegel et al., 1996), and inefficient visuospatial working memory (Levitt et al., 2004) demonstrated by fMRI (Koenigsberg et al., 2005). Finally, animal models have demonstrated that stereotactic infusions of NMDA will lesion hippocampi (Bardgett et al., 2006). These rats have deficits on delayed spatial alternation tasks. Deficits, which can be reversed by chronic clozapine, suggesting that spatial alternation tasks may be an effective probe of hippocampal function in schizophrenia spectrum subjects (Bardgett et al., 2006).

Research regarding possible anatomic contributions to clinical and social impairments in SPD is limited. In schizophrenia, however, more work has been done. For example, smaller right hippocampus has been correlated with negative symptoms (Szendi et al., 2006). Moreover, it has been hypothesized that the delusions experienced by paranoid schizophrenics may be linked to hyperactivity of the dopamine-sensitive CA1 region neurons (Krieckhaus et al., 1992). With respect to the CSP, larger CSP have been associated with abnormalities in the verbal domain, specifically, with lower verbal IQ scores (Nopoulos et al., 2000); with the thinking disturbance factor from the BPRS (Kasai et al., 2004); and with poorer prognosis as measured by years of hospitalization (Fukuzako and Kodama, 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.