Interestingly, the STG gray matter volume reduction was specific to SPD subjects who met full criteria, as contrasted with its absence in the limited comparison with the sub-threshold subjects, who met only 3–4 of the required 5 SPD DSM-IV diagnostic criteria. If this pilot finding holds as the number of sub-threshold subjects increases, this may support the validity of the DSM-IV criteria for SPD. The comorbid diagnoses in our SPD subject group serve to strengthen our findings as it would not be predicted that a diverse set of diagnoses would have the same anatomic abnormality.
A key point in our study was the ability to follow the same MRI and ROI protocol used previously by our laboratory in the study of schizophrenia (Shenton et al 1992
). ROI were similarly hand traced as opposed to automatically segmented—current automated programs have difficulty distinguishing subtle gray/white matter distinctions, particularly in morphometrically complex structures such as the hippocampus, and manual tracing remains the current standard for ROI definition (see consensus report of a recent neuroimaging conference, McCarley et al 1996
; and reviews, Shenton et al 1997
; McCarley et al 1999
). In the original study of chronic schizophrenics by Shenton and colleagues, the schizophrenics compared with their matched control group showed left hemisphere volume reductions in the STG, anterior amygdala/hippocampus complex and parahippocampus (Shenton et al 1992
). That was a more extensive set of abnormalities than was found in this current study of SPD subjects, where we have shown the SPD subjects to have left sided abnormalities only in the left STG compared with their matched control group.
The abnormal TDI scores in SPD finding is consistent with a recent study that used the TDI with biological relatives of schizophrenic probands who were were adopted away at about one month of age. These relatives were given a semi-structured interview (SADS) not unlike the SCID. Six of the subjects met criteria for either borderline schizophrenia (n
= 3) or SPD (n
= 3) and this combined group of six did exhibit a trend toward an elevated TDI not found in the control adoptees (Kinney et al 1997
). Of the three SPD subjects, two had TDI scores greater than the siblings of the control group and one had a TDI score higher than the mean for the schizophrenics (Dr. Kinney, personal communication). In their comments, Kinney et al, suggested that the thought disorder may be due to genetic factors in the schizophrenia spectrum (Kinney et al 1997
). As the STG is thought to be an important substrate for language processing, the finding of abnormal STG morphology SPD is consonant with the clinical symptomatology of language abnormalities (see review McCarley et al 1993a
). Unlike the chronic schizophrenic sample (Shenton et al 1992
) there was no direct correlation between the TDI scores and the left STG gray matter volume, nor with the volume of any other ROI in these SPD subjects. This may reflect, in SPD subjects, a more subtle relationship between clinical variables and any one structural ROI than in the schizophrenic sample, or a relationship between TDI and one or more of the ROI we did not examine.
An important general question in studies of the schizophrenia spectrum is why are schizophrenics psychotic, although SPD subjects are not, given their similar genetic diathesis. This paper has shown that SPD subjects have left STG volume reduction and parahippocampal asymmetry although schizophrenics have more extensive abnormalities, especially in the medial temporal lobe (Shenton et al 1992
). In the absence of a specific gene found for schizophrenia, it is not possible to determine causation, but it is conceivable that the additional structural abnormalities in schizophrenia may account, in part, for the difference in clinical severity. The features of SPD may be due to a series of cognitive and language/thought processing abnormalities occurring along a circuit in the temporal lobe. We have demonstrated reduced gray matter volume of the left STG, an important area of language processing. Information from the STG passes to the parahippocampal complex. What forms of information processing might occur in the parahippocampus is less well known, but this structure is the key input/output zone for the hippocampus (Squire and Zola-Morgan 1991
). Recently, direct electrical recordings from the anterior medial temporal lobe (including the hippocampus/parahippocampus) have implicated this area in the processing of semantic representations (McCarthy et al 1995
) as well as being important for memory retrieval. Schizophrenics have volume reductions in both in the STG and medial temporal portions of this circuit although SPD subjects have only STG volume reductions. This difference might account, in part, for the additional clinical symptoms in schizophrenia such as overt auditory hallucinations and paranoid ideation. For example, recent neuroimaging studies of schizophrenics have shown abnormal hippocampal activation during hallucinations (Silbersweig et al 1995
). Whether additional structural abnormalities exist in other brain regions in SPD and whether females with SPD are similarly effected remains to be further elucidated.
Another important question concerns the potential mechanisms leading to greater structural alterations in schizophrenia. One mechanism might be gene interactions during brain development that occur in schizophrenia but not SPD, although another, non-exclusive possibility is post-natal medial temporal lobe volume reduction in schizophrenia (McCarley et al 1996
). Data presented here suggest that the singular volume reduction of the STG might be regarded as a potential biological marker of the schizophrenia spectrum, a component of the “endophenotype.” The possible role of environmental factors in triggering a full-blown schizophrenic episode suggests also that the STG volume reduction might be a vulnerability marker. If patients can be differentiated into those who will have a more benign course and those who will have a more serious illness, early in their presentation, then research might be directed toward early intervention either with different social, cognitive, or pharmacologic treatments that may allow better compensation for the anatomic abnormalities.