Regional FA differed in the UHR and HC groups in the SLF, and cross-sectional analyses indicated differences in the pattern of age-associated change, suggesting an altered developmental trajectory of WM in UHR youth. Further, WM alterations at baseline in the UHR sample were predictive of changes in social and role functioning over the ensuing 15 months, indicating that structural brain changes are detectable before illness onset and may differentiate patients who will and will not deteriorate functionally over time.
Overall, UHR patients had lower baseline FA than controls in the SLF, a fronto-parietal connection, which is consistent with previous findings in first-episode schizophrenia patients (16
). Previous structural neuroimaging work in UHR subjects has identified gray matter reduction in frontal and temporal lobe structures and the cerebellum (34
). However, findings regarding gray matter abnormalities prior to illness onset in medial temporal structures such as the hippocampus are inconsistent (50
). A prior study of individuals at clinical high risk revealed differences in callosal shape, supporting the notion that WM alterations may exist prior to illness onset (52
). However, UHR samples are highly heterogeneous with regards to age and clinical outcome, which may sometimes obscure group differences and contribute to trend level differences, for instance, a study examining fiber tracking in a smaller sized UHR group also did not find simple group differences when compared to controls (53
). Exploration of factors that contribute to such variance, and how they relate to WM alterations, may elucidate differences that are relevant within the UHR samples but that make comparisons between UHR and control samples problematic.
Our results suggest different developmental patterns in temporal lobe WM tracts (MTL and ILF) between UHR youth and healthy controls, such that UHR youth fail to show the expected age-associated increase in FA. This result is consistent with previous longitudinal findings in adolescents with schizophrenia, in which significantly greater gray matter loss over time was seen in patients than controls, suggesting abnormal frontal and temporal development (54
). Additionally, hippocampal volume decreases were observed across adolescence in schizophrenia patients but not controls (55
), with specific hippocampal subregions showing distinct developmental trajectories, which differed between adolescent schizophrenia patients and healthy controls (56
). Moreover, in late adolescence and early adulthood schizophrenia patients show abnormal developmental trajectories in both gray and WM (57
), with greater tissue loss seen in patients with poor outcome. While schizophrenia is considered to be a developmental disorder with both early and late developmental influences (58
), it is of interest whether the changes seen in adulthood arise as the result of a normal process exerted on a compromised structure or an abnormal developmental process (9
). Our findings indicating that the slope of developmental change differs UHR cases and controls are consistent with the theory that there is a disruption in the developmental process itself.
Finally, lower baseline FA in temporal regions was predictive of a course of declining social and role function in UHR youth. Thus, early microstructural changes may indicate a pervasive neurologically-based deficit, as opposed to a transient symptomatically-based deficit. Although FA in these regions did not predict conversion to a categorical psychosis diagnosis, we had limited power to examine this question as only 6 subjects converted over the follow-up period. This is a common obstacle for UHR studies examining conversion to psychosis as the primary outcome variable (60
). However, conversion was highly correlated with functional outcome, particularly social functioning at long-term follow-up (p=.003). This analysis of social and role functioning, rather than conversion, in relationship to structural brain changes provides a unique contribute to the literature. The results indicate that, while functional outcome and DSM-IV diagnosis are closely related, additional power and information can be gained through use of a continuous variable (i.e., functioning). Our findings further suggest that DTI measures of WM integrity may be a powerful prognostic indicator in at-risk youth. Previous findings in FA and other high risk groups (17
) support the idea that neural changes are present early in the progression of the illness. However, the use of a longitudinal design in which FA predicts later outcome is novel. That these effects are largely in temporal lobe regions is interesting and consistent with what we know about normal adolescent development- that the temporal lobes are expected to be myelinating during this time and thus have the potential to show changes quite proximal to disease onset. This pattern is also consistent with cognitive findings in the prodrome, in which functions thought to rely on the temporal lobes such as verbal learning and memory are impaired (38
Our study is limited in part by sample size and heterogeneity. By their nature, UHR groups contain subjects who are experiencing transient changes and patients who are prodromal for other non-psychotic psychiatric disorders in addition to those truly prodromal schizophrenia subjects. Therefore, larger follow-up cohorts may provide additional insight. Additionally, while some UHR participants had been medicated for a relatively brief period of time, none of the FA measures were significantly correlated with antipsychotic use (all p>.05), so there is no evidence that medication use influenced the direction of the results. Although gender distribution differed between groups, gender was included a covariate in all analyses to account for its potential relationship with DTI measures. With only 6 directions in the DTI sequence, our analysis was limited to FA, but future studies in which more directions are measured and in which analyses such as tractography can be performed, will be very informative. Further, due to susceptibility artifacts in the orbitofrontal regions that occur with echo planar imaging scans, the signal for the uncinate should be interpreted with caution. Finally, given the low conversion rate we also must consider other potential explanations, for instance, that WM integrity is predictive of decline across a variety of psychopathologies and not just schizophrenia. However, these subjects did have symptoms consistent with those associated with the prodromal phase of schizophrenia.
In conclusion, our cross-sectional findings suggest a different pattern of WM development in UHR youth relative to healthy controls, particularly in temporal lobe regions, such that UHR youth fail to show the normal progressive increase in FA with age. Further, lower baseline FA in temporal WM tracts predicted deterioration in social and role functioning over follow up. These data thus provide the first evidence that structural brain changes in temporal lobe WM may predict outcome in young people at ultra high risk for psychosis.