UHR cohorts have provided another unique sample to investigate the development of psychosis-related disorders. Based upon a number of criteria including current mental state, state (ie, symptomatic and help-seeking) and trait (ie, family history) characteristics, the UHR group are at an increased risk of developing psychosis.70,71
The Melbourne UHR cohorts in the imaging studies have a mean age of around 19 ± 3.5 years, with about 58% male, and almost 50% of those making the transition to psychosis develop a schizophreniform illness.72
Although the transition from UHR status to a psychotic disorder is not considered inevitable, almost 40% of the initial cohorts made the transition to psychosis over a 12-month period. This provides the opportunity to document early and late dynamic brain changes as psychosis develops and also to assess brain structural changes longitudinally at the earliest stages of illness.9,18,39
While the hope has been to identify a premorbid marker to evaluate an individual’s susceptibility to develop a psychotic illness, examining trajectories of change of these potential markers would be more informative than limiting the assessment to cross-sectional evaluation.11,73
In a series of cross-sectional and longitudinal investigations, the Melbourne and other groups investigating UHR individuals have assessed a number of cortical and subcortical structures and contrasted the findings with those in first-episode psychosis and chronic schizophrenia. While changes in various regions have been found more consistently across these regions in patients with established schizophrenia, the findings at or before illness onset have been inconsistent, while progressive changes are apparent particularly in the earliest illness stages.
Meta-analyses of voxel-based morphometry studies in schizophrenia have shown reduced GM volume in anterior cingulate cortex (ACC) and medial frontal cortex, insula bilaterally, medial and lateral temporal lobes, STG, lateral PFC, thalamic, and subcortical regions.74,75
However, these changes are less apparent in first-episode patients with evidence for cortical progression.76
Cross-sectional studies in UHR have identified reduced volume in some of these regions pre-psychosis onset, such as the insular cortex45
and ACC thickness,77
as well as corpus callosum thickness.78
In contrast, other findings did not discriminate between those developing psychosis compared with those who did not, including hippocampus and amygdala,72,79,80
or midline abnormalities, such as adhesio interthalamica84
and cavum septum pellucidum.85
In contrast to the cross-sectional findings in UHR, longitudinal studies have been more consistent in discriminating UHR developing psychosis from those not progressing to illness. In the first such study, examining longitudinal changes in UHR, baseline scans prior to psychosis onset were compared with follow-up scans taken post psychosis onset or at least 12 months later (in those not developing psychosis). The UHR-psychosis group showed progressive loss of GM in left medial temporal and inferior temporal regions, left OFC, and ACC bilaterally. These changes were not observed in the UHR-non-psychotic individuals.39,72,80
These findings have since been supported by a study in a separate sample at another research centre investigating a similar cohort,41
which reported changes in frontal, temporal, and parietal GM in those who transitioned to psychosis, while no changes were seen in patients who did not. Furthermore, these changes were also seen in a genetic cohort from the Edinburgh high-risk study, with findings showing that these changes were not explained by medication.40
In order to address some of the methodological issues identified in these studies, such as the relatively thick image slice and small sample size, we combined 2 approaches—a cortical pattern matching technique68
and a longitudinal cortical surface motion technique.86
Using this methodology, we examined the cortical surface in detail, although other cortical regions of interest in psychotic disorders, such as the insula and the STG could not be examined because the methodology could not accurately assess cortical surface motion in these deep sulci. We again showed significant reductions (GM retraction) in patients who progressed to psychosis compared with those who did not, with changes localized to the lateral PFC.42
Furthermore, these changes continued over the first 2–4 years of the illness in a first-episode group.43
In this latter study, we also demonstrated that the pattern of GM retraction represented an amplification of the normal pattern and that this occurred across the entire brain but reaching significance in lateral PFC.
The PFC has received much attention, especially in consideration of the cognitive and functional deficits associated with schizophrenia including attention, working memory, and executive functioning.87–90
Hypofunction in the PFC in UHR groups compared with controls has been reported,91
as well as in neuroleptic-naïve first-episode schizophreniform psychosis.92
WM changes also implicate PFC regions. Reduced thickness of the corpus callosum has been found in first episode and chronic schizophrenia as well as in prepsychotic UHR individuals, consistent with disruption to fiber tracts connecting with PFC.78,93
In a longitudinal study of WM abnormalities in the Melbourne UHR group, Walterfang and colleagues94
reported that individuals who later developed psychosis had larger baseline volumes of WM in the frontal lobe, while longitudinally they showed a reduction in WM volume in the region of the left fronto-occipital fasciculus. More recently, Bloemen and colleagues95
identified lower fractional anisotropy (FA) values in medial frontal cortex, bilaterally in UHR individuals developing psychosis compared with controls, while compared with those not developing psychosis, they reported lower FA in left STG and in a region lateral to the right putamen. Further studies examining the changes in WM over development in UHR subjects should map the trajectories in relation to normal development of WM.
In addition to these structural abnormalities, executive functions are consistently found to be impaired in schizophrenia, implicating impaired integrity of the PFC.96
The Melbourne group has reported deficits in spatial working memory (SWM) from before psychosis onset,97
which are similar in degree to patients with first-episode schizophrenia98
and established schizophrenia.99,100
These researchers have also demonstrated that performance on this same SWM task shows an inverted U
function over the course of development from age 8 to 65 years, with optimal performance reached between ages 25 and 30 years.36,52
These findings would be consistent with developmental arrest of important functions during adolescence and adulthood as schizophrenia is developing.
As evident from the above summary, results have thus far been difficult to interpret and inconsistent, and understanding the timing of brain changes still requires additional work.18,101
Longitudinal investigations have generally proved more informative, given that patients have been followed through the period of transition to illness.9,12,13,39,40,102
However, a neuroanatomical marker to predict the development of psychosis in UHR cohorts is yet to be identified or validated, though there are some possible leads.103
This may be because neuroanatomical changes within the UHR group need to be placed within the context of normal developmental processes. Alternatively, the observed inconsistencies in this “transitional” group could reflect on the interplay of vulnerability vs compensatory processes in the underlying brain. A greater understanding of how environmental factors contribute and/or interact to result in the transition to psychosis could be provided from further studies of this group.