We found normal hippocampal structure and function, in the context of intact relational memory performance, in many early psychosis patients. This finding is in contrast to our hypothesis derived from previous studies of chronic schizophrenia patients (35
). Our results provide new evidence that some of the well-established abnormalities of brain structure and function found in chronic psychosis patients are not fully present in all early psychosis patients. These findings support the notion that memory deficits and hippocampal abnormalities may be amenable to early intervention and, possibly, prevention.
Previous studies of early psychosis patients have found reductions in hippocampal volume, but results are equivocal. Diagnostic heterogeneity and varied durations of illness likely contribute to these inconsistent findings, as previous studies have shown that patients with a brief (< 6 months) duration of illness, and those experiencing their first episode of an affective psychosis do not exhibit reductions in hippocampal volume (21
). While an appropriate diagnosis can be identified at the time of study, it is often difficult to determine the ultimate diagnostic class for early psychosis patients. For example, when followed over 2 years, a significant number of psychotic patients will be reclassified, mainly from the non-affective to the affective psychosis group (62
). Future studies which evaluate hippocampal structure and function in early psychosis patients should include these factors in their analyses. In our early psychosis sample we collected follow-up clinical data on 29/41 participants to verify diagnoses (see Table S1
). Hippocampal volume did not differ by diagnostic category, though schizophreniform patients had the numerically largest volumes. In our sample, a large number of patients with schizophreniform disorder (n=13) and a relatively short mean duration of illness (about 6 months) likely contribute to the finding of normal hippocampal volumes. While hippocampal volume reductions are not apparent at the group level, the 25% of patients who failed to meet memory training criteria for the final fMRI analysis had the smallest hippocampal volumes. This supports a link between relational memory and hippocampal integrity, and indicates that memory deficits and hippocampal volume reductions are present in some early psychosis patients.
Our study is the first to investigate the neural correlates of relational memory retrieval in early psychosis patients. While a number of studies have documented relational memory deficits in chronic schizophrenia patients (33
), only three have tested relational memory ability in first-episode psychosis patients. Two behavioral studies found normal relational memory performance in first-episode psychosis patients during a pattern-location associative learning test (64
) and a brief verbal paired associates task (65
). A single fMRI study investigated brain activation during relational memory encoding in first-episode psychosis patients, finding evidence for reduced activation of the hippocampus and other areas during associative encoding of arbitrary image pairs, and a selective recognition deficit for these pairs (44
). In contrast, early psychosis patients included in our final fMRI analysis did not exhibit a selective relational memory deficit, and showed similar medial temporal lobe activity during memory recognition of the non-overlapping pairs. In the TI contrast, neither group showed robust hippocampal activation as predicted based on previous studies (41
). Neural activity during TI did not differ between early psychosis patients and healthy controls in the context of matched inference performance. However, only healthy controls showed a significant, positive correlation between inference performance and hippocampal activation.
With respect to overall cognitive function, studies of early psychosis patients find evidence for a broad, stable profile of generalized cognitive deficits (2
), with the most pronounced impairments on verbal (6
) and working (7
) memory. While most cognitive studies have focused on non-affective patients, two studies that compared cognition between affective and non-affective first-episode psychosis patients found more selective impairments in memory and executive function in the affective group (7
). In our sample, inference performance did not differ between affective and non-affective psychosis patients, making it unlikely that the inclusion of non-affective patients artificially inflated inference performance. Our finding of normal TI performance in early psychosis patients indicates that some cognitive functions may be preserved early in the disease course.
There are several limitations to the study. First, the training performance criteria necessary to test for a selective inference deficit severely limit the generalizability of the findings to all psychotic patients. Over 25% (11/41) of the early psychosis subjects, but only 9% (3/34) of control subjects, who completed the fMRI study were excluded from final analyses based on poor training performance (9 patients, 3 controls) or poor task compliance (2 patients, 0 controls). While isolation of a selective memory deficit is a current goal in schizophrenia research (68
), the methods employed to achieve this goal are complicated by differential task difficulty (40
) and the exclusion of patients who cannot reach a set inclusion criteria in a baseline condition (34
). In the current study our performance criteria excluded patients with smaller hippocampal volumes, which reduced our ability to detect between-group differences. Second, the block design does not allow for analysis of the crucial BD inference pair in isolation, or for an analysis of correct trials only (69
). An event-related fMRI version of this paradigm was developed to address this concern (51
), but the task proved very difficult for healthy controls, making it impossible to use in psychotic patients. Finally, most of the early psychosis patients were treated with antipsychotic medications; however, only 7/41 patients had a duration of treated illness greater than 6 months, and this factor was not correlated with inference performance (p>0.4).
In summary, this study is the first to assess TI, and only the second to directly evaluate hippocampal activation during memory performance, in patients during the early stage of psychosis. In a large sample of well-characterized, early psychosis patients with a short duration of illness we find normal mean hippocampal volume and intact hippocampal activation during relational memory performance. Of note, hippocampal volumes were smallest in those psychosis patients who failed to meet memory training criteria. These findings indicate that hippocampal dysfunction, well-established in chronic schizophrenia patients, is not present at the onset of psychosis in all early psychosis patients, providing an opportunity for clinical intervention and prevention.