The results of this analysis generally support the hypothesis that greater activation in the distributed verbal WM network is associated with better functioning and less severe clinical symptoms. Additionally, though not predicted by our initial hypotheses, these results suggest that appropriately lateralized regional brain activation during performance of a verbal WM task in patients with schizophrenia is related to the severity of clinical presentation. In other words, greater activation in right (as opposed to left) frontal-subcortical circuitry during verbal WM is related to poorer social functioning.
Deficits in the WM system are thought to be a core feature of schizophrenia, one that is tied closely to the pathophysiology of the syndrome. Specifically, findings of reduced synaptic connectivity, most prominently in the frontal lobes (Goldman-Rakic and Selemon, 1997
; Selemon et al., 1998
), and potentially in more widespread cortical areas (Selemon et al., 1995
; Selemon and Goldman-Rakic, 1999
) could potentially be at the root of reduced WM capacity in these patients. In addition, Selemon and Goldman-Rakic (1999)
have suggested that even very subtle depletion in neuropil could have significant functional consequences because these connections form local and distributed circuits that are responsible for a wide variety of cognitive functions. Interpreted in the context of this prior work, our results might indicate that the degree or severity of the neuropathology that impacts with WM system (i.e., reduced synaptic connectivity) as indexed by fMRI, is related to functional and clinical status.
Role functioning and social functioning were found to covary with indices of the neural underpinnings of WM. This finding is consistent with - and extends upon - previous neuropsychological research suggesting that verbal WM function is linked to functional status (Green, 1996
; Green and Braff, 2001
; Green, 2007
). It is also consistent with previous neuropsychological and neuroimaging studies, negative and disorganized symptoms were related to activation during the verbal WM task (Menon et al., 2001
; Perlstein et al., 2001
Interestingly, despite the fact that most previous research in this area has focused the DLPFC, these results do not imply that this area is uniquely related to clinical severity, as other frontal areas, the parietal lobes, and thalamus are also implicated. This pattern suggests that it is the distributed activity of the WM circuit, and not only the frontal lobe node of this circuit, that is tied to clinical severity, role, and social functioning. In addition, our findings suggest that better social functioning may be associated with appropriate lateralization of activity during this verbal task, since greater activation in right frontal and subcortical areas was associated with poorer social functioning. Unexpectedly, although representing a more minor component of the covariance pattern, greater activation in right frontal and subcortical areas was also related to less severe positive symptoms. This relationship is difficult to interpret, particularly because the structure of the latent variable suggests that fewer positive symptoms are associated with poorer social functioning, a pattern not typically observed in samples of schizophrenia patients. Previous work also has not typically found a relationship between positive symptoms and frontal cortical activation (Whalley et al., 2007
; Wible et al., 2008
). However, given that the significance of the second pair of LVs is also not confirmed by the PLS procedure, which performs a permutation test only for the first pair, these secondary results should be interpreted with caution. It is possible that, given a greater number of subjects, a more stable covariance structure would emerge to better explain the relationship between positive symptoms and regional brain activity.
These findings indicate a linear relationship between brain activation and clinical presentation. Rather than testing each individual’s activation based on within-subjects variation in task difficulty, this study controls for task difficulty by assessing each subject at their own WM capacity. This approach allows for a linear test of a between-subjects model by examining individual differences at the apex of each individual’s WM function, and improves on prior work by ensuring that performance is intact and controlled for. This linear relationship, in which greater activation in the left hemisphere during verbal WM processing is associated with better functioning, is consistent with and extends previous work demonstrating a similar relationship between activation and behavioral accuracy on WM tasks in patients (Karlsgodt et al., 2007
; Karlsgodt et al., in press
). Namely, high performing patients tend to activate DLPFC more than low performing patients. Taken together, these results appear to suggest that high performing patients show a compensatory increase in activation (when compared with controls) to achieve similar levels of performance, and that this compensatory increase is also linked to a less severe clinical presentation. Conversely, relative hypo-activation in the low performing subjects may represent greater levels of changes in cellular microcircuitry or disruption in glutamatergic/dopaminergic signaling, which preclude such compensatory activation. Interpreted within this framework, an absence of compensatory activation during WM would then be related to poorer functioning and greater severity of negative and disorganized symptoms.
The term “cortical inefficiency” has often been employed to describe findings of hyperactivation in patients with schizophrenia (e.g., Callicott et al., 2000
). However, the results of this study also suggest that a single, simple linear increase in activation in a region of interest may not be the only definition of neural inefficiency. The lateralization findings suggest a form of “allocative” inefficiency, or a non-optimal distribution of resources. In other words, compensatory increases observed outside of the verbal WM network may also represent inefficient processes (Glahn et al., 2005
). Indeed, recent studies have shown when receiving atypical neuroleptic medication, patients do not demonstrate appropriate lateralization of task activity during spatial and verbal WM tasks, even in the absence of hypofrontality when compared to controls (Walter et al., 2003
). In this sense, hyper- and hypoactivavtion both indicate disrupted patterns of activation, with hypoactivation representing an inability to activate WM circuitry sufficiently and hyperactivation representing more functional but still faulty activation of the WM circuitry. The current study did not include controls because it would be unlikely to find a meaningful range of “clinical” symptoms or functional status in this group. It would be interesting, however, to investigate the possibility of different levels of activation in typically developing individuals, or in relatives of individuals with schizophrenia.
Overall, this study demonstrates a relationship between activation in the distributed WM system and clinical severity of schizophrenia. This finding expands on previous work showing relationships between activation in frontal regions and disorganized symptoms (Menon et al., 2001
; Perlstein et al., 2001
; Yoon et al., 2008
) by demonstrating a wider pattern of covariance between clinical presentation and distributed functional activation. The mechanisms underlying the relationships between regional brain activity and clinical presentation remain to be determined, but reductions in neuropil, and thus functional connectivity within the WM circuitry, represent prominent theoretical suspects.