The present analyses suggest that serological evidence of infection to two neurotropic viral agents, namely HSV1 and CMV, is associated with impaired cognitive functioning among patients with schizophrenia. The associations with HSV1 are consistent with an earlier report (Dickerson et al. 2003
). To our knowledge, this is the first study to report that serological evidence of infections with CMV has a significant effect on cognition in patients with schizophrenia. We found a positive association with cognitive impairment that may be qualitatively different from the associations with HSV1 exposure, although others have found similar trends with CMV exposure in schizophrenia patients (Dickerson et al. 2003
). The different patterns may be affected by the relatively large variation in the test values noted here. Alternatively, our observation may reflect a larger effect of HSV1 exposure than CMV on performance on these cognitive tasks. The statistically significant associations here explain a relatively small portion of the variability, but are important as they may be remediable. The rates of seropositivity reported here are similar to those found by others (Marshall and Stout 2005
; Niebuhr et al. 2008
; Yolken 2004
SZ patients exposed to CMV took longer to complete the TMT A, but did not commit significantly more errors on TMT-A. This suggests that SZ patients exposed to CMV emphasized accuracy over speed when completing the TMT-A. Else, they may experience difficulty in integrating visual scanning, motor coordination and spatial orientation, and perhaps slower processing. With enough time, however, they could perform with comparable number of errors to unexposed patients. On the other hand, SZ patients exposed to CMV committed more errors on the more challenging TMT-B, with no significantly increased time compared to those not exposed. This suggests that SZ patients exposed to CMV may emphasize time over accuracy for complex tasks that involve integration of multiple cognitive processes to generate an appropriate output.
SZ patients exposed to HSV1 had a different pattern of performance. They did not show significant differences in the response time or the errors committed on the TMT-A compared to those not exposed. On the relatively more difficult TMT-B, those exposed to HSV1 took longer and committed more errors. The results may reflect impaired executive subprocesses as suggested by differences in the derived measure ((B-A)/A). This observation is partly supported by the brain regions affected by HSV1 exposure. Whereas CMV is known to affect the limbic regions (Hanshaw 1976
), HSV1 primarily affects the prefrontal, parietal and temporal cortical regions (Cleator and Klapper 2004
). Although such explanations are speculative at present, the pattern of differences in task performance may be due to real differences in the pattern of impairment, variable effect size associated with each of these viruses, or stochastic variations. Given that these cognitive skills are used in both TMT parts A and B it is surprising that there is no significant difference in TMT part B time for those infected with CMV. These results should be evaluated using other cognitive tests, as the TMT may not discriminate precisely between these skills. Both viruses were also associated with increased errors on TMT part B. Performance on these measures may thus reflect the same cognitive functions influencing time for completion, such as working memory or set switching. It is also possible that our results indicate other areas of cognitive functioning that are influenced by exposure to CMV, as well as HSV1.
The results suggesting worse (B-A)/A and increased errors among individuals exposed to HSV1 are consistent with previous findings, which used the Repeatable Battery for the Assessment of Cognitive Status (RBANS) as a measure of cognitive function in schizophrenia patients. The difference in performance could best be attributed to impaired working memory (Dickerson et al. 2003
). They are also consistent with our prior report (Prasad et al. 2007
) in which we noted decreased gray matter volumes in the DLPFC among HSV1 seropositive individuals with schizophrenia because some components of working memory are known to be regulated by the DLFPC
(Barch et al. 2001
; Callicott et al. 2003
). Taken together, our observations suggest that HSV1 may mediate impaired cognitive functions through abnormalities in the DLPFC (Brodmann areas 9 and 46). However, the structure-function correlation may be more complex. Demakis (Demakis 2004
) in a metaanalysis elegantly points out the complexity in associating neuropsychological test performance purported to tap the frontal lobe function with the function of this region in comparison to non-frontal regions. Surprisingly, this metaanalysis shows statistically significant association of TMT-A but not TMT-B performance with frontal lobe function. The derived value ((B-A)/A) that represents executive function was not included in this metaanalysis. However, as Demakis (Demakis 2004
) points out the studies included in the metaanalysis tended to collapse all frontal regions into frontal lobe, which may be an oversimplification of a functionally complex lobe. An integrative study using concurrent functional imaging of the brain while performing these tests may help answer this question.
For individuals with serological evidence of exposure to TOX or HSV2, there was a trend towards slower times to completion, but these results were not statistically significant. The number of individuals with serological evidence of exposure was much smaller for these infectious agents, so our sample had less power to effectively evaluate associations with for effect sizes similar to those observed here for HSV1 and CMV.
Antibody titers do not indicate the precise time when infection occurs. Our serological analysis is based on samples that were taken well after the diagnosis of schizophrenia. Our explanation is that reactivation of latent infection maintains elevated antibody levels and allows us to distinguish with reasonable accuracy between infection exposed and unexposed individuals. However, from our data we are unable to address the important question of whether cognitive effects are due to acute influences on brain functioning or disturbances in brain development related to exposure to these infectious agents.
There are few reports of the impact of HSV1 and CMV on cognitive function among other diagnostic groups or among individuals who do not manifest any overt disorder but have serological evidence of viral exposure. Hence it is uncertain whether our results indicate a specific effect among individuals with schizophrenia. Recently, HSV1 and CMV have been associated with decreased cognitive functioning in elderly patients (Aiello et al. 2006
; Strandberg et al. 2003
). In addition, Dickerson and colleagues have found impaired memory to be associated with serological evidence of HSV-1 infection in individuals without a psychiatric disease (Dickerson et al. 2008
). Impairment in cognitive function due to viral infection may not be specific to schizophrenia pathogenesis, but only noticeable when there is already baseline cognitive deficit, such as that caused by the aging process. Cognitive dysfunction in schizophrenia is relatively stable, and does not progress with age differently than it does in similarly aged healthy subjects (Eyler Zorrilla et al. 2000
; Nayak Savla et al. 2006
). On the other hand, cognitive dysfunction appears to be an early manifestation of schizophrenia, unrelated to age of onset or duration of illness (Heaton et al. 1994
; O’Donnell 2007
The mechanisms by which viruses cause cognitive dysfunction are likewise unclear.
We have found that genetic variants in some genes that are associated with schizophrenia are also associated with HSV1 antibody titer status (Shirts et al. 2007a
; Shirts et al. 2007b
), suggesting there may be similar mechanisms associated with viral central nervous system infection and schizophrenia. It appears that infections such as HSV1 act directly on the central nervous system or through local immune mediators as there are measurable gray matter volume changes in schizophrenia cases infected with HSV1
(Prasad et al. 2007
). However, infections may also act indirectly through activation of systemic cytokines and stress factors, whose levels have been found to be differently expressed in schizophrenia cases and which are known to modulate cognitive functioning (Leonard 2007
; Potvin et al. 2008
Further analysis of cognitive function and infection may be necessary to determine if viral influence on cognition is a general phenomenon or specific to schizophrenia. Regardless of specificity to schizophrenia, treatment of HSV1 and CMV exposed schizophrenia patients with antivirals could potentially improve cognitive function and clinical outcomes. Randomized controlled studies will be necessary to determine the clinical benefit of such treatment.