Elsevier

Schizophrenia Research

Volume 193, March 2018, Pages 161-167
Schizophrenia Research

Emotion discrimination in humans: Its association with HSV-1 infection and its improvement with antiviral treatment

https://doi.org/10.1016/j.schres.2017.08.001Get rights and content

Abstract

Background

Herpes simplex virus, type 1 (HSV-1) infects over 3.4 billion people, world-wide. Though it can cause encephalitis, in the vast majority it is asymptomatic, with lifelong latent infection in neurons. HSV-1 infected individuals have greater cognitive dysfunction than uninfected individuals, particularly persons with schizophrenia – even without encephalitis. We investigated whether HSV-1 related cognitive dysfunction is progressive or remediable.

Methods

In a prospective naturalistic follow up sample (PNFU), temporal changes in cognitive functions were analyzed in relation to baseline HSV-1 infection in persons with/without schizophrenia (N = 226). Independently, in a randomized controlled trial (RCT), HSV-1 infected, clinically stabilized SZ outpatients received Valacyclovir (VAL, an HSV-1 specific antiviral, 1.5 G twice daily for 16 weeks) or placebo (PLA) added to standard antipsychotic treatment, using a stratified randomization design, following placebo run-in (N = 67). In both samples, HSV-1 infection (seropositivity) was estimated using serum IgG antibodies. Clinical evaluations were blinded to HSV-1 or treatment status. Standardized Z scores for accuracy on eight cognitive domains were analyzed for temporal trajectories using generalized linear models (PNFU) and VAL/PLA differences compared with intent to treat analyses (RCT).

Results

PNFU: At baseline, HSV-1 infected participants had significantly lower accuracy scores for Emotion Identification and Discrimination (EMOD), Spatial memory and Spatial ability, regardless of SZ diagnosis (p = 0.025, 0.029, 0.046, respectively). They also had significantly steeper temporal worsening for EMOD (p = 0.03). RCT: EMOD improved in VAL-treated patients (p = 0.048, Cohen's d = 0.43).

Conclusions

A proportion of age related decline in EMOD is attributable to HSV-1 infection.

Introduction

HSV-1 causes lifelong infection in approximately 3.4 billion people (Looker et al., 2015). It produces sporadic productive, lytic eruptions on mucosal surfaces, interspersed with latent, apparently asymptomatic infection restricted to neurons (Steiner et al., 2007). HSV-1 induced encephalitis is rare (0.004%) (Steiner et al., 2007), but many cross-sectional studies indicate cognitive dysfunction in working memory, attention and related domains in seropositive persons (Dickerson et al., 2003; Dickerson et al., 2004, Dickerson et al., 2008, Dickerson et al., 2012, Prasad et al., 2007, Prasad et al., 2012, Schretlen et al., 2010, Shirts et al., 2008, Strandberg et al., 2003, Tarter et al., 2014, Thomas et al., 2013, Watson et al., 2013, Yolken et al., 2011). Among healthy children, HSV-1 seropositivity is associated with lower reading and spatial reasoning test scores (Tarter et al., 2014). The associations are detectable among persons without a history of encephalitis and after accounting for potential socio-economic and infectious confounding factors (Studies cited above). Fruchter et al. (2015) studied associations between cognitive function and HSV-1 exposure among healthy young soldiers and found that HSV-1 exposed individuals were significantly more impaired. Other studies of non-psychiatric samples also reported that cognitive functions were more significantly impaired among HSV-1 exposed persons (Strandberg et al., 2003, Tarter et al., 2014; Jonker et al., 2014).

Cortical volume reductions in frontotemporal regions are also detectable in HSV-1 infected persons (Prasad et al., 2007). Though HSV-1 has not been etiologically linked with SZ (Thomas et al., 2013), the cognitive dysfunction is observed frequently among persons with SZ (Dickerson et al., 2003b; McGrath et al., 1997, Yolken et al., 2011). In sum, the cognitive dysfunction associated with persistent HSV-1 infection is distinct from the global, severe cognitive dysfunction among survivors of HSV-1 encephalitis (Hokkanen and Launes, 2007, McGrath et al., 1997, Prasad et al., 2007). It is reminiscent of ‘cognitive aging’, i.e., minor cognitive dysfunction among otherwise healthy adults that can compromise or magnify other physical and mental disabilities (Blazer et al., 2011). Like cognitive aging, varying trajectories of temporal cognitive decline have also been reported (Table 1). To test whether the HSV-1 associated cognitive dysfunction is remediable, we previously conducted a small randomized controlled adjunctive trial (RCT, N = 24) among US SZ patients with HSV-1 infection and found that 18-week adjunctive treatment with valacyclovir (VAL), an antiviral drug with high specificity for HSV-1 infection significantly improved verbal memory, working memory and visual object learning, compared with placebo augmentation of antipsychotic treatment (Prasad et al., 2013). Valacyclovir is highly specific as an antiviral agent, and studies have shown that it is very safe drug (Tyring et al., 2002). To evaluate the prognosis of HSV-1 associated cognitive dysfunction, we used a prospective, naturalistic follow up (PNFU) design to assess patterns of temporal change in cognitive functions among persons with and without HSV-1 infection. As our initial RCT was relatively small (Prasad et al., 2013), we separately evaluated a larger, independent sample using the same protocol.

Section snippets

Methods

The study was conducted at Dr. Ram Manohar Lohia Hospital, Delhi, India (RMLH). All participants were assessed with the Diagnostic Interview for Genetic Studies and consensus diagnoses were assigned as described (Thomas et al., 2013). Cognitive functions were assessed using the validated Penn Cognitive Neuropsychological Battery (PennCNB), which estimates accuracy and speed estimates for ten cognitive domains (Gur et al., 2001a, Gur et al., 2001b; Watson et al., 2013). As the accuracy and speed

Comparison between HSV-1 infected and HSV-1 uninfected participants at study entry

We recruited 412 participants after informed consent (patients n = 265 and controls n = 146) at baseline and blood samples were drawn. Out of these 65 individuals (cases 44, control 21) were equivocal on lab testing and we could not get report of 24 individuals. The sample with follow-up information comprised 138 patients with SZ and 88 individuals without psychosis. The sample included some participants from our published cross-sectional study (overlap: SZ, N = 29, non-psychotic, N = 46) (Thomas et

Discussion

At study entry in the PNFU sample, significant dysfunction was observed among HSV-1 infected participants in three of eight cognitive domains, consistent with prior cross-sectional studies. In particular, HSV-1 infected persons not only performed worse at study entry with regard to EMOD, but they also had a greater decline in EMOD over time. The greater temporal EMOD decline is notable because it also improved significantly following VAL treatment in the RCT sample. Taken together, the results

Acknowledgements

We thank our research participants and their families, as well as our dedicated research team members N.N.Mishra, PhD, Gyan Deepak Shah, MSc, Hemant Pande, Deepak Malik, M.Phil. and Nupur Kumari, M.Phil.. We also thank Dr. Ashutosh, MD; Dr.Rahul Saha, M.D., Dr. Shrikant Sharma, M.D., Dr. Kiran Jakhar, M.D.; Dr. Mona Chowdhary, M.D.; Dr. Aastha Sharma, M.D.; Dr. Aishwarya George, M.D. and all other clinicians at the Dept. of Psychiatry, PGIMER-Dr. RML Hospital; study consultant Dr. Rajesh

Conflict of interest

There is no conflict of interest to be reported by any of the authors.

Contributors

Triptish Bhatia: Review of literature, design, retrieving data, preparing first draft.

Joel Wood: Statistical analysis and drafting and reviewing manuscript.

Satish Iyengar: Designing statistical analyses, review and interpreting results.

Rampratap Beniwal: Revision of the manuscript and review of literature.

Sreelatha S. Narayanan: Retrieving data and review of literature.

Konasale M Prasad: Critical revision of the manuscript and design.

Kehui Chen: Statistical analyses, interpreting the data and

Role of funding source

Funds for this research are from Grants from the Department of Science and Technology, Government of India, Delhi to SND (SR/CSI/63/2010(G); the Stanley Medical Research Institute, Bethesda MD to RHY, VLN (07R-1712) and FBD (07R-1690); NIH, Bethesda MD to VLN (MH63480; D43 TW009114). The funding agencies are not responsible for the design and conduct of the study; collection, management, analysis, or interpretation of the data; nor for preparation, review, or approval of the manuscript.

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