DNA methylation of the serotonin transporter gene (SLC6A4) is associated with brain function involved in processing emotional stimuli

Background

The aim of the present study was to investigate the association of fMRI blood oxygen–level dependent (BOLD) reactivity with the level of epigenetic methylation of SLC6A4 in blood DNA from a sample of healthy participants and patients with major depressive disorder (MDD).

Methods

We investigated patients with MDD and healthy controls using fMRI and an emotional attention-shifting task. We assessed site-specific DNA methylation of a previously characterized SLC6A4 region in peripheral blood DNA using pyrosequencing.

Results

Our study involved 25 patients with MDD and 35 healthy controls. Activation in the anterior insula elicited by negative emotional content was significantly positively associated with the degree of SLC6A4 methylation. Significantly negative associations were observed between activation in the posterior insula and the degree of SLC6A4 methylation when judging the geometry of pictures after seeing negative in contrast to positive emotional stimuli. Healthy controls with a high degree of SLC6A4 methylation depicted significantly more activity elicited by positive stimuli in limbic regions and more activity elicited by negative stimuli in limbic as well as cognitive control regions than those with a low degree of SLC6A4 methylation.

Limitations

It is impossible to measure methylation directly in the brain and thus we assessed peripheral methylation of SLC6A4. Since the association was cross-sectional, no conclusion about cause and effect can be drawn.

Conclusion

Our study provides further support to the hypothesis that particular DNA methylation states that are associated with brain function during emotion processing are detectable in the periphery.     

Positive association of the pericentrin (PCNT) gene with major depressive disorder in the Japanese population

Background

Pericentrin (PCNT) interacts with disruption-in-schizophrenia 1 (DISC1), a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). We sought to determine whether the PCNT gene is implicated in MDD.

Methods

We performed case–control association analyses in the Japanese population. We analyzed 9 single nucleotide polymorphisms (SNPs) in 173 patients with MDD and 348 healthy controls.

Results

We found a significant allelic association between 3 SNPs (rs3788265, rs2073376 and rs2073380) of the PCNT gene and MDD (p = 0.006, 0.005 and 0.021, respectively). After correction for multiple testing, 2 SNPs (rs3788265 and rs2073376) retained significant allelic associations with MDD. In addition, we found a significant association between the 2 marker haplotypes (r3788265 and rs2073376) and MDD (permutation p = 0.011).

Limitations

Our sample was small and comprised only Japanese participants. In addition, owing to the late onset of MDD, it is possible that the disorder will develop in at least some participants in our control group. Finally, we did not show how SNPs of the PCNT gene alter its function.

Conclusion

Our results suggest that genetic variations in the PCNT gene may play a significant role in the etiology of MDD in the Japanese population.     

Impaired interhemispheric connectivity in medication-naive patients with major depressive disorder

Background

Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in major depressive disorder (MDD). The purpose of this study was to investigate interhemispheric connectivity in medication-naive patients with MDD by measuring fractional anisotropy in the CC with diffusion tensor imaging (DTI) techniques.

Methods

We obtained DTI scans from medication-naive patients with MDD and from matched healthy controls. Fractional anisotropy values were compared using semiautomatic region of interest methods to localize the regional CC differences between these 2 groups.

Results

We enrolled 27 patients and 27 controls in our study. Fractional anisotropy values were significantly lower in the anterior genu of the CC in the MDD group than in the control group (p = 0.009, corrected); results were not significantly different in any other CC subregions.

Limitations

As patients with MDD were already experiencing acute episodes, future studies of individuals at risk for MDD are warranted to elucidate the interhemispheric connectivity abnormalities associated with the predisposition to MDD.

Conclusion

The findings demonstrate abnormalities in the structural integrity of the anterior genu of the CC in medication-naive individuals with MDD, which may contribute to impairment of interhemispheric connectivity in patients with this disorder.     

Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder

Background

Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala–PFC functional connectivity during emotional face processing in medication-naive individuals with MDD.

Methods

Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups.

Results

Our study included 28 individuals with MDD and 30 controls. Decreased amygdala–left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions.

Limitations

All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population.

Conclusion

Medication-naive individuals with MDD showed decreased amygdala–left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala–left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD.     

No Effect of Serotoninergic Gene Variants on Response to Interpersonal Counseling and Antidepressants in Major Depression

Objective

Gene variants within the serotonin pathway have been associated with major depressive disorder (MDD) treatment outcomes, however a possible different modulation on pharmacological or psychological treatments has never been investigated.

Methods

One hundred sixty MDD patients were partially randomized to either inter-personal counseling (IPC) or antidepressants. The primary outcome was remission at week 8. Five serotonergic polymorphisms were investigated (COMT rs4680, HTR1A rs6295, HTR2A rs2224721, HTR2A rs7997012 and SLC6A4 rs421417).

Results

IPC (n=43) and antidepressant (n=117) treated patients did not show any difference in remission rates at week 8 (corrected for baseline severity, age and center). None of the studied gene variants impacted on response and remission rates at week 8 neither in the IPC nor in the antidepressant group. An analysis of the whole sample showed a trend of association between rs7997012 AA genotype and a better treatment outcome.

Conclusion

Our study confirms that IPC is an effective psychological intervention comparable to antidepressants in mild-moderate MDD. Polymorphisms related to the serotonin system did not exert a major effect on clinical outcomes in none of the treatment groups.     

A Sex-Specific Comparison of Major Depressive Disorder Symptomatology in the Canadian Forces and the General Population

Objective:

To compare major depressive disorder (MDD) symptomatology within men and women in a large, representative sample of Canadian military personnel and civilians.

Method:

We used the Canadian Community Health Survey: Mental Health and Well-Being (Cycle 1.2 and Canadian Forces Supplement) (n = 36 984 and n = 8441, respectively) to compare past-year MDD symptomatology among military and civilian women, and military and civilian men. Logistic regression models were used to determine differences in the types of depressive symptoms endorsed in each group.

Results:

Men in the military with MDD were at lower odds than men in the general population to endorse numerous symptoms of depression, such as hopelessness (adjusted odds ratio [AOR] 0.44; 99% CI 0.23 to 0.83) and inability to cope (AOR 0.53; 99% CI 0.31 to 0.92). Military women with MDD were at lower odds of thinking about their death (AOR 0.52; 99% CI 0.32 to 0.86), relative to women with MDD in the general population.

Conclusion:

Different MDD symptomatology among males and females in the military, compared with those in the general population, may reflect selection effects (for example, personality characteristics and patterns of comorbidity) or occupational experiences unique to military personnel. Future research examining the mechanisms behind MDD symptomatology in military personnel and civilians is required.     

Microarray Analysis of the Major Depressive Disorder mRNA Profile Data

Objective

Major depressive disorder (MDD) is a common mood disorder associated with several psychophysiological changes like disturbances of sleep, appetite, or sexual desire, and it affects the patients'' life seriously. We aimed to explore a genetic method to investigate the mechanism of MDD.

Methods

The mRNA expression profile ({"type":"entrez-geo","attrs":{"text":"GSE53987","term_id":"53987"}}GSE53987) of MDD was downloaded from Gene Expression Omnibus database, including 105 samples of three brain regions in post-mortem tissue suffered from MDD and unaffected controls. Differentially expressed genes (DEGs) in MDD were identified using the Limma package in R. Gene Ontology functions and Kyoto Enrichment of Genes and Genomes pathways of the selected DEGs were enriched using Database for Annotation, Visualization and Integrated Discovery. Protein-protein interactive network of DEGs was constructed using the Cytoscape software.

Results

Totally, 241 DEGs in MDD-hip group, 218 DEGs in MDD-pfc group, and 327 DEGs in MDD-str group were identified. Also, different kinds of biological processes of DEGs in each group were enriched. Besides, glycan biosynthesis of DEGs in MDD-str group, RIG-I-like receptor signaling and pyrimidine metabolism of DEGs in the MDD-hip group were enriched, respectively. Moreover, several DEGs like PTK2, TDG and CETN2 in MDD-str group, DCT, AR and GNRHR in MDD-pfc group, and AKT1 and IRAK1 in MDD-hip group were selected from PPI network.

Conclusion

Our data suggests that the brain striatum tissue may be greatly affected by MDD, and DEGs like PTK2, GALNT2 and GALNT2 in striatum, AR in prefrontal cortex and IRAK1 and IL12A in hippocampus may provide novel therapeutic basis for MDD treatment.     

The Mistreatment of Major Depressive Disorder

Objective:

To examine the effects of classification on treatment in major depressive disorder (MDD).

Method:

This is a narrative review.

Results:

MDD is a highly heterogeneous category, leading to problems in classification and in specificity of treatment. Current models classify all depressions within a single category. However, the construct of MDD obscures important differences between severe disorders that require pharmacotherapy, and mild-to-moderate disorders that can respond to psychotherapy or remit spontaneously. Patients with mild-to-moderate MDD are being treated with routine or overly aggressive pharmacotherapy.

Conclusions:

The current classification fails to address the heterogeneity of depression, leading to mistreatment.     

Characterization of major depressive disorder using a multiparametric classification approach based on high resolution structural images

Background

Major depressive disorder (MDD) is one of the most disabling mental illnesses. Previous neuroanatomical studies of MDD have revealed regional alterations in grey matter volume and density. However, owing to the heterogeneous symptomatology and complex etiology, MDD is likely to be associated with multiple morphometric alterations in brain structure. We sought to distinguish first-episode, medication-naive, adult patients with MDD from healthy controls and characterize neuroanatomical differences between the groups using a multiparameter classification approach.

Methods

We recruited medication-naive patients with first-episode depression and healthy controls matched for age, sex, handedness and years of education. High-resolution T₁-weighted images were used to extract 7 morphometric parameters, including both volumetric and geometric features, based on the surface data of the entire cerebral cortex. These parameters were used to compare patients and controls using multivariate support vector machine, and the regions that informed the discrimination between the 2 groups were identified based on maximal classification weights.

Results

Thirty-two patients and 32 controls participated in the study. Both volumetric and geometric parameters could discriminate patients with MDD from healthy controls, with cortical thickness in the right hemisphere providing the greatest accuracy (78%, p ≤ 0.001). This discrimination was informed by a bilateral network comprising mainly frontal, temporal and parietal regions.

Limitations

The sample size was relatively small and our results were based on first-episode, medication-naive patients.

Conclusion

Our investigation demonstrates that multiple cortical features are affected in medication-naive patients with first-episode MDD. These findings extend the current understanding of the neuropathological underpinnings of MDD and provide preliminary support for the use of neuroanatomical scans in the early detection of MDD.     

A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder

Background

Some, although not all, studies report small hippocampal volume in patients with major depressive disorder (MDD) relative to healthy controls. Here, we explore the contribution of key demographic and clinical variables to this difference.

Methods

We used meta-analytic techniques to provide an updated analysis of data from 32 magnetic resonance imaging studies of hippocampal volume in patients with MDD.

Results

Our analysis confirmed the difference in hippocampal volume, but only among patients with MDD whose duration of illness was longer than 2 years or who had more than 1 disease episode. We found no such effect in studies that included patients who did not fit these criteria. The effect was limited to children and middle-aged or older adults. Analyzed collectively, studies including young adult patients showed equivalent hippocampal volumes across MDD patients and controls, a result that may be attributable to a reduced burden of illness in this population. Age at onset of disease, severity of depression at the time of scanning, sex and slice thickness did not contribute to differences in hippocampal volume between patients with MDD and controls.

Limitations

The small size of many of the clinical and demographic subgroups may have limited statistical power to detect between-group differences.

Conclusion

Although all studies were cross-sectional, our results suggest that hippocampal volume reductions generally occur after disease onset in patients with MDD. These findings have implications for the timing of clinical interventions aimed at reducing the impact of MDD on neuronal structure and function.     

Descriptive Epidemiology of Major Depressive Disorder in Canada in 2012

Objective:

The epidemiology of major depressive disorder (MDD) was first described in the Canadian national population in 2002. Updated information is now available from a 2012 survey: the Canadian Community Health Study—Mental Health (CCHS-MH).

Method:

The CCHS-MH employed an adaptation of the World Health Organization World Mental Health Composite International Diagnostic Interview and had a sample of n = 25 113. Demographic variables, treatment, comorbidities, suicidal ideation, and perceived stigma were assessed. The analysis estimated adjusted and unadjusted frequencies and prevalence ratios. All estimates incorporated analysis methods to account for complex survey design effects.

Results:

The past-year prevalence of MDD was 3.9% (95% CI 3.5% to 4.2%). Prevalence was higher in women and in younger age groups. Among respondents with past-year MDD, 63.1% had sought treatment and 33.1% were taking an antidepressant (AD); 4.8% had past-year alcohol abuse and 4.5% had alcohol dependence. Among respondents with past-year MDD, the prevalence of cannabis abuse was 2.5% and that of dependence was 2.9%. For drugs other than cannabis, the prevalence of abuse was 2.3% and dependence was 2.9%. Generalized anxiety disorder was present in 24.9%. Suicide attempts were reported by 6.6% of respondents with past-year MDD. Among respondents accessing treatment, 37.5% perceived that others held negative opinions about them or treated them unfairly because of their disorder.

Conclusions:

MDD is a common, burdensome, and stigmatized condition in Canada. Seeking help from professionals was reported at a higher frequency than in prior Canadian studies, but there has been no increase in AD use among Canadians with MDD.     

Structural changes in the hippocampus in major depressive disorder: contributions of disease and treatment

Background

Previous magnetic resonance imaging (MRI) studies of patients with major depressive disorder (MDD) have consistently shown bilateral and unilateral reductions in hippocampal volume relative to healthy controls. Recent structural MRI studies have addressed the question of whether changes in the volume of hippocampal subregions may be associated with MDD.

Methods

We used a comprehensive and reliable 3-dimensional tracing protocol that enables delineation of hippocampal subregions (head, body, tail) to study changes in the hippocampus of patients with MDD. We recruited 39 MDD patients (16 medicated, 23 unmedicated) and 34 healthy age- and sex-matched controls. We acquired images using a magnetization-prepared rapid acquisition gradient echo sequence on a 1.5-T scanner with a spatial resolution of 1.5 mm × 0.5 mm × 0.5 mm. We performed volumetric analyses, blinded to diagnosis, using the interactive software package Display. All volumes were adjusted for intracranial volume.

Results

We found a significant reduction in the volume of the hippocampal tail bilaterally, right hippocampal head and right total hippocampus in MDD patients. Medicated MDD patients showed increased hippocampal body volume compared with both healthy controls and unmedicated patients.

Limitations

This study was cross-sectional. Further prospective studies are needed to determine the direct effect of antidepressant treatment.

Conclusion

Our results suggest that decreased hippocampal tail and hippocampal head volumes could be trait changes, whereas hippocampal body changes may be dependent on treatment. We showed that long-term antidepressant treatment may affect hippocampal volume in patients with MDD.     

Depression and Employment Status in Primary and Tertiary Care Settings

Objective:

Major depressive disorder (MDD) is a leading cause of disability. Impairment in work function considerably adds to symptom burden and increases the economic impact of this disorder. Our study aimed to investigate the factors associated with work status in MDD within primary and tertiary care.

Method:

We used data from 2 large databases for our analysis—Study 1: the InSight database, a chart review of MDD patients treated by primary care physicians across Canada (n = 986); and Study 2: the International Mood Disorders Collaborative Project, a cross-sectional study of mood disorder patients (Canadian data only: n = 274).

Results:

Both studies demonstrated high rates of unemployment and disability (30.3% to 42.1%). Quebec showed the highest rate of unemployment (21%) and British Columbia had the greatest percentage of patients on disability (15%). Employed and unemployed groups were similar based on clinical characteristics; however, unemployed people may have higher age, prevalence of medical comorbidity, and greater likelihood of receiving a benzodiazepine. Increased disability rates were associated with history of childhood abuse, duration of current major depressive episode, comorbidity, benzodiazepine use, as well as greater depression and anxiety severity. The unemployed–disability groups had greater somatic symptoms and anhedonia. In keeping with this, anhedonia was the strongest predictor of disability. Absenteeism was also high across both studies.

Conclusions:

Unemployment and disability rates in MDD are high. The presence of anhedonia and medical comorbidity significantly influenced work status, emphasizing the need for treatment strategies to alleviate the additional symptom burden in this subpopulation.     

Decreased Total Antioxidant Activity in Major Depressive Disorder Patients Non-Responsive to Antidepressant Treatment

Objective

This study aimed to evaluate the total antioxidant activity (TAA) in patients with major depressive disorder (MDD) and the effect of antidepressants on TAA using a novel potentiometric method.

Methods

Twenty-eight patients with MDD and thirty-one healthy controls were enrolled in this study. The control group comprised 31 healthy individuals matched for gender, drinking and smoking status. We assessed symptoms of depression using the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI). We measured TAA using potentiometry. All measurements were made at baseline and four and eight weeks later.

Results

There was a significant negative correlation between BDI scores and TAA. TAA was significantly lower in the MDD group than in controls. When the MDD group was subdivided into those who showed clinical response to antidepressant therapy (response group) and those who did not (non-response group), only the non-response group showed lower TAA, while the response group showed no significant difference to controls at baseline. After eight weeks of antidepressant treatment, TAA in both the response and non-response groups was similar, and there was no significant difference among the three groups.

Conclusion

These results suggest that the response to antidepressant treatment in MDD patients might be predicted by measuring TAA.     

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

Background

Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.

Methods

Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.

Results

A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.

Limitations

The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.

Conclusion

The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.     

Structural MRI correlates for vulnerability and resilience to major depressive disorder

Background

In major depressive disorder (MDD), it is unclear to what extent structural brain changes are associated with depressive episodes or represent part of the mechanism by which the risk for illness is mediated. The aim of this study was to investigate whether structural abnormalities are related to risk for the development of MDD.

Methods

We compared healthy controls with a positive family history for MDD (HC-FHP), healthy controls with no family history of any psychiatric disease (HC-FHN) and patients with MDD. Groups were age- and sex-matched. We analyzed data from high-resolution magnetic resonance imaging using voxel-based morphometry. We performed small volume corrections for our regions of interest (hippocampus, dorsolateral [DLPFC] and dorsomedial prefrontal cortex [DMPFC], anterior cingulate cortex [ACC] and basal ganglia) using a family-wise error correction (p < 0.05) to control for multiple comparisons.

Results

There were 30 participants in the HC-FHP group, 64 in the HC-FHN group and 33 patients with MDD. The HC-FHP group had smaller right hippocampal and DLPFC grey matter volumes compared with the HC-FHN group, and even smaller right hippocampal volumes compared with patients with MDD. In addition, the HC-FHP group exhibited smaller white matter volumes in the DLPFC and left putamen but also greater volumes in 2 areas of the DMPFC compared with the HC-FHN group. Patients with MDD exhibited smaller volumes in the ACC, DMPFC, DLPFC and the basal ganglia compared with healthy controls.

Limitations

The retrospective identification of family history might result in a bias toward unidentified participants in the control group at risk for MDD, diminishing the effect size.

Conclusion

Volume reductions in the hippocampus and DLPFC might be associated with a greater risk for MDD. The HC-FHP group had smaller hippocampal volumes compared with patients with MDD, which is suggestive for neuroplastic effects of treatment. The HC-FHP group had not yet experienced a depressive episode and therefore might have been resilient and might have had some protective strategies. Whether resilience is associated with the larger white matter volumes in the DMPFC (e.g., owing to compensatory, neuroplastic remodelling mechanisms) needs to be confirmed in future studies.     

Distinguishing Quantitative Electroencephalogram Findings between Adjustment Disorder and Major Depressive Disorder

Objective

Adjustment disorder (ADJ) is a common diagnosis. However, it is difficult to distinguish ADJ from other major Axis I disorders, such as major depressive disorder (MDD). The aim of this study was to determine the distinguishing neurophysiological characteristics between ADJ and MDD using quantitative analysis of an electroencephalogram (QEEG).

Methods

The study included 30 patients with ADJ and 51 patients with MDD. Resting (eye closed) vigilance controlled EEG recordings were assessed at 19 electrode sites according to the international 10/20 system. QEEG absolute power and coherence were calculated for the delta, theta, alpha and beta bandwidths.

Results

Absolute powers of alpha and high beta bands, particularly at the frontocentral area, differed between MDD and ADJ group (p<0.05). Interhemispheric coherence values for the delta and beta bands were lower in the ADJ group than in the MDD group (p<0.05). Intrahemispheric coherence values for the alpha band were also lower in the ADJ group (p<0.05).

Conclusion

The differences in QEEG power and coherence in our investigation suggest that underlying pathophysiologic mechanisms may be different between ADJ and MDD.     

Persistent Infection by HSV-1 Is Associated With Changes in Functional Architecture of iPSC-Derived Neurons and Brain Activation Patterns Underlying Working Memory Performance

Background:

Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.

Methods:

Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.

Results:

HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10^{− 4}; 2-back, P = 1.39 × 10^{− 5}) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.

Conclusions:

The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.Key words: memory, induced pluripotent stem cells, herpes simplex virus type 1, fMRI, herpes