Mismatch negativity as a marker of auditory pattern separation.

To what extent does incidental encoding of auditory stimuli influence subsequent episodic memory for the same stimuli? We examined whether the mismatch negativity (MMN), an event-related potential generated by auditory change detection, is correlated with participants' ability to discriminate those stimuli (i.e. targets) from highly similar lures and from dissimilar foils. We measured the MMN in 30 young adults (18-32 years, 18 females) using a passive auditory oddball task with standard and deviant 5-tone sequences differing in pitch contour. After exposure, all participants completed an incidental memory test for old targets, lures, and foils. As expected, participants at test exhibited high sensitivity in recognizing target items relative to foils and lower sensitivity in recognizing target items relative to lures. Notably, we found a significant correlation between MMN amplitude and lure discrimination, but not foil discrimination. Our investigation shows that our capacity to discriminate sensory inputs at encoding, as measured by the MMN, translates into precision in memory for those inputs.

Structural neuroimaging phenotypes of a novel multi-gene risk score in youth bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is among the most heritable psychiatric disorders, particularly in early-onset cases, owing to multiple genes of small effect. Here we examine a multi-gene risk score (MGRS), to address the gap in multi-gene research in early-onset BD. METHODS: MGRS was derived from 34 genetic variants relevant to neuropsychiatric diseases and related systemic processes. Multiple MGRS were calculated across a spectrum of inclusion p-value thresholds, based on allelic associations with BD. Youth participants (123 BD, 103 healthy control [HC]) of European descent were included, of which 101 participants (58 BD, 43 HC) underwent MRI T1-weighted structural neuroimaging. Hierarchical regressions examined for main effects and MGRS-by-diagnosis interaction effects on 6 regions-of-interest (ROIs). Vertex-wise analysis also examined MGRS-by-diagnosis interactions. RESULTS: MGRS based on allelic association p≤0.60 was most robust, explaining 6.8% of variance (t(226)=3.46, p=.001). There was an MGRS-by-diagnosis interaction effect on ventrolateral prefrontal cortex surface area (vlPFC; ß=.21, p=.0007). Higher MGRS was associated with larger vlPFC surface area in BD vs. HC. There were 8 significant clusters in vertex-wise analyses, primarily in fronto-temporal regions, including vlPFC. LIMITATIONS: Cross-sectional design, modest sample size. CONCLUSIONS: There was a diagnosis-by-MGRS interaction effect on vlPFC surface area, a region involved in emotional processing, emotional regulation, and reward response. Vertex-wise analysis also identified several clusters overlapping this region. This preliminary study provides an example of an approach to imaging-genetics that is intermediate between candidate gene and genome-wide association studies, enriched for genetic variants with established relevance to neuropsychiatric diseases.

Proof-of-concept study of a multi-gene risk score in adolescent bipolar disorder.

BACKGROUND: Few studies have examined multiple genetic variants concurrently for the purpose of classifying bipolar disorder (BD); the literature among youth is particularly sparse. We selected 35 genetic variants, previously implicated in BD or associated characteristics, from which to identify the most robustly predictive group of genes. METHODS: 215 Caucasian adolescents (114 BD and 101 healthy controls (HC), ages 13-20 years) were included. Psychiatric diagnoses were determined based on semi-structured diagnostic interviews. Genomic DNA was extracted from saliva for genotyping. Two models were used to calculate a multi-gene risk score (MGRS). Model 1 used forward and backward regressions, and model 2 used a PLINK generated method. RESULTS: In model 1, GPX3 rs3792797 was significant in the forward regression, DRD4 exonIII was significant in the backward regression; IL1ß rs16944 and DISC1 rs821577 were significant in both the forward and backward regressions. These variants are involved in dopamine neurotransmission; inflammation and oxidative stress; and neuronal development. Model 1 MGRS did not significantly discriminate between BD and HC. In model 2, ZNF804A rs1344706 was significantly associated with BD; however, this association did not predict diagnosis when entered into the weighted model. LIMITATIONS: This study was limited by the number of genetic variants examined and the modest sample size. CONCLUSIONS: Whereas regression approaches identified four genetic variants that significantly discriminated between BD and HC, those same variants no longer discriminated between BD and HC when computed as a MGRS. Future larger studies are needed evaluating intermediate phenotypes such as neuroimaging and blood-based biomarkers.