Target‐related parietal P3 and medial frontal theta index the genetic risk for problematic substance use

Abstract

Theoretical and empirical work suggests that problematic substance use (PSU) is associated with individual differences in prefrontal cortex activity. While research has strongly linked parietal P3 amplitude reduction (P3AR) to genetic risk for problematic substance use, few studies have tested whether prefrontal EEG measures are sensitive to this genetic liability. In addition to P3, oddball target detection tasks elicit medial frontal theta power, reflecting attentional allocation, and parietal delta, indexing decision making or stimulus-response link updating. Midfrontal theta and parietal delta may index neurocognitive processes relevant to PSU beyond P3AR.The present investigation examined the etiological relationship between PSU and P3, frontal theta, and parietal delta in a large twin sample (N = 754). EEG was recorded during a visual oddball task. Greater PSU was associated with reduced target P3 amplitude and midfrontal theta/parietal delta power, and increased mean reaction time and reaction time variability (RTV; indexing attentional fluctuations). P3, theta, and RTV, but not delta or mean RT, explained unique variance in PSU (R 2 = 0.04). Twin biometric modeling indicated a genetic relationship between PSU and P3, theta, and RTV. Theta accounted for distinct genetic variance in PSU beyond P3 and RTV. Together, 23% of the total additive genetic variance in PSU was explained by the three endophenotypes. Results replicate P3AR as an endophenotype and provide support for additional behavioral (RTV) and neurophysiological (midfrontal theta) endophenotypes of PSU. Reduced theta and greater RTV may reflect variations in a prefrontal attentional network that confers genetic risk for substance use problems.

Midfrontal Theta Activity in Psychiatric Illness: An Index of Cognitive Vulnerabilities Across Disorders

“…Future longitudinal research is necessary to examine the potential feedback loops that might exist between theta-related neural changes and alcohol abuse. Reduced FM power may share genetic influences with problematic substance use in general (111). This study also identified a strong genetic relationship between FM power and inconsistency in responding (RTV), confirming an earlier study in ADHD (19).…”

Parietal P3 and midfrontal theta prospectively predict the development of adolescent alcohol use

“…These findings provide important evidence supporting the endophenotypic construct validity of midfrontal target-related theta (Iacono et al ., 2017). Theta is associated with normative and pathological alcohol use (Jones et al ., 2006; Andrew and Fein, 2010; Yoon et al ., 2013; Harper et al ., 2019); heritable (Harper et al ., 2019); diminished in first-degree relatives with AUD (Rangaswamy et al ., 2007); shares genetic variance with alcohol use (Harper et al ., 2019); and predicts alcohol use development (as shown here); all of which are important criterion for an endophenotype (Gottesman and Gould, 2003; Iacono et al ., 2017). Midfrontal theta elicited by other experimental tasks and cognitive processes, such as inhibitory control (Kamarajan et al ., 2006; however, see Harper et al ., 2018 b ), response conflict (Harper et al ., 2017 a , 2018 a ), and feedback processing (Kamarajan et al ., 2015) may also reflect candidate endophenotypes for clinical and non-clinical drinking.…”

“…Continuous 61-channel EEG was collected at age-14 and processed as described in our previous reports (Harper et al ., 2017 b , 2019) (see online Supplementary Material).…”

“…Prior work from our group and others suggests that reduced target-related theta power is associated with alcohol and substance use/externalizing psychopathology (Jones et al ., 2006; Andrew and Fein, 2010; Yoon et al ., 2013; Burwell et al ., 2014). Diminished target-related theta is also observed in the high-risk adolescent offspring of alcoholics (Rangaswamy et al ., 2007), and is heritable and shares genetic variance with problematic alcohol/substance use (Harper et al ., 2019), which offer evidence that theta represents a potential candidate endophenotype for alcohol use. However, it is unknown whether reduced midfrontal theta before alcohol initiation can prospectively predict the development of alcohol use emerging in adolescence.…”

Using multivariate endophenotypes to identify psychophysiological mechanisms associated with polygenic scores for substance use, schizophrenia, and education attainment

“…P3 amplitude reduction is reliably associated with schizophrenia and several forms of substance use, including alcohol, nicotine, and cannabis ( Anokhin et al 2000 ; Bramon, Rabe-Hesketh, Sham, Murray, & Frangou, 2004 ; Euser et al 2012 ; Iacono & Malone, 2011 ; Iacono et al 2017 ; Solowij, Michie, & Fox, 1991 ). Reduced θ and δ energies and ITPC are also associated with substance use and schizophrenia ( Burwell, Malone, Bernat, & Iacono, 2014 ; Ethridge et al 2015 , 2012 ; Ford, Roach, Hoffman, & Mathalon, 2008 ; Harper, Malone, & Iacono, 2019b ; Jones et al 2006 ; Rangaswamy et al 2007 ; Yoon, Malone, Burwell, Bernat, & Iacono, 2013 ).…”