Expanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders.

SCN2A-related disorders secondary to altered function in the voltage-gated sodium channel NaV1.2 are rare with clinically heterogeneous expressions that include epilepsy, autism, and multiple severe to profound impairments and other conditions. To advance understanding of the clinical phenotypes and their relation to channel function, 81 patients (36, 44% female, median age 5.4 years) with 69 unique SCN2A variants were systematically phenotyped and their NaV1.2 channel function systematically assessed. Participants were recruited through the FamileSCN2A Foundation. Primary phenotype (epilepsy of neonatal-onset, N=27; infant onset, N=18; and later onset N=24; and autism without seizures, (N=12) was strongly correlated with a non-seizure severity index (p=0.002), which was based on presence of severe impairments in gross motor, fine motor, communication abilities, gastrostomy tube dependence, and diagnosis of cortical visual impairment and scoliosis. Non-seizure severity was greatest in the neonatal-onset group and least in the autism group (p=0.002). Children with the lowest severity indices were still severely impaired, as reflected by an average Vineland adaptive behavior composite score of 49.5 (>3 SD below the test's norm-referenced mean). Epileptic spasms were significantly more common in infant onset (67%) than in neonatal (22%) or later-onset (29%) epilepsy (p=0.007). Primary phenotype also strongly correlated with variant function (p<0.0001); gain of function and mixed function variants predominated in neonatal-onset epilepsy, shifting to moderate loss of function in infant-onset epilepsy, and severe and complete loss of function in later-onset epilepsy and autism groups. Exploratory cluster analysis identified five groups representing (1) primarily later-onset epilepsy with moderate loss of function variants and low severity indices, (2) mostly infant-onset epilepsy with moderate loss of function variants but higher severity indices, (3) late-onset and autism only with the lowest severity indices (mostly 0) and severe/complete loss of function variants. Two exclusively neonatal clusters were distinguished from each other largely on non-seizure severity scores and secondarily on variant function. The relation between primary phenotype and variant function emphasizes the role of developmental factors in the differential clinical expression of SCN2A variants based on their effects on NaV1.2 channel function. The non-seizure severity of SCN2A disorders depends on a combination of the age at seizure onset (primary phenotype) and variant function. As precision therapies for SCN2A-related disorders advance toward clinical trials, knowledge of the relationship between variant function and clinical disease expression will be valuable for identifying appropriate patients for these trials and in selecting efficient clinical outcomes.

Negative affect and alcohol craving in trauma-exposed young adult drinkers.

BACKGROUND: Clinical research indicates that successful posttraumatic stress disorder (PTSD) treatment does not lead to improvements in alcohol use outcomes in comorbid PTSD and alcohol use disorder (AUD). Emerging theory suggests that treating PTSD may not disrupt an association between negative affect and alcohol craving, which underlies negative reinforcement drinking. The goal of the current study was to determine the respective influences of PTSD symptoms, coping motives, and negative affect on trauma and alcohol cue reactivity to inform theoretical models of co-occurring PTSD and AUD. METHODS: The sample consisted of 189 young adults (50.3% women; 49.2% current PTSD; 84.0% current AUD) who endorsed interpersonal trauma (e.g., sexual/physical assault) and current weekly alcohol use. Participants completed a trauma and alcohol cue reactivity assessment, in which subjective (e.g., craving, affect) and physiological (i.e., salivation) measures were recorded in response to 4 narrative (i.e., personalized trauma or standard neutral) and in vivo beverage (i.e., personalized alcohol or water) cue combinations. RESULTS: Forward-fitted linear mixed-effects (LME) models confirmed that trauma cue-elicited craving was elevated among those high but not low in PTSD symptoms, consistent with prior research and theory. Trauma cue-elicited craving was fully explained by increases in negative affect, with no evidence of a direct effect of trauma cue on craving. PTSD symptoms moderated an association between trauma cue and negative affect (but not negative affect and craving), and coping motives for alcohol moderated an association between negative affect and craving (but not trauma cue and negative affect). CONCLUSIONS: This study provides novel laboratory evidence for the respective contributions of negative affect, PTSD symptoms, and coping motives on alcohol craving in trauma-exposed drinkers. It offers a methodological framework in which to evaluate novel strategies that aim to disrupt negative reinforcement drinking in individuals with co-occurring PTSD and AUD.

Empirically derived symptom profiles in adults with attention-Deficit/hyperactivity disorder: An unsupervised machine learning approach.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with various cognitive, behavioral, and mood symptoms that complicate diagnosis and treatment. The heterogeneity of these symptoms may also vary depending on certain sociodemographic factors. It is therefore important to establish more homogenous symptom profiles in patients with ADHD and determine their association with the patient's sociodemographic makeup. The current study used unsupervised machine learning to identify symptom profiles across various cognitive, behavioral, and mood symptoms in adults with ADHD. It was then examined whether symptom profiles differed based on relevant sociodemographic factors. METHODS: Participants were 382 adult outpatients (62% female; 51% non-Hispanic White) referred for neuropsychological evaluation for ADHD. RESULTS: Employing Gaussian Mixture Modeling, we identified two distinct symptom profiles in adults with ADHD: "ADHD-Plus Symptom Profile" and "ADHD-Predominate Symptom Profile." These profiles were primarily differentiated by internalizing psychopathology (Cohen's d = 1.94-2.05), rather than by subjective behavioral and cognitive symptoms of ADHD or neurocognitive test performance. In a subset of 126 adults without ADHD who were referred for the same evaluation, the unsupervised machine learning algorithm only identified one symptom profile. Group comparison analyses indicated that female patients were most likely to present with an ADHD-Plus Symptom Profile (χ2 = 5.43, p < .001). CONCLUSION: The machine learning technique used in this study appears to be an effective way to elucidate symptom profiles emerging from comprehensive ADHD evaluations. These findings further underscore the importance of considering internalizing symptoms and patients' sex when contextualizing adult ADHD diagnosis and treatment.

Negative urgency, PTSD symptoms, and alcohol risk in college students.

Theoretical models of trauma and alcohol use suggest that trauma-exposed individuals with higher levels of PTSD symptoms are at increased risk of problematic and coping-oriented alcohol use to alleviate unwanted internal states. The goal of the current study was to evaluate whether these associations are enhanced among young adults who report engaging in impulsive behavior in the context of negative affect (i.e., high negative urgency). It was hypothesized that (a) higher negative urgency would be associated with problematic alcohol use; and that (b) negative urgency would moderate the association between PTSD symptoms and problematic alcohol use. Methods: This study used a cross-sectional, secondary data analysis design run on 213 participants: college students, ages 18-25, who endorsed both having an interpersonal traumatic event and current weekly alcohol use. Participants completed a series of assessments and self-report questionnaires. Results: Results of hierarchical linear regression models indicated that greater negative urgency was significantly associated with greater negative alcohol-related consequences and greater coping motives for alcohol, but not past 30-day binge frequency or past 30-day alcohol quantity. Negative urgency did not moderate associations between PTSD symptoms and alcohol outcomes. Conclusions: PTSD symptoms and negative urgency are uniquely associated with indices of alcohol risk in college students with a history of trauma exposure. However, individuals high in negative urgency are not necessarily consuming more alcohol, nor does negative urgency increase the association between PTSD symptoms and drinking outcomes in this population.

The Influences of Posttraumatic Stress Disorder and Distress Tolerance on Trauma and Alcohol Cue Reactivity in a Sample of Trauma-Exposed College Students.

OBJECTIVE: Models of comorbid posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) often emphasize negative reinforcement drinking (i.e., drinking to reduce negative affect) as a key etiological and maintenance factor. However, potential risk factors related to negative reinforcement drinking in PTSD-AUD are less understood. Distress tolerance exhibits theoretical and empirical promise as one possible, malleable, risk factor. The current study used a trauma and alcohol cue reactivity paradigm to elucidate the role of perceived (i.e., self-reported) distress tolerance in trauma-related alcohol risk. METHOD: Participants were 185 university students (50.3% female) endorsing lifetime interpersonal trauma exposure and current weekly alcohol consumption. Subjective craving for alcohol was assessed in response to four combinations of audio narrative (personalized trauma vs. neutral) and beverage (alcohol vs. water) cues. Forward-fitting linear mixed-effects models were used to evaluate study hypotheses. RESULTS: Perceived distress tolerance significantly interacted with beverage cue in relation to craving (ß = -.293, p = .011), such that individuals low, as compared with high, in perceived distress tolerance reported greater craving for alcohol in response to the alcohol, but not water, beverage cue. Although low perceived distress tolerance was associated with greater alcohol coping motives and alcohol use problems at baseline, there were no main effects of perceived distress tolerance in relation to craving, and perceived distress tolerance did not significantly interact with trauma cues to predict craving (ps > .05). CONCLUSIONS: Among trauma-exposed young adult drinkers, low perceived distress tolerance may influence alternative processes of AUD risk, such as susceptibility to conditioned craving responses to alcohol.

Lifetime trauma endorsement, posttraumatic stress disorder, and alcohol dependence as a function of sexual minority status.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) frequently co-occur, with elevated rates of both disorders in lesbian, gay, or bisexual (LGB) samples. Few studies have compared the strength of PTSD-AUD associations between LGB and heterosexual individuals or evaluated the role of nontraumatic LGB discrimination in these relationships among sexual minorities. METHOD: The current study utilized nationally representative epidemiological data (N = 29,646) to (a) examine whether associations between lifetime trauma endorsement/PTSD and lifetime alcohol dependence (AD) differ as a function of sexual minority status and (b) evaluate the role of LGB-specific discrimination in trauma/PTSD and AD associations among LGB individuals. RESULTS: Logistic regression analyses showed the association between lifetime trauma endorsement and lifetime AD was significantly greater in magnitude for LGB individuals (odds ratio [OR] = 2.17) compared to heterosexual individuals (OR = 1.32; Z = 2.51, p < .05). The magnitude of the association between lifetime PTSD and lifetime AD was not greater in the LGB subsample (OR = 2.11) than the heterosexual subsample (OR = 1.71; Z = 0.63, p > .05), after controlling for trauma endorsement. Among the LGB subsample, logistic regression analyses did not support a significant main effect for LGB discrimination nor an interaction between trauma endorsement and nontraumatic LGB discrimination, nor between PTSD and nontraumatic LGB discrimination, on lifetime AD (ps > .05). CONCLUSIONS: LGB individuals demonstrate stronger associations between lifetime trauma endorsement and AD, relative to heterosexual counterparts; however, this association may not be accounted for or moderated by nontraumatic LGB discrimination. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Trauma and alcohol characteristics related to high intensity binge drinking during college.

High intensity (HI) binge drinking has emerged as a high-risk drinking phenotype in young adult drinkers, yet few studies have evaluated clinically meaningful correlates of HI binge drinking among young adults at risk for co-occurring psychopathologies, such as interpersonal trauma-exposed drinkers. The present study compared three groups (i.e., HI binge, standard binge, non-binge drinkers) of interpersonal trauma-exposed college student drinkers (N = 221) on alcohol and interpersonal trauma characteristics. Results of one-way ANOVAs indicated that the HI binge group endorsed significantly greater negative alcohol-related consequences relative to the other two groups. The HI binge group endorsed significantly greater enhancement motives compared to the non-binge group, and no group differences were detected for PTSD and interpersonal trauma characteristics. Individuals who engage in HI binge drinking may experience greater alcohol problems due to their use of alcohol to enhance positive mood. HI binge drinking does not differentiate individuals on the basis of interpersonal trauma experiences or related psychopathology.

Cardiovascular risk as a moderator of associations among anxiety sensitivity, distress tolerance, PTSD and depression symptoms among trauma-exposed firefighters.

BACKGROUND: Firefighters experience frequent and severe trauma exposure, which places them at elevated risk for posttraumatic stress disorder (PTSD) and major depression. Cardiovascular issues may exacerbate the effects of mental health risk factors, such as anxiety sensitivity (AS) and distress tolerance (DT), on PTSD and depression. The current study investigated cardiovascular risk as a moderator of associations between risk factors (AS and DT) and psychiatric symptoms (PTSD and depression) among firefighters. METHODS: Participants were 836 trauma-exposed active duty firefighters (93.90% men; with mean age 38 years, [SD = 9]). Participants endorsing at least one of three cardiovascular risk items-experiencing current high blood pressure, history of heart problems, and experiencing chest pains in the past 2 years-were considered high in cardiovascular risk. RESULTS: A structural equation model indicated that higher AS was associated with greater PTSD (ß = 0.38, p < .01) and depression symptoms (ß = 0.32, p < .01); lower DT was associated with greater PTSD (ß = -0.18, p < .01) and depression symptoms (ß = -0.31, p < .01). Multigroup analyses showed that cardiovascular risk moderated the association between 1) AS and PTSD symptoms, but not 2) AS and depression symptoms, 3) DT and PTSD symptoms, or 4) DT and depression symptoms. For those high in cardiovascular risk, higher AS was associated more strongly with greater PTSD symptoms (high cardiovascular risk group: ß = 0.46, p < .01]; low cardiovascular risk group: ß = 0.33, p < .01). CONCLUSIONS: High cardiovascular risk may contribute to PTSD symptoms among trauma-exposed firefighters with high AS. These results highlight the importance of considering physical and mental health vulnerabilities in first responder populations.

Posttraumatic stress disorder symptoms, relationship quality, and risky alcohol use among trauma-exposed students.

Individuals with posttraumatic stress disorder (PTSD) are at increased risk for alcohol use disorder (AUD), in part due to the use of alcohol as a coping strategy. High quality romantic relationships can buffer individuals against risk for psychopathology; however, no studies have evaluated romantic relationship quality in risk for PTSD-AUD in non-clinical samples. The current study examined the main and interactive effects of PTSD symptoms and romantic relationship quality on alcohol consumption (i.e., past 30-day alcohol use quantity, frequency, and binge frequency) and alcohol-related consequences in a sample of 101 college students (78.2% women) with a history of interpersonal trauma (i.e., physical/sexual assault, excluding intimate partner violence) who reported being in a romantic relationship. Relationship quality significantly moderated the association between PTSD symptom severity and alcohol use quantity (B = -0.972, p = .016) and alcohol-related consequences (B = -0.973, p = .009), such that greater PTSD symptoms were associated with greater alcohol use quantity and consequences among those low, but not high, in relationship quality. The interaction between PTSD symptom severity and relationship quality in relation to binge drinking was marginally significant (B = -0.762, p = .063), and relationship quality did not significantly moderate the association between PTSD symptom severity and alcohol use frequency. The main effect of PTSD symptom severity was significantly associated with alcohol-related consequences, but no other alcohol outcomes; the main effect of relationship quality was not associated with alcohol use outcomes or consequences. High quality romantic relationships may serve as a buffer for young adults at risk for alcohol problems.