Neurobehavioral Disinhibition Research Articles

The Challenge of Managing Patients Suffering from TBI: The Utility of Multiparametric MRI

Traumatic brain injury (TBI) is a complex phenomenon affecting multiple areas of the brain in multiple ways. Both right and left hemispheres are affected as well as supratentorial and infratentorial compartments. These multifocal injuries are caused by many factors including acute mechanical injury, focal intracranial hemorrhage, blunt and rotational forces, epidural and subdural hematoma, hypoxemia, hypotension, edema, axonal damage, neuronal death, gliosis and blood brain barrier disruption. Clinicians and patients benefit by precise information about the neuroanatomical areas that are affected macroscopically, microscopically and biochemically in an individual patient.Standard imaging studies are frequently negative or grossly underestimate the severity of TBI and may exacerbate and prolong patient suffering with an imaging result of "no significant abnormality". Specifically, sophisticated imaging tools have been developed which reveal significant damage to the brain structure including atrophy, MRI spectroscopy showing variations in neuronal metabolite N-acetyl-aspartate, elevations of membrane related Choline, and the glial metabolite myo-inositol is often observed to be increased post injury. In addition, susceptibility weighted imaging (SWI) has been shown to be more reliable for detecting microbleeds versus calcifications.We have selected two TBI patients with diffuse traumatic brain injury.The first patient is a 43-year-old male who suffered severe traumatic brain injury from a motorcycle accident in 2016. Following the accident, the patient was diagnosed with seizures, major depression, and intermittent explosive disorder.He has attempted suicide and has neurobehavioraldisinhibition including severe anger, agitation and irritability.He denies psychiatric history prior to TBI and has negative family history.Following the TBI, he became physically aggressive and assaultive in public with minimal provocation.He denies symptoms of thought disorder and mania. He is negative for symptoms ofcognitive decline or encephalopathy.The second patient is a 49-year-old male who suffered at least 3 concussive blasts in the Army and a parachute injury.Following the last accident, the patient was diagnosed with major depressive disorder, panic disorder, PTSD and generalized anxiety disorder.He denies any psychiatric history prior to TBI including negative family history of psychiatric illness. In addition, he now suffers from nervousness, irritability, anger, emotional lability and concurrent concentration issues, problems completing tasks and alterations in memory.Both patients underwent 1.5T multiparametric MRI using standard T2, FLAIR, DWI and T1 sequences, and specialized sequences including susceptibility weighted (SWAN/SWI), 3D FLAIR, single voxel MRI spectroscopy (MRS), diffusion tensor imaging (DTI), arterial spin labeling perfusion (ASL) and volumetric MRI (NeuroQuant).Importantly, this exam can be performed in 30-45 minutes and requires no injections other than gadolinium in some patients. We will discuss the insights derived from the MRI which detail the injured areas, validate the severity of the brain damage, and provide insight into the psychological, motivational and physical disabilities that afflict these patients. It is our expectation that this kind of imaging study will grow in value as we link specific patterns of injury to specific symptoms and syndromes resulting in more targeted therapies in the future.

P.6.d.006 - Gender differences in ‘impulsive choice’ and ‘impulsive action’ among opiate and stimulant users in protracted abstinence

Inhibition of prepotent responses plays a key role in cognitive executive control of goal-directed behavior. Response inhibition in Go/No-Go tasks elicits a distinct midfrontal ERP component, the N2, localized in previous studies to the anterior cingulate cortex. We assessed heritability of the No-Go N2 and the succeeding positive P3 component in 194 young female twins (52 monozygotic and 45 dizygotic pairs) who completed a cued version of the Continuous Performance Test. Genetic model-fitting analysis showed that about 60% of the variance in N2 and P3 amplitudes can be attributed to genetic factors, suggesting that frontal No-Go N2 and P3 components may index genetically transmitted individual differences in brain activity related to conflict processing and can potentially serve as endophenotypes for genetic studies of disorders characterized by neurobehavioral disinhibition.

Risk of Neurobehavioral Disinhibition in Prenatal Methamphetamine–Exposed Young Children With Positive Hair Toxicology Results

The objective was to evaluate the effects of prenatal methamphetamine exposure (PME) and postnatal drug exposures identified by child hair analysis on neurobehavioral disinhibition at 6.5 years of age. Mother-infant pairs were enrolled in the Infant Development, Environment, and Lifestyle (IDEAL) Study in Los Angeles, Honolulu, Tulsa, and Des Moines. PME was determined by maternal self-report and/or positive meconium results. At the 6.5-year follow-up visit, hair was collected and analyzed for methamphetamine, tobacco, cocaine, and cannabinoid markers. Child behavioral and executive function test scores were aggregated to evaluate child neurobehavioral disinhibition. Hierarchical linear regression models assessed the impact of PME, postnatal substances, and combined PME with postnatal drug exposures on the child's neurobehavioral disinhibition aggregate score. Past year caregiver substance use was compared with child hair results. A total of 264 children were evaluated. Significantly more PME children (n = 133) had hair positive for methamphetamine/amphetamine (27.1% versus 8.4%) and nicotine/cotinine (38.3% versus 25.2%) than children without PME (n = 131). Overall, no significant differences in analyte hair concentrations were noted between groups. Significant differences in behavioral and executive function were observed between children with and without PME. No independent effects of postnatal methamphetamine or tobacco exposure, identified by positive hair test, were noted and no additional neurobehavioral disinhibition was observed in PME children with postnatal drug exposures, as compared with PME children without postnatal exposure. Child hair testing offered a noninvasive means to evaluate postnatal environmental drug exposure, although no effects from postnatal drug exposure alone were seen. PME, alone and in combination with postnatal drug exposures, was associated with behavioral and executive function deficits at 6.5 years.

Physiological Correlates of Neurobehavioral Disinhibition that Relate to Drug Use and Risky Sexual Behavior in Adolescents with Prenatal Substance Exposure

Physiological correlates of behavioral and emotional problems, substance use onset and initiation of risky sexual behavior have not been studied in adolescents with prenatal drug exposure. We studied the concordance between baseline respiratory sinus arrhythmia (RSA) at age 3 and baseline cortisol levels at age 11. We hypothesized that children who showed concordance between RSA and cortisol would have lower neurobehavioral disinhibition scores which would in turn predict age of substance use onset and first sexual intercourse. The sample included 860 children aged 16 years participating in the Maternal Lifestyle Study, a multisite longitudinal study of children with prenatal exposure to cocaine and other substances. Structural equation modeling was used to test pathways between prenatal substance exposure, early adversity, baseline RSA, baseline cortisol, neurobehavioral disinhibition, drug use, and sexual behavior outcomes. Concordance was studied by examining separate male and female models in which there were statistically significant interactions between baseline RSA and cortisol. Prenatal substance exposure was operationalized as the number of substances to which the child was exposed. An adversity score was computed based on caregiver postnatal substance use, depression and psychological distress, number of caregiver changes, socioeconomic and poverty status, quality of the home environment, and child history of protective service involvement, abuse and neglect. RSA and cortisol were measured during a baseline period prior to the beginning of a task. Neurobehavioral disinhibition, based on composite scores of behavioral dysregulation and executive dysfunction, substance use and sexual behavior were derived from questionnaires and cognitive tests administered to the child. Findings were sex specific. In females, those with discordance between RSA and cortisol (high RSA and low cortisol or low RSA and high cortisol) had the most executive dysfunction which, in turn, predicted earlier initiation of alcohol by age 16. Among boys, there also existed a significant baseline RSA by baseline cortisol interaction. Boys with low baseline RSA and high baseline cortisol had the highest levels of behavioral dysregulation. This increase in behavioral dysregulation was in turn related to initiation of alcohol use by age 16 and lower age of first sexual intercourse. We found sex-specific pathways to the initiation of alcohol use and risky sexual behavior through the combined activity of parasympathetic and neuroendocrine functioning. The study of multiple physiological systems may suggest new pathways to the study of age of onset of substance use and engagement in risky sexual behavior in adolescents.

The contributions of early adverse experiences and trajectories of respiratory sinus arrhythmia on the development of neurobehavioral disinhibition among children with prenatal substance exposure.

Neurobehavioral disinhibition (ND) is a complex condition reflecting a wide range of problems involving difficulties with emotion regulation and behavior control. Respiratory sinus arrhythmia (RSA) is a physiological correlate of emotion regulation that has been studied in a variety of at-risk populations; however, there are no studies of RSA in children with ND. Data were drawn from a prospective longitudinal study of prenatal substance exposure that included 1,073 participants. Baseline RSA and RSA reactivity to an attention-demanding task were assessed at 3, 4, 5, and 6 years. ND was assessed at ages 8/9, 11, and 13/14 years via behavioral dysregulation and executive dysfunction composite measures. Greater exposure to early adversity was related to less RSA reactivity at 3 years, increases in RSA reactivity from ages 3 to 6 years, and increased behavioral dysregulation from ages 8/9 to 13/14. RSA reactivity was examined as a moderator of the association between early adversity and changes in ND. A significant Early Adversity × RSA Reactivity quadratic interaction revealed that children with decelerations in RSA reactivity exhibited increases in behavioral dysregulation, regardless of their exposure to early adversity. However, greater exposure to early adversity was related to greater increases in behavioral dysregulation, but only if children exhibited accelerations in RSA reactivity from ages 3 to 6 years. The results contribute to our understanding of how interactions across multiple levels of analysis contribute to the development of ND.

Psychological dysregulation during adolescence mediates the association of parent-child attachment in childhood and substance use disorder in adulthood

Objective: This prospective study tested the hypothesis that psychological dysregulation in mid-adolescence (age 16) mediates the association between parent-child attachment in late childhood (age 10–12) and development of substance use disorder (SUD) in adulthood (age 22). Method: The Youth Attachment to Parents Scale (YAPS) was developed in 10–12-year-old boys and girls (N = 694) at baseline residing in western Pennsylvania. Psychological dysregulation was measured by the neurobehavior disinhibition trait. Substance use was assessed at ages 10–12, 12–14, 16 and 19. SUD was diagnosed at age 22 using the Structured Clinical Interview for DSM Disorders. The mediation of parent-child attachment and SUD by neurobehavior disinhibition was tested separately for mothers and fathers while controlling for baseline substance use. Results: Psychological dysregulation mediates the association between attachment to mothers and SUD, and partially mediates the association between attachment to fathers and SUD. Significant mediation effects remains after controlling for baseline substance use. Conclusion: Optimal prevention of SUD should include ameliorating both psychological dysregulation predisposing to SUD and quality of the parent-child relationship.

Examining the relationships between prenatal methamphetamine exposure, early adversity, and child neurobehavioral disinhibition.

Methamphetamine use is a growing problem among pregnant women in the United States. Many negative consequences of methamphetamine use have been documented for the users, but little research has examined the long-term association between prenatal methamphetamine exposure (PME) and childhood outcomes. The current study examined the extent to which PME was predictive of childhood neurobehavioral disinhibition (ND), as well as the extent to which early adversity mediated this relationship. A sample of 320 mother-infant dyads (162 PME) was followed from birth through 6.5 years of age. ND was conceptualized as a two factor model consisting of deficits in (a) behavioral and emotional control, and (b) executive function. PME was associated with behavioral and emotional control at 5 years, which was associated with executive function deficits at 6.5 years. Early adversity (birth through year 3) significantly mediated the relationship between PME and ND. Associations with previous research and implications for prevention are discussed.

Longitudinal Associations From Neurobehavioral Disinhibition to Adolescent Risky Sexual Behavior in Boys: Direct and Mediated Effects Through Moderate Alcohol Consumption

This longitudinal study tested the hypothesis that neurobehavioral disinhibition (ND) in childhood, mediated by alcohol use, portends risky sexual behavior (number of sexual partners) in midadolescence. Participants were 410 adolescent boys. Neurobehavioral disinhibition was assessed at11.3 years of age. Frequency and quantity of alcohol use on a typical drinking occasion wereassessed at 13.4 years of age at first follow-up, and sexual behavior at 16.0 years at second follow-up. Quantity of alcohol consumed on a typical drinking occasion, but not frequency of alcohol use, mediated the relation between ND and number of sexual partners. These findings indicate that number of sexual partners in midadolescence is predicted by individual differences in boys' psychological self-regulation during childhood and moderate alcohol consumption in early adolescence, and that ND may be a potential target for multi-outcome public health interventions.

High and Low Neurobehavior Disinhibition Clusters within Locales: Implications for Community Efforts to Prevent Substance Use Disorder

Background: Knowledge of where substance use and other such behavioral problems frequently occur has aided policing, public health, and urban planning strategies to reduce such behaviors. Identifying locales characterized by high childhood neurobehavioral disinhibition (ND), a strong predictor of substance use and consequent disorder (SUD), may likewise improve prevention efforts. Objectives: The distribution of ND in 10–12-year olds was mapped to metropolitan Pittsburgh, PA, and tested for clustering within locales. Methods: The 738 participating families represented the population in terms of economic status, race, and population distribution. ND was measured using indicators of executive cognitive function, emotion regulation, and behavior control. Innovative geospatial analyzes statistically tested clustering of ND within locales while accounting for geographic barriers (large rivers, major highways), parental SUD severity, and neighborhood quality. Results: Clustering of youth with high and low ND occurred in specific locales. Accounting for geographic barriers better delineated where high ND is concentrated, areas which also tended to be characterized by greater parental SUD severity and poorer neighborhood quality. Conclusions and Significance: Offering programs that have been demonstrated to improve inhibitory control in locales where youth have high ND on average may reduce youth risk for SUD and other problem behaviors. As demonstrated by the present results, geospatial analysis of youth risk factors, frequently used in community coalition strategies, may be improved with greater statistical and measurement rigor.

Neuroimaging in Addictionedited by AdinoffBryon, M.D., and SteinElliot A., Ph.D. West Sussex, United Kingdom, Wiley-Blackwell, 2011, 372 pp., $165.50.

Neuroimaging in Addictionedited by AdinoffBryon, M.D., and SteinElliot A., Ph.D. West Sussex, United Kingdom, Wiley-Blackwell, 2011, 372 pp., $165.50.

Neurobehavioral disinhibition predicts initiation of substance use in children with prenatal cocaine exposure

BackgroundIn previous work we (Fisher et al., 2011) examined the emergence of neurobehavioral disinhibition (ND) in adolescents with prenatal substance exposure. We computed ND factor scores at three age points (8/9, 11 and 13/14 years) and found that both prenatal substance exposure and early adversity predicted ND. The purpose of the current study was to determine the association between these ND scores and initiation of substance use between ages 8 and 16 in this cohort as early initiation of substance use has been related to later substance use disorders. Our hypothesis was that prenatal cocaine exposure predisposes the child to ND, which, in turn, is associated with initiation of substance use by age 16. MethodsWe studied 386 cocaine exposed and 517 unexposed children followed since birth in a longitudinal study. Five dichotomous variables were computed based on the subject's report of substance use: alcohol only; tobacco only; marijuana only; illicit substances and any substance. ResultsCox proportional hazard regression showed that the 8/9 year ND score was related to initiation of alcohol, tobacco, illicit and any substance use but not marijuana use. The trajectory of ND across the three age periods was related to substance use initiation in all five substance use categories. Prenatal cocaine exposure, although initially related to tobacco, marijuana and illicit substance initiation, was no longer significant with ND scores in the models. ConclusionPrenatal drug exposure appears to be a risk pathway to ND, which by 8/9 years portends substance use initiation.

The combined effects of prenatal drug exposure and early adversity on neurobehavioral disinhibition in childhood and adolescence

The negative effects of prenatal substance exposure on neurobiological and psychological development and of early adversity are clear, but little is known about their combined effects. In this study, multilevel analyses of the effects of prenatal substance exposure and early adversity on the emergence of neurobehavioral disinhibition in adolescence were conducted. Neurobehavioral disinhibition has previously been observed to occur frequently in multiproblem youth from high-risk backgrounds. In the present study, neurobehavioral disinhibition was assessed via behavioral dysregulation and poor executive function composite measures. Data were drawn from a prospective longitudinal investigation of prenatal substance exposure that included 1,073 participants followed from birth through adolescence. The results from latent growth modeling analyses showed mean stability but significant individual differences in behavioral dysregulation and mean decline with individual differences in executive function difficulties. Prior behavioral dysregulation predicted increased executive function difficulties. Prenatal drug use predicted the emergence and growth in neurobehavioral disinhibition across adolescence (directly for behavioral dysregulation and indirectly for executive function difficulties via early adversity and behavioral dysregulation). Prenatal drug use and early adversity exhibited unique effects on growth in behavioral dysregulation; early adversity uniquely predicted executive function difficulties. These results are discussed in terms of implications for theory development, social policy, and prevention science.

Early age alcohol use and later alcohol problems in adolescents: Individual and peer mediators in a bi-national study.

This paper examines whether there is cross-national similarity in the longitudinal relationship between early age alcohol use and adolescent alcohol problems. Potential mechanisms underlying this relationship also are examined, testing adolescent alcohol use, low self-regulation, and peer deviance as possible mediators. Students (N = 1,945) participating in the International Youth Development Study, a longitudinal panel survey study, responded to questions on alcohol use and influencing factors, and were followed annually over a 3-year period from 2002 to 2004 (98% retention rate). State-representative, community student samples were recruited in grade 7 in Washington State, United States (US, n = 961, 78% of those eligible; Mage = 13.09, SD = .44) and Victoria, Australia (n = 984, 76% of those eligible; Mage = 12.93, SD = .41). Analyses were conducted using multiple-group structural equation modeling. In both states, early age alcohol use (age 13) had a small but statistically significant association with subsequent alcohol problems (age 15). Overall, there was little evidence for mediation of early alcohol effects. Low self-regulation prospectively predicted peer deviance, alcohol use, and alcohol problems in both states. Peer deviance was more positively related to alcohol use and low self-regulation among students in Victoria compared to students in Washington State. The small but persistent association of early age alcohol use with alcohol problems across both samples is consistent with efforts to delay alcohol initiation to help prevent problematic alcohol use. Self-regulation was an important influence, supporting the need to further investigate the developmental contribution of neurobehavioral disinhibition.

Developmental consequences of prenatal tobacco exposure.

This paper reviews results from published, in press, and conference proceedings from 2007 and 2008 that link in-utero tobacco exposure to neurodevelopmental outcomes in exposed offspring. Prenatal tobacco exposure (PTE) affected speech processing, levels of irritability and hypertonicity, attention levels, ability to self-regulate, need to be handled, and response to novelty preference in infants. In early childhood, PTE effects were mostly behavioral outcomes including activity and inattention and externalizing behaviors, including conduct disorder and antisocial behavior. In adolescents, PTE predicted increased attention deficit hyperactivity disorder, modulation of the cerebral cortex and white matter structure, and nicotine addiction. Several studies found moderating effects with PTE and genetic susceptibilities including dopamine transporter, serotonergic synaptic function, and monomine oxidase pathways. Other studies suggested that environmental and genetic factors might be more important than the direct teratological effects of PTE. The majority of studies reviewed were prospective and tobacco exposure was quantified biologically. Most demonstrated a direct association between PTE and neurodevelopmental outcomes. More work is needed to examine multifactorial influences. Effects of PTE on the offspring appear to be moderated by genetic variability, neurobehavioral disinhibition, and sex.

Neurobehavior disinhibition, parental substance use disorder, neighborhood quality and development of cannabis use disorder in boys

This prospective investigation examined the contribution of neighborhood context and neurobehavior disinhibition to the association between substance use disorder (SUD) in parents and cannabis use disorder in their sons. It was hypothesized that both neighborhood context and son's neurobehavior disinhibition mediate this association. Two hundred and sixteen boys were tracked from ages 10–12 to age 22. The extent to which neighborhood context and neurobehavior disinhibition mediate the association between parental SUD and son's cannabis use disorder was evaluated using structural equation modeling. The best fitting model positioned neighborhood context and neurobehavior disinhibition as mediators of the association between parental SUD and cannabis use disorder in sons. Neurobehavior disinhibition also was a mediator of the association between neighborhood context and son's cannabis use. The implications of this pattern of association between parental SUD, neighborhood context and individual risk for SUD for improving prevention are discussed.

Prospective Study of the Association Between Neurobehavior Disinhibition and Peer Environment on Illegal Drug Use in Boys and Girls

Background: Individual and contextual factors jointly participate in the onset and progression of substance abuse; however, the pattern of their relationship in males and females has not been systematically studied. Objectives: Male and female children and adolescents were compared to determine the relative influence of individual susceptibility (neurobehavior disinhibition or ND) and social environment (deviancy in peers) on use of illegal drugs. Methods: Boys (N = 380) and girls (N = 127) were prospectively tracked from age 10–12 to age 16 to delineate the role of ND and peer deviancy on use of illegal drugs. Results: Girls exhibited lower ND scores than boys in childhood and were less inclined to affiliate with deviant peers. These differences were reduced or disappeared by mid-adolescence. In boys only, peer deviancy in childhood mediated the association between ND and illegal drug use at age 16. In both genders, peer deviancy in mid-adolescence mediated ND and substance abuse at age 16. Conclusions: Individual and contextual risk factors promoting substance abuse are more salient at a younger age in boys compared to girls. Scientific Significance: These results point to the need for earlier screening and intervention for boys.

Brain Activation, Response Inhibition, and Increased Risk for Substance Use Disorder

Youth at high risk for developing substance use disorders (SUDs) often exhibit differences which suggest inhibitory impairments when compared to average risk youth. To examine the underlying neural activity related to these impairments, functional MRI (fMRI) was employed in adolescents during an antisaccade task requiring inhibition of an eye movement response. Each subject's level of neurobehavioral disinhibition (ND) was assessed using a multi-informant, multi-method approach, which has been shown to be highly predictive of SUD onset. The fMRI data was categorized into neural regions of interest according to total frontal, parietal, occipital, and temporal lobe activation. Results demonstrated that ND score was negatively correlated with total amount of frontal activation, but was not significantly correlated with total activation in any other neural region. These results indicate deficits in frontal activation in youth with high amounts of ND, suggesting a possible developmental delay of executive processes in high-risk youth.

Peer Environment Mediates Parental History and Individual Risk in the Etiology of Cannabis Use Disorder in Boys: A 10-Year Prospective Study

Previous research has shown that a trait termed neurobehavior disinhibition (ND) measured in childhood predicts substance use disorder by young adulthood. The present investigation extends these findings by determining the degree to which peer environment mediates the association between ND and development of cannabis use disorder (CUD). ND was measured in a sample of 216 boys 10–12 years of age. The peer environment was assessed at age 16. Current CUD was determined at age 22. Paternal and maternal SUD predicted son's ND which, in turn, predicted son's peer environment and, subsequently, son's cannabis use frequency and CUD. Peer environment mediated the association between ND and cannabis use and ND and CUD. Maternal and paternal SUD predicted the peer environment. Parental SUD, son's ND, and son's peer environment predicted CUD at age 22 with 84% accuracy.

Social dominance mediates the association of testosterone and neurobehavioral disinhibition with risk for substance use disorder.

This investigation determined the influence of testosterone and neurobehavioral disinhibition (ND) on risk for substance use disorder (SUD). Testosterone level during puberty was hypothesized to promote social dominance associated with norm-violating behavior that, in turn, predisposes individuals to use of illicit drugs and, subsequently, SUD. Using a prospective paradigm, the authors recruited 179 boys (mean age=11.62 years, SD=0.88) and followed up when participants were ages 12-14, 16, 19, and 22. Results indicated that social dominance/norm-violating behavior (SD/NVB) at age 16 mediated the association between testosterone level (ages 12-14) and SUD (age 22). In addition, SD/NVB mediated the association between ND and SUD. These findings suggest that development of SUD is influenced by androgen-dependent and neurobehavioral processes via a social motivational style characterized by SD/NVB.

Childhood Neurobehavior Disinhibition Amplifies the Risk of Substance Use Disorder: Interaction of Parental History and Prenatal Alcohol Exposure

This investigation examined the influence of parental substance use disorder (SUD) and mother's alcohol consumption during pregnancy on neurobehavior disinhibition (ND) measured in 10- to 12-year-old children. The extent to which ND predicted SUD outcome 7 to 9 years later was also determined. SUD was documented in each parent and as the outcome variable in their 19-year-old sons. Average daily alcohol consumption during the mother's pregnancy was recorded using a structured interview. ND was assessed using indicators of behavior undercontrol, affect modulation and executive cognitive functions. Paternal SUD and the interaction between maternal SUD and alcohol consumption during pregnancy predicted child's ND score. ND at 10 to 12 years of age was a significant predictor of SUD at age 19. The disinhibitory disturbance associated with risk of SUD has both transmissible and teratogenic causes. The ramifications of this finding for pediatric practice are discussed.