Resume

• 2012

  Doctor of Philosophy (Ph.D.)

  Clinical Psychology

  University of Pittsburgh

• 2009

  MA

  Neuropsychology

  San Diego State University-California State University

• 2003

  BA

  Psychology

• 75

  Objective: Individuals with multiple alcohol-dependent (AD) relatives are at increased risk for substance use disorders (SUDs). Prospective

  longitudinal studies of high-risk (HR) individuals afford the opportunity to determine potential risk markers of SUDs. The current study assessed the effect of familial risk and genetic variation on Iowa Gambling Task (IGT) performance and tested for an association between IGT performance and SUD outcomes. Method: Individuals from multiplex AD families (n = 63) and low-risk (LR; n = 45) control families

  ages 16–34 years

  were tested using a computerized version of the IGT. SUD outcomes were assessed at approximately yearly intervals. 5-HTTLPR and COMT genotypes were available for the majority of participants (n = 86). Results: HR offspring showed poorer performance overall on the IGT and especially poor performance on the final trial block (Block 5)

  indicating a failure to improve decision making with previous experience. The 5-HTTLPR short-allele homozygote participants performed worse than long-allele carriers

  with HR S/S carriers exhibiting particularly poor performance. There was no main effect of COMT on IGT performance and no significant COMT by Risk interaction. Significantly more individuals in the HR than LR group met criteria for SUD. Importantly

  disadvantageous performance on IGT Block 5 was significantly associated with an earlier age at SUD onset. Conclusions: This is the first study to show that both familial risk of SUD and 5-HTTLPR variation impact performance on the IGT. Poorer IGT performance was associated with earlier onset of SUD

  suggesting that HR individuals who fail to appropriately attend to long-term costs and benefits during a decision-making task are especially at risk for developing SUD in adolescence and young adulthood. (J. Stud. Alcohol Drugs

  643–652

  2014)

  Maladaptive Decision Making and Substance Use Outcomes in High-Risk Individuals: Preliminary Evidence for the Role of 5-HTTLPR Variation

  Shirley Y. Hill

  Maladaptive Decision Making Predicts Substance Use Outcomes in High Risk Individuals.

  Jessica

  O'Brien

  Kennedy Krieger Institute

  San Diego State University

  University of Pittsburgh

  Pittsburgh

  PA

  Graduate Student Research Assistant

  University of Pittsburgh

  San Diego

  CA

  Center for Behavioral Teratology

  Graduate Student Research Assistant

  San Diego State University

  Laboratory for Neurocognitive and Imaging Research

  Kennedy Krieger Institute

• Matlab

  M-Plus

  SPSS

  Analysis of Functional NeuroImages (AFNI)

  E-Prime

  DRD2 Variation Predicts Resilience to Substance Use Disorders in High Risk Offspring from Multiplex Alcohol Dependence Families.

  Shirley Y. Hill

  DRD2 Variation Predicts Resilience to Substance Use Disorders in High Risk Offspring from Multiplex Alcohol Dependence Families.

  Shirley Y. Hill

  Maladaptive Decision Making Predicts Substance Use Outcomes in High Risk Individuals

  Shirley Y. Hill

  It has long been known that Alcohol Use Disorders (AUDs) run in families with substantial heritability. Determining the specific genetic underpinnings of these disorders has been challenging because of the clinical heterogeneity and variable expression across the lifespan. The search for endophenotypic biological variation associated with the AUD and related substance use disorder (SUD) phenotypes is based on the belief that an endophenotype is more proximal to the causative gene. Identification of genes conferring increased susceptibility has important implications for treatment through the potential development of medications that target specific genetic pathways. High risk family designs that contrast offspring with and without a familial/genetic background have provided valuable insights into the psychological characteristics (executive control

  affective regulation

  decision making and social cognition) that differentiate such individuals. The current chapter will review these with a focus on brain morphology of specific regions

  the coordinated activity of neural networks

  and developmental trajectories of electrophysiological activity.

  Psychological and Neurobiological Precursors of Alcohol Use Disorders in High Risk Youth

  Sarah N. Mattson

  Prenatal exposure to alcohol is the leading preventable cause of birth defects

  developmental disorders and mental retardation in children.1 The prevalence of fetal alcohol spectrum disorders (FASD) is estimated to be at least 9.1 per 1

  000 live births

  2 or about 1% of the population

  and has been identified in all racial and ethnic groups.3 Children prenatally exposed to alcohol can suffer from serious cognitive deficits and behavioural problems as well as alcohol-related changes in brain structure. Heavy prenatal alcohol exposure is associated with decreased intellectual functioning

  deficits in learning

  memory and executive functioning

  and problem behaviours including hyperactivity

  impulsivity

  poor socialization and communication skills

  and development of substance use problems.

  Neurobehavioural Profiles of Individuals with Fetal Alcohol Spectrum Disorders*

  Shirley Y. Hill

  Brian Holmes

  Scott Stiffler

  Nicholas Zezza

  Bobby L. Jones

  Familial Risk for Alcohol Dependence and Developmental Changes in BMI: the Moderating Influence of Addiction and Obesity Genes

  Shirley Y. Hill

  Prenatal exposures to alcohol

  cigarettes

  and other drugs of abuse are associated with numerous adverse consequences for affected offspring

  including increased risk for substance use and abuse. However

  maternal substance use during pregnancy appears to occur more often in those with a family history of alcohol dependence. Utilizing a sample that is enriched for familial alcohol dependence and includes controls selected for virtual absence of familial alcohol dependence could provide important information on the relative contribution of familial risk and prenatal exposures to offspring substance use.\n

  Effects of Prenatal Alcohol and Cigarette Exposure on Offspring Substance Use in Multiplex

  Alcohol-Dependent Families

  Brian Holmes

  Michael McDermott

  Shirley Y. Hill

  Brain Morphology

  Adolescent Binge Drinking

  and Familial Risk for Alcohol Dependence.

  Offspring from families with multiple cases of alcohol dependence have a greater likelihood of developing alcohol dependence and related substance use disorders. Greater susceptibility for these disorders may be related to cerebellar morphology. Because posterior regions of the cerebellum are associated with cognitive abilities

  we investigated whether high-risk offspring would display regionally specific differences in cerebellar morphology and whether these would be related to working memory performance. The relationship to externalizing and internalizing psychopathology was of interest because cerebellar morphology has previously been associated with a cognitive affective syndrome. A total of 131 participants underwent magnetic resonance imaging (MRI) with volumes of the cerebellar lobes obtained with manual tracing. These individuals were from high-risk (HR) for alcohol dependence families (N = 72) or from low-risk (LR) control families (N = 59). All were enrolled in a longitudinal follow-up that included repeated clinical assessments during childhood and young-adulthood prior to the scan that provided information on Axis I psychopathology. The Working Memory Index of the Wechsler Memory Scale was given at the time of the scan. Larger volumes of the corpus medullare and inferior posterior lobes and poorer working memory performance were found for the HR offspring relative to LR controls. Across all subjects

  a significant positive association between working memory and total volume of corpus of the cerebellum was seen

  controlling for familial risk. Presence of an internalizing or externalizing disorder interacting with familial risk was also associated with volume of the corpus medullare.

  Volumetric Differences in Cerebellar Lobes in Individuals from Multiplex Alcohol Dependence Families and Controls: Their Relationship to Externalizing and Internalizing Disorders and Working Memory

  Sarah Mattson

  Ed Riley

  Susan Tapert

  Kenneth Lyon Kones

  Andrea Spadoni

  Andria Norman

  Heavy prenatal alcohol exposure leads to widespread cognitive deficits

  including problems with spatial working memory (SWM). Neuroimaging studies report structural and functional abnormalities in FASD

  but interpretations may be complicated by the co-occurrence of a family history of alcoholism. Since

  this history is also linked to cognitive deficits and brain abnormalities

  it is difficult to determine the extent to which deficits are unique to prenatal alcohol exposure. \nAge-matched subjects selected from two neuroimaging studies

  underwent functional imaging while engaging in a task assessing memory for spatial locations relative to a vigilance condition assessing attention. Pairwise comparisons were made for the following three groups: children with histories of heavy prenatal alcohol exposure (ALC

  n=18); those with no prenatal alcohol exposure

  but a confirmed family history of alcoholism (FHP

  n=18); and non-exposed

  family history negative controls (CON

  n=17). \nRelative to CON and FHP

  the ALC group showed increased BOLD response in the left middle and superior frontal gyri for the spatial working memory condition relative to the vigilance condition (SWM contrast). Additionally

  the ALC group showed unique BOLD response increases in the left lingual gyrus and right middle frontal gyrus relative to CON

  and left cuneus and precuneus relative to FHP. Both ALC and FHP showed greater activation compared to CON in the lentiform nucleus and insular region. \nThese results confirm previous studies suggesting SWM deficits in FASD. Differences between the ALC group and the CON and FHP groups suggest the left middle and superior frontal region may be specifically affected in alcohol-exposed children. Conversely

  differences from the CON group in the lentiform nucleus and insular region for the ALC and FHP groups may indicate this region is associated with family history of alcoholism rather than specifically with prenatal alcohol exposure.

  An fMRI study of spatial working memory in children with prenatal alcohol exposure: contribution of familial history of alcohol use disorders

  Sarah Mattson

  Ed Riley

  Elizabeth Sowell

  Phillip May

  Julie Kable

  Claire Coles

  Scott Roesch

  Ben Deweese

  Nicole Crocker

  Ashley L. Ware

  Prenatal exposure to alcohol often results in disruption to discrete cognitive and behavioral domains

  including executive function (EF) and adaptive functioning. In the current study

  the relation between these 2 domains was examined in children with histories of heavy prenatal alcohol exposure

  nonexposed children with a diagnosis of attention-deficit/hyperactivity disorder (ADHD)

  and typically developing controls.\nAs part of a multisite study

  3 groups of children (8 to 18 years

  M = 12.10) were tested: children with histories of heavy prenatal alcohol exposure (ALC

  n = 142)

  nonexposed children with ADHD (ADHD

  n = 82)

  and typically developing controls (CON

  n = 133) who did not have ADHD or a history of prenatal alcohol exposure. Children completed subtests of the Delis-Kaplan Executive Function System (D-KEFS)

  and their primary caregivers completed the Vineland Adaptive Behavior Scales-II. Data were analyzed using regression analyses.\nAnalyses showed that EF measures were predictive of adaptive abilities

  and significant interactions between D-KEFS measures and group were present. For the ADHD group

  the relation between adaptive abilities and EF was more general

  with 3 of the 4 EF measures showing a significant relation with adaptive score. In contrast

  for the ALC group

  this relation was specific to the nonverbal EF measures. In the CON group

  performance on EF tasks did not predict adaptive scores over the influence of age.\nThese results support prior research in ADHD

  suggesting that EF deficits are predictive of poorer adaptive behavior and extend this finding to include children with heavy prenatal exposure to alcohol. However

  the relation between EF and adaptive ability differed by group

  suggesting unique patterns of abilities in these children. These results provide enhanced understanding of adaptive deficits in these populations

  as well as demonstrate the ecological validity of laboratory measures of EF.

  Executive function predicts adaptive behavior in children with histories of heavy prenatal alcohol exposure and attention deficit/hyperactivity disorder

  Sarah Mattson

  Ed Riley

  Kenneth Lyons Jones

  Martin Paulus

  Susan Tapert

  Susanna Fryer

  Andria Norman

  Heavy prenatal exposure to alcohol leads to widespread cognitive deficits

  including problems with attention and response inhibition. This study examined blood oxygen level-dependent (BOLD) response in children with and without histories of heavy prenatal alcohol exposure during a task of response inhibition consisting of cued and non-cued trials. \nChildren and adolescents (ages 8-18y) with (AE=20) and without (CON=15) histories of heavy prenatal exposure to alcohol underwent functional magnetic resonance imaging (fMRI) while performing a go/no-go task. Unbeknownst to subjects

  a predictive cue preceded the no-go stimulus in 87% of trials. \nGroups were matched on demographic variables and did not differ on most measures of task performance. However

  following cued stimuli

  the AE group demonstrated a lower hit rate to go stimuli and more conservative response bias than the CON group. Alcohol-exposed participants demonstrated more activation during no-go trials (inhibition) relative to go trials in the left precuneus

  cingulate gyrus

  anterior cingulate

  and right medial frontal gyrus. During cue-dependent response inhibition

  the AE group demonstrated less activation in the left pre-central and post-central gyrus compared to the CON group. \nConsistent with previous studies of response inhibition

  alcohol-exposed children demonstrated greater frontal and parietal activation when attempting to inhibit prepotent responses than controls

  despite similar rates of commission errors. This study further demonstrated that alcohol-exposed children had impaired behavioral performance on cued trials and demonstrated less activation in pre-central and post-central gyri relative to controls on these trials. This investigation provides evidence of impaired behavioral and neural processing of sequential information in FASD

  which can help improve inhibition in typical populations.

  Effect of Predictive Cuing on Response Inhibition in Children with Heavy Prenatal Alcohol Exposure*

  Comprehensive Examination of Frontal Regions in Boys and Girls With Attention-Deficit/Hyperactivity Disorder

  Stewart H. Mostofksy

  Martha B. Denckla

  Walter E. Kaufmann

  Deana Crocetti

  Marin E. Ranta

  E. Mark Mahone

  The current study examined regional frontal lobe volumes based on functionally relevant subdivisions in contemporaneously recruited samples of boys and girls with and without attention-deficit/hyperactivity disorder (ADHD). Forty-four boys (21 ADHD

  23 control) and 42 girls (21 ADHD

  21 control)

  ages 8-13 years

  participated. Sulcal-gyral landmarks were used to manually delimit functionally relevant regions within the frontal lobe: primary motor cortex

  anterior cingulate

  deep white matter

  premotor regions [supplementary motor complex (SMC)

  frontal eye field

  lateral premotor cortex (LPM)]

  and prefrontal cortex (PFC) regions [medial PFC

  dorsolateral PFC (DLPFC)

  inferior PFC

  lateral orbitofrontal cortex (OFC)

  and medial OFC]. Compared to sex-matched controls

  boys and girls with ADHD showed reduced volumes (gray and white matter) in the left SMC. Conversely

  girls (but not boys) with ADHD showed reduced gray matter volume in left LPM; while boys (but not girls) with ADHD showed reduced white matter volume in left medial PFC. Reduced left SMC gray matter volumes predicted increased go/no-go commission rate in children with ADHD. Reduced left LPM gray matter volumes predicted increased go/no-go variability

  but only among girls with ADHD. Results highlight different patterns of anomalous frontal lobe development among boys and girls with ADHD beyond that detected by measuring whole lobar volumes.

  Comprehensive Examination of Frontal Regions in Boys and Girls With Attention-Deficit/Hyperactivity Disorder

  E. Mark Mahone

  Martha B. Denckla

  Stewart H. Mostofksy

  Lauren R. Dowell

  The majority of research on neurobehavioral functioning among children with Attention-Deficit/Hyperactivity Disorder (ADHD) is based on samples comprised primarily (or exclusively) of boys. Although functional impairment is well established

  available research has yet to specify a neuropsychological profile distinct to girls with ADHD. The purpose of this study was to examine performance within four components of executive function (EF) in contemporaneously recruited samples of girls and boys with ADHD. Fifty-six children with ADHD (26 girls) and 90 controls (42 girls)

  ages 8-13

  were administered neuropsychological tests emphasizing response inhibition

  response preparation

  working memory

  and planning/shifting. There were no significant differences in age or SES between boys or girls with ADHD or their sex-matched controls; ADHD subtype distribution did not differ by sex. Compared with controls

  children with ADHD showed significant deficits on all four EF components. Girls and boys with ADHD showed similar patterns of deficit on tasks involving response preparation and working memory; however

  they manifested different patterns of executive dysfunction on tasks related to response inhibition and planning. Girls with ADHD showed elevated motor overflow

  while boys with ADHD showed greater impairment during conscious

  effortful response inhibition. Girls

  but not boys with ADHD

  showed impairment in planning. There were no differences between ADHD subtypes on any EF component. These findings highlight the importance of studying boys and girls separately (as well as together) when considering manifestations of executive dysfunction in ADHD.

  Neuropsychological profile of executive function in girls with attention-deficit/hyperactivity disorder*

  Ashley Ware

  Heavy prenatal alcohol exposure results in a range of deficits

  including both volumetric and functional changes in brain regions involved in response inhibition such as the prefrontal cortex and striatum. The current study examined blood oxygen level-dependent (BOLD) response during a stop signal task in adolescents (ages 13-16y) with histories of heavy prenatal alcohol exposure (AE

  n=21) and controls (CON

  n=21). Task performance was measured using percent correct inhibits during three difficulty conditions: easy

  medium

  and hard. Group differences in BOLD response relative to baseline motor responding were examined across all inhibition trials and for each difficulty condition separately. The contrast between hard and easy trials was analyzed to determine whether increasing task difficulty affected BOLD response. Groups had similar task performance and demographic characteristics

  except for full scale IQ scores (AE

  sensorimotor

  striatal

  and cingulate regions relative to controls

  especially as task difficulty increased. When contrasting hard vs. easy inhibition trials

  the AE group showed greater medial/superior frontal and cuneus BOLD response than controls. Results were unchanged after demographics and FAS diagnosis were statistically controlled. This was the first fMRI study to utilize a stop signal task

  isolating fronto-striatal functioning

  to assess response inhibition and the effects task difficulty in adolescents with prenatal alcohol exposure. Results suggest that heavy prenatal alcohol exposure disrupts neural function of this circuitry

  resulting in immature cognitive processing and motor-association learning and neural compensation during response inhibition.

  An fMRI study of behavioral response inhibition in adolescents with and without histories of heavy prenatal alcohol exposure.

  Shirley Y. Hill

  DRD2 Variation Predicts Resilience to Substance Use Disorders in High Risk Offspring from Multiplex Alcohol Dependence Families.

  Phillip May

  Julie Kable

  Claire Coles

  Scott Roesch

  Ben Deweese

  Nicole Crocker

  Ashley Ware

  BACKGROUND:\n\nThis study examined prevalence of psychiatric disorders and behavioral problems in children with and without prenatal alcohol exposure (AE) and attention-deficit/hyperactivity disorder (ADHD).\nMETHODS:\n\nPrimary caregivers of 344 children (8 to 16 years

  M = 12.28) completed the Computerized Diagnostic Interview Schedule for Children-IV (C-DISC-4.0) and the Child Behavior Checklist (CBCL). Subjects comprised 4 groups: AE with ADHD (AE+

  n = 85) and without ADHD (AE-

  n = 52)

  and nonexposed with ADHD (ADHD

  n = 74) and without ADHD (CON

  n = 133). The frequency of specific psychiatric disorders

  number of psychiatric disorders (comorbidity)

  and CBCL behavioral scores were examined using chi-square and analysis of covariance techniques.\nRESULTS:\n\nClinical groups had greater frequency of all psychiatric disorders

  except for anxiety

  where the AE- and CON groups did not differ. There was a combined effect of AE and ADHD on conduct disorder. For comorbidity

  children with ADHD had increased psychiatric disorders regardless of AE

  which did not have an independent effect on comorbidity. For CBCL scores

  there were significant main effects of AE and ADHD on all scores and significant AE × ADHD interactions for Withdrawn/Depressed

  Somatic Complaints

  Attention

  and all Summary scores. There was a combined effect of AE and ADHD on Externalizing

  Total Problems

  and Attention Problems.\nCONCLUSIONS:\n\nFindings indicate that ADHD diagnosis elevates children's risk of psychiatric diagnoses

  regardless of AE

  but suggest an exacerbated relation between AE and ADHD on conduct disorder and externalizing behavioral problems in children. Findings affirm a poorer behavioral prognosis for alcohol-exposed children with ADHD and suggest that more than 1 neurobehavioral profile may exist for individuals with AE.

  The Effects of Prenatal Alcohol Exposure and Attention-Deficit/Hyperactivity Disorder on Psychopathology and Behavior

  Offspring from multiplex

  alcohol-dependent families are at heightened risk for substance use disorders (SUDs) in adolescence and young adulthood. These high-risk offspring have also been shown to have atypical structure and function of brain regions implicated in emotion regulation

  social cognition

  and reward processing. This study assessed the relationship between amygdala and orbitofrontal cortex (OFC) volumes obtained in adolescence and SUD outcomes in young adulthood among high-risk offspring and low-risk controls. A total of 78 participants (40 high-risk; 38 low-risk) from a longitudinal family study

  ages 8–19

  underwent magnetic resonance imaging; volumes of the amygdala and OFC were obtained with manual tracing. SUD outcomes were assessed at approximately yearly intervals. Cox regression survival analyses were used to assess the effect of regional brain volumes on SUD outcomes. The ratio of OFC to amygdala volume significantly predicted SUD survival time across the sample; reduction in survival time was seen in those with smaller ratios for both high-risk and low-risk groups. Morphology of prefrontal relative to limbic regions in adolescence prospectively predicts age of onset for substance use disorders.

  Neural Predictors of Substance Use Disorders in Young Adulthood

  Shirley Y. Hill

  Ph.D.