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Item Aberrant Neural Activity in Cortico-Striatal-Limbic Circuitry Underlies Behavioral Deficits in a Mouse Model of Neurofibromatosis Type 1(2022-05) Drozd, Hayley Paulina; McKinzie, David L.; Clapp, D. Wade; Shekhar, Anantha; Lukkes, Jodi L.; Lapish, Christopher L.; Block, Michelle L.Nearly 18% of children are diagnosed with developmental disabilities. Autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) are increasingly common developmental disabilities, but neither is well understood. ADHD and ASD are both prevalent in the genetic disorder Neurofibromatosis type 1 (NF1) which impairs the Ras-MAPK/ERK pathway through mutation of the neurofibromin gene (NF1+/−). More broadly, syndromic forms of developmental disorders are often caused by mutations of proteins in pathways interconnected with Ras including TSC1/2, FMR1, and SynGAP. Of NF1 patients, around 30-50% are diagnosed with ASDs and more than 60% with ADHD. These studies are the first to show that male mice haploinsufficient for the Nf1 gene (Nf1+/−) exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD. They exhibit hyperactivity and impulsivity in an open field, delay discounting task, and cliff avoidance reaction test, rescuable through treatment with the clinically effective ADHD drug, guanfacine (α2A adrenergic receptor agonist). Previous experiments in our lab identified social deficits including deficits in consolidation of social memory. Using optogenetics and awake behaving electrode recordings, we explored the role of the cortico-striatal-limbic circuitry in impulsivity and in social deficits in male Nf1+/− mice. Manipulation of the prefrontal cortex, nucleus accumbens, or basolateral amygdala through optogenetics rescued social deficits. These studies are the first to record brain activity in a preclinical model of NF1 during impulsive behavior, finding broad spectrum changes across slow, delta, theta, and gamma oscillatory frequencies and decreased synchrony of the prefrontal cortex and nucleus accumbens during a delay discounting task. Overall, Nf1+/− male mice with deletion of a single NF1 gene recapitulate cognitive phenotypes of NF1 patients and are a useful model system to identify alterations in neural circuitry associated with ASD and ADHD.Item Altered intrinsic functional connectivity of the cingulate cortex in children with severe temper outbursts(Cambridge University Press, 2018-05) Roy, Amy Krain; Bennett, Randi; Posner, Jonathan; Hulvershorn, Leslie; Castellanos, F. Xavier; Klein, Rachel G.; Psychiatry, School of MedicineSevere temper outbursts (STO) in children are associated with impaired school and family functioning and may contribute to negative outcomes. These outbursts can be conceptualized as excessive frustration responses reflecting reduced emotion regulation capacity. The anterior cingulate cortex (ACC) has been implicated in negative affect as well as emotional control, and exhibits disrupted function in children with elevated irritability and outbursts. This study examined the intrinsic functional connectivity (iFC) of a region of the ACC, the anterior midcingulate cortex (aMCC), in 5- to 9-year-old children with STO (n = 20), comparing them to children with attention-deficit/hyperactivity disorder (ADHD) without outbursts (ADHD; n = 18). Additional analyses compared results to a sample of healthy children (HC; n = 18) and examined specific associations with behavioral and emotional dysregulation. Compared to the ADHD group, STO children exhibited reduced iFC between the aMCC and surrounding regions of the ACC, and increased iFC between the aMCC and precuneus. These differences were also seen between the STO and HC groups; ADHD and HC groups did not differ. Specificity analyses found associations between aMCC-ACC connectivity and hyperactivity, and between aMCC-precuneus iFC and emotion dysregulation. Disruption in aMCC networks may underlie the behavioral and emotional dysregulation characteristic of children with STO.Item Associations between repetitive head impact exposure and midlife mental health wellbeing in former amateur athletes(Frontiers Media, 2024-05-28) Buddenbaum, Claire V.; Recht, Grace O.; Rodriguez, Adriana K.; Newman, Sharlene D.; Kawata, Keisuke; Pediatrics, School of MedicineIntroduction: Repetitive head impacts (RHI) have been suggested to increase the risk of developing a neurodegenerative disease, and many of these individuals develop a preceding mental health diagnosis. Given the lack of studies among amateur athletes, this study aimed to examine mental health outcomes in middle-aged amateur athletes who have been exposed to RHI through contact sport participation. Methods: This is a single site, cohort study involving former amateur athletes aged between 30 and 60 with at least 10 years of organized contact or non-contact sport participation. All participants completed demographic and mental health questionnaires. Mental health outcomes included symptoms related to depression, anxiety, post-traumatic stress disorder (PTSD), attention deficit hyperactive disorder (ADHD), and aggression. Self-reported data on mental health diagnoses and associated prescription were elicited and used to estimate odds ratios (OR). Results: Data from 41 contact athletes and 22 age/sex-matched non-contact athletes were available for analysis. The contact group exhibited a 2.25-fold higher likelihood of being diagnosed with mental health disorders and 1.29-fold higher likelihood of using associated medications compared to the non-contact group. The contact group reported significantly higher PTSD-related symptoms [4.61 (0.03,9.2), p=0.05] compared to the non-contact control group. While not statistically significant, the contact group showed increased depressive [2.37 (0.05, 4.79), p=0.07] and ADHD symptoms [4.53 (0.51, 9.57), p=0.08] compared to controls. In a secondary analysis, a distinct trend emerged within the contact group, revealing pronounced elevations in mental health symptoms among individuals with lower socioeconomic status (<$50,000/year) compared to higher income subgroups, and these symptoms decreased as income levels rose [depression: -3.08 (-4.47, -1.7), p<0.001; anxiety: -1.95 (-3.15, -0.76), p=0.002; ADHD: -4.99 (-8.28, -1.69), p=0.004; PTSD: -4.42 (-7.28, -1.57), p=0.003; aggression: -6.19 (-11.02, -1.36), p=0.01]. This trend was absent in the non-contact control group. Discussion: Our data suggest that even individuals at the amateur level of contact sports have an increased likelihood of being diagnosed with mental health disorders or experiencing mental health symptoms compared to non-contact athletes. Our findings indicate that socioeconomic status may have an interactive effect on individuals' mental health, particularly among those with a long history of RHI exposure.Item Atypical Cortical Activation during Risky Decision-making in Disruptive Behavior Disordered Youth with Histories of Suicidal Ideation(Elsevier, 2020) Dir, Allyson L.; Allebach, Christian L.; Hummer, Tom A.; Adams, Zachary; Aalsma, Matthew C.; Finn, Peter R.; Nurnberger, John I.; Hulvershorn, Leslie A.; Psychiatry, School of MedicineBackground: Suicidality is a leading cause of death among adolescents. In addition to other psychiatric conditions, youths with attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs) are at heightened risk for suicide. Decision-making deficits are a hallmark symptom of ADHD and DBDs and are also implicated in suicidal behavior. We examined behavioral and neural differences in decision making among youths with ADHD and DBDs with (SI+) and without (SI-) histories of suicidal ideation. Methods: The Balloon Analog Risk Task, a risky decision-making task, was completed by 57 youths with ADHD and DBDs (38% SI+) during functional magnetic resonance imaging. Mean stop wager (mean wager at which youths bank money) was the primary measure of risk taking. We conducted whole-brain and region-of-interest analyses in the anterior cingulate cortex and orbitofrontal cortex (OFC) during choice (win vs. inflate) and outcome (inflate vs. explode) contrasts using parametric modulators accounting for probability of balloon explosion. Results: There were no differences between SI+ and SI- youths in Balloon Analog Risk Task performance. SI+ youths showed decreasing activation in the right medial frontal gyrus when choosing inflate as explosion probability increased compared with SI- youths. During explosions, SI- youths showed increasing activation in the left OFC as explosions became more likely. SI+ showed increasing left medial OFC activity in response to inflations as explosion probability increased. Conclusions: SI+ youths may show heightened sensitivity to immediate reward and decreased sensitivity to potential loss as evidenced by medial frontal gyrus activity. OFC findings suggest that SI+ youths may be drawn to reward even when there is high probability of loss.Item Beyond Massive Univariate Tests: Covariance Regression Reveals Complex Patterns of Functional Connectivity Related to Attention-Deficit/Hyperactivity Disorder, Age, Sex, and Response Control(Elsevier, 2022) Zhao, Yi; Nebel, Mary Beth; Caffo, Brian S.; Mostofsky, Stewart H.; Rosch, Keri S.; Biostatistics and Health Data Science, School of MedicineBackground: Studies of brain functional connectivity (FC) typically involve massive univariate tests, performing statistical analysis on each individual connection. In this study we apply a novel whole-matrix regression approach referred to as Covariate Assisted Principal (CAP) regression to identify resting-state FC brain networks associated with attention-deficit/hyperactivity disorder (ADHD) and response control. Methods: Participants included 8-12 year-old children with ADHD (n=115, 29 girls) and typically developing controls (n=102, 35 girls) who completed a resting-state fMRI scan and a go/no-go task (GNG). We modeled three sets of covariates to identify resting-state networks associated with an ADHD diagnosis, sex, and response inhibition (commission errors) and variability (ex-Gaussian parameter tau). Results: The first network includes FC between striatal-cognitive control (CC) network subregions and thalamic-default mode network (DMN) subregions and is positively related to age. The second consists of FC between CC-visual-somatomotor regions and between CC-DMN subregions and is positively associated with response variability in boys with ADHD. The third consists of FC within the DMN and between DMN-CC-visual regions and differs between boys with and without ADHD. The fourth consists of FC between visual-somatomotor regions and between visual-DMN regions and differs between girls and boys with ADHD and is associated with response inhibition and variability in boys with ADHD. Unique networks were also identified in each of the three models suggesting some specificity to the covariates of interest. Conclusions: These findings demonstrate the utility of our novel covariance regression approach to studying functional brain networks relevant for development, behavior, and psychopathology.Item Causal effects of psychostimulants on neural connectivity: a mechanistic, randomized clinical trial(Wiley, 2022) Wang, Yun; Kessel, Ellen; Lee, Seonjoo; Hong, Susie; Raffanello, Elizabeth; Hulvershorn, Leslie A.; Margolis, Amy; Peterson, Bradley S.; Posner, Jonathan; Psychiatry, School of MedicineBackground: Psychostimulants are frequently used to treat attention-deficit/hyperactivity disorder (ADHD), but side effects are common leading to many patients discontinuing treatment. Identifying neural mechanisms by which psychostimulants attenuate symptoms may guide the development of more refined and tolerable therapeutics. Methods: We conducted a 12-week, randomized, placebo-controlled trial (RCT) of a long-acting amphetamine, lisdexamfetamine (LDEX), in patients with ADHD, ages 6-25 years old. Of the 58 participants who participated in the RCT, 49 completed pre- and post-RCT magnetic resonance imaging scanning with adequate data quality. Healthy controls (HCs; n = 46) were included for comparison. Treatment effects on striatal and thalamic functional connectivity (FC) were identified using static (time-averaged) and dynamic (time-varying) measures and then correlated with symptom improvement. Analyses were repeated in independent samples from the Adolescent Brain Cognitive Development study (n = 103) and the ADHD-200 Consortium (n = 213). Results: In 49 participants (25 LDEX; 24 Placebo), LDEX increased static and decreased dynamic FC (DFC). However, only DFC was associated with the therapeutic effects of LDEX. Additionally, at baseline, DFC was elevated in unmedicated-ADHD participants relative to HCs. Independent samples yielded similar findings - ADHD was associated with increased DFC, and psychostimulants with reduced DFC. Static FC findings were inconsistent across samples. Conclusions: Changes in dynamic, but not static, FC were associated with the therapeutic effects of psychostimulants. While prior research has focused on static FC, DFC may offer a more reliable target for new ADHD interventions aimed at stabilizing network dynamics, though this needs confirmation with subsequent investigations.Item Communication about ADHD and its treatment during pediatric asthma visits(Springer, 2014-02) Sleath, Betsy; Sulzer, Sandra H.; Carpenter, Delesha M.; Slota, Catherine; Gillette, Christopher; Sayner, Robyn; Davis, Stephanie; Sandler, Adrian; Department of Pediatrics, IU School of MedicineThe objectives of the study were to examine provider-family communication about attention deficit disorder during pediatric asthma visits. Children with asthma, aged 8 through 16 and their parents were recruited at five pediatric practices. All medical visits were audio-taped. There were 296 asthmatic children enrolled into the study and 67 of them also had attention deficit hyperactivity disorder (ADHD). ADHD communication elements suggested by national guidelines were discussed infrequently. Providers were more likely to discuss, educate, and ask one or more questions about ADHD medications if the visit was non-asthma related. Providers included child input into the ADHD treatment regimen during 3% of visits and they included parent input during 4.5% of visits. Only one child and three parents asked questions about ADHD. Providers may neglect essential aspects of good ADHD management and communication in children who have ADHD plus another chronic condition such as asthma. Providers should set appropriate treatment expectations, establish target symptoms, and encourage children and parents to ask questions so mutual decision-making can occur.Item Cue-Dependent Inhibition in Posttraumatic Stress Disorder and Attention- Deficit/Hyperactivity Disorder(Elsevier, 2017-10) Adams, Zachary W.; Meinzer, Michael; Mandel, Howard; Voltin, Joshua; Caughron, Blaine; Sallee, Floyd R.; Hmner, Mark; Wang, Zhewu; Department of Psychiatry, School of MedicineObjective Attention-deficit/hyperactivity disorder (ADHD) and posttraumatic stress disorder (PTSD) are common among military veterans, but the comorbidity of these two psychiatric disorders remains largely unstudied. Evaluating response inhibition and cue-dependent learning as behavioral and neurocognitive mechanisms underlying ADHD/PTSD can inform etiological models and development of tailored interventions. Method A cued go/no-go task evaluated response inhibition in 160 adult males. Participants were recruited from the community and a Veterans Administration medical center. Four diagnostic groups were identified: ADHD-only, PTSD-only, ADHD + PTSD, controls. Results Group differences were observed across most indices of inhibitory functioning, reaction time, and reaction time variability, whereby PTSD-only and ADHD + PTSD participants demonstrated deficits relative to controls. No cue dependency effects were observed. Conclusion Finding complement prior work on neurocognitive mechanisms underlying ADHD, PTSD, and ADHD + PTSD. Lack of expected group differences for the ADHD-only group may be due to limited power. Additional work is needed to better characterize distinctions among clinical groups, as well as to test effects among women and youth.Item Developmental trajectory of subtle motor signs in attention-deficit/hyperactivity disorder: a longitudinal study from childhood to adolescence(Taylor & Francis, 2021-04) Crasta, Jewel E.; Zhao, Yi; Seymour, Karen E.; Suskauer, Stacy J.; Mostofsky, Stewart H.; Rosch, Keri S.; Biostatistics, School of Public HealthThis study examined the developmental trajectory of neurodevelopmental motor signs among boys and girls with attention-deficit/hyperactivity disorder (ADHD) and typically-developing (TD) children. Seventy children with ADHD and 48 TD children, aged 8–17 years, were evaluated on at least two time-points using the Physical and Neurological Assessment of Subtle Signs (PANESS). Age-related changes in subtle motor signs (overflow, dysrhythmia, speed) were modeled using linear mixed-effects models to compare the developmental trajectories among four subgroups (ADHD girls and boys and TD girls and boys). Across visits, both boys and girls with ADHD showed greater overflow, dysrhythmia, and slower speed on repetitive motor tasks compared to TD peers; whereas, only girls with ADHD were slower on sequential motor tasks than TD girls. Developmental trajectory analyses revealed a greater reduction in overflow with age among boys with ADHD than TD boys; whereas, trajectories did not differ among girls with and without ADHD, or among boys and girls with ADHD. For dysrhythmia and speed, there were no trajectory differences between the subgroups, with all groups showing similar reductions with age. Children with ADHD show developmental trajectories of subtle motor signs that are consistent with those of TD children, with one clear exception: Boys with ADHD show more significant reductions in overflow from childhood to adolescence than do their TD peers. Our findings affirm the presence of subtle motor signs in children with ADHD and suggest that some of these signs, particularly motor overflow in boys, resolve through adolescence while dysrhythmia and slow speed, may persist.Item Distinct Patterns of Impaired Cognitive Control Among Boys and Girls with ADHD Across Development(Springer, 2021) DeRonda, Alyssa; Zhao, Yi; Seymour, Karen E.; Mostofsky, Stewart H.; Rosch, Keri S.; Biostatistics, School of Public HealthThis study examined whether girls and boys with ADHD show similar impairments in cognitive control from childhood into adolescence and the developmental relationship between cognitive control and ADHD symptoms. Participants include 8-17-year-old children with ADHD (n = 353, 104 girls) and typically developing (TD) controls (n = 241, 86 girls) with longitudinal data obtained from n = 137. Participants completed two go/no-go (GNG) tasks that varied in working memory demand. Linear mixed-effects models were applied to compare age-related changes in cognitive control for each GNG task among girls and boys with ADHD and TD controls and in relation to ADHD symptoms. Boys with ADHD showed impaired response inhibition and increased response variability across tasks. In contrast, girls with ADHD showed impaired response inhibition only with greater working memory demands whereas they displayed increased response variability regardless of working memory demands. Analysis of age-related change revealed that deficits in cognitive control under minimal working memory demands increase with age among girls with ADHD and decrease with age among boys with ADHD. In contrast, deficits in cognitive control with greater working memory demands decrease with age among both boys and girls with ADHD compared to TD peers. Among children with ADHD poor response inhibition during childhood predicted inattentive symptoms in adolescence and was associated with less age-related improvement in inattentive symptoms. These findings suggest that girls and boys with ADHD show differential impairment in cognitive control across development and response inhibition in childhood may be an important predictor of ADHD symptoms in adolescence.