Preclinical Models of Attention Deficit Hyperactivity Disorder: Neurobiology, Drug Discovery, and Beyond.

OBJECTIVE: We offer an overview of ADHD research using mouse models of nicotine exposure. METHOD: Nicotine exposure of C57BL/6 or Swiss Webster mice occurred during prenatal period only or during the prenatal and the pre-weaning periods. Behavioral, neuroanatomical and neurotransmitter assays were used to investigate neurobiological mechanisms of ADHD and discover candidate ADHD medications. RESULTS: Our studies show that norbinaltorphimine, a selective kappa opioid receptor antagonist is a candidate novel non-stimulant ADHD treatment and that a combination of methylphenidate and naltrexone has abuse deterrent potential with therapeutic benefits for ADHD. Other studies showed transgenerational transmission of ADHD-associated behavioral traits and demonstrated that interactions between untreated ADHD and repeated mild traumatic brain injury produced behavioral traits not associated with either condition alone. CONCLUSION: Preclinical models contribute to novel insights into ADHD neurobiology and are valuable tools for drug discovery and translation to benefit humans with ADHD.

Editorial: Height and Stimulant Treatment in Attention-Deficit/Hyperactivity Disorder Youth: Mind the Gap.

In this issue of the Journal, the important story of height and weight issues related to stimulant medication in attention-deficit/hyperactivity disorder (ADHD) is yet again addressed, in the largest study to date.1 Controversy related to potential growth decrements in youth with ADHD receiving stimulants has been around for decades. In fact, in a quick PubMed search of the literature, we identified more than 100 studies, 15 reviews, and meta-analyses in this area. In a general score card, about three-fourths of studies seem to support some degree of decrement, but clinical significance has yet to be determined. What is not being debated anymore is the short- and longer-term effectiveness of stimulants for ADHD with reductions in mood disorders, suicide, substance use/disorders, criminality, motor vehicle accidents, injuries, concussions, and academic failure documented in the Swedish and other register studies.2 Many of these improvements are linked with a decrease in major morbidity and even mortality. Hence, we need to put the issue of potential stimulant-related growth velocity changes in the context of the very real adverse outcomes associated with non-treatment of ADHD.

Comparative effectiveness of prolonged exposure and cognitive processing therapy for military service members in an intensive treatment program.

OBJECTIVE: While the comparative efficacy of prolonged exposure (PE) and cognitive processing therapy (CPT) has been examined in outpatient settings, there is a dearth of literature on the relative effectiveness of these interventions when adapted for an intensive treatment format. In an expanded secondary analysis of a previous study, we sought to examine the comparative effectiveness of PE and CPT delivered in the naturalistic setting of an intensive treatment format including maintenance of outcomes through a 6-month follow-up period. METHOD: A sample of 296 veterans with posttraumatic stress disorder (PTSD) received either PE (n = 186) or CPT (n = 90), alongside other trauma-informed interventions, in a 2-week intensive clinical program. Treatment selection was determined collaboratively between patient and therapist. Our primary outcome was self-reported PTSD symptom severity (i.e., PTSD Checklist for DSM-5, PCL-5); secondarily, we examined self-reported depression (i.e., Patient Health Questionnaire) symptom severity outcomes. RESULTS: A mixed-model regression controlling for age and gender revealed a significant effect of time from baseline to endpoint (p < .001), 3-month (p < .001), and 6-month follow-up (p < .001) on PCL-5 scores but no significant effect of treatment or effect of treatment by time interaction (all ps > .05; model: Wald's χ² = 232.38, p < .001). Results were similar for depression outcomes. Attrition at posttreatment was not significantly different between groups: 7.2% for CPT and 6.5% PE (z score = 0.22). CONCLUSIONS: Both PE and CPT are associated with comparable improvements when delivered as part of a 2-week intensive outpatient program. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Frontal Cortical Monoamine Release, Attention, and Working Memory in a Perinatal Nicotine Exposure Mouse Model Following Kappa Opioid Receptor Antagonism.

Perinatal nicotine exposure (PNE) produces frontal cortical hypo-dopaminergic state and attention and working memory deficits consistent with neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD). Methylphenidate alleviates ADHD symptoms by increasing extracellular dopamine and noradrenaline. Kappa opioid receptor (KOR) antagonism may be another mechanism to achieve the same results because KOR activation inhibits frontal cortical dopamine release. We administered the selective KOR antagonist norbinaltorphimine (norBNI) (20 mg/kg; intraperitoneal) or methylphenidate (0.75 mg/kg; intraperitoneal) to PNE mouse model and examined frontal cortical monoamine release, attention, and working memory. Both compounds increased dopamine and noradrenaline release but neither influenced serotonin release. Both compounds improved object-based attention and working memory in the PNE group, with norBNI's effects evident at 2.5 h and 5.5 h but absent at 24 h. Methylphenidate's effects were evident at 0.5 h but not at 2.5 h. norBNI's effects temporally coincided with frontal cortical c-Jun N-terminal kinase phosphorylation. norBNI did not alter tissue dopamine content in the nucleus accumbens, offering preliminary support for lack of reinforcement.

A pilot study of a mind-body stress management program for student veterans.

BACKGROUND: Student veterans are an at-risk population given the challenges of military experience, reintegration to civilian life, and attending college. Therefore, there is a need for innovative programs to support student veterans. The present study sought to determine the acceptability and effectiveness of a 10-week mind-body stress reduction intervention for student veterans, or Resilient Student Warrior. MATERIALS AND METHODS: Eighty-six student veterans took part in the 10-week mind-body stress reduction course, Resilient Student Warrior. RESULTS: Results showed a significant improvement in reports of stress reactivity, mindfulness, sleep disturbance and coping skills for stress (p < 0.05), but not self-efficacy, perceived stress, depressive or post-traumatic stress disorder symptoms. The intervention was reported as helpful by 96% of participants, with 95% of participants stating they would recommend the course to others. CONCLUSION: Future studies should further assess the effectiveness of mind-body interventions among the student veteran population.

Transgenerational transmission of behavioral phenotypes produced by exposure of male mice to saccharin and nicotine.

The use of non-nutritive sweeteners such as saccharin is widely prevalent. Although saccharin is considered safe for human consumption, it produces behavioral changes in experimental animals. We report that saccharin's behavioral effects are much more pervasive than currently recognized. In a mouse model, saccharin exposure produced motor impulsivity not only in the saccharin-exposed males but also in their offspring. In addition, the offspring showed locomotor hyperactivity and working memory deficit not observed in fathers. Spermatazoal DNA was hypermethylated in the saccharin-exposed fathers, especially at dopamine receptor promoter regions, suggesting that epigenetic modification of germ cell DNA may mediate transgenerational transmission of behavioral phenotypes. Dopamine's role in hyperactivity was further highlighted by the finding that the stimulant drug methylphenidate mitigated the hyperactivity. Nicotine is another substance that is widely used. Its use via smokeless tobacco products, some of which contain saccharin, is on the rise contributing to concerns about adverse outcomes of co-exposure to saccharin and nicotine. We found that co-exposure of male mice to saccharin and nicotine produced significant behavioral impairment in their offspring. Thus, our data point to potential adverse neurobehavioral consequences of exposure to saccharin alone or saccharin and nicotine for the exposed individuals and their descendants.

Toward operationalizing deficient emotional self-regulation in newly referred adults with ADHD: A receiver operator characteristic curve analysis.

BACKGROUND: A growing body of research suggests that deficient emotional self-regulation (DESR) is common and morbid among attention-deficit/hyperactivity disorder (ADHD) patients. The main aim of the present study was to assess whether high and low levels of DESR in adult ADHD patients can be operationalized and whether they are clinically useful. METHODS: A total of 441 newly referred 18- to 55-year-old adults of both sexes with Diagnostic and Statistical Manual of Mental Disorders: Fifth Edition (DSM-5) ADHD completed self-reported rating scales. We operationalized DESR using items from the Barkley Current Behavior Scale. We used receiver operator characteristic (ROC) curves to identify the optimal cut-off on the Barkley Emotional Dysregulation (ED) Scale to categorize patients as having high- versus low-level DESR and compared demographic and clinical characteristics between the groups. RESULTS: We averaged the optimal Barkley ED Scale cut-points from the ROC curve analyses across all subscales and categorized ADHD patients as having high- (N = 191) or low-level (N = 250) DESR (total Barkley ED Scale score ≥8 or <8, respectively). Those with high-level DESR had significantly more severe symptoms of ADHD, executive dysfunction, autistic traits, levels of psychopathology, and worse quality of life compared with those with low-level DESR. There were no major differences in outcomes among medicated and unmedicated patients. CONCLUSIONS: High levels of DESR are common in adults with ADHD and when present represent a burdensome source of added morbidity and disability worthy of further clinical and scientific attention.

Collaborative Songwriting Intervention for Veterans with Post-Traumatic Stress Disorder.

Objectives: Given that veterans are significantly more likely to suffer from post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), depression, and anxiety than civilians, yet current gold-standard treatments for PTSD are not effective for all patients, the present study sought to examine the feasibility and acceptability of a collaborative songwriting intervention (CSI) while exploring its potential effectiveness in improving physical and mental health outcomes for veterans with PTSD. Design: Ten veterans took part in the CSI. A variety of pre- and postintervention measures were administered, including the Measurement of Current Status (MOCS), the Coping Expectancies Scale (CES), the Post-traumatic Stress Disorder Checklist-Military (PCL-M), and the Patient Health Questionnaire-9 (PHQ-9). Participants also wore a Fitbit to track average heart rate, sleep, and step count. Intervention: The CSI consisted of each veteran meeting with a professional songwriter, trained specifically for co-writing original material with the veteran population. There were three phases of songwriting that took about an hour and 15 min total. Veterans were instructed to listen to their song daily for 5 weeks. Results: Participants reported that the intervention was helpful and relevant to them, and most participants (95%) would refer others to this treatment. We found that the CSI reduced participant's PTSD symptoms (d = 0.869), specifically the Numbing (d = 0.853) and Hyperarousal (d = 1.077) subscales. Depressive symptoms (d = 0.72) and stress reactivity (d = 0.785) also marginally decreased. There was no significant change in physiological data (i.e., sleep, no. of steps) from pre- to postintervention. Conclusion: These data suggest that a CSI is an acceptable intervention for veterans with PTSD that may also improve their PTSD symptoms.

Acceptability of an adjunct equine-assisted activities and therapies program for veterans with posttraumatic stress disorder and/or traumatic brain injury.

OBJECTIVE: Equine-assisted activities and therapies (EAATs) have been a growing adjunctive integrative health modality, as they allow participants to practice mindfulness, emotional regulation, and self-mastery or self-esteem building skills. Preliminary evidence suggests that these programs may be helpful in reducing posttraumatic stress disorder (PTSD), anxiety, and depressive symptoms. The current study examines the acceptability of integrating an EAAT program as part of a two-week, intensive clinical program for veterans with PTSD and/or traumatic brain injury (TBI). METHODS: A family member or support person could accompany veterans and participate in the program. One hundred and six participants (veteran n = 62, family n = 44) left the urban environment in an intensive outpatient program (IOP) to attend a two-day, weekend EAAT in rural New Hampshire. Satisfaction surveys were conducted on the last day of the program and examined using thematic analysis. RESULTS: The following themes were reported in the surveys: ability of horses to catalyze emotional rehabilitation, effectiveness of immersion in equine-assisted activities, program's ability to foster interpersonal relationships and necessity of education about PTSD for staff. Participants also reported enjoying the program as highlighted by qualitative feedback, a mean score of 9.76 (standard deviation [SD] = 0.61) as reported by veterans and a mean score of 9.91 (SD = 0.29) as reported by family members on a 10-point visual analog scale with higher scores indicating a greater overall experience. CONCLUSION: These data offer preliminary evidence that an adjunct EAAT program is acceptable for veterans with PTSD and/or TBI participating in an IOP.

The Relationship Between Executive Function Deficits and DSM-5-Defined ADHD Symptoms.

Objectives: To identify the relationship between the core Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ADHD symptoms and executive function deficits (EFDs), to evaluate ADHD characteristics of those with executive dysfunction (ED), and to examine the predictive utility of the Adult ADHD Investigator Symptom Rating Scale (AISRS) in identifying those with adult ADHD and ED. Method: Two samples (referred and primary care practice) were pooled together for present analysis. Results: Final analysis included 297 respondents, 171 with adult ADHD. Spearman correlation coefficients and binary logistic regressions demonstrated that ADHD inattentive (IA) and hyperactive-impulsive (H-I) symptoms were moderately to strongly correlated with and highly predictive of EFDs. Receiver operating characteristic curve analysis showed that an AISRS DSM 18-item score of ⩾ 28 was most predictive of clinical ED. Conclusion: ADHD symptoms were strongly correlated with and predictive of EFDs, clinicians should screen adults with ADHD for EFDs and ADHD treatment providers should track EFD improvement in addition to DSM-5 ADHD symptoms.

Informativeness of Self-Reports of ADHD Symptoms in Monitoring Response to Stimulant Treatment in Clinically Referred Adults With ADHD.

Objective: To investigate the informativeness of self-reports of ADHD symptoms in adults with ADHD in the clinical setting. Method: Subjects were clinically referred adults aged 19 years to 67 years of age of both sexes (N = 54). All subjects were on stable doses of stimulant and were considered responders to treatment. ADHD symptoms were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) and the ADHD Self-Report Scale (ASRS). Spearman's rank correlations were used to assess the correlations between clinician-assessed ADHD and patients' self-reports. Results: Spearman's rank correlation analysis found evidence of a strong, positive association between total scores on the AISRS and the ASRS (rs = .65, df = 52, p< .001). Conclusion: Results have important implications for the management and monitoring of treatment response in the clinical setting through patients' self-report.

Is Paternal Smoking at Conception a Risk for ADHD? A Controlled Study in Youth With and Without ADHD.

Objective: Based on emerging preclinical findings suggesting that paternal smoking at conception may be a risk for ADHD in the offspring, we investigated whether a similar effect can be observed in humans. Method: We analyzed data from an opportunistic dataset of girl probands with (N = 140) and without (N = 122) ADHD with available information on paternal smoking at conception. Data were analyzed using Pearson's chi-square tests and multiple logistic regression. Results: ADHD probands had a significantly higher rate of paternal smoking at conception than controls (35% vs. 23%, χ2 = 3.82, p = .05) with a significant odds ratio of 1.5. However, the association lost significance after controlling for paternal ADHD, most likely due to limited statistical power. Conclusion: While preliminary, findings suggest that paternal smoking at conception may be a risk factor for ADHD in the offspring.

Dasotraline in Children with Attention-Deficit/Hyperactivity Disorder: A Six-Week, Placebo-Controlled, Fixed-Dose Trial.

OBJECTIVE: Dasotraline is a potent inhibitor of presynaptic dopamine and norepinephrine reuptake with a pharmacokinetic profile characterized by slow absorption and a long elimination half-life. The aim of this study was to evaluate the efficacy and safety of dasotraline in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children aged 6-12 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of ADHD were randomized to 6 weeks of double-blind once-daily treatment with dasotraline (2 or 4 mg) or placebo. The primary efficacy endpoint was change from baseline in the ADHD Rating Scale Version IV-Home Version (ADHD RS-IV HV) total score at week 6. RESULTS: A total of 342 patients were randomized to dasotraline or placebo (mean age 9.1 years, 66.7% male). Treatment with dasotraline was associated with significant improvement at study endpoint in the ADHD RS-IV HV total score for the 4 mg/day dose versus placebo (-17.5 vs. -11.4; p < 0.001; effect size [ES], 0.48), but not for the 2 mg/day dose (-11.8 vs. -11.4; ns; ES, 0.03). A regression analysis confirmed a significant linear dose-response relationship for dasotraline. Significant improvement for dasotraline 4 mg/day dose versus placebo was also observed across the majority of secondary efficacy endpoints, including the Clinical Global Impression (CGI)-Severity score, the Conners Parent Rating Scale-Revised scale (CPRS-R) ADHD index score, and subscale measures of hyperactivity and inattentiveness. Discontinuation rates due to adverse events (AEs) were higher in the dasotraline 4 mg/day group (12.2%) compared with the 2 mg/day group (6.3%) and placebo (1.7%). The most frequent AEs associated with dasotraline were insomnia, decreased appetite, decreased weight, and irritability. Psychosis-related symptoms were reported as AEs by 7/219 patients treated with dasotraline in this study. There were no serious AEs or clinically meaningful changes in blood pressure or heart rate on dasotraline. CONCLUSION: In this placebo-controlled study, treatment with dasotraline 4 mg/day significantly improved ADHD symptoms and behaviors, including attention and hyperactivity, in children aged 6-12 years. The most frequently reported AEs observed on dasotraline included insomnia, decreased appetite, decreased weight, and irritability.

A General Framework for Assessing In vitro/In vivo Correlation as a Tool for Maximizing the Benefit-Risk Ratio of a Treatment Using a Convolution-Based Modeling Approach.

The net benefit of a treatment can be defined by the relationship between clinical improvement and risk of adverse events: the benefit-risk ratio. The optimization of the benefit-risk ratio can be achieved by identifying the most adequate dose (and/or dosage regimen) jointly with the best-performing in vivo release properties of a drug. A general in silico tool is presented for identifying the dose, the in vitro and the in vivo release properties that maximize the benefit-risk ratio using convolution-based modeling, an exposure-response model, and a surface response analysis. A case study is presented to illustrate how the benefit-risk ratio of methylphenidate for the treatment of attention deficit hyperactivity disorder can be maximized using the proposed strategy. The results of the analysis identified the characteristics of an optimized dose and in vitro/in vivo release suitable to provide a sustained clinical response with respect to the conventional dosage regimen and formulations.

Validation of the Expanded Versions of the Adult ADHD Self-Report Scale v1.1 Symptom Checklist and the Adult ADHD Investigator Symptom Rating Scale.

Objective: The aim of this study is to validate the Adult ADHD Self-Report Scale (ASRS) and Adult ADHD Investigator Symptom Rating Scale (AISRS) expanded versions, including executive function deficits (EFDs) and emotional dyscontrol (EC) items, and to present ASRS and AISRS pilot normative data. Method: Two patient samples (referred and primary care physician [PCP] controls) were pooled together for these analyses. Results: Final analysis included 297 respondents, 171 with adult ADHD. Cronbach's alphas were high for all sections of the scales. Examining histograms of ASRS 31-item and AISRS 18-item total scores for ADHD controls, 95% cutoff scores were 70 and 23, respectively; histograms for pilot normative sample suggest cutoffs of 82 and 26, respectively. Conclusion: (a) ASRS- and AISRS-expanded versions have high validity in assessment of core 18 adult ADHD Diagnostic and Statistical Manual of Mental Disorders (DSM) symptoms and EFD and EC symptoms. (b) ASRS (31-item) scores 70 to 82 and AISRS (18-item) scores from 23 to 26 suggest a high likelihood of adult ADHD.

Sport concussion and attention deficit hyperactivity disorder in student athletes: A cohort study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is associated with impulsive behavior and inattention, making it a potential risk factor for sport-related concussion (SRC). The objectives of this study were to determine whether ADHD is an antecedent risk factor for SRC and whether ADHD complicates recovery from SRC in youth athletes. METHODS: Student athletes with a history of SRC were evaluated for the presence of ADHD using diagnostic interview and to determine whether ADHD symptoms began before or after SRC. Concussion-specific measures of concussive symptoms and cognitive function were compared in SRC + ADHD and SRC + No ADHD groups to assess SRC recovery between groups. RESULTS: ADHD was overrepresented in youth with SRC compared with population rates. ADHD was found to be an antecedent risk factor for SRC, with age at ADHD onset earlier than the date of SRC. Student athletes with SRC and ADHD reported more concussive symptoms compared with athletes without ADHD and were more likely to have a history of greater than one concussion. CONCLUSIONS: The results of this study support our hypothesis that ADHD is an antecedent risk factor for SRC and may contribute to a more complicated course of recovery from SRC. Future research should focus on determining whether screening, diagnosis, and treating ADHD in youth athletes may prevent SRC. Providers that care for youth athletes with ADHD should be aware of the vulnerabilities of this population toward SRC and its complications.

Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.

Use of tobacco products is injurious to health in men and women. However, tobacco use by pregnant women receives greater scrutiny because it can also compromise the health of future generations. More men smoke cigarettes than women. Yet the impact of nicotine use by men upon their descendants has not been as widely scrutinized. We exposed male C57BL/6 mice to nicotine (200 µg/mL in drinking water) for 12 wk and bred the mice with drug-naïve females to produce the F1 generation. Male and female F1 mice were bred with drug-naïve partners to produce the F2 generation. We analyzed spontaneous locomotor activity, working memory, attention, and reversal learning in male and female F1 and F2 mice. Both male and female F1 mice derived from the nicotine-exposed males showed significant increases in spontaneous locomotor activity and significant deficits in reversal learning. The male F1 mice also showed significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression. Examination of the F2 generation showed that male F2 mice derived from paternally nicotine-exposed female F1 mice had significant deficits in reversal learning. Analysis of epigenetic changes in the spermatozoa of the nicotine-exposed male founders (F0) showed significant changes in global DNA methylation and DNA methylation at promoter regions of the dopamine D2 receptor gene. Our findings show that nicotine exposure of male mice produces behavioral changes in multiple generations of descendants. Nicotine-induced changes in spermatozoal DNA methylation are a plausible mechanism for the transgenerational transmission of the phenotypes. These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.

Are Adult ADHD Patients Good Informants of Their Symptoms? A Qualitative Literature Review of Concordance Between Clinician and Self-Report ADHD Symptoms.

To conduct a comprehensive review on the agreement between clinician-rated and self-reported attention-deficit/hyperactivity disorder (ADHD) symptoms in adults, the following terms were searched in PubMed: "ADHD self-concordance," "Self-report AND ADHD AND Valid," "(self-report) AND ADHD AND clinician," and "(self-report) AND ADHD AND versus AND investigator." Nine articles met our inclusion and exclusion criteria (English language, operationalized measures of clinician-rated and self-reported ADHD, and neither a review nor opinion article). Among the clinical studies, correlation coefficients were on average 0.69 for the total ADHD symptoms score. The epidemiological studies had an average kappa statistic of 0.58 for ADHD diagnoses. The studies of adult relatives of youth with ADHD had an average correlation coefficient of 0.74 for the ADHD total symptoms score. Our review supports the informativeness of self-reported assessments of ADHD symptoms, which has important implications for management and monitoring of ADHD.

Attention and working memory deficits in a perinatal nicotine exposure mouse model.

BACKGROUND: Cigarette smoking by pregnant women is associated with a significant increase in the risk for cognitive disorders in their children. Preclinical models confirm this risk by showing that exposure of the developing brain to nicotine produces adverse behavioral outcomes. Here we describe behavioral phenotypes resulting from perinatal nicotine exposure in a mouse model, and discuss our findings in the context of findings from previously published studies using preclinical models of developmental nicotine exposure. METHODOLOGY/PRINCIPAL FINDINGS: Female C57Bl/6 mice received drinking water containing nicotine (100µg/ml) + saccharin (2%) starting 3 weeks prior to breeding and continuing throughout pregnancy, and until 3 weeks postpartum. Over the same period, female mice in two control groups received drinking water containing saccharin (2%) or plain drinking water. Offspring from each group were weaned at 3-weeks of age and subjected to behavioral analyses at 3 months of age. We examined spontaneous locomotor activity, anxiety-like behavior, spatial working memory, object based attention, recognition memory and impulsive-like behavior. We found significant deficits in attention and working memory only in male mice, and no significant changes in the other behavioral phenotypes in male or female mice. Exposure to saccharin alone did not produce significant changes in either sex. CONCLUSION/SIGNIFICANCE: The perinatal nicotine exposure produced significant deficits in attention and working memory in a sex-dependent manner in that the male but not female offspring displayed these behaviors. These behavioral phenotypes are associated with attention deficit hyperactivity disorder (ADHD) and have been reported in other studies that used pre- or perinatal nicotine exposure. Therefore, we suggest that preclinical models of developmental nicotine exposure could be useful tools for modeling ADHD and related disorders.