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.

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.

Towards operationalising internal distractibility (Mind Wandering) in adults with ADHD.

OBJECTIVE: To investigate whether specific symptoms of attention deficit hyperactivity disorder (ADHD) can help identify ADHD patients with mind wandering. METHODS: Subjects were adults ages 18-55 of both sexes (n=41) who completed the Mind-Wandering Questionnaire (MWQ) and the ADHD module of the Schedule for Affective Disorders and Schizophrenia for School-Age Children Epidemiologic Version. We used Spearman's rank correlation and Pearson's χ2 analyses to examine associations between the ADHD module and the MWQ and receiver operator characteristic (ROC) analyses to evaluate the diagnostic efficiency of the ADHD module. RESULTS: Out of the three ADHD domains, the inattentive ADHD scores had the strongest association with the MWQ (total: r s=0.34, df=39, p=0.03; inattentive: r s=0.38, df=39, p=0.02; Hyperactive: r s=0.17, df=39, p=0.28). Correlation analyses between individual items on the ADHD module and the MWQ showed that two inattention items ('failure to pay attention to detail' and 'trouble following instructions') were positively associated with total scores on the MWQ (p=0.02). These two inattention items had the strongest association with the MWQ (r s=0.45, df=38, p=0.004). ROC analyses showed that the combined score of the two significant inattention items had the highest efficiency (AUC=0.71) in classifying high-level mind wanderers as defined by scores greater than the median split on the MWQ. The combined score of the two inattention items best identified high-level mind wanderers. CONCLUSION: Results suggest a way to operationalise mind wandering using the symptoms of ADHD.

Transgenerational transmission of hyperactivity in a mouse model of ADHD.

Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder affecting children and adults. Genetic and environmental factors are associated with the etiology of ADHD. Among the environmental factors, exposure of the developing brain to nicotine is considered a major risk factor. Recent evidence suggests that environmental influences on the brain and behavior may be transmitted from one generation to the next. We used a prenatal nicotine exposure (PNE) mouse model of ADHD to test the hypothesis that PNE-induced hyperactivity, a proxy for human ADHD phenotype, is transmitted from one generation to the next. Our data reveal transgenerational transmission of PNE-induced hyperactivity in mice via the maternal but not the paternal line of descent. We suggest that transgenerational transmission is a plausible mechanism for propagation of environmentally induced ADHD phenotypes in the population.

Mild Traumatic Brain Injury and Attention-Deficit Hyperactivity Disorder in Young Student Athletes.

A recent meta-analysis documented a significant statistical association between mild traumatic brain injury (mTBI) and attention deficit hyperactivity disorder (ADHD) (Adeyemo et al., 2014), but the direction of this effect was unclear. In this study, we hypothesized that ADHD would be an antecedent risk factor for mTBI. Participants were student athletes ages 12 to 25 who had sustained a mTBI and Controls of similar age and sex selected from studies of youth with and without ADHD. Subjects were assessed for symptoms of ADHD, concussion severity, and cognitive function. mTBI subjects had a significantly higher rate of ADHD than Controls, and in all cases the age of onset of ADHD was before mTBI onset. mTBI+ADHD subjects also had more severe concussion symptoms (fatigue and poor concentration) than mTBI-ADHD subjects. These results support ADHD as an antecedent risk factor for mTBI in student athletes and that its presence complicates the course of mTBI.

Attention-deficit/hyperactivity disorder and adverse health outcomes in adults.

Whereas the adverse impact of attention-deficit/hyperactivity disorder (ADHD) on emotional and psychosocial well-being has been well investigated, its impact on physical health has not. The main aim of this study was to assess the impact of ADHD on lifestyle behaviors and measures of adverse health risk indicators. Subjects were 100 untreated adults with ADHD and 100 adults without ADHD of similar age and sex. Unhealthy lifestyle indicators included assessments of bad health habits, frequency of visits to healthcare providers, and follow through with recommended prophylactic tests. Assessments of adverse health risk indicators included measurements of cardiovascular and metabolic parameters, weight, body mass index, and waist circumference. No differences were identified in health habits between subjects with and without ADHD, but robust differences were found in a wide range of adverse health risk indicators. ADHD is associated with an adverse impact in health risk indicators well known to be associated with high morbidity and mortality.

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.

Prenatal nicotine exposure mouse model showing hyperactivity, reduced cingulate cortex volume, reduced dopamine turnover, and responsiveness to oral methylphenidate treatment.

Cigarette smoking, nicotine replacement therapy, and smokeless tobacco use during pregnancy are associated with cognitive disabilities later in life in children exposed prenatally to nicotine. The disabilities include attention deficit hyperactivity disorder (ADHD) and conduct disorder. However, the structural and neurochemical bases of these cognitive deficits remain unclear. Using a mouse model we show that prenatal nicotine exposure produces hyperactivity, selective decreases in cingulate cortical volume, and radial thickness, as well as decreased dopamine turnover in the frontal cortex. The hyperactivity occurs in both male and female offspring and peaks during the "active" or dark phase of the light/dark cycle. These features of the mouse model closely parallel the human ADHD phenotype, whether or not the ADHD is associated with prenatal nicotine exposure. A single oral, but not intraperitoneal, administration of a therapeutic equivalent dose (0.75 mg/kg) of methylphenidate decreases the hyperactivity and increases the dopamine turnover in the frontal cortex of the prenatally nicotine exposed mice, once again paralleling the therapeutic effects of this compound in ADHD subjects. Collectively, our data suggest that the prenatal nicotine exposure mouse model has striking parallels to the ADHD phenotype not only in behavioral, neuroanatomical, and neurochemical features, but also with respect to responsiveness of the behavioral phenotype to methylphenidate treatment. The behavioral, neurochemical, and anatomical biomarkers in the mouse model could be valuable for evaluating new therapies for ADHD and mechanistic investigations into its etiology.

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.

Further understanding of the comorbidity between Attention-Deficit/Hyperactivity Disorder and bipolar disorder in adults: an MRI study of cortical thickness.

Although Attention-Deficit/Hyperactivity Disorder (ADHD) and Bipolar Disorder (BPD) frequently co-occur and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this comorbidity is scarce. Our aim was to evaluate cortical thickness in ADHD and BPD, testing the hypothesis that comorbid subjects (ADHD+BPD) would have neuroanatomical correlates of both disorders. Magnetic Resonance Imaging (MRI) findings were compared between 31 adults with ADHD+BPD, 18 with BPD, 26 with ADHD, and 23 healthy controls. Cortical thickness analysis of regions of interest was estimated as a function of ADHD and BPD status, using linear regression models. BPD was associated with significantly thicker cortices in 13 regions, independently of ADHD status and ADHD was associated with significantly thinner neocortical gray matter in 28 regions, independent of BPD. In the comorbid state of ADHD plus BPD, the profile of cortical abnormalities consisted of structures that are altered in both disorders individually. Results support the hypothesis that ADHD and BPD independently contribute to cortical thickness alterations of selective and distinct brain structures, and that the comorbid state represents a combinatory effect of the two. Attention to comorbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD.

Reliability and validity of the Time-Sensitive ADHD Symptom Scale in adults.

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Time-Sensitive ADHD Symptom Scale (TASS) to evaluate change of attention-deficit/hyperactivity disorder (ADHD) symptoms over the course of a day in adults. METHODS: Eighty adults with ADHD participated in 1 or 2 visits, 1 to 9 weeks apart. At each visit, participants completed the TASS followed by raters administering the ADHD Rating Scale (ADHD-RS). Additional TASS and ADHD-RS ratings were completed 2 to 6 hours after each visit via telephone. Internal consistency of TASS items was assessed by Cronbach's α. Convergent validity of TASS and ADHD-RS total mean item scores was assessed using Pearson's correlation coefficients. κ correlations were calculated to assess item-by-item reliability between TASS and ADHD-RS items. RESULTS: Internal consistency of TASS items was high, with an overall Cronbach's α coefficient of .93. The Pearson's correlation coefficient between the TASS and ADHD-RS was significant for all visits (r = 0.70, P < .0001). There was moderate agreement between individual items on the TASS and ADHD-RS, with significant κ coefficients for almost all items (P < .05). DISCUSSION: The TASS showed high internal consistency and concurrent validity with the clinician-administered ADHD-RS and is a valid and reliable scale for measuring change in ADHD symptoms over the course of a day in adults.

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).

A naturalistic 10-year prospective study of height and weight in children with attention-deficit hyperactivity disorder grown up: sex and treatment effects.

OBJECTIVE: To assess the effect of attention-deficit/hyperactivity disorder (ADHD) and its treatment on growth outcomes in children followed into adulthood. STUDY DESIGN: Two identically designed, longitudinal, case-control studies of males and females with and without ADHD were combined; 124 and 137 control and subjects with ADHD, respectively, provided growth information at the 10- to 11-year follow-up. We used linear growth curve models to estimate the effect of time on change in height and whether this effect differed by sex and ADHD status. We also examined the effect of stimulant treatment on growth outcomes. RESULTS: We found no evidence that ADHD was associated with trajectories of height over time or differences at follow-up in any growth outcomes. Similarly, we found no evidence that stimulant treatment was associated with differences in growth. However, among subjects with ADHD, major depression was associated with significantly larger weight in females and smaller height in males. CONCLUSIONS: Our results do not support an association between deficits in growth outcomes and either ADHD or psychostimulant treatment for ADHD. These findings extend the literature on this topic into young adulthood and should assist clinicians and parents in formulating treatment plans for children with ADHD.

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.

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.

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.

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.

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.