Neurodevelopmental Effects of Cannabis Use in Adolescents and Emerging Adults with ADHD: A Systematic Review.

OBJECTIVE: Systematically review the scientific literature to characterize the effects of cannabis use on brain structure, function, and neurodevelopmental outcomes in adolescents and young adults with ADHD. METHOD: Systematic review following PRISMA guidelines utilizing PubMed, Embase, PsycINFO, and Cochrane CENTRAL trials register from inception until 1 January 2020. Articles that examined the impact of cannabis use on youth with ADHD were included. RESULTS: Eleven studies were identified that compared outcomes for individuals with ADHD who used cannabis or synthetic cannabinoids against those with ADHD who did not. Seven of these studies used neuroimaging techniques, including fMRI, structural MRI, and SPECT. Differential regions of activation were identified, including the right hippocampus and cerebellar vermis, and bilateral temporal lobes. Morphological differences were identified in the right precentral and postcentral gyri, left nucleus accumbens, right superior frontal and postcentral gyri. No study identified any additive or ADHD × cannabis use interaction on neuropsychological tasks of executive function. Two studies found adverse differential impacts of early-onset cannabis use in this population. CONCLUSION: A dearth of evidence is available on the impact of cannabis use on the developing brain and functioning for individuals with ADHD, despite the elevated risk for substance use in this population. The limited, potentially underpowered evidence does not support the hypothesis that cannabis use has a deleterious impact on neuropsychological tasks in transitional age youth with ADHD. Larger and longer-term studies are needed, however, to better inform clinicians and patients as to the impacts of cannabis use in youth with ADHD.

StopWatch: Pilot study for an Apple Watch application for youth with ADHD.

INTRODUCTION: To address the need for non-pharmacologic, scalable approaches for managing attention-deficit and hyperactivity disorder (ADHD) in young people, we report the results of a study of an application developed for a wearable device (Apple Watch) that was designed to track movement and provide visual and haptic feedback for ADHD. METHODS: Six-week, open label pilot study with structured rating scales ADHD and semi-structured qualitative interview. Apple Watch software application given to users that uses actigraphy and graphic interface as well as haptic feedback to provide feedback to users about level of movement during periods of intentional focus. Linear mixed models to estimate trajectories. RESULTS: Thirty-two participants entered the study. This application was associated with improvement in ADHD symptoms over the 6 weeks of the study. We observed an ADHD-Rating Scale change of ß = -1.2 units/week (95% CI = -0.56 to -1.88, F = 13.4, P = .0004). CONCLUSIONS: These positive clinical outcomes highlight the promise of such wearable applications for ADHD and the need to pursue their further development.

Correction: Paying attention to attention in depression.

In the original Article, Naoise Mac Giollabhui was incorrectly cited as "Giollabhui, N. M" instead of "Mac Giollabhui, N" in reference 163. This has been updated in the HTML and PDF versions of this Article.

Paying attention to attention in depression.

Attention is the gate through which sensory information enters our conscious experiences. Oftentimes, patients with major depressive disorder (MDD) complain of concentration difficulties that negatively impact their day-to-day function, and these attention problems are not alleviated by current first-line treatments. In spite of attention's influence on many aspects of cognitive and emotional functioning, and the inclusion of concentration difficulties in the diagnostic criteria for MDD, the focus of depression as a disease is typically on mood features, with attentional features considered less of an imperative for investigation. Here, we summarize the breadth and depth of findings from the cognitive neurosciences regarding the neural mechanisms supporting goal-directed attention in order to better understand how these might go awry in depression. First, we characterize behavioral impairments in selective, sustained, and divided attention in depressed individuals. We then discuss interactions between goal-directed attention and other aspects of cognition (cognitive control, perception, and decision-making) and emotional functioning (negative biases, internally-focused attention, and interactions of mood and attention). We then review evidence for neurobiological mechanisms supporting attention, including the organization of large-scale neural networks and electrophysiological synchrony. Finally, we discuss the failure of current first-line treatments to alleviate attention impairments in MDD and review evidence for more targeted pharmacological, brain stimulation, and behavioral interventions. By synthesizing findings across disciplines and delineating avenues for future research, we aim to provide a clearer outline of how attention impairments may arise in the context of MDD and how, mechanistically, they may negatively impact daily functioning across various domains.

Medical Students' Experiences of Unplanned Leaves of Absence.

CONTEXT: Many medical students take leaves of absence (LOA), both planned and unplanned. Unplanned LOA relate to personal or academic situations which arise and create the need for a student to temporarily suspend their medical education. This can be a high-stakes decision for the student and the school. However, there is a dearth of published literature regarding the experience of students who take a LOA to guide decision-makers. The aim of this study is to examine the experiences of medical students who took an unplanned LOA and subsequently returned to school. METHODS: A phenomenological analysis of semi-structured interviews of eight medical students returning from unplanned LOAs at two urban, academic medical centers was conducted. Transcripts were analyzed and themes were coded, and consensus regarding all themes was reached through an iterative process. RESULTS: Eight themes were identified. Some important concerns included having a sense of choice to take a LOA, the burden of logistical issues, clear communication from administrators, and worries about stigma upon return. The students retrospectively viewed their LOA as helpful and their subsequent return as less stressful than feared. DISCUSSION: The experiences of these students indicate several primary concerns that medical schools can anticipate in order to support students considering or taking an unplanned LOA. The more information a school is able to share with these students, the greater the potential to reduce anxiety at this vulnerable stage. Future research should attempt to explore these findings in a larger sample and correlate them with academic and other outcomes.

A Signature of Attention-Elicited Electrocortical Activity Distinguishes Response From Non-Response to the Non-Stimulant Atomoxetine in Children and Adolescents With ADHD.

OBJECTIVE: Atomoxetine has several characteristics that make it an attractive alternative to stimulants for treating ADHD, but there are currently no tests identifying individuals for whom the medication should be a first-line option. METHOD: Within the ADHD Controlled Trial Investigation Of a Non-stimulant (ACTION) study, we examined neuro-cortical activity in 52 youth with ADHD. Baseline event-related potentials (ERP) were compared between those who subsequently responded to 6 weeks of atomoxetine versus those who did not. RESULTS: Responders were distinguished by significantly lower auditory oddball N2 amplitudes than both non-responders and typically developing controls, particularly in the right frontocentral region ( p = .002, Cohen's d = 1.1). Leave-one-out cross validation determined that N2 amplitude in this region was able to accurately predict non-responders with a specificity of 80.8%. There were no P3 differences between responders and non-responders. CONCLUSION: The N2 amplitude is a biomarker that may have utility in predicting response to atomoxetine for youth with ADHD.

Response inhibition and emotional cognition improved by atomoxetine in children and adolescents with ADHD: The ACTION randomized controlled trial.

Although the non-stimulant medication atomoxetine is effective for attention-deficit hyperactivity disorder (ADHD) in children and adolescents, there are still significant gaps in our knowledge about whether atomoxetine improves anxiety symptoms or cognition in children. Furthermore, while cognition has been proposed as an intermediate phenotype for ADHD dysfunction, the relationships between clinical and cognitive outcomes are not yet understood. We addressed these knowledge gaps in a controlled trial using objective assessments of both general and emotional cognitive functions implicated in ADHD and in anxiety, which commonly co-occurs with ADHD. A total of 136 children and adolescents with ADHD (ages 6-17years; 80% male; 31.6% with a comorbid anxiety disorder) were enrolled in a randomized double-blind, placebo-controlled, cross-over trial of 6-weeks treatment with atomoxetine. Of these, 109 completed the second cross-over phase. Selected cognitive domains associated with ADHD and anxiety disorders (Sustained attention, response inhibition and fearful face identification) were assessed using a normed, computerized test battery. Symptom outcomes were assessed by parent reports on the ADHD Rating Scale-IV and Conners' Anxious-Shy subscale. For completers, atomoxetine caused a greater improvement in the primary cognitive outcomes of response inhibition and fear identification compared to placebo, but not in sustained attention. Atomoxetine also improved ADHD and anxiety symptoms. Anxiety symptoms improved most for ADHD and anxiety disorder combined, but presence of an anxiety disorder did not moderate any other outcomes. Changes in cognitive and clinical outcomes were not correlated. These findings contribute to the foundations of measurement-based treatment planning and offer targets for probing the mechanisms of atomoxetine action.

Identification of biotypes in Attention-Deficit/Hyperactivity Disorder, a report from a randomized, controlled trial.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder. Current subtypes lack longitudinal stability or prognostic utility. We aimed to identify data-driven biotypes using multiple cognitive measures, then to validate these biotypes using EEG, ECG, and clinical response to atomoxetine as external validators. Study design was a double-blind, randomized, placebo-controlled crossover trial of atomoxetine including 116 subjects ages 6 through 17 with diagnosis of ADHD and 56 typically developing controls. Initial features for unsupervised machine learning included a cognitive battery with 20 measures affected in ADHD. External validators included baseline mechanistic validators (using electroencephalogram/EEG and electrocardiogram/ECG) and clinical response (ADHD Rating Scale and correlation with cognitive change). One biotype, labeled impulsive cognition, was characterized by increased errors of commission and shorter reaction time, had greater EEG slow wave (theta/delta) power and greater resting heart rate. The second biotype, labeled inattentive cognition, was characterized by longer/more variable reaction time and errors of omission, had lower EEG fast wave (beta) power, resting heart rate that did not differ from controls, and a strong correlation (r = -0.447, p < 0.001) between clinical response to atomoxetine and improvement in verbal memory immediate recall. ADHD comprises at least two biotypes that cut across current subtype criteria and that may reflect distinct arousal mechanisms. The findings provide evidence that further investigation of cognitive subtypes may be at least as fruitful as symptom checklist-based subtypes for development of biologically-based diagnostics and interventions for ADHD.

RETRACTED: Sluggish Cognitive Tempo, Internalizing Symptoms, and Executive Function in Adults With ADHD.

Leikauf, J. E., & Solanto, M. V. (2016). Sluggish Cognitive Tempo, Internalizing Symptoms, and Executive Function in Adults With ADHD. Journal of Attention Disorders. Advance online publication. doi: 10.1177/1087054716659361.

Sluggish Cognitive Tempo, Internalizing Symptoms, and Executive Function in Adults With ADHD.

OBJECTIVE: We sought to characterize relationships between sluggish cognitive tempo (SCT) and both internalizing symptoms and executive functioning in adults with ADHD. METHOD: A total of 102 adults with ADHD completed clinical interviews and clinical rating scales. Hierarchical regression analyses were conducted to ascertain the independent predictive power of SCT symptoms for deficits in executive function (EF) after considering severity of ADHD inattentive and hyperactive-impulsive symptoms and internalizing symptoms. RESULTS: SCT correlated with ADHD inattentive symptoms and dimensional measures of depression and anxiety but not with clinical diagnosis of depression or anxiety. SCT predicted EF deficits over and above the effects of internalizing and ADHD symptoms. This relationship between SCT and EF was limited to the subset of participants ( n = 48) receiving stimulant treatment. CONCLUSION: SCT in adults with ADHD is associated with internalizing symptoms, ADHD inattentive symptoms, and, independently, with EF deficits. Further research is needed to ascertain why this relationship occurred primarily in adults concurrently receiving stimulants.

Patient-clinician agreement on treatment type and helpfulness: results from a WTC rescue and recovery worker cohort.

OBJECTIVE: This study assessed patient and clinician agreement about treatment type and its association with treatment helpfulness among World Trade Center rescue and recovery workers. METHODS: A total of 187 outpatients and 280 clinicians completed a survey, which gathered information on patient characteristics, treatment types, and treatment helpfulness. Kappa statistics and sensitivity and specificity analyses were used, and the association between patient-clinician agreement and reported treatment benefit was determined. RESULTS: Patient-clinician agreement was highest for group therapy, medication management, eye movement desensitization and reprocessing, and couples therapy. Agreement about medication management, individual psychotherapy, and workers' compensation evaluation was associated with higher reported treatment benefits. CONCLUSIONS: Findings support the hypothesis that agreement regarding treatment type is associated with higher reported benefit and extend findings of previous studies to a linguistically diverse, naturalistic sample exposed to a disaster trauma. Results also highlight the need for better understanding of eclectic therapies offered in real-world clinical practice.

Comparisons of self-reported and chart-identified chronic diseases in inner-city seniors.

OBJECTIVES: To examine agreement between self-report of chronic disease and medical record data for inner-city seniors, their sensitivity and specificity, and the association between patient characteristics and accuracy of self-reports. DESIGN: Cross-sectional analysis. SETTING: Two hospital-based primary care practices serving a low-income inner-city population. PARTICIPANTS: Adults aged 65 and older (n=323). MEASURES: Data on self-reported asthma, depression, diabetes mellitus, and hypertension were collected through interviewer-administered surveys (in English and Spanish) and chart abstraction. Chart-based disease was defined in two ways: physician documentation and physician documentation plus use of a medication to treat that condition. Sensitivity, specificity, and agreement were calculated. Univariate and multivariable regression analyses were used to determine the associations between patient characteristics and patient-chart agreement. RESULTS: Agreement between self-report and chart data was high for diabetes mellitus (kappa=0.94) intermediate for asthma (kappa=0.66), and hypertension (kappa=0.54) and low for depression (kappa=0.4). Sensitivity and specificity were high for diabetes mellitus (0.99 and 0.96, respectively) and low for depression (0.74 and 0.72, respectively). Specificity for hypertension was lowest (0.67). Age, education, health literacy, and other patient characteristics did not have clear associations across conditions. CONCLUSION: Self-reports may be most reliable for diabetes mellitus and least reliable for depression for surveys involving older, inner-city adults. Survey research with older adults should include confirmatory data when assessing presence of depression, hypertension, and asthma.

Expression of Th1/Th2 cytokines in human blood after in vitro treatment with chlorpyrifos, and its metabolites, in combination with endotoxin LPS and allergen Der p1.

Exposure to organophosphate (OP) pesticides has been associated with respiratory symptoms and may be related to asthma; however, few studies have examined the molecular basis for these associations. Asthma and allergic disorders are characterized by elevated Th2 cytokines (IL-4, IL-5, IL-13), whereas the chronic inflammatory response in asthmatic airways is maintained by Th1 cytokine IFN-gamma. The goal of this in vitro study was to examine the effects of OP chlorpyrifos (CPF), and its metabolites chlorpyrifos-oxon (CPO) and 3,5,6-trichloro-2-pyridinol (TCP), singly, and in combination with endotoxin lipopolysaccharide (LPS) or house dust mite Dermatophagoides pteronyssinus (Der p1) allergen, on expression of IFN-gamma and IL-4, Th1 and Th2 signature cytokines, respectively. Cytokine expression was measured by ELISA and flow cytometry. Human blood cultures were treated with CPF/CPO/TCP (1-1000 microg ml(-1)) and LPS (1.5-2.5 microg ml(-1)) or Der p1 (200 AU ml(-1)) and supernatants were collected at 48 h. Pesticides CPF, CPO and TCP did not induce cytokine expression in vitro, while LPS and Der p1 induced IFN-gamma and IL-4 expression, respectively. Whole blood cultures treated with low doses of CPO (1 and 10 microg ml(-1)), in combination with LPS, expressed higher levels of IFN-gamma than LPS alone (P < 0.05). While CPO increased LPS-dependent induction of IFN-gamma, CPO treatment did not alter Der p1 induction of IL-4. The interaction between CPO and LPS, which results in an increased type 1 immune response, should be investigated further, particularly since the combination of OP pesticides and endotoxin is common in rural, agricultural communities.

Acute lung injury: functional genomics and genetic susceptibility.

Initiated by numerous factors, acute lung injury is marked by epithelial and endothelial cell perturbation and inflammatory cell influx that leads to surfactant disruption, pulmonary edema, and atelectasis. This syndrome has been associated with a myriad of mediators including cytokines, oxidants, and growth factors. To better understand gene-environmental interactions controlling this complex process, the sensitivity of inbred mouse strains was investigated following acute lung injury that was induced by fine nickel sulfate aerosol. Measuring survival time, protein and neutrophil concentrations in BAL fluid, lung wet-to-dry weight ratio, and histology, we found that these responses varied between inbred mouse strains and that susceptibility is heritable. To assess the progression of acute lung injury, the temporal expression of genes and expressed sequence tags was assessed by complementary DNA microarray analysis. Enhanced expression was noted in genes that were associated with oxidative stress, antiprotease function, and extracellular matrix repair. In contrast, expression levels of surfactant proteins (SPs) and Clara cell secretory protein (ie, transcripts that are constitutively expressed in the lung) decreased markedly. Genome-wide analysis was performed with offspring derived from a sensitive and resistant strain (C57BL/6xA F(1) backcrossed with susceptible A strain). Significant linkage was identified for a locus on chromosome 6 (proposed as Aliq4), a region that we had identified previously following ozone-induced acute lung injury. Two suggestive linkages were identified on chromosomes 1 and 12. Using haplotype analysis to estimate the combined effect of these regions (along with putative modifying loci on chromosomes 9 and 16), we found that five loci interact to account for the differences in survival time of the parental strains. Candidate genes contained in Aliq4 include SP-B, aquaporin 1, and transforming growth factor-alpha. Thus, the functional genomic approaches of large gene set expression (complementary DNA microarray) and genome-wide analyses continue to provide novel insights into the genetic susceptibility of lung injury.

Genetic susceptibility to respiratory syncytial virus infection in inbred mice.

Differences in the severity of respiratory syncytial virus (RSV)-induced lower respiratory disease in infants have been attributed to multiple environmental and genetic factors. To identify the genetic factor(s) influencing RSV susceptibility, we examined RSV infection in eight inbred mouse strains. Lung RSV titers differed significantly between mouse strains: the RSV titers were 15-fold higher in AKR/J (permissive) mice compared with C57BL/6J (resistant) mice at 4 days after inoculation. This strain-specific difference in RSV titers suggested that susceptibility to RSV infection was attributable to genetic differences between strains. To examine the mode of inheritance of RSV susceptibility, F1 and backcross (F1 x AKR/J) progeny were infected and RSV titers determined. RSV titers in the F1 progeny were similar to those found in the resistant (C57BL/6J) parent, suggesting resistance was inherited as a dominant trait. The distribution of RSV titers in backcross progeny were discordant with that predicted for a single gene effect, suggesting susceptibility was influenced by more than one gene. These data suggest that RSV susceptibility is a multigenic trait that should be amenable to resolution by genomic analysis.