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Objective: Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear., Methods: Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 TSC patients followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36-month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores., Results: Patients clustered into two neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36-month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36-month neurodevelopmental group with 82% accuracy and an area under the curve of .86., Significance: These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric difficulties, appropriately termed TSC-Associated Neuropsychiatric Disorders (TAND). The objectives of the study were to analyze the rates of TAND symptoms in a cohort of patients seen at the TSC Center of Excellence at Cincinnati Children's Hospital and to identify clinically meaningful profiles based on TAND symptoms., Methods: Data from the TAND Checklist was obtained from participants seen at the TSC Center of Excellence at Cincinnati Children's Hospital Medical Center from June 2015 to August 2018. Cluster and factor analyses for each TAND symptom were performed. Factor scores were then calculated for participants, and a K-means cluster analysis of these scores was used to empirically identify distinct overall TAND symptom profiles occurring in TSC., Results: A total of 1545 checklists was completed for 668 participants (37% adults and 63% children). Approximately 90% of participants reported at least one TAND symptom with an average of 12 symptoms (out of 29). Symptom rates ranged between 5 and 60%. The most common symptoms were neuropsychologic symptoms. A seven-cluster and seven-factor solution were found to be optimal. K-means cluster analysis resulted in a seven-profile solution, ranging from low to high symptom burden., Conclusion: This study is the first to identify natural phenotypic profiles of TAND symptoms. Study of specific TAND subpopulations with shared profiles may facilitate better understanding of the underlying biology of TAND and better assessment of more targeted treatments., (© 2021. The Author(s).)

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.

Objectives: Assess agreement between self-ratings via the adult attention-deficit/hyperactivity disorder (ADHD) Self-Report Scale (ASRS)-v1.1 Symptom Checklist and clinician ratings via the adult ADHD Investigator Symptom Rating Scale (AISRS) expanded version using DSM-5 adult ADHD patients (referred sample) and ADHD controls (recruited from a primary care physician practice)., Methods: The ASRS v1.1 Symptom Checklist was administered to measure self-reported ADHD symptoms and impairment, the Adult ADHD Clinical Diagnostic Scale v1.2 was used to establish an adult ADHD diagnosis and the childhood and adult/current sections of the scale were used to provide scores to measure symptoms of childhood ADHD and recent symptoms of adult ADHD, the AISRS to measure ADHD current symptom severity., Results: Participants (n = 299; range 18-58), of which 171 were ADHD+ and 128 ADHD-. ASRS and AISRS total scores and individual subsections examining inattention, hyperactivity, emotional dysfunction (EF), and emotional dyscontrol (EC) were all significantly correlated (Spearman's ρ's = 0.78-0.89, ps < 0.01). Correlations remained significant when controlling for demographic factors and psychiatric conditions., Conclusions: The ASRS (self) and AISRS (clinician rated) scales have high agreement. This agreement extended not only the to the core 18 DSM symptoms, but also to the additional 13 symptoms that examine EC and EF.

Objectives: To examine the test-retest reliability of the DSM-IV Adult ADHD Self-Report Scale (ASRS) v1.1 Screener in adults without ADHD. Prior studies have not examined test-retest reliability of the Screener in non-ADHD controls., Methods: Subjects completed the Screener in a primary care physician (PCP) waiting room (T1); those who screened negative for ADHD (n = 104) (<4/6 significant Screener items) symptoms were further assessed on the phone (T2). T2 included phone administration of the full ASRS v1.1 Symptom Checklist (which contains the six items from the Screener). Spearman's correlations and intra-class correlation coefficients (ICCs) between T1 and T2 were calculated for the total Screener score and for each Screener item. McNemar-Bowker tests were conducted for the Screener total score and each item to check for significant changes from T1 to T2., Results: Screener T1 and T2 total scores were significantly correlated (Spearman's rho = 0.78, P < 0.0001), as were individual items. Correlations remained significant when controlling for a variety of demographic factors and psychiatric conditions. Confirming the significant Spearman correlations, ICCs for Screener total score and each item were also significant (ICC = 0.75, P < 0.0001). The McNemar-Bowker tests showed no significant differences for Screener total score and for the IA items; however, the H-I items were somewhat higher at T1 versus T2., Conclusions: The DSM-IV ASRS v1.1 Screener has high test-retest reliability in patients without ADHD.

Although DSM-5 stipulates that symptoms of attention-deficit hyperactivity disorder (ADHD) are the same for adults as children, clinical observations suggest that adults have more diverse deficits than children in higher-level executive functioning and emotional control. Previous psychometric analyses to evaluate these observations have been limited in ways addressed in the current study, which analyzes the structure of an expanded set of adult ADHD symptoms in three pooled US samples: a national household sample, a sample of health plan members, and a sample of adults referred for evaluation at an adult ADHD clinic. Exploratory factor analysis found four factors representing executive dysfunction/inattention (including, but not limited to, all the DSM-5 inattentive symptoms, with non-DSM symptoms having factor loadings comparable to those of DSM symptoms), hyperactivity, impulsivity, and emotional dyscontrol. Empirically-derived multivariate symptom profiles were broadly consistent with the DSM-5 inattentive-only, hyperactive/impulsive-only, and combined presentations, but with inattention including executive dysfunction/inattention and hyperactivity-only limited to hyperactivity without high symptoms of impulsivity. These results show that executive dysfunction is as central as DSM-5 symptoms to adult ADHD, while emotional dyscontrol is more distinct but nonetheless part of the combined presentation of adult ADHD., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Lisdexamfetamine (LDX) is a prodrug and consists of an active moiety, d-amphetamine, bound to lysine. Clinically, d-amphetamine becomes available postcleavage of the prodrug in the blood stream. Clinical effects of LDX in attention-deficit/hyperactivity disorder (ADHD) have been shown to persist up to 14 hours; however, pharmacokinetic (PK) data of LDX and amphetamine in ADHD adults are not currently available., Objectives: (1) To examine PK data of LDX and d-amphetamine in plasma and (2) to compare such PK data with Time-Sensitive ADHD Symptom Scale (TASS) ratings (PK vs. pharmacodynamic [PD])., Methods: Plasma d-amphetamine/LDX levels and TASS ratings were obtained immediately before morning dosing and then 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdosing in 21 adults with ADHD treated with 5 weeks of single-blind LDX up to 70 mg/day (after 1 week single-blind placebo). ADHD Rating Scale scores were obtained at the beginning of the visit, before morning dosing., Results: LDX levels peaked at 1.5 hours after administration (T max ) and then rapidly declined (levels were negligible at 6 hours and area under the plasma concentration versus time curve, AUC = 45.9, C max  = 25.0, and half-life [t 1/2 ] = 0.5 hours). Levels of d-amphetamine peaked at (T max ) 4.4 hours and then slowly declined (AUC = 641.6, C max  = 67.9, and t 1/2  = 17.0 hours). No statistically significant correlations were seen between d-amphetamine levels and TASS scores., Conclusions: (1) Prodrug LDX levels peaked fairly rapidly and declined, while d-amphetamine levels peaked 3 hours later than LDX levels and persisted throughout the day and (2) the absence of PK/PD correlations between PK data and TASS ratings may be due to the subjects being tested in a controlled nonattention demanding environment.

Objectives: To examine the clinical effects of equivalent doses of single-blind (SB; patient-blind) lisdexamfetamine (LDX) and mixed amphetamine salts-immediate release (MAS-IR) on adult attention-deficit/hyperactivity disorder (ADHD) in a placebo (PBO)-controlled, crossover design., Methods: Twenty-four subjects were treated sequentially in a fixed order with (1) SB PBO (matching LDX) for 1 week, (2) SB LDX (up to 70 mg/day) for 5 weeks, (3) SB PBO washout for 3 weeks, and (4) open-label treatment MAS-IR (tid up to 45 mg/day) for 5 weeks. Clinical effects on ADHD and executive function were assessed weekly throughout the trial with the ADHD Rating Scale with adult prompts, the Clinical Global Impression Severity Scale (CGI-S), and the Behavior Rating Inventory of Executive Function (BRIEF)., Results: Lisdexamfetamine and MAS-IR were generally well tolerated. Significant and equal reductions on ADHD clinician ratings were seen. Significantly greater reductions in CGI-S and selected BRIEF subsets were observed in LDX over MAS-IR treatment. However, in general, baseline scores for MAS-IR treatment did not fully return to the LDX baseline. Adherence in this structured and monitored clinical trial was good for once daily LDX and 3 times a day MAS-IR., Conclusions: In this crossover study, both LDX and MAS-IR had significant effects on ADHD clinician ratings and measures of executive function (with response rates of about 80%); patients in this monitored clinical trial were adherent with once daily LDX and 3 times a day MAS-IR, which may not be the case in real-world clinical practice. The findings of some superiority of LDX over MAS-IR on the CGI-S and BRIEF ratings may be influenced by the variability in the baselines used, but nevertheless should be further investigated in larger scale, parallel-design clinical trials.

Non-associative habituation and odor recognition tasks have been widely used to probe questions of social recognition, odor memory duration, and odor memory specificity. Among others, these paradigms have provided valuable insight into how neuromodulation, and specifically norepinephrine/noradrenaline (NE) influences odor memory. In general, NE levels are modulated by arousal, stress, and behavioral state, but there is sparse evidence of a direct relationship between NE and odor memory in adult rodents. The present study uses simple mild psychological stressors (bright light and sound) to modulate NE levels physiologically in order to probe stressors NE-dependent effect on odor recognition memory. In rats with bilateral bulbar cannulations, we show that these stressors modulate olfactory memory and that this effect is at least partially mediated by the olfactory bulb. Specifically, we show that the presence of stressors during the acquisition of odor memory suppresses memory for an odor when tested 30 min after familiarization to that odor. This suppression is blocked by infusing NE antagonists into the olfactory bulb prior to odor acquisition. Additionally, we find that infusion of bulbar NE is sufficient to suppress odor memory in a manner mimicking that of our stressors. These effects are unlikely to be solely mediated by locomotor/exploratory changes produced by stressors, although these stressors influence certain behaviors not directly related to odor investigation. This study provides important information about how behaviorally relevant changes in NE can influence top-down sensory processing and odor memory.

Neuromodulatory systems such as noradrenaline (NE), acetylcholine (ACh), and serotonin (5HT) serve important functions in sensory perception. We use the olfactory bulb (OB) as a model system to study the roles of individual neuromodulators in sensory perception. Using a spontaneous, nonreward motivated detection task, as well as a reward-motivated task, we show that rats can easily respond to odorants at very low concentrations when motivated to do so in a food-rewarded task, despite not showing spontaneous responses to these low concentration odorants. Using the same tasks paired with local bulbar infusions of noradrenergic and cholinergic drugs, we then show that rats engage their noradrenergic, but not their cholinergic system, to better respond to near threshold odorants. These results suggest that while cholinergic modulation of OB function is mostly important for odor decorrelation and discrimination, noradrenergic modulation is important for signal-to-noise modulation., (PsycINFO Database Record (c) 2012 APA, all rights reserved.)

This clinical report presents the treatment of a patient with a severely atrophic mandible. The report details the clinical successes and failures over nearly a 20-year period. Clinical and surgical procedures are presented in a longitudinal fashion, as well as the rationale at the time to support each procedure.

The association between blood lead level and dental caries was evaluated in cross-sectional analyses of baseline data for 543 children 6-10 years old screened for enrollment in the Children's Amalgam Trial, a study designed to assess potential health effects of mercury in silver fillings. Approximately half of the children were recruited from an urban setting (Boston/Cambridge, MA, USA) and approximately half from a rural setting (Farmington, ME, USA). Mean blood lead level was significantly greater among the urban subgroup, as was the mean number of carious tooth surfaces. Blood lead level was positively associated with number of caries among urban children, even with adjustment for demographic and maternal factors and child dental practices. This association was stronger in primary than in permanent dentition and stronger for occlusal, lingual, and buccal tooth surfaces than for mesial or distal surfaces. In general, blood lead was not associated with caries in the rural subgroup. The difference between the strength of the associations in the urban and rural settings might reflect the presence of residual confounding in the former setting, the presence of greater variability in the latter setting in terms of important caries risk factors (e.g., fluoride exposure), or greater exposure misclassification in the rural setting. These findings add to the evidence supporting a weak association between children's lead exposure and caries prevalence. A biologic mechanism for lead cariogenicity has not been identified, however. Our data are also consistent with residual confounding by factors associated with both elevated lead exposure and dental caries.