Search

Utilizing a randomized control design, this mixed method study aimed to assess the impact of a personalized music intervention on mood, agitation level, and psychotropic drug use in individuals with moderate to advanced dementia residing in long-term care facilities. The sample comprised of 261 participants, with 148 in the intervention group and 113 in the control group. Data were collected from three sources: quantitative data from the Minimum Data Set and the Cohen-Mansfield Agitation Inventory, observational data of music-listening sessions, and an administrator survey regarding the lead staff person's perceptions of the intervention. Findings, based on Mixed Effect Models and content analyses, revealed positive impacts of the personalized music intervention on residents living with dementia. This low-cost, easily implementable intervention, requiring no special licensure for administration, can significantly enhance the quality of life for nursing facility residents., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

It is well known that infants born very preterm (VPT) often demonstrate deficits in mathematical abilities in early childhood which are associated with poorer academic outcomes. Mathematic skills are also critical for other areas of functioning. However, it is not known whether mathematics skills are associated with adaptive functioning in children born preterm. Infants born at ≤31 weeks gestation and full term were recruited at birth and followed over time. At the 36-month corrected age assessment, children were administered the Early Number Concepts subtest of the Differential Abilities Scale, Second Edition, and caregivers completed the Adaptive Behavior Assessment System, Third Edition. After controlling for age, sex, cognitive abilities, and caregiver education, performance on the mathematics measure was uniquely and positively associated with adaptive behavior for preschool children in the VPT group only. Exploratory analyses revealed this association to be specifically related to the Practical and Social composites. Knowledge of concepts of number and quantity were associated with better adaptive functioning, particularly for behaviors related to functioning at home and in the community and play/social functioning, for children born VPT. Although replication is warranted, it would appear that mathematical skills may be an important early intervention target for children born VPT.

Objective: Improve data-driven research to inform clinical decision-making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC-Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi-site pediatric epilepsy surgery cohort in the United States., Methods: Pediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics., Results: Positive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non-Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full-scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities., Significance: We established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity., (© 2023 International League Against Epilepsy.)

The COVID-19 pandemic has changed healthcare utilization patterns and clinical practice, including pediatric mTBI evaluation and management. Providers treating pediatric mTBI, including neuropsychologists, have a unique role in evaluating and managing an already complex injury in the context of the COVID-19 pandemic with limited empirically based guidelines. In the present paper, we review usual, evidence-based pediatric mTBI care, highlight changes experienced by healthcare providers since the onset of the pandemic, and provide possible considerations and solutions. Three primary challenges to usual care are discussed, including changes to post-injury evaluation, management, and treatment of persistent symptoms. Changing patterns of healthcare utilization have created unique differences in mTBI identification and evaluation, including shifting injury frequency and mechanism, reluctance to seek healthcare, and increasing access to telemedicine. Typical injury management has been compromised by limited access to usual systems/activities (i.e., school, sports, social/leisure activities). Patients may be at higher risk for prolonged recovery due to pre-injury baseline elevations in acute and chronic stressors and reduced access to rehabilitative services targeting persistent symptoms. Considerations and solutions for addressing each of the three challenges are discussed. Neuropsychologists and other pediatric healthcare providers will need to continue to flexibly adapt to the changing needs of youth recovering from mTBI through the duration of the pandemic and beyond. Consistent with pre-pandemic consensus statements, neuropsychologists remain uniquely qualified to evaluate and manage mTBI and provide an increasingly integral role as members of multidisciplinary teams in the context of the global pandemic. Abbreviations : AAP: American Academy of Pediatrics; CDC: Centers for Disease Control and Prevention; COVID-19: coronavirus disease 19; ED: emergency department; mTBI: Mild traumatic brain injury.

Purpose: To assess which pediatric patients experiencing persistent post-concussive symptoms (PCS) benefit most from multidisciplinary treatment including specialists in Neurology, Neuropsychology, Physical Therapy, and Athletic Training, and to explore the effectiveness of this approach., Methods: A retrospective chart review of 56 adolescents 10-20 years old (M = 15.0 ± 2.1) receiving multidisciplinary care for PCS (>30 days) was conducted., Results: Systolic blood pressure and Body Mass Index predicted time to concussion resolution ( p < .05), such that higher values were associated with slower resolution. PCS scores significantly decreased between participants' initial and final clinic visits, p < .01, and among the 25 participants for whom pre-intervention PCS scores were available, symptom severity scores significantly declined following multidisciplinary intervention compared to pre-referral values ( p < .01)., Conclusions: Exploratory analyses reveal that multidisciplinary treatment is a promising approach for reducing symptoms among adolescents with PCS, and that those with greater levels of physical fitness may benefit most.

Objective: To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB)., Methods: In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer., Results: Of the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex -42.10 ± 18.52 cm 3 /year [mean ± SD], cerebral white matter -4.37 ± 11.82 cm 3 /year, subcortical gray matter -6.54 ± 3.63 cm 3 /year, corpus callosum -0.18 ± 0.62 cm 3 /yr) and in cerebellar cortex (-0.49 ± 12.57 cm 3 /year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm 3 /year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen., Conclusions: Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation., (Copyright © 2021. Published by Elsevier Inc.)

Objective: To evaluate the feasibility and potential benefits of a manualized, brief cognitive-behavioral therapy-based intervention program for children and adolescents with persistent postconcussive symptoms., Setting: Two outpatient pediatric concussion programs in the United States., Participants: Patients aged 8 to 17 years who sustained concussions between 2 and 12 months prior to enrollment., Design: Pre-/postretrospective study., Main Measures: SCAT-3; HBI; PedsQL 4.0 Generic Core Scales; and RCADS., Results: Thirty children and adolescents completed the treatment program. Self- and parent-reported postconcussive symptoms, quality of life, and internalizing symptoms significantly improved with treatment. Mixed-effects models revealed a significant decline in self-reported postconcussive symptoms across treatment sessions, a = -2.07, SE = 0.25, P < .001. The largest change occurred between sessions 2 and 3, following the session focusing on concussion psychoeducation and sleep hygiene (estimated mean change between sessions 2 and 3 = -4.72, P < .0001)., Conclusions: Our findings indicate that a 6-session manualized cognitive behavioral intervention is feasible to initiate in an outpatient clinic 1 to 12 months following a pediatric mild traumatic brain injury. With a manualized format, clinicians at most levels of training should be able to implement this treatment manual and flexibly adapt as needed when working with children and adolescents who are experiencing delayed symptom recovery following concussion., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine the comparative effectiveness of 3 modes of family problem-solving therapy (F-PST): therapist-guided online, self-guided online, and face-to-face., Setting: Four children's hospitals and a general hospital with pediatric commitment., Participants: A total of 150 adolescents aged 14 to 18 years, previously hospitalized with traumatic brain injury (TBI), and evidence of behavior problems at enrollment., Design: Multicenter, randomized clinical trial., Main Measures: Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite (GEC), Behavior Regulation Index, and Metacognition Index, and Strengths and Difficulties Questionnaire (SDQ) Total at baseline and 6 and 9 months later., Results: Mixed-model intention-to-treat analyses of comparative effectiveness failed to reveal statistically significant differences among treatment groups. At 6 months, parent BRIEF-GEC improved for the therapist-guided and self-guided, online groups. Effects remained significant and increased in magnitude at 9 months for the self-guided online group. Scores for the Self-guided online group significantly improved from baseline to 9 months on the SDQ Total., Conclusions: This comparative effectiveness study supports the utility of both self- and therapist-guided online F-PST in improving executive function behaviors in adolescents following TBI. Further work regarding clinical implementation and how best to integrate telehealth with ongoing rehabilitation care is warranted.

Objective: To examine changes in depression and distress in parents of adolescents receiving family-problem-solving therapy (F-PST) following traumatic brain injury., Method: Families of adolescents hospitalized for moderate to severe traumatic brain injury were randomized to face-to-face F-PST (34), therapist-guided online F-PST (56), or self-guided online F-PST (60). Outcomes were assessed pretreatment and 6 and 9 months later. Parents rated depression and distress on the Center for Epidemiological Studies Depression Scale and the Brief Symptom Inventory, respectively. Mixed modeling was used to examine changes over time and treatment moderators., Results: The therapist-guided online group had significant reductions in parental depression over time. Analyses of slopes of recovery revealed differential improvement on the Center for Epidemiological Studies Depression Scale between the 2 online groups, with no significant change in depressive symptoms following self-guided F-PST. On the Brief Symptom Inventory Global Severity Index, the therapist-guided online group reported significant improvement from baseline to 6 months that was maintained at 9 months. The face-to-face and self-guided online groups reported significant reductions in distress between 6 and 9 months with corresponding large effect sizes. Differences on the Center for Epidemiological Studies Depression Scale between therapist-guided and self-guided online groups at the 9-month follow-up were more pronounced in families of lower socioeconomic status, t103 = -2.87; P = .005., Conclusions: Findings provide further support for the utility of therapist-guided online F-PST in reducing parental depression and distress following pediatric traumatic brain injury and offer limited evidence of the efficacy of self-guided online treatment for these outcomes. Families of lower socioeconomic status may benefit more from therapist involvement.

Objective: To examine changes in quality of life (QoL) in adolescents receiving family problem-solving therapy (F-PST) following traumatic brain injury (TBI)., Method: Adolescents hospitalized for moderate-to-severe TBI were randomized to 1 of 3 ten-session, 6-month long treatments: face-to-face F-PST (n = 34), therapist-guided online F-PST (n = 56), and self-guided online F-PST (n = 60). Participants included 96 boys and 54 girls, of whom 124 were White and 6 were Hispanic. Outcomes were assessed pretreatment and 6 and 9 months later. Adolescents and parents rated adolescent QoL and TBI-related symptoms on the PedsQL and Health and Behavior Inventory (HBI), respectively. We used mixed modeling to examine changes over time and moderators of treatment efficacy., Results: Therapist- and self-guided online groups demonstrated improvements in parent-proxy QoL from baseline to 9 months, Cohen's d = 0.75; p = .004 and Cohen's d = 1.30; p < .001, respectively. The face-to-face group had poorer parent-proxy QoL at 6 months (M = 62, SE = 3.4) than either the therapist- (M = 70.9, SE = 2.8) or self-guided online group (M = 71.1, SE = 2.6). There were no changes or group differences in self-reported QoL over time. Similar findings were observed on the HBI. Differential treatment effects on parent-proxy outcomes were found in boys versus girls and in those from single versus 2-parent households. Improvements in parent-proxy HBI ratings mediated QoL improvements., Conclusions: Both online treatments, but not face-to-face F-PST, were associated with clinical improvements, raising questions about our current delivery paradigm. Individual and family moderators of treatment efficacy underscore the potential of personalized treatment. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: To characterize treatment preferences for delivery of family problem-solving treatment (F-PST) to adolescents with behavioral challenges following traumatic brain injury (TBI) and to examine associations with attrition, adherence, satisfaction, and efficacy., Method: Adolescents who had been hospitalized for moderate to severe TBI were randomized to face-to-face F-PST (n = 34), therapist-guided online F-PST (n = 56), and self-guided online F-PST (n = 60). Adolescents and parents rated treatment convenience and anticipated benefit before group assignment. Sessions completed served as an index of adherence. Satisfaction was rated posttreatment. The Behavior Rating Inventory of Executive Function and Strengths and Difficulties Questionnaire were used to assess parent-reported behavioral concerns., Results: Both parents and adolescents were more likely to agree or strongly agree that they anticipated self-guided online F-PST to be the most convenient relative to either of the therapist-involved approaches. Parents were also less likely to anticipate face-to-face treatment as most beneficial, relative to the two online treatments. Adolescent preferences were significantly related to attrition with 27% versus 13% dropout rates for those assigned to nonpreferred and preferred treatments, respectively. Parent and adolescent preferences before treatment were unrelated to post-intervention satisfaction, adherence, or improvements in parent-reported child behavior problems., Conclusions: Online treatments are perceived favorably among adolescents with TBI and their parents. For adolescents, these pretreatment preferences influenced treatment completion. Poor correspondence between initial preferences and posttreatment satisfaction and benefit suggests that therapeutic experience more strongly influences ultimate satisfaction., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The objective of this manuscript is to describe the methodology that will be used to test the comparative effectiveness, feasibility, and acceptability of three formats of family problem solving therapy (F-PST) for improving functional outcomes of complicated mild to severe adolescent TBI., Methods: Three-arm comparative effectiveness, randomized clinical trial (RCT) design. We describe the protocol of a three-arm RCT comparing the effectiveness of three modalities of F-PST to reduce executive dysfunction and behavior problems following TBI in adolescence. The RCT will compare the relative effectiveness among face-to-face; online and self-directed; and therapist-supported online modes of treatment., Ethics and Dissemination: It is anticipated that findings from this work will inform future clinical care practices, with implications for treatment of other patient populations of youth with psychological symptoms arising from neurological conditions. Institutional review board approval will be obtained from all sites prior to commencement of the study.

This study aims to evaluate the efficacy of a brief cognitive behavioral intervention program for children and adolescents experiencing persistent post-concussion symptoms. A total of 31 patients aged 10 to 18 years participated in the intervention. The median time since injury at treatment onset was 95 days though the range was large (23-720 days). Treatment was on average four sessions in duration. Sessions included concussion education, activity scheduling, sleep hygiene relaxation training, and cognitive restructuring. Outcomes were measured using symptom reports on the Sports Concussion Assessment Tool - Third Edition (SCAT-3) and parent-reported quality of life on the Pediatric Quality of Life Inventory (PedsQL). Mixed-effects models revealed that symptom reports did not decrease prior to the initiation of this treatment, though significant symptom improvement occurred following treatment. Quality of life scores significantly improved across domains, with the largest gains made in the emotional and school domains. Participant characteristics including age, sex, maternal education, and previous mental health problems were not found to be significantly related to treatment outcomes. Contrary to predictions, length of time since injury was not related to symptom changes. The primary limitation of this study is that it lacks randomization and an experimental control group. The results suggest that brief cognitive behavioral intervention may be a promising treatment for children and adolescents experiencing persistent post-concussive symptoms and warrants further investigation.

Background/objective: Conventional neuroimaging is not recommended for the routine diagnosis of concussion, but some patients with concussion undergo computed tomography (CT) or magnetic resonance imaging (MRI). The objective of this study was to explore the clinical factors that predict neuroimaging utilization in concussion., Methods: Concussion-related CT and MRI data were analysed from 1953 patients, aged 10-19 years, who presented to a sports concussion clinic within 30 days of injury., Results: The majority of CT scans (n = 193) were obtained during the acute concussion period (mean = 2.7 days post-concussion), whereas MRI scans (n = 134) were ordered later during recovery (mean = 39.4 days post-concussion). Predictors of CT utilization included loss of consciousness, amnesia and vomiting (all p < 0.001). Prior concussion (p = 0.002) and continued participation in activity after injury (p = 0.03) predicted greater MRI utilization. Neuroimaging with either CT (p = 0.024, hazard ratio = 1.2) or MRI (p < 0.001, hazard ratio = 2.75) was associated with prolonged symptoms. Only 3.1% of CTs and 1.5% of MRIs demonstrated signs of traumatic brain injury., Conclusion: Several clinical factors predict neuroimaging utilization in patients with concussion. CT is generally used acutely, while MRI is used in the sub-acute and chronic post-concussion periods. In a sports concussion clinic, delayed neuroimaging has limited clinical yield.

Mucopolysaccharidosis type III is a group of four autosomal recessive enzyme deficiencies leading to tissue accumulation of heparan sulfate. Central nervous system disease is prominent, with initial normal development followed by neurocognitive decline leading to death. In order to define outcome measures suitable for gene transfer trials, we prospectively assessed disease progression in MPS IIIA and IIIB subjects >2years old at three time points over one year (baseline, 6 and 12months). Fifteen IIIA (9 male, 6 female; age 5.0±1.9years) and ten IIIB subjects (8 male, 2 female; age 8.6±3years) were enrolled, and twenty subjects completed assessments at all time points. Cognitive function as assessed by Mullen Scales maximized at the 2.5 to 3year old developmental level, and showed a significant age-related decline over a 6month interval in three of five subdomains. Leiter nonverbal IQ (NVIQ) standard scores declined toward the test floor in the cohort by 6 to 8years of age, but showed significant mean declines over a 6month interval in those <7years old (p=0.0029) and in those with NVIQ score≥45 (p=0.0313). Parental report of adaptive behavior as assessed by the Vineland-II composite score inversely correlated with age and showed a significant mean decline over 6month intervals (p=0.0004). Abdominal MRI demonstrated increased volumes in liver (mean 2.2 times normal) and spleen (mean 1.9 times normal) without significant change over one year; brain MRI showed ventriculomegaly and loss of cortical volume in all subjects. Biochemical measures included urine glycosaminoglycan (GAG) levels, which although elevated showed a decline correlating with age (p<0.0001) and approached normal values in older subjects. CSF protein levels were elevated in 32% at enrollment, and elevations of AST and ALT were frequent. CSF enzyme activity levels for either SGSH (in MPS IIIA subjects) or NAGLU (in MPS IIIB) significantly differed from normal controls. Several other behavioral or functional measures were found to be uninformative in this population, including timed functional motor tests. Our results suggest that cognitive development as assessed by the Mullen and Leiter-R and adaptive behavior assessment by the Vineland parent interview are suitable functional outcomes for interventional trials in MPS IIIA or IIIB, and that CSF enzyme assay may be a useful biomarker to assess central nervous system transgene expression in gene transfer trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Redirecting T cells to attack cancer using engineered chimeric receptors provides powerful new therapeutic capabilities. However, the effectiveness of therapeutic T cells is constrained by the endogenous T cell response: certain facets of natural response programs can be toxic, whereas other responses, such as the ability to overcome tumor immunosuppression, are absent. Thus, the efficacy and safety of therapeutic cells could be improved if we could custom sculpt immune cell responses. Synthetic Notch (synNotch) receptors induce transcriptional activation in response to recognition of user-specified antigens. We show that synNotch receptors can be used to sculpt custom response programs in primary T cells: they can drive a la carte cytokine secretion profiles, biased T cell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch T cells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To identify the clinical factors that influence the duration of postconcussion symptoms among youth referred to a sports concussion clinic., Study Design: A retrospective cohort study was conducted to evaluate several potential predictors of symptom duration via a Cox proportional hazards analyses. The individual postconcussion symptom scores were highly correlated, so these symptoms were analyzed in the statistical model as coefficients derived from principal component analyses., Results: Among 1953 youth with concussion, 1755 (89.9%) had dates of reported symptom resolution. The remainder (10.1%) were lost to follow-up and censored. The median time to recovery was 18 days (range 1-353 days). By 30 days, 72.6% had recovered; by 60 days, 91.4% had recovered; and by 90 days, 96.8% had recovered. Several variables in a multivariate Cox model predicted postconcussion symptom duration: female sex (P < .001, hazard ratio [HR] = 1.28), continued activity participation (P = .02, HR = 1.13), loss of consciousness (P = .03, HR = 1.18), anterograde amnesia (P = .04, HR = 1.15), premorbid headaches (P = .03, HR = 1.15), symptom components from the day of concussion (emotion, P = .03, HR = 1.08), and the day of clinic evaluation (cognitive-fatigue, P < .001, HR = 1.22; cephalalgic, P < .001, HR = 1.27; emotional, P = .05, HR = 1.08; arousal-stimulation, P = .003, HR = 1.1). In univariate analyses, greater symptom scores generally predicted longer symptom durations. Worsening of symptoms from the day of concussion to the day of clinic evaluation also predicted longer recovery (P < .001, HR = 1.59)., Conclusions: Several factors help to predict protracted postconcussion symptom durations among youth referred to a sports concussion clinic., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The term "post-traumatic migraine" (PTM) has been used to describe post-traumatic headaches (PTHs) that have associated migraine features, but studies of this relationship are lacking. The objective of the present study was to determine whether PTH correlates strongly with migraine symptoms among youth with concussion., Methods: Twenty-three symptoms were analyzed from a retrospective cohort of 1953 pediatric patients with concussion. A principal component analysis (PCA) with oblique Promax rotation was conducted to explore underlying symptom relationships in the full cohort and in subcohorts stratified by the presence (n = 414) or absence (n = 1526) of premorbid headache., Results: The mean patient age was 14.1 years; 63% were male. Headache was the most common postconcussion symptom, acknowledged by 69.4% of patients. When considering the full cohort, the PCA demonstrated clustering of headache with photophobia, phonophobia, nausea, dizziness, and neck pain. Similar clustering was present among patients without premorbid headaches. Repeating the analysis in the patients with preconcussion headaches led to elimination of neck pain from the cluster., Conclusions: PTH correlates strongly with other migraine symptoms among youth with concussion, regardless of premorbid headaches. This clustering of migraine symptoms supports the existence of PTM as a distinct clinical entity in some patients., (© International Headache Society 2015.)

T cells can be re-directed to kill cancer cells using chimeric antigen receptors (CARs) or T cell receptors (TCRs). This approach, however, is constrained by the rarity of tumor-specific single antigens. Targeting antigens also found on bystander tissues can cause life-threatening adverse effects. A powerful way to enhance ON-target activity of therapeutic T cells is to engineer them to require combinatorial antigens. Here, we engineer a combinatorially activated T cell circuit in which a synthetic Notch receptor for one antigen induces the expression of a CAR for a second antigen. These dual-receptor AND-gate T cells are only armed and activated in the presence of dual antigen tumor cells. These T cells show precise therapeutic discrimination in vivo-sparing single antigen "bystander" tumors while efficiently clearing combinatorial antigen "disease" tumors. This type of precision dual-receptor circuit opens the door to immune recognition of a wider range of tumors. VIDEO ABSTRACT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Participation in school is vital to a child's academic and social development. Following concussion, returning the student to school can pose several challenges for families, healthcare providers and school personnel. The complex constellation of postconcussion symptoms can impair learning and can make the school environment intolerable. Research evidence to guide the return to school process is lacking, but protocols have been proposed that outline a gradual reintroduction to school with academic accommodations tailored to the student's specific symptoms. Key medical and school personnel must understand their respective roles to optimize the process. This review of the current literature examines the available data and expert recommendations that can support a student's successful return to school following concussion., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.

Directed migration of diverse cell types plays a critical role in biological processes ranging from development and morphogenesis to immune response, wound healing, and regeneration. However, techniques to direct, manipulate, and study cell migration in vitro and in vivo in a specific and facile manner are currently limited. We conceived of a strategy to achieve direct control over cell migration to arbitrary user-defined locations, independent of native chemotaxis receptors. Here, we show that genetic modification of cells with an engineered G protein-coupled receptor allows us to redirect their migration to a bioinert drug-like small molecule, clozapine-N-oxide (CNO). The engineered receptor and small-molecule ligand form an orthogonal pair: The receptor does not respond to native ligands, and the inert drug does not bind to native cells. CNO-responsive migration can be engineered into a variety of cell types, including neutrophils, T lymphocytes, keratinocytes, and endothelial cells. The engineered cells migrate up a gradient of the drug CNO and transmigrate through endothelial monolayers. Finally, we demonstrate that T lymphocytes modified with the engineered receptor can specifically migrate in vivo to CNO-releasing beads implanted in a live mouse. This technology provides a generalizable genetic tool to systematically perturb and control cell migration both in vitro and in vivo. In the future, this type of migration control could be a valuable module for engineering therapeutic cellular devices.

Objective: To examine the relative contributions of injury characteristics and noninjury child and family factors as predictors of postconcussive symptoms (PCS) following mild traumatic brain injury (TBI) in children., Method: Participants were 8- to 15-year-old children, 186 with mild TBI and 99 with mild orthopedic injuries (OI). Parents and children rated PCS shortly after injury and at 1, 3, and 12 months postinjury. Hierarchical regression analyses were conducted to predict PCS from (1) demographic variables; (2) premorbid child factors (WASI IQ; WRAT-3 Reading; Child Behavior Checklist; ratings of preinjury PCS); (3) family factors (Family Assessment Device General Functioning Scale; Brief Symptom Inventory; and Life Stressors and Social Resources Inventory); and (4) injury group (OI, mild TBI with loss of consciousness [LOC] and associated injuries [AI], mild TBI with LOC but without AI, mild TBI without LOC but with AI, and mild TBI without LOC or AI)., Results: Injury group predicted parent and child ratings of PCS but showed a decreasing contribution over time. Demographic variables consistently predicted symptom ratings across time. Premorbid child factors, especially retrospective ratings of premorbid symptoms, accounted for the most variance in symptom ratings. Family factors, particularly parent adjustment, consistently predicted parent, but not child, ratings of PCS., Conclusions: Injury characteristics predict PCS in the first months following mild TBI but show a decreasing contribution over time. In contrast, noninjury factors are more consistently related to persistent PCS.

Obstructive sleep apnea (OSA) is a nocturnal respiratory disorder associated with cognitive and behavioral sequelae, including impairments in executive functioning (EF). Previous literature has focused on "cool" EF, meaning abilities such as working memory and planning that do not involve affective control requirements. Little is known about the impact OSA may have on "hot" EF that involves regulation of affect and risk-related decision-making, and that may be particularly salient during adolescence, when these skills are rapidly developing. This study examined performance on the Iowa Gambling Task (IGT), a task believed to assess aspects of "hot" EF, in overweight adolescents at risk for OSA. Consistent with hypotheses, individuals without OSA made more beneficial decisions on the IGT over time, but participants with OSA did not benefit from feedback and continued to make choices associated with higher initial rewards, but greater long-term losses. The relationship between developmental level and IGT performance was moderated by OSA status. Individuals with OSA did not demonstrate the expected developmental gains in performance during the IGT. This finding suggests that OSA may impact the development of critical aspects of EF, or at least the expression of these skills during the developmentally important period of adolescence.

High rates of asthma treatment nonadherence have been reported, particularly in economically disadvantaged African American youth. The relationship between adherence to combined medication treatment and asthma outcomes has potential clinical significance but is not well understood. Using electronic monitoring, we describe the pattern of adherence to daily corticosteroid (fluticasone) and leukotriene receptor antagonist (montelukast) medication over the course of 1 year in a population of African American youth with moderate to severe asthma. On average, adherence to montelukast was higher than adherence to fluticasone (p < 0.01); however, for both medications, adherence rates significantly declined over the course of the study. After 1 year, participants took only 31% of prescribed doses of montelukast and 23% of prescribed doses of fluticasone. The decline in adherence to both fluticasone (p < 0.05) and montelukast (p < 0.001) was related to increased healthcare utilization. Furthermore, asthma symptom ratings were related montelukast (p < 0.001), but not fluticasone adherence. These results suggest that adherence promotion intervention strategies are warranted to improve health-related outcomes in families who are at-risk for treatment nonadherence.

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Distinguishing psychogenic nonepileptic seizures (PNES) from epileptic seizures (ES) is a difficult task that is often aided by neuropsychological evaluation. In the present study, signal detection theory (SDT) was used to examine differences between these groups in neuropsychological performance on the Wechsler Memory Scale, Third Edition, Word List Test (WMS-III WLT). The raw WMS-III WLT scores on this task failed to discriminate the two groups; however, with the use of SDT, patients with PNES were found to have a negative response bias and increased memory sensitivity as compared with patients with ES. When patients with left (LTLE) and right (RTLE) temporal lobe epilepsy were compared, the patients with LTLE demonstrated decreased memory sensitivity but a similar response bias as compared with the patients with RTLE. Memory impairment in patients with PNES may be related to faulty decision-making strategies, rather than true memory impairment, whereas memory performance differences between the LTLE and RTLE groups are likely related to actual differences in memory abilities.

Here we report preliminary findings from a small-sample functional magnetic resonance imaging (fMRI) study of healthy adolescents who completed a working memory task in the context of a chronic sleep restriction experiment. Findings were consistent with those previously obtained on acutely sleep-deprived adults. Our data suggest that, when asked to maintain attention and burdened by chronic sleep restriction, the adolescent brain responds via compensatory mechanisms that accentuate the typical activation patterns of attention-relevant brain regions. Specifically, it appeared that regions that are normally active during an attention-demanding working memory task in the well-rested brain became even more active to maintain performance after chronic sleep restriction. In contrast, regions in which activity is normally suppressed during such a task in the well-rested brain showed even greater suppression to maintain performance after chronic sleep restriction. Although limited by the small sample, study results provide important evidence of feasibility, as well as guidance for future research into the functional neurological effects of chronic sleep restriction in general, the effects of sleep restriction in children and adolescents, and the neuroscience of attention and its disorders in children.

Subtypes of psychogenic nonepileptic seizures (PNES) have emerged via classification of seizure semiology, psychological variables, or both. PNES subtypes that differ with respect to etiology may be amenable to targeted treatment strategies. The aim of the present study was to investigate the relationship between semiology type and Minnesota Multiphasic Personality Inventory-2 (MMPI-2) profile among patients with PNES. We did so by modifying a classification scheme proposed by Selwa et al. Our main hypothesis was that there would be significant associations of semiology-based subtypes with psychological profiles among patients with PNES. We found significant differences in mean scores on MMPI-2 clinical scales 1 (Hypochondriasis) and 3 (Hysteria) and Harris-Lingoes subscales D5 (Brooding) and Sc5 (Lack of Ego Mastery, Defective Inhibition) across PNES subtypes (catatonic, minor motor, major motor). The results of the present study enhance understanding of the nosology of PNES by identifying psychopathological correlates of semiology-based subtypes of PNES. Our study also may inform the methodology of future investigations of psychopathology among patients with PNES by providing support for content-based interpretation of the MMPI.

Purpose: Regions of seizure onset and propagation in human generalized tonic-clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions., Methods: ECT stimulation induces a typical generalized tonic-clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis., Results: In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex., Conclusions: Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical-cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Purpose: The goal of neuroimaging in epilepsy is to localize the region of seizure onset. Single-photon emission computed tomography with tracer injection during seizures (ictal SPECT) is a promising tool for localizing seizures. However, much uncertainty exists about how to interpret late injections, or injections done after seizure end (postictal SPECT). A widely available and objective method is needed to interpret ambiguous ictal and postictal scans, with changes in multiple brain regions., Methods: Ictal or postictal SPECT scans were performed by using [99mTc]-labeled hexamethyl-propylene-amine-oxime (HMPAO), and images were analyzed by comparison with interictal scans for each patient. Forty-seven cases of localized epilepsy were studied. We used methods that can be implemented anywhere, based on freely downloadable software and normal SPECT databases (http://spect.yale.edu). Statistical parametric mapping (SPM) was used to localize a single region of seizure onset based on ictal (or postictal) versus interictal difference images for each patient. We refer to this method as ictal-interictal SPECT analyzed by SPM (ISAS)., Results: With this approach, ictal SPECT identified a single unambiguous region of seizure onset in 71% of mesial temporal and 83% of neocortical epilepsy cases, even with late injections, and the localization was correct in all (100%) cases. Postictal SPECT, conversely, with injections performed soon after seizures, was very poor at localizing a single region based on either perfusion increases or decreases, often because changes were similar in multiple brain regions. However, measuring which hemisphere overall had more decreased perfusion with postictal SPECT, lateralized seizure onset to the correct side in approximately 80% of cases., Conclusions: ISAS provides a validated and readily available method for epilepsy SPECT analysis and interpretation. The results also emphasize the need to obtain SPECT injections during seizures to achieve unambiguous localization.

Temporal lobe seizures are accompanied by complex behavioral phenomena including loss of consciousness, dystonic movements and neuroendocrine changes. These phenomena may arise from extended neural networks beyond the temporal lobe. To investigate this, we imaged cerebral blood flow (CBF) changes during human temporal lobe seizures with single photon emission computed tomography (SPECT) while performing continuous video/EEG monitoring. We found that temporal lobe seizures associated with loss of consciousness produced CBF increases in the temporal lobe, followed by increases in bilateral midline subcortical structures. These changes were accompanied by marked bilateral CBF decreases in the frontal and parietal association cortex. In contrast, temporal lobe seizures in which consciousness was spared were not accompanied by these widespread CBF changes. The CBF decreases in frontal and parietal association cortex were strongly correlated with increases in midline structures such as the mediodorsal thalamus. These results suggest that impaired consciousness in temporal lobe seizures may result from focal abnormal activity in temporal and subcortical networks linked to widespread impaired function of the association cortex.

Generalized seizures are commonly thought to involve the entire brain homogeneously. However, recent evidence suggests that selective cortical-subcortical networks may be crucial for the initiation, propagation, and behavioral manifestations of generalized seizures, while other brain regions are relatively spared. Here we review previous studies, and describe a new human model system for the investigation of generalized seizures: single-photon emission computed tomography, ictal-interictal difference imaging of generalized tonic-clonic seizures induced by electroconvulsive therapy (ECT). Bitemporal ECT activates focal bilateral frontotemporal and parietal association cortex, sparing other regions; bifrontal ECT activates mainly prefrontal cortex; while in right unilateral ECT the left frontotemporal region is relatively spared. Associated midline subcortical networks are also involved. Focal verbal memory deficits parallel the focal regions involved in these neuroimaging studies. Further studies of this kind may elucidate specific networks in generalized tonic-clonic seizures, providing targets for new therapeutic interventions in epilepsy.

The anatomical brain regions involved in the therapeutic and adverse actions of electroconvulsive therapy (ECT) are unknown. Previous studies suggest that bifrontal vs. bitemporal ECT differ in therapeutic efficacy and cognitive side effects. We therefore performed cerebral blood flow (CBF) imaging during bitemporal vs. bifrontal ECT-induced seizures to identify regions crucial for the differences between these treatments. Patients with major depression, undergoing bitemporal or bifrontal ECT, were studied. Ictal-interictal SPECT images were analyzed with statistical parametric mapping for bitemporal (n=11 image pairs in 8 patients) and bifrontal (n=4 image pairs in 2 patients) ECT-induced seizures to identify regions of ictal CBF changes. Bifrontal ECT was found to cause increases in CBF in prefrontal and anterior cingulate regions. Bitemporal ECT, however, caused CBF increases in the lateral frontal cortex and in the anterior temporal lobes. In bifrontal ECT, a greater increase in prefrontal activation, while sparing the temporal lobes, may result in a better therapeutic response and fewer adverse effects on memory than bitemporal ECT.

Pigeons received equal variable-interval reinforcement during presentations of two line-orientation stimuli while five other orientations appeared in extinction. Component duration was 30 seconds for all orientations and the sequence was arranged so that each orientation preceded itself and each other orientation equally often. The duration of one component (0 degrees ) was shortened to 10 seconds and the other (90 degrees ) was lengthened to 50 seconds. All animals showed large increases in response rate in the shortened component and this increase was recoverable after an interpolated condition in which all components were again 30 seconds in duration. This effect was replicated in a second experiment in which component duration was changed from 150 seconds to 50 seconds and 250 seconds. An examination of local contrast effects during the first experiment showed that the shortened component produced local contrast during subsequent presentations of the lengthened component, just as would a component associated with more frequent reinforcement. When the presentation sequence was changed so that the lengthened component was always followed by the shortened component, response rates generally increased during the lengthened component. When the sequence was arranged so that the shortened component always preceded the longer component, response rate decreased in the former. These effects, as well as the increases in response rate following change in component length, seem not to be the product of local contrast effects among components.