Miya R. Asato

White Matter Development in Adolescence: A DTI Study

Adolescence is a unique period of physical and cognitive development that includes concurrent pubertal changes and sex-based vulnerabilities. While diffusion tensor imaging (DTI) studies show white matter maturation throughout the lifespan, the state of white matter integrity specific to adolescence is not well understood as are the contributions of puberty and sex. We performed whole-brain DTI studies of 114 children, adolescents, and adults to identify age-related changes in white matter integrity that characterize adolescence. A distinct set of regions across the brain were found to have decreasing radial diffusivity across age groups. Region of interest analyses revealed that maturation was attained by adolescence in broadly distributed association and projection fibers, including those supporting cortical and brain stem integration that may underlie known enhancements in reaction time during this period. Maturation after adolescence included association and projection tracts, including prefrontal-striatal connections, known to support top-down executive control of behavior and interhemispheric connectivity. Maturation proceeded in parallel with pubertal changes to the postpubertal stage, suggesting hormonal influences on white matter development. Females showed earlier maturation of white matter integrity compared with males. Together, these findings suggest that white matter connectivity supporting executive control of behavior is still immature in adolescence.

Neurodevelopment and executive function in autism

Autism is a neurodevelopmental disorder characterized by social and communication deficits, and repetitive behavior. Studies investigating the integrity of brain systems in autism suggest a wide range of gray and white matter abnormalities that are present early in life and change with development. These abnormalities predominantly affect association areas and undermine functional integration. Executive function, which has a protracted development into adolescence and reflects the integration of complex widely distributed brain function, is also affected in autism. Evidence from studies probing response inhibition and working memory indicate impairments in these core components of executive function, as well as compensatory mechanisms that permit normative function in autism. Studies also demonstrate age-related improvements in executive function from childhood to adolescence in autism, indicating the presence of plasticity and suggesting a prolonged window for effective treatment. Despite developmental gains, mature executive functioning is limited in autism, reflecting abnormalities in wide-spread brain networks that may lead to impaired processing of complex information across all domains.

Developmental Stages and Sex Differences of White Matter and Behavioral Development through Adolescence: A Longitudinal Diffusion Tensor Imaging (DTI) Study

White matter (WM) continues to mature through adolescence in parallel with gains in cognitive ability. To date, developmental changes in human WM microstructure have been inferred using analyses of cross-sectional or two time-point follow-up studies, limiting our understanding of individual developmental trajectories. The aims of the present longitudinal study were to characterize the timing of WM growth and investigate how sex and behavior are associated with different developmental trajectories. We utilized diffusion tensor imaging (DTI) in 128 individuals aged 8-28, who received annual scans for up to 5 years and completed motor and cognitive tasks. Flexible nonlinear growth curves indicated a hierarchical pattern of WM development. By late childhood, posterior cortical-subcortical connections were similar to adults. During adolescence, WM microstructure reached adult levels, including frontocortical, frontosubcortical and cerebellar connections. Later to mature in adulthood were major corticolimbic association tracts and connections at terminal gray matter sites in cortical and basal ganglia regions. These patterns may reflect adolescent maturation of frontal connectivity supporting cognitive abilities, particularly the protracted refinement of corticolimbic connectivity underlying cognition-emotion interactions. Sex and behavior also played a large role. Males showed continuous WM growth from childhood through early adulthood, whereas females mainly showed growth during mid-adolescence. Further, earlier WM growth in adolescence was associated with faster and more efficient responding and better inhibitory control whereas later growth in adulthood was associated with poorer performance, suggesting that the timing of WM growth is important for cognitive development.

White Matter Development in Adolescence: Diffusion Tensor Imaging and Meta-Analytic Results

BACKGROUND In light of the evidence for brain white matter (WM) abnormalities in schizophrenia, study of normal WM maturation in adolescence may provide critical insights relevant to the neurodevelopment of the disorder. Voxel-wise diffusion tensor imaging (DTI) studies have consistently demonstrated increases in fractional anisotropy (FA), a putative measure of WM integrity, from childhood into adolescence. However, the WM tracts that show FA increases have been variable across studies. Here, we aimed to assess which WM tracts show the most pronounced changes across adolescence. METHODS DTI was performed in 78 healthy subjects aged 8-21 years, and voxel-wise analysis conducted using tract-based spatial statistics (TBSS). In addition, we performed the first meta-analysis of TBSS studies on WM development in adolescence. RESULTS In our sample, we observed bilateral increases in FA with age, which were most significant in the left superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, and anterior thalamic radiation. These findings were confirmed by the meta-analysis, and FA increase in the bilateral SLF was the most consistent finding across studies. Moreover, in our sample, FA of the bilateral SLF showed a positive association with verbal working memory performance and partially mediated increases in verbal fluency as a function of increasing age. CONCLUSIONS These data highlight increasing connectivity in the SLF during adolescence. In light of evidence for compromised SLF integrity in high-risk and first-episode patients, these data suggest that abnormal maturation of the SLF during adolescence may be a key target in the neurodevelopment of schizophrenia.

Topical Review : Neuropsychiatric Problems in Tuberous Sclerosis Complex

Tuberous sclerosis complex is an autosomal dominant disorder characterized by abnormal cellular differentiation and proliferation, as well as abnormal neuronal migration. It is a disease affecting multiple organ systems and typically has brain involvement, causing severe disabilities. This article reviews the literature of the commonly associated neuropsychiatric complications, including mental retardation, autism-like features, and other behavior problems, which are discussed in the context of the neuropathology and epilepsy observed in tuberous sclerosis complex. The potential pathogenesis of neuropsychiatric problems is explored, including links to the genetics, neuropathology, neurotrophins, and epilepsy factors associated with tuberous sclerosis complex. Treatment of neuropsychiatric symptoms, including autism-like features, attention deficits, and sleep disorders, is also discussed. (J Child Neurol 2004;19:241-249).

Adolescent and Caregiver Experiences With Epilepsy

Epilepsy during adolescence can impede the development of psychosocial independence and typical biological maturational processes. We examined in parallel the experiences and perceptions of adolescent patients with epilepsy and their caregivers. Specifically, we focused on frequency and type of seizures, comorbid conditions, adherence to therapies, productivity, clinical and quality of life consequences of seizures, estimated use and content of seizure emergency plans, and the patient—physician relationship. Two cross-sectional online surveys were conducted among 153 adolescent patients with epilepsy and their respective caregivers. A total of 35% of adolescents indicated that they had been nonadherent to antiepileptic medications in the prior month. Adolescents scored significantly lower compared with their peers on quality-of-life measures. Adolescents and caregivers reported similarly on nearly all domains. An adolescent-centered epilepsy management program may help alleviate concerns and also help the adolescent independently manage their epilepsy as they transition into adulthood.

Pediatric psychogenic nonepileptic seizures: A study of assessment tools

The goal of this study was to identify assessment tools and associated behavioral domains that differentiate children with psychogenic nonepileptic seizures (PNES) from those with epilepsy. A sample of 24 children with PNES (mean age 14.0 years, 14 female), 24 children with epilepsy (mean age 13.6 years, 13 female), and their parents were recruited from five epilepsy centers in the United States. Participants completed a battery of behavioral questionnaires including somatization, anxiety, and functional disability symptoms. Children with PNES had significantly higher scores on the Childhood Somatization and Functional Disability Inventories, and their parents reported more somatic problems on the Child Behavior Checklist (CBCL). Depression, anxiety, and alexithymia instruments did not differentiate the groups. Measures of somatization and functional disability may be promising tools for differentiating the behavioral profile of PNES from that of epilepsy. Increased somatic awareness and perceived disability emphasize the similarity of PNES to other pediatric somatoform disorders.

Epilepsy and comorbidities —What are we waiting for?

During the past several decades, a vast world literature has beenamassedthat unequivocally demonstratestheimportanceof the cogni-tive, psychiatric,linguistic,and social comorbidities associatedwith pe-diatric and adult epilepsies across the lifespan (reviewed in [1,2]). Inindividuals with normal intelligence, there is a wide and diverse rangeof psychopathology andvariable severity of cognitiveandlinguisticim-pairmentthatispresent,problematic,unrelatedtoepilepsysyndromes,and observed even in the “benign” syndromes (reviewed in [1,2]). Epi-lepsy leaves a lasting mark, including in cases of remitted epilepsy intermsofsubsequentacademicachievement[3]andvocationalindepen-dence [4,5]thatclearlyalertsustothedevelopmentalimpactofseizuresat younger ages.Epilepsy increases the likelihood of depression, anxiety disorders,attention deficit hyperactivity disorder (ADHD), a schizophrenia-likeinterictal psychosis, autism, as well as suicidal behavior in patientswith an unprovoked seizure, focal epilepsy, idiopathic cryptogenic epi-lepsy, and self-reported epilepsy [6–10]. Individuals with these psychi-atric diagnoses and suicidal behavior are more likely to have epilepsy[6,9,11,12]. The bidirectional relationship between psychopathologyandepilepsyisunrelatedtotheseverityofepilepsy,epilepsysyndrome,and type of psychiatric disorder. The likelihood for depression, anxiety,substanceabuse,andsuicidalbehaviorisincreasedinthe3 yearsbeforeand 2 years after the onset of epilepsy [9]. Similarly, the risk of an un-provoked seizure is increased in the 2 years before and 2 years afterpsychiatric hospitalization for depression or psychosis [6]. These rela-tionshipsunderscoretheinterrelatednatureofepilepsyandthepsychi-atric comorbidity and highlight critical periods for timely assessmentand intervention of psychopathology.In fact, the role of psychopathology rather than seizures in the poorlong-term outcome of child- [5] and adolescent-onset epilepsy [4] andof psychopathology [13–15] and cognition [16] in the quality of lifeof children and adults with epilepsy, together with the previouslydescribed poor academic achievement and vocational outcome, unam-biguously emphasizes the continuing unmet needs of patients withepilepsy.However, despite decades of research, despite characterization ofthese problems across countries and cultures, despite greater under-standing of the importance of the comorbidites for well-being acrossthe lifespan, and despite numerous federal studies, benchmarks, andrecommendations, contemporary standards of practice fail to integratescreening and treatment of the comorbidities into routine clinical care.Again and again it is pointed out that the comorbidities continue to beunderrecognized and undertreated and that patients with epilepsyhave significant unmet mental health needs [17]. Nonetheless, there isnoindicationthatthisdisappointingstateofaffairswillchangeanytimesoon.Translation of research data to clinical practice may be hindered bytime constraints in the clinical setting, limited reimbursement for criticalpsychiatric and cognitive evaluations, understaffing, and at times disin-terest onthepartof criticallyimportantdisciplines. Providerinteractionswithpatientsareincreasinglydrivenbyadministrativedirectivesregard-ing patient flow, access, and financial issues. Furthermore, adequatetreatment of the comorbidities is handcuffed by lack of evidence-basedstudies. While research can often address unmet clinical needs whichotherwise may not be funded, the number of funded RCT designed toprovideClass1evidencetoimprovethecognitive,psychiatric,vocational,and social complications of epilepsy is embarrassingly rare [1].Critical national initiatives such as the NINDS Epilepsy Benchmarks,Institute of Medicine report on epilepsy, and the CDC Living Well withEpilepsy meetings have all underscored the need to advance basic andclinical researchand providecomprehensive care for patients with epi-lepsy. However, too often, there has been a lack of attached new reve-nue to support these large-scale efforts to achieve the stated goals.One of the earliest publically supported reports on epilepsy was thePlan for Nationwide Action on Epilepsy produced by the Commission fortheControlofEpilepsyandItsConsequences(1977).Tothisday,thisre-mains a remarkable multivolume document for its process, findings,and recommendations. Although many of the recommendations arestillcurrent,viable,andrepeatedinsubsequentefforts,theystillremainunfunded. We simply cannot allow yet more decades to pass withoutmajor fiscal support to move forward on the clinical and researchfront of treatment and intervention. The time has come for aggressivebut respectful advocacy and collaborative efforts by all concernedparties —clinicians,researchers,patientsandtheirfamilies,andnationalepilepsy organizations.Hindering progress toward these aims is the fact that we are nowfirmly entrenched in one of the most complicated and challengingfunding environments that will likely persist for the foreseeable future.Fiscal constraints and cutbacks in the public and private sectors at bothstate and national levels are widespread. These constraints have

Clinicians’ Views on Antiepileptic Medication Management in Nonepileptic Seizures

Discontinuation of antiepileptic drugs should be a first step in treatment of nonepileptic seizures without comorbid epilepsy. However, clinical practices vary and standardized guidelines are not available. The aim of this study was to survey members of the American Epilepsy and Child Neurology Societies about factors that influence their decision about antiepileptic drug management in patients with nonepileptic seizures. A total of 236 respondents completed this survey, of whom 84% were academic pediatric neurologists and 96.2% were very willing to discontinue antiepileptic drugs in these patients. Clinicians with sufficient knowledge about nonepileptic seizures had fewer concerns about the potential for medical errors, were less influenced by requests made by patients or parents to continue antiepileptic drugs, and were comfortable making this decision if patients receive ongoing psychiatric care. Results of this survey highlight the need to examine if the same factors are involved in a large sample of community clinicians.

Delivery of epilepsy care to adults with intellectual and developmental disabilities

Epilepsy is common in people with intellectual and developmental disabilities (IDD). In adulthood, patients with IDD and epilepsy (IDD-E) have neurologic, psychiatric, medical, and social challenges compounded by fragmented and limited care. With increasing neurologic disability, there is a higher frequency of epilepsy, especially symptomatic generalized and treatment-resistant epilepsies. The causes of IDD-E are increasingly recognized to be genetic based on chromosomal microarray analysis to identify copy number variants, gene panels (epilepsy, autism spectrum disorder, intellectual disability), and whole-exome sequencing. A specific genetic diagnosis may guide care by pointing to comorbid disorders and best therapy. Therapy to control seizures should be individualized, with drug selection based on seizure types, epilepsy syndrome, concomitant medications, and comorbid disorders. There are limited comparative antiepileptic drug data in the IDD-E population. Vagus nerve and responsive neural stimulation therapies and resective surgery should be considered. Among the many comorbid disorders that affect patients with IDD-E, psychiatric and sleep disorders are common but often unrecognized and typically not treated. Transition from holistic and coordinated pediatric to adult care is often a vulnerable period. Communication among adult health care providers is complex but essential to ensure best care when these patients are seen in outpatient, emergency room, and inpatient settings. We propose specific recommendations for minimum care standards for people with IDD-E.