Catherine Stamoulis

Effect of Early Institutionalization and Foster Care on Long-term White Matter Development: A Randomized Clinical Trial

IMPORTANCE Severe neglect in early life is associated with compromises in brain development and associated behavioral functioning. Although early intervention has been shown to support more normative trajectories of brain development, specific improvements in the white matter pathways that underlie emotional and cognitive development are unknown. OBJECTIVE To examine associations among neglect in early life, early intervention, and the microstructural integrity of white matter pathways in middle childhood. DESIGN, SETTING, AND PARTICIPANTS The Bucharest Early Intervention Project is a randomized clinical trial of high-quality foster care as an intervention for institutionally reared children in Bucharest, Romania, from 2000 through the present. During infancy, children were randomly selected to remain in an institution or to be placed in foster care. Those who remained in institutions experienced neglect, including social, emotional, linguistic, and cognitive impoverishment. Developmental trajectories of these children were compared with a group of sociodemographically matched children reared in biological families at baseline and several points throughout development. At approximately 8 years of age, 69 of the original 136 children underwent structural magnetic resonance imaging scans. MAIN OUTCOMES AND MEASURES Four estimates of white matter integrity (fractional anisotropy [FA] and mean [MD], radial [RD], and axial [AD] diffusivity) for 48 white matter tracts throughout the brain were obtained through diffusion tensor imaging. RESULTS Significant associations emerged between neglect in early life and microstructural integrity of the body of the corpus callosum (FA, β = 0.01 [P = .01]; RD, β = -0.02 [P = .005]; MD, β = -0.01 [P = .02]) and tracts involved in limbic circuitry (fornix crus [AD, β = 0.02 (P = .046)] and cingulum [RD, β = -0.01 (P = .02); MD, β = -0.01 (P = .049)]), frontostriatal circuitry (anterior [AD, β = -0.01 (P = .02)] and superior [AD, β = -0.02 (P = .02); MD, β = -0.01 (P = .03)] corona radiata and external capsule [right FA, β = 0.01 (P = .03); left FA, β = 0.01 (P = .03); RD, β = -0.01 (P = .01); MD, β = -0.01 (P = .03)]), and sensory processing (medial lemniscus [AD, β = -0.02 (P = .045); MD, β = -0.01 (P = .04)] and retrolenticular internal capsule [FA, β = -0.01 (P = .002); RD, β = 0.01 (P = .003); MD, β = 0.01 (P = .04)]). Follow-up analyses revealed that early intervention promoted more normative white matter development among previously neglected children who entered foster care. CONCLUSIONS AND RELEVANCE Results suggest that removal from conditions of neglect in early life and entry into a high-quality family environment can support more normative trajectories of white matter growth. Our findings have implications for public health and policy efforts designed to promote normative brain development among vulnerable children. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00747396.

Effect of Early Institutionalization and Foster Care on Long-term White Matter Development

IMPORTANCE Severe neglect in early life is associated with compromises in brain development and associated behavioral functioning. Although early intervention has been shown to support more normative trajectories of brain development, specific improvements in the white matter pathways that underlie emotional and cognitive development are unknown. OBJECTIVE To examine associations among neglect in early life, early intervention, and the microstructural integrity of white matter pathways in middle childhood. DESIGN, SETTING, AND PARTICIPANTS The Bucharest Early Intervention Project is a randomized clinical trial of high-quality foster care as an intervention for institutionally reared children in Bucharest, Romania, from 2000 through the present. During infancy, children were randomly selected to remain in an institution or to be placed in foster care. Those who remained in institutions experienced neglect, including social, emotional, linguistic, and cognitive impoverishment. Developmental trajectories of these children were compared with a group of sociodemographically matched children reared in biological families at baseline and several points throughout development. At approximately 8 years of age, 69 of the original 136 children underwent structural magnetic resonance imaging scans. MAIN OUTCOMES AND MEASURES Four estimates of white matter integrity (fractional anisotropy [FA] and mean [MD], radial [RD], and axial [AD] diffusivity) for 48 white matter tracts throughout the brain were obtained through diffusion tensor imaging. RESULTS Significant associations emerged between neglect in early life and microstructural integrity of the body of the corpus callosum (FA, β = 0.01 [P = .01]; RD, β = -0.02 [P = .005]; MD, β = -0.01 [P = .02]) and tracts involved in limbic circuitry (fornix crus [AD, β = 0.02 (P = .046)] and cingulum [RD, β = -0.01 (P = .02); MD, β = -0.01 (P = .049)]), frontostriatal circuitry (anterior [AD, β = -0.01 (P = .02)] and superior [AD, β = -0.02 (P = .02); MD, β = -0.01 (P = .03)] corona radiata and external capsule [right FA, β = 0.01 (P = .03); left FA, β = 0.01 (P = .03); RD, β = -0.01 (P = .01); MD, β = -0.01 (P = .03)]), and sensory processing (medial lemniscus [AD, β = -0.02 (P = .045); MD, β = -0.01 (P = .04)] and retrolenticular internal capsule [FA, β = -0.01 (P = .002); RD, β = 0.01 (P = .003); MD, β = 0.01 (P = .04)]). Follow-up analyses revealed that early intervention promoted more normative white matter development among previously neglected children who entered foster care. CONCLUSIONS AND RELEVANCE Results suggest that removal from conditions of neglect in early life and entry into a high-quality family environment can support more normative trajectories of white matter growth. Our findings have implications for public health and policy efforts designed to promote normative brain development among vulnerable children. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00747396.

Neurointerventions in Children: Radiation Exposure and Its Import

BACKGROUND AND PURPOSE: Neurointerventions in children have dramatically improved the clinical outlook for patients with previously intractable cerebrovascular conditions, such as vein of Galen malformations and complex arteriovenous fistulas. However, these complex and sometimes lengthy procedures are performed under fluoroscopic guidance and thus unavoidably expose vulnerable pediatric patients to the effects of ionizing radiation. Recent epidemiologic evidence from a national registry of children who underwent CT scans suggests a higher-than-expected incidence of secondary tumors. We sought to calculate the predicted risk of secondary tumors in a large cohort of pediatric neurointerventional patients. MATERIALS AND METHODS: We reviewed our cohort of pediatric neurointerventions, tabulated radiation dose delivered to the skin, and calculated the range of likely brain-absorbed doses by use of previously developed mathematical models. The predicted risk of secondary tumor development as a function of brain-absorbed dose in this cohort was then generated by use of the head CT registry findings. RESULTS: Maximal skin dose and brain-absorbed doses in our cohort were substantially lower than have been previously described. However, we found 1) a statistically significant correlation between radiation dose and age at procedure, as well as number and type of procedures, and 2) a substantial increase in lifetime predicted risk of tumor above baseline in the cohort of young children who undergo neurointerventions. CONCLUSIONS: Although neurointerventional procedures have dramatically improved the prognosis of children facing serious cerebrovascular conditions, the predicted risk of secondary tumors, particularly in the youngest patients and those undergoing multiple procedures, is sobering.

Advance cueing produces enhanced action-boundary patterns of spike activity in the sensorimotor striatum

One of the most characteristic features of habitual behaviors is that they can be evoked by a single cue. In the experiments reported here, we tested for the effects of such advance cueing on the firing patterns of striatal neurons in the sensorimotor striatum. Rats ran in a T-maze with instruction cues about the location of reward given at the start of the runs. This advance cueing about reward produced a highly augmented task-bracketing pattern of activity at the beginning and end of procedural task performance relative to the patterns found previously with midtask cueing. Remarkably, the largest increase in activity early during the T-maze runs was not associated with the instruction cues themselves, the earliest predictors of reward; instead, the highest peak of early activity was associated with the beginning of the motor period of the task. We suggest that the advance cueing, reducing midrun demands for decision making but adding a working-memory load, facilitated chunking of the maze runs as executable scripts anchored to sensorimotor aspects of the task and unencumbered by midtask decision-making demands. Our findings suggest that the acquisition of stronger task-bracketing patterns of striatal activity in the sensorimotor striatum could reflect this enhancement of behavioral chunking. Deficits in such representations of learned sequential behaviors could contribute to motor and cognitive problems in a range of neurological disorders affecting the basal ganglia, including Parkinsons disease.

Distal femoral valgus deformity following plate fixation of pediatric femoral shaft fractures.

BACKGROUND This study investigated the frequency and potential risk factors associated with the development of distal femoral valgus deformity following plate fixation of diaphyseal femoral fractures in children. METHODS Records of eighty-five skeletally immature patients who underwent plate fixation of a diaphyseal femoral fracture at a tertiary-care pediatric center from January 2003 to December 2010 were reviewed. Demographic data and clinical information were analyzed. Radiographic measurement of the distance from the distal plate edge to the distal femoral physis and of the anatomic lateral distal femoral angle was performed. Development of distal femoral valgus deformity was defined as a change in the anatomic lateral distal femoral angle of ≥5° in the valgus direction. Logistic regression analysis and contingency tables were used to relate the development of distal femoral valgus deformity with retention of hardware, patient age, fracture site, plate-to-physis distance, and the location of a bend in the plate at fixation. RESULTS Midshaft fractures (45%) were more common than proximal or distal diaphyseal fractures. Intraoperatively, the plate was bent proximally or distally, or both, in 80% of the patients. Distal femoral valgus deformity of ≥5° was seen in ten patients, eight of whom had distal diaphyseal fractures. Three of the ten patients developed symptoms as a result of the distal femoral valgus deformity that required at least one unplanned additional surgical procedure. On the basis of the statistical analysis, patients with a plate-to-physis distance of ≤20 mm (relative risk= 12.77, p = 0.005) and a distal fracture (relative risk = 11.0, p < 0.001) were at a significantly higher risk of developing distal femoral valgus deformity. Although not clearly an independent factor, a distal bend was also found to be associated with distal femoral valgus deformity (p = 0.004) but was not predictive of the pathology. CONCLUSIONS Distal femoral valgus deformity occurred in 30% of patients with distal diaphyseal fractures and in 12% overall. We advocate long-term monitoring of patients with femoral plate fixation, particularly those in whom the plate is placed ≤20 mm from the distal femoral physis.

Application of matched-filtering to extract EEG features and decouple signal contributions from multiple seizure foci in brain malformations

Developmental brain malformations often cause intractable and in many cases generalized and/or multifocal seizures. Surgical intervention is not possible in these cases as it is difficult to isolate the epileptogenic foci. Scalp EEG signals recorded during such seizures include coupled contributions from different sources. If it was possible to decouple these contributions based on differences in both their signatures and inter-arrival times at different electrodes, it would subsequently be possible to estimate the locations of the seizure foci. For this purpose, we applied matched filtering to scalp EEG data from 3 patients with multifocal seizures, using patient-specific source-related short EEG segments as the template waveforms. These segments were assumed to be seizure-related based on distinct sets of inter-arrival times at different channels and alternating signal polarities. We present preliminary results and demonstrate that matched filtering can be successfully applied to extract decoupled signal components from the EEG, generated by potentially distinct sources, and thus with distinct inter-arrival times but partially overlapping spectra.

Pediatric CT Dose Reduction for Suspected Appendicitis: A Practice Quality Improvement Project Using Artificial Gaussian Noise—Part 2, Clinical Outcomes

OBJECTIVE. The purpose of this study was to determine the effect of a nominal 50% reduction in median absorbed radiation dose on sensitivity, specificity, and negative appendectomy rate of CT for acute appendicitis in children. MATERIALS AND METHODS. On the basis of a departmental practice quality improvement initiative using computer-generated gaussian noise for CT dose reduction, we applied a nominal dose reduction of 50% to abdominal CT techniques used for bowel imaging. This retrospective study consisted of 494 children who underwent a CT for suspected acute appendicitis before (n = 244; mean age, 133 months) and after (n = 250; mean age, 145 months) the nominal 50% dose reduction. Test performance characteristics of CT for acute appendicitis and impact on the negative appendectomy rate were compared for both time periods. Primary analyses were performed with histologic diagnosis as the outcome standard. Volume CT dose index and dose-length product were recorded from dose reports and size-specific dose estimates were calculated. RESULTS. The nominal 50% dose reduction resulted in an actual 39% decrease in median absorbed radiation dose. Sensitivity of CT for diagnosis of acute appendicitis was 98% (95% CI, 91-100%) versus 97% (91-100%), and specificity was 93% (88-96%) versus 94% (90-97%) before and after dose reduction, respectively. The negative appendectomy rate was 4.5% (0.8-10.25%) before dose reduction and 4.0% (0.4-7.6%) after dose reduction. CONCLUSION. The negative appendectomy rate and performance characteristics of the CT-based diagnosis of acute appendicitis were not affected by a 39% reduction in median absorbed radiation dose.

High-frequency neuronal network modulations encoded in scalp EEG precede the onset of focal seizures

Modulations of neuronal network interactions by seizure precursors are only partially understood and difficult to measure, in part due to inherent intra- and inter-patient seizure heterogeneities and EEG variability. This study investigated preictal neuromodulations associated with seizures originating in the temporal and/or frontal lobes, using information theoretic parameters estimated from awake scalp EEGs in two frequency ranges, ≤100 Hz and >100 Hz, respectively. Seizure-related activity at high frequencies has not been extensively estimated in awake scalp EEGs. Based on the statistical similarity of preictal and ictal information parameters, preictal network interactions appeared to be specifically modulated at frequencies >100 Hz, but not at lower frequencies. The dynamics of these parameters varied distinctly according to the origin of seizure onset (temporal versus frontal). Although preliminary, and based on a small patient sample for which the potential heterogeneity of multiple anticonvulsive medications was difficult to control, these results suggest that preictal modulations may be estimated from high-frequency scalp EEGs using directional information measures with high specificity to ictal events, and may thus be promising for improving seizure prediction.

A novel signal processing approach for the detection of copy number variations in the human genome

MOTIVATION Human genomic variability occurs at different scales, from single nucleotide polymorphisms (SNPs) to large DNA segments. Copy number variations (CNVs) represent a significant part of our genetic heterogeneity and have also been associated with many diseases and disorders. Short, localized CNVs, which may play an important role in human disease, may be undetectable in noisy genomic data. Therefore, robust methodologies are needed for their detection. Furthermore, for meaningful identification of pathological CNVs, estimation of normal allelic aberrations is necessary. RESULTS We developed a signal processing-based methodology for sequence denoising followed by pattern matching, to increase SNR in genomic data and improve CNV detection. We applied this signal-decomposition-matched filtering (SDMF) methodology to 429 normal genomic sequences, and compared detected CNVs to those in the Database of Genomic Variants. SDMF successfully detected a significant number of previously identified CNVs with frequencies of occurrence ≥10%, as well as unreported short CNVs. Its performance was also compared to circular binary segmentation (CBS). through simulations. SDMF had a significantly lower false detection rate and was significantly faster than CBS, an important advantage for handling large datasets generated with high-resolution arrays. By focusing on improving SNR (instead of the robustness of the detection algorithm), SDMF is a very promising methodology for identifying CNVs at all genomic spatial scales. AVAILABILITY The data are available at http://tcga-data.nci.nih.gov/tcga/ The software and list of analyzed sequence IDs are available at http://www.hsph.harvard.edu/~betensky/ A Matlab code for Empirical Mode Decomposition may be found at: http://www.clear.rice.edu/elec301/Projects02/empiricalMode/code.html CONTACT caterina@mit.edu.

Early psychosocial neglect adversely impacts developmental trajectories of brain oscillations and their interactions

Rhythmicity is a fundamental property of neural activity at multiple spatiotemporal scales, and associated oscillations represent a critical mechanism for communication and transmission of information across brain regions. During development, these oscillations evolve dynamically as a function of neural maturation and may be modulated by early experiences, positive and/or negative. This study investigated the impact of psychosocial deprivation associated with institutional rearing in early life and the effects of subsequent foster care intervention on developmental trajectories of neural oscillations and their cross-frequency correlations. Longitudinally acquired nontask EEGs from three cohorts of children from the Bucharest Early Intervention Project were analyzed. These included abandoned children initially reared in institutions and subsequently randomized to be placed in foster care or receive care as usual (prolonged institutional rearing) and a group of never-institutionalized children. Oscillation trajectories were estimated from 42 to 96 months, that is, 1–3 years after all children in the intervention arm of the study had been placed in foster care. Significant differences between groups were estimated for the amplitude trajectories of cognitive-related gamma, beta, alpha, and theta oscillations. Similar differences were identified as a function of time spent in institutions, suggesting that increased time spent in psychosocial neglect may have profound and widespread effects on brain activity. Significant group differences in cross-frequency coupling were estimated longitudinally between gamma and lower frequencies as well as alpha and lower frequencies. Lower cross-gamma coupling was estimated at 96 months in the group of children that remained in institutions at that age compared to the other two groups, suggesting potentially impaired communication between local and long-distance brain networks in these children. In contrast, higher cross-alpha coupling was estimated in this group compared to the other two groups at 96 months, suggesting impaired suppression of alpha–theta and alpha–delta activity, which has been associated with neuropsychiatric disorders. Age at foster care placement had a significant positive modulatory effect on alpha and beta trajectories and their mutual coupling, although by 96 months these trajectories remained distinct from those of never-institutionalized children. Overall, these findings suggest that early psychosocial neglect may profoundly impact neural maturation, particularly the evolution of neural oscillations and their interactions across a broad frequency range. These differences may result in widespread deficits across multiple cognitive domains.