A unique pattern of cortical connectivity characterizes patients with attention deficit disorders: a large electroencephalographic coherence study.

BACKGROUND: Attentional disorders (ADD) feature decreased attention span, impulsivity, and over-activity interfering with successful lives. Childhood onset ADD frequently persists to adulthood. Etiology may be hereditary or disease associated. Prevalence is 5% but recognition may be 'overshadowed' by comorbidities (brain injury, mood disorder) thereby escaping formal recognition. Blinded diagnosis by MRI has failed. ADD may not itself manifest a single anatomical pattern of brain abnormality but may reflect multiple, unique responses to numerous and diverse etiologies. Alternatively, a stable ADD-specific brain pattern may be better detected by brain physiology. EEG coherence, measuring cortical connectivity, is used to explore this possibility. METHODS: Participants: Ages 2 to 22 years; 347 ADD and 619 neurotypical controls (CON). Following artifact reduction, principal components analysis (PCA) identifies coherence factors with unique loading patterns. Discriminant function analysis (DFA) determines discrimination success differentiating ADD from CON. Split-half and jackknife analyses estimate prospective diagnostic success. Coherence factor loading constitutes an ADD-specific pattern or 'connectome'.  RESULTS: PCA identified 40 factors explaining 50% of total variance. DFA on CON versus ADD groups utilizing all factors was highly significant (p≤0.0001). ADD subjects were separated into medication and comorbidity subgroups. DFA (stepping allowed) based on CON versus ADD without comorbidities or medication treatment successfully classified the correspondingly held out ADD subjects in every instance. Ten randomly generated split-half replications of the entire population demonstrated high-average classification success for each of the left out test-sets (overall: CON, 83.65%; ADD, 90.07%). Higher success was obtained with more restricted age sub-samples using jackknifing: 2-8 year olds (CON, 90.0%; ADD, 90.6%); 8-14 year olds (CON, 96.8%; ADD 95.9%); and 14-20 year-olds (CON, 100.0%; ADD, 97.1%). The connectome manifested decreased and increased coherence. Patterns were complex and bi-hemispheric; typically reported front-back and left-right loading patterns were not observed. Subtemporal electrodes (seldom utilized) were prominently involved.  CONCLUSIONS: Results demonstrate a stable coherence connectome differentiating ADD from CON subjects including subgroups with and without comorbidities and/or medications. This functional 'connectome', constitutes a diagnostic ADD phenotype. Split-half replications support potential for EEG-based ADD diagnosis, with increased accuracy using limited age ranges. Repeated studies could assist recognition of physiological change from interventions (pharmacological, behavioral).

Corticosteroid therapy in regressive autism: a retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior.

BACKGROUND: Up to a third of children with Autism Spectrum Disorder (ASD) manifest regressive autism (R-ASD).They show normal early development followed by loss of language and social skills. Absent evidence-based therapies, anecdotal evidence suggests improvement following use of corticosteroids. This study examined the effects of corticosteroids for R-ASD children upon the 4 Hz frequency modulated evoked response (FMAER) arising from language cortex of the superior temporal gyrus (STG) and upon EEG background activity, language, and behavior. An untreated clinical convenience sample of ASD children served as control sample. METHODS: Twenty steroid-treated R-ASD (STAR) and 24 not-treated ASD patients (NSA), aged 3 - 5 years, were retrospectively identified from a large database. All study participants had two sequential FMAER and EEG studies;Landau-Kleffner syndrome diagnosis was excluded. All subjects' records contained clinical receptive and expressive language ratings based upon a priori developed metrics. The STAR group additionally was scored behaviorally regarding symptom severity as based on the Diagnostic and Statistical Manual IV (DSM-IV) ASD criteria list. EEGs were visually scored for abnormalities. FMAER responses were assessed quantitatively by spectral analysis. Treated and untreated group means and standard deviations for the FMAER, EEG, language, and behavior, were compared by paired t-test and Fisher's exact tests. RESULTS: The STAR group showed a significant increase in the 4 Hz FMAER spectral response and a significant reduction in response distortion compared to the NSA group. Star group subjects' language ratings were significantly improved and more STAR than NSA group subjects showed significant language improvement. Most STAR group children showed significant behavioral improvement after treatment. STAR group language and behavior improvement was retained one year after treatment. Groups did not differ in terms of minor EEG abnormalities. Steroid treatment produced no lasting morbidity. CONCLUSIONS: Steroid treatment was associated with a significantly increased FMAER response magnitude, reduction of FMAER response distortion, and improvement in language and behavior scores. This was not observed in the non-treated group. These pilot findings warrant a prospective randomized validation trial of steroid treatment for R-ASD utilizing FMAER, EEG, and standardized ASD, language and behavior measures, and a longer follow-up period.Please see related article http://www.biomedcentral.com/1741-7015/12/79.

The relationship of Asperger's syndrome to autism: a preliminary EEG coherence study.

BACKGROUND: It has long been debated whether Asperger's Syndrome (ASP) should be considered part of the Autism Spectrum Disorders (ASD) or whether it constitutes a unique entity. The Diagnostic and Statistical Manual, fourth edition (DSM-IV) differentiated ASP from high functioning autism. However, the new DSM-5 umbrellas ASP within ASD, thus eliminating the ASP diagnosis. To date, no clear biomarkers have reliably distinguished ASP and ASD populations. This study uses EEG coherence, a measure of brain connectivity, to explore possible neurophysiological differences between ASP and ASD. METHODS: Voluminous coherence data derived from all possible electrode pairs and frequencies were previously reduced by principal components analysis (PCA) to produce a smaller number of unbiased, data-driven coherence factors. In a previous study, these factors significantly and reliably differentiated neurotypical controls from ASD subjects by discriminant function analysis (DFA). These previous DFA rules are now applied to an ASP population to determine if ASP subjects classify as control or ASD subjects. Additionally, a new set of coherence based DFA rules are used to determine whether ASP and ASD subjects can be differentiated from each other. RESULTS: Using prior EEG coherence based DFA rules that successfully classified subjects as either controls or ASD, 96.2% of ASP subjects are classified as ASD. However, when ASP subjects are directly compared to ASD subjects using new DFA rules, 92.3% ASP subjects are identified as separate from the ASD population. By contrast, five randomly selected subsamples of ASD subjects fail to reach significance when compared to the remaining ASD populations. When represented by the discriminant variable, both the ASD and ASD populations are normally distributed. CONCLUSIONS: Within a control-ASD dichotomy, an ASP population falls closer to ASD than controls. However, when compared directly with ASD, an ASP population is distinctly separate. The ASP population appears to constitute a neurophysiologically identifiable, normally distributed entity within the higher functioning tail of the ASD population distribution. These results must be replicated with a larger sample given their potentially immense clinical, emotional and financial implications for affected individuals, their families and their caregivers.

EEG spectral coherence data distinguish chronic fatigue syndrome patients from healthy controls and depressed patients--a case control study.

BACKGROUND: Previous studies suggest central nervous system involvement in chronic fatigue syndrome (CFS), yet there are no established diagnostic criteria. CFS may be difficult to differentiate from clinical depression. The study's objective was to determine if spectral coherence, a computational derivative of spectral analysis of the electroencephalogram (EEG), could distinguish patients with CFS from healthy control subjects and not erroneously classify depressed patients as having CFS. METHODS: This is a study, conducted in an academic medical center electroencephalography laboratory, of 632 subjects: 390 healthy normal controls, 70 patients with carefully defined CFS, 24 with major depression, and 148 with general fatigue. Aside from fatigue, all patients were medically healthy by history and examination. EEGs were obtained and spectral coherences calculated after extensive artifact removal. Principal Components Analysis identified coherence factors and corresponding factor loading patterns. Discriminant analysis determined whether spectral coherence factors could reliably discriminate CFS patients from healthy control subjects without misclassifying depression as CFS. RESULTS: Analysis of EEG coherence data from a large sample (n = 632) of patients and healthy controls identified 40 factors explaining 55.6% total variance. Factors showed highly significant group differentiation (p < .0004) identifying 89.5% of unmedicated female CFS patients and 92.4% of healthy female controls. Recursive jackknifing showed predictions were stable. A conservative 10-factor discriminant function model was subsequently applied, and also showed highly significant group discrimination (p < .001), accurately classifying 88.9% unmedicated males with CFS, and 82.4% unmedicated male healthy controls. No patient with depression was classified as having CFS. The model was less accurate (73.9%) in identifying CFS patients taking psychoactive medications. Factors involving the temporal lobes were of primary importance. CONCLUSIONS: EEG spectral coherence analysis identified unmedicated patients with CFS and healthy control subjects without misclassifying depressed patients as CFS, providing evidence that CFS patients demonstrate brain physiology that is not observed in healthy normals or patients with major depression. Studies of new CFS patients and comparison groups are required to determine the possible clinical utility of this test. The results concur with other studies finding neurological abnormalities in CFS, and implicate temporal lobe involvement in CFS pathophysiology.

The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) with Kangaroo Mother Care (KMC): Comprehensive Care for Preterm Infants.

State-of-the-art Newborn Intensive Care Units (NICUs), instrumental in the survival of high-risk and ever-earlier-born preterm infants, often have costly human repercussions. The developmental sequelae of newborn intensive care are largely misunderstood. Developed countries eager to export their technologies must also transfer the knowledge-base that encompasses all high-risk and preterm infants' personhood as well as the neuro-essential importance of their parents. Without such understanding, the best medical care, while assuring survival jeopardizes infants' long-term potential and deprives parents of their critical role. Exchanging the womb for the NICU environment at a time of rapid brain growth compromises preterm infants' early development, which results in long-term physical and mental health problems and developmental disabilities. The Newborn Individualized Developmental Care and Assessment Program (NIDCAP) aims to prevent the iatrogenic sequelae of intensive care and to maintain the intimate connection between parent and infant, one expression of which is Kangaroo Mother Care. NIDCAP embeds the infant in the natural parent niche, avoids over-stimulation, stress, pain, and isolation while it supports self-regulation, competence, and goal orientation. Research demonstrates that NIDCAP improves brain development, functional competence, health, and life quality. It is cost effective, humane, and ethical, and promises to become the standard for all NICU care.

Effects of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) at age 8 years: preliminary data.

The current study reports the effects of NIDCAP (Newborn Individualized Developmental Care and Assessment Program) at 8 years of age for a randomized controlled trial of 38 very early born (< or =29 weeks postmenstrual age), high-risk preterm infants. It was hypothesized that the experimental group at school age in comparison with the control group would perform significantly better neuropsychologically and neuroelectrophysiologically. Twenty-two (11 control, 11 experimental) children of the original 38 (18 control, 20 experimental) participants were studied at school age with a detailed neuropsychological battery and with EEG spectral coherence measures. Results indicated significantly better right hemisphere and frontal lobe function in the experimental group than the control group, both neuropsychologically and neurophysiologically. Neurobehavioral and physiological results in the newborn period successfully predicted the beneficial brain function effects at age 8 years. Results support the conclusion that the NIDCAP intervention has lasting effects into school age.

Displacement of brain regions in preterm infants with non-synostotic dolichocephaly investigated by MRI.

Regional investigations of newborn MRI are important to understand the appearance and consequences of early brain injury. Previously, regionalization in neonates has been achieved with a Talairach parcellation, using internal landmarks of the brain. Non-synostotic dolichocephaly defines a bi-temporal narrowing of the preterm infant's head caused by pressure on the immature skull. The impact of dolichocephaly on brain shape and regional brain shift, which may compromise the validity of the parcellation scheme, has not yet been investigated. Twenty-four preterm and 20 fullterm infants were scanned at term equivalent. Skull shapes were investigated by cephalometric measurements and population registration. Brain tissue volumes were calculated to rule out brain injury underlying skull shape differences. The position of Talairach landmarks was evaluated. Cortical structures were segmented to determine a positional shift between both groups. The preterm group displayed dolichocephalic head shapes and had similar brain volumes compared to the mesocephalic fullterm group. In preterm infants, Talairach landmarks were consistently positioned relative to each other and to the skull base, but were displaced with regard to the calvarium. The frontal and superior region was enlarged; central and temporal gyri and sulci were shifted comparing preterm and fullterm infants. We found that, in healthy preterm infants, dolichocephaly led to a shift of cortical structures, but did not influence deep brain structures. We concluded that the validity of a Talairach parcellation scheme is compromised and may lead to a miscalculation of regional brain volumes and inconsistent parcel contents when comparing infant populations with divergent head shapes.

Regional brain development in serial magnetic resonance imaging of low-risk preterm infants.

OBJECTIVE: MRI studies have shown that preterm infants with brain injury have altered brain tissue volumes. Investigation of preterm infants without brain injury offers the opportunity to define the influence of early birth on brain development and provide normative data to assess effects of adverse conditions on the preterm brain. In this study, we investigated serial MRI of low-risk preterm infants with the aim to identify regions of altered brain development. METHODS: Twenty-three preterm infants appropriate for gestational age without magnetic resonance-visible brain injury underwent MRI twice at 32 and at 42 weeks' postmenstrual age. Fifteen term infants were scanned 2 weeks after birth. Brain tissue classification and parcellation were conducted to allow comparison of regional brain tissue volumes. Longitudinal brain growth was assessed from preterm infants' serial scans. RESULTS: At 42 weeks' postmenstrual age, gray matter volumes were not different between preterm and term infants. Myelinated white matter was decreased, as were unmyelinated white matter volumes in the region including the central gyri. The gray matter proportion of the brain parenchyma constituted 30% and 37% at 32 and 42 weeks' postmenstrual age, respectively. CONCLUSIONS: This MRI study of preterm infants appropriate for gestational age and without brain injury establishes the influence of early birth on brain development. No decreased cortical gray matter volumes were found, which is in contrast to findings in preterm infants with brain injury. Moderately decreased white matter volumes suggest an adverse influence of early birth on white matter development. We identified a sharp increase in cortical gray matter volume in preterm infants' serial data, which may correspond to a critical period for cortical development.

Early experience alters brain function and structure.

OBJECTIVE: To investigate the effects of early experience on brain function and structure. METHODS: A randomized clinical trial tested the neurodevelopmental effectiveness of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP). Thirty preterm infants, 28 to 33 weeks' gestational age (GA) at birth and free of known developmental risk factors, participated in the trial. NIDCAP was initiated within 72 hours of intensive care unit admission and continued to the age of 2 weeks, corrected for prematurity. Control (14) and experimental (16) infants were assessed at 2 weeks' and 9 months' corrected age on health status, growth, and neurobehavior, and at 2 weeks' corrected age additionally on electroencephalogram spectral coherence, magnetic resonance diffusion tensor imaging, and measurements of transverse relaxation time. RESULTS: The groups were medically and demographically comparable before as well as after the treatment. However, the experimental group showed significantly better neurobehavioral functioning, increased coherence between frontal and a broad spectrum of mainly occipital brain regions, and higher relative anisotropy in left internal capsule, with a trend for right internal capsule and frontal white matter. Transverse relaxation time showed no difference. Behavioral function was improved also at 9 months' corrected age. The relationship among the 3 neurodevelopmental domains was significant. The results indicated consistently better function and more mature fiber structure for experimental infants compared with their controls. CONCLUSIONS: This is the first in vivo evidence of enhanced brain function and structure due to the NIDCAP. The study demonstrates that quality of experience before term may influence brain development significantly.

A three-center, randomized, controlled trial of individualized developmental care for very low birth weight preterm infants: medical, neurodevelopmental, parenting, and caregiving effects.

Medical, neurodevelopmental, and parenting effects of individualized developmental care were investigated in a three-center, randomized, controlled trial. A total of 92 preterm infants, weighing less than 1250 g and aged less than 28 weeks, participated. Outcome measures included medical, neurodevelopmental and family function. Quality of care was also assessed. Multivariate analysis of variance investigated group, site, and interaction effects; correlation analysis identified individual variable contributions to significant effects. The results consistently favored the experimental groups. The following contributed to the group effects: shorter duration of parenteral feeding, transition to full oral feeding, intensive care, and hospitalization; lower incidence of necrotizing enterocolitis; reduced discharge ages and hospital charges; improved weight, length, and head circumferences; enhanced autonomic, motor, state, attention, and self-regulatory functioning; reduced need for facilitation; and lowered family stress and enhanced appreciation of the infant. Quality of care was measurably improved. Very low birth weight infants and their parents, across diverse settings, may benefit from individualized developmental care.

Event-related correlations in learning impaired children during A hybrid go/no-go choice reaction visual-motor task.

One hundred sixty-nine learning impaired (LI) and 71 non-learning impaired (NLI) children underwent a hybrid go/no-go choice reaction time visual-motor task to study the behavioral and physiological fundamentals of learning disorders. A left button was pressed for Left Arrow (LA) stimuli, a right for Right Arrow (RA) stimuli, none (no-go) for a non-directional arrow. Stimulus specific visual evoked potentials were formed and, with PZ as index electrode, were lag-correlated to frontal electrodes to form Event-Related Correlations (ERC). Exploratory t-statistic significance probability maps (t-SPM) were used to define regions of interest (ROI). Behaviorally, there was a right-hand advantage over the left in the NLI group, but less in the LI group. Electrophysiologically, RA and LA conditions increased correlation between visual areas (PZ) and contralateral frontal areas (F3 and F4). A unilateral ROI, at electrode FC1, also preceded both left- and right-handed responses. Neurobehaviorally, increased visual-motor correlation was associated with better performance, especially for the left hemisphere, at F3 and FC1. Surprisingly, visual-motor correlations were not associated with performance for the NLI group in the RA and no-go condition. Our data support previously reported difficulties of learning impaired children in low-level information processing. Furthermore, we hypothesize that LI, in contrast to NLI children, demonstrate difficulty in automatizing routine tasks.

Infant EEG spectral coherence data during quiet sleep: unrestricted principal components analysis--relation of factors to gestational age, medical risk, and neurobehavioral status.

EEG spectral coherence data in quiet sleep of 312 infants were evaluated, at 42 weeks post-menstrual age. All were medically healthy and living at home by time of evaluation. The sample consisted of prematurely bom infants with a wide spectrum of underlying risk factors, as well as healthy full-term infants. Initial 3040 coherence variables were reduced by principal components analysis in an unrestricted manner, which avoided the folding of spectral and spatial information into among-subject variance. One hundred fifty factors explained 90% of the total variance; 40 Varimax rotated factors explained 65% of the variance yielding a 50:1 data reduction. Factor loading patterns ranged from multiple spectral bands for a single electrode pair to multiple electrode pairs for a single spectral band and all intermediate possibilities. Simple left-right and anterior-posterior pairings were not observed within the factor loadings. By multiple regression analysis, the 40 factors significantly predicted gestational age at birth. By canonical correlation, significant relationships were demonstrated between the coherence factors and medical risk factors as well as neurobehavioral factors. Using discriminant analysis, the coherence factors successfully discriminated between infants with high and low medical risk status and between those with the best and worst neurobehavioral status. The two factors accounting for the most variance, and chosen across several analyses, indicated increased left central-temporal coherence from 6-24 Hz, and increased frontal-occipital coherence at 10 Hz, for the infants born closest to term with lowest medical risk factors and best neurobehavioral performance.