Rufinamide for the treatment of epileptic spasms.

OBJECTIVE: The purpose of this study was to determine the safety and efficacy of rufinamide for treatment of epileptic spasms. METHODS: We retrospectively reviewed patients treated with rufinamide for epileptic spasms from January 2009 to March 2010. Age, presence of hypsarrhythmia, change in seizure frequency following rufinamide initiation, and side effects were assessed. Patients who had a ≥ 50% reduction in spasm frequency were considered responders. RESULTS: Of all 107 children treated with rufinamide during the study period, 38 (36%) had epileptic spasms. Median patient age was 7 years (range: 17 months to 23). One patient had hypsarrhythmia at the time of treatment with rufinamide, and 9 other patients had a history of hypsarrhythmia. Median starting dose of rufinamide was 9 mg/kg/day (range: 2-18) and median final treatment dose was 39 mg/kg/day (range: 8-92). All patients were receiving concurrent antiepileptic drug therapy, with the median number of antiepileptic drugs being 3 (range: 2-6). Median duration of follow-up since starting rufinamide was 171 days (range: 10-408). Responder rate was 53%. Median reduction in spasm frequency was 50% (interquartile range=-56 to 85%, P<0.05). Two patients (5%) achieved a >99% reduction in spasms. Rufinamide was discontinued in 7 of 38 patients (18%) because of lack of efficacy, worsening seizures, or other side effects. Minor side effects were reported in 14 of 38 patients (37%). CONCLUSIONS: Rufinamide appears to be a well-tolerated and efficacious adjunctive therapeutic option for children with epileptic spasms. A prospective study is warranted to validate our observations.

EEG source analysis of epileptiform activity using a 1 mm anisotropic hexahedra finite element head model.

The major goal of the evaluation in presurgical epilepsy diagnosis for medically intractable patients is the precise reconstruction of the epileptogenic foci, preferably with non-invasive methods. This paper evaluates whether surface electroencephalography (EEG) source analysis based on a 1 mm anisotropic finite element (FE) head model can provide additional guidance for presurgical epilepsy diagnosis and whether it is practically feasible in daily routine. A 1 mm hexahedra FE volume conductor model of the patient's head with special focus on accurately modeling the compartments skull, cerebrospinal fluid (CSF) and the anisotropic conducting brain tissues was constructed using non-linearly co-registered T1-, T2- and diffusion-tensor-magnetic resonance imaging data. The electrodes of intra-cranial EEG (iEEG) measurements were extracted from a co-registered computed tomography image. Goal function scan (GFS), minimum norm least squares (MNLS), standardized low resolution electromagnetic tomography (sLORETA) and spatio-temporal current dipole modeling inverse methods were then applied to the peak of the averaged ictal discharges EEG data. MNLS and sLORETA pointed to a single center of activity. Moving and rotating single dipole fits resulted in an explained variance of more than 97%. The non-invasive EEG source analysis methods localized at the border of the lesion and at the border of the iEEG electrodes which mainly received ictal discharges. Source orientation was towards the epileptogenic tissue. For the reconstructed superficial source, brain conductivity anisotropy and the lesion conductivity had only a minor influence, whereas a correct modeling of the highly conducting CSF compartment and the anisotropic skull was found to be important. The proposed FE forward modeling approach strongly simplifies meshing and reduces run-time (37 ms for one forward computation in the model with 3.1 million unknowns), corroborating the practical feasibility of the approach.

Somatosensory system: organizational hierarchy from single units in monkey area 5.

The receptive fields of single cells in area 5 of monkey parietal cortex were studied by extracellular recording. Cells were driven primarily by gentle manipulation of multiple joints residing on one or more limbs. Both excitatory and inhibitory convergence were demonstrated. It is postulated that the multijoint receptive fields of area 5 are the result of convergence from single-joint cells of the primary receiving area. An analogy is drawn between the modification of information in the visual and somatosensory systems.

Neuronal supersensitivity to acetylcholine induced by kindling in the rat hippocampus.

Kindling is an experimental model of epilepsy in which periodic brain stimulation induces the progressive development of electrical and behavioral seizures. A kindling-induced electrical seizure (afterdischarge) in the rat hippocampus produces prolonged neuronal supersensitivity to microiontophoretically applied acetylcholine after a latency of 40 to 60 minutes. Neuronal acetylcholine supersensitivity is correlated with the further progression of kindling. A larger hippocampal after-discharge is elicited by a subsequent kindling stimulus delivered in the presence of acetylcholine supersensitivity, but not by one delivered before the onset of the supersensitivity. The results suggest that alteration of synaptic sensitivity to acetylcholine may contribute to kindling and epileptogenesis.

Individualized developmental care for a large sample of very preterm infants: health, neurobehaviour and neurophysiology.

AIM: To assess medical and neurodevelopmental effects of Newborn Individualized Developmental Care and Assessment Program (NIDCAP) for a large sample of very early-born infants. METHODS: One hundred and seven singleton inborn preterm infants, <29 weeks gestational age (GA), <1250 g birth weight, enrolled in three consecutive phases, were randomized within phase to NIDCAP (treatment, E) or standard care (C). Treatment extended from admission to the Newborn Intensive Care Unit to 2 weeks corrected age (wCA). Outcome included medical, neurobehavioural and neurophysiological status at 2 wCA, and growth and neurobehavioural status at 9 months (m) CA. RESULTS: The C- and E-group within each of the three consecutive phases and across the three phases were comparable in terms of all background measures; they therefore were treated as one sample. The results indicated for the E-group significant reduction in major medical morbidities of prematurity as well as significantly improved neurodevelopmental (behaviour and electrophysiology) functioning at 2 wCA; significantly better neurobehavioural functioning was also found at 9 mCA. CONCLUSION: The NIDCAP is an effective treatment for very early-born infants. It reduces health morbidities and enhances neurodevelopment, functional competence and life quality for preterm infants at 2 w and 9 mCA.

Altered P300 topography in schizophrenia.

The spatiotemporal evolution of the P300 waveform was topographically mapped in a group of ten male chronic schizophrenics, using the technique of brain electrical activity mapping. Group-average P300 waveforms were constructed for the schizophrenic group and a group of matched controls. The control group's P300 showed a concentric development about a maximum in the centroparietal area, slightly displaced toward the left. In contrast, the schizophrenic group's P300 maximum was more anterior and to the right, with a deficiency in left temporal activity. Using the technique of significance probability mapping, it was demonstrated that the maximum between-group difference was localized to the left-middle and posterior temporal regions, where the schizophrenic group was deficient in activity.

Brain electrical activity mapping (BEAM) in schizophrenic patients.

A new topographic approach, brain electrical activity mapping, summarizes EEG and evoked potential data as color maps. Eleven drug-free and 14 medicated schizophrenic patients and 11 normal controls were studied with this technique. Compared with controls, both schizophrenic groups had more slow activity (delta, 0 to 3.5 Hz), greatest in frontal regions, and more fast activity (beta, 20 to 31.5 Hz) in postcentral regions. Both schizophrenic groups were different from controls late in the visual evoked potential and in the middle of the auditory evoked potential. Overall, using multivariate discriminant analysis, a very significant group separation effect was found, and retrospective classification was 95% successful in discriminating both schizophrenic groups from controls. To estimate the ability of our features to assign subjects prospectively to control or patient groups, we employed "jackknifing," which resulted in overall classification success rates of 84.0% for medicated schizophrenic patients v controls and 81.8% for drug-free schizophrenic patients v controls.

CT abnormalities in schizophrenia. A preliminary study of their correlations with P300/P200 electrophysiological features and positive/negative symptoms.

Computed tomographic scans were scored blindly for the size of cerebrospinal fluid spaces in a group of nine medicated schizophrenics and a group of nine age-matched normal volunteers without psychiatric or medical problems. Overall, ten of the 18 computed tomography (CT) features measured were significantly enlarged in the schizophrenic group. These abnormal CT features were then correlated with electrophysiological and clinical measurements performed on the schizophrenic patients. Left sylvian fissure enlargement, thought to reflect temporal lobe tissue loss, was highly correlated with a left temporal scalp region feature of the auditory P300 measure (T3 electrode) that differentiated schizophrenics and normals, and both the left sylvian fissure enlargement and the P300 measure were highly correlated with positive symptoms (total score on the Scale for the Assessment of Positive Symptoms). Frontal superficial (cortical) sulcal enlargement was prominent in the schizophrenic group and was highly correlated with another electrophysiological measure, auditory P200, at left central scalp locations. There was no significant correlation between left sylvian fissure and frontal sulcal enlargement within the schizophrenic group, and intercorrelations between CT variables in the schizophrenic group were, in general, less significant than in the control group. Although we should be cautious about generalizability because of the small number of patients, these data are compatible with the hypothesis that different subgroups of schizophrenic pathological features are characterized by different CT, electrophysiological, and clinical presentations.

COMBINED DELAY AND GRAPH EMBEDDING OF EPILEPTIC DISCHARGES IN EEG REVEALS COMPLEX AND RECURRENT NONLINEAR DYNAMICS.

The dynamical structure of the brain's electrical signals contains valuable information about its physiology. Here we combine techniques for nonlinear dynamical analysis and manifold identification to reveal complex and recurrent dynamics in interictal epileptiform discharges (IEDs). Our results suggest that recurrent IEDs exhibit some consistent dynamics, which may only last briefly, and so individual IED dynamics may need to be considered in order to understand their genesis. This could potentially serve to constrain the dynamics of the inverse source localization problem.

Abnormal flash visual evoked response in melancholia: a replication study.

Grand mean flash visual evoked responses (FVER) were measured in two new groups of depressed patients with melancholia to replicate findings of an abnormal FVER in a previously reported pilot study (Vasile et al 1989). These different, independently collected groups of melancholic patients demonstrated a statistically significant negative deviation of the FVER 224-300 msec poststimulus maximal in the midline centroparietal region when compared with appropriate normative age-matched control groups (n = 56) in each group). We utilized the identical computer-based quantified neurophysiological technique with mapping to analyze the data in all three melancholic patient groups--the pilot group (n = 9) with mean age 73.1 years, an older replication group (n = 14) with mean age 75.5 years, and a younger replication group (n = 15) with mean age 63.8 years. We also studied a group of depressed patients without melancholia (n = 11) with mean age 65.2 years, and found a similar, but less pronounced, alteration of the FVER. Lastly, we studied a group of nondepressed neuropsychiatric patients (n = 10) with mean age 61.9 years and found no abnormality of the FVER. Our data suggest that a gradient of FVER abnormality exists in depressed patients, most prominent, but not limited to elderly melancholic patients.

P300 in schizophrenia: confirmation and statistical validation of temporal region deficit in P300 topography.

Comparison of normal and medicated schizophrenic groups on the auditory P300 component of the event-related potential confirmed our earlier finding of a left temporal deficit in P300 amplitude in schizophrenia. A difference in P300 topography between groups was evident in both color mapping and in grand-averaged waveforms, which was statistically validated by the presence of a group-by-scalp region interaction (p less than 0.05). The left temporal area in schizophrenics was denoted as the region of greatest deficit and of maximal statistical separation (p less than 0.05) relative to normals by t statistic mapping (SPM), Hotelling's T-squared "protected" contrasts of individual scalp regions, and the relative ratio of left scalp amplitudes to right scalp amplitudes. The left temporal scalp region yielding maximal group separation in the previous study also statistically separated the schizophrenic group from the normal group. This feature correctly differentiated 9 of 11 schizophrenics and 7 of 9 controls. These findings are compatible with other histological, metabolic, and electrophysiological studies suggesting temporal lobe abnormality in schizophrenia.

Correlations between abnormal auditory P300 topography and positive symptoms in schizophrenia: a preliminary report.

P300 component amplitude in the left temporal scalp region, shown in three previous studies to differentiate normals from schizophrenics, was found to be significantly correlated with the Thought Disorder Index (TDI) and the Scale for the Assessment of Positive Symptoms (SAPS). These correlations occurred primarily in the P300 waveform derived from the Goodin paradigm. These findings suggest a brain processing disturbance in positive symptom schizophrenia that may be reflected by electrophysiological abnormalities detectable in the temporal scalp region.

Low-level sensory processing in obsessive-compulsive disorder: an evoked potential study.

This study used visual and auditory evoked potentials (VEP and AEP) to study low-level sensory processing in a group of 15 unmedicated subjects with obsessive-compulsive disorder (OCD) and 30 age-matched, gender-matched, and handedness-matched normal controls. EPs were recorded to flash (VEP) and binaural click (AEP) stimulation. OCD subjects were found to have significantly shorter latencies on N1 and P2 of the AEP, and no differences were found in the VEP. Results indicate abnormal information processing states in OCD during low-level auditory processing, but not during low-level visual processing. Neural generators of the VEP and AEP are briefly reviewed and results are discussed in relation to current neurobiological models of OCD.

The pattern of age-related differences in electrophysiological activity of healthy males and females.

Age-related differences in quantified electrophysiological measures were examined in 202 subjects (109 females; 93 males) ages 30-80 all of whom were judged to be optimally healthy on a wide variety of criteria. The study utilized both absolute and relative measures from EEG spectral analysis as well as additional measures from long latency-evoked potentials. The same findings were noted for the 109 newly studied females as were reported for 63 previously studied male subjects. Results indicate that there is a broad trend for decreased EEG slow and increased fast activity with age, however, some of the measures change linearly and others are best represented by nonlinear functions. There is no decade where activities remain stable. Overall the pattern of change for males and females is similar, however, gender differences in both the EEG and EP data were present. The females had higher magnitudes for almost all absolute spectral and fast relative spectral measures. However, females demonstrated lower absolute alpha amplitude, lower relative slow activity, and lower late-latency EP data. Moreover, the absolute slow activity measure showed a gender X age interaction, indicating that the females had a different change in pattern of activity with increasing age than the males. Thus, gender-related findings were complex and could not be expressed as simple differences in overall amplitude. Age-related change is not a simple linear process but differs for differing EEG spectral bands, relative, and absolute spectral measures and for males and females. The overall findings contradict the common wisdom that EEG and alpha slow with age and that age related EEG change is on a continuum with findings in Alzheimer's disease where increased slowing predominates.

Effects of age upon interhemispheric EEG coherence in normal adults.

Age-related differences in quantified electrophysiological measures of interhemispheric EEG coherence were studied in 371 subjects (171 males and 200 females), ages 20-80, all of whom were judged to be optimally healthy. Principal components analysis (PCA) was performed on interhemispheric coherence of Laplacian referenced data from eight homologous left-right electrode pairs, from 0.5 to 32 Hz. Regression procedures, using signals from artifact monitoring channels, were used to minimize effects of eye movement and muscle artifact. Forty-six factors described 80% of the total variance, with electrode location the primary source of communality in factor formation. Within 350 right-handed subjects, results indicated a broad trend for decreased interhemispheric coherence with advancing age. Using canonical correlation, the coherence-based factors also successfully predicted spectral variables, previously found to maximally illustrate age-related EEG desynchronization. We speculate that age-related reduction of interhemispheric coherence may in part explain age-related EEG desynchrony and stems from age-related reduction of cortical connectivity. Gender differences of interhemispheric coherence were also evident. Females demonstrated higher interhemispheric coherence than males. Within a smaller subpopulation of 63 subjects (21 left and 42 right handed), there was a gender-by-handedness interaction, with higher interhemispheric coherence in right-handed females than right-handed males and the reverse in left-handed male and female subjects.

Dark rearing prolongs physiological but not anatomical plasticity of the cat visual cortex.

Recent studies (Cynader and Mitchell, '80; Mower et al., '81) have shown that total dark rearing prolongs susceptibility to the physiological effects of monocular deprivation (MD) in visual cortex beyond the normal age limits. The present study addressed whether this delayed physiological plasticity is accompanied by delayed anatomical plasticity in the geniculocortical pathway. Ocular dominance (OD) columns as defined by transsynaptic autoradiography following injection of 3H proline into one eye were studied both qualitatively and quantitatively in 17 cats. Compared to normal rearing (N-3), both binocular eyelid suture (N-2) and total dark rearing (N-3) resulted in incomplete segregation of OD columns in area 17. This apparent immaturity after binocular deprivation, however, did not reflect a delayed capacity for development and plasticity. Visual experience after dark rearing produced no marked changes. In cats who experienced MD after dark rearing, injection of either the nondeprived (N-2) or deprived eye (N-3) resulted in a nearly uniform distribution of label throughout layer IV of area 17. The same result occurred with binocular vision after dark rearing (N-1). MD from birth, however, produced expansion of columns from the nondeprived eye (N-1) and contraction of columns from the deprived eye (N-1). MD imposed after 4 months of normal vision resulted in normal OD columns (N-1). Electrophysiological studies revealed a high proportion of binocular cells within layer IV in cats who experienced monocular or binocular vision after dark rearing. Outside of layer IV there were clear environmental effects on OD of single cells in these cats. Measurements of cell sizes in the clateral geniculate nucleus showed shrinkage of cells innervated by the deprived eye when MD was initiated at birth (N-3). MD after dark rearing (N-4) produced no differences in cell sizes. It is concluded that visual input is necessary for the formation of normal OD columns, the critical period for formation and environmental modification of OD columns is limited to early life, and the physiological effects of visual experience after dark rearing reflect changes occurring beyond the geniculocortical pathway.

Electrophysiologic comparisons between two groups of patients with Alzheimer's disease.

Two groups of patients with Alzheimer's disease were compared using brain electrical activity mapping. The patients were selected on the basis of their cognitive history. The initial symptom of disease of the patients in group 1 was a significant and profound memory deficit, whereas the patients in group 2 initially presented with a gradually progressive spatial impairment. Fourteen topographic features distinguished the groups. Eleven of the 14 features pertained to electrical activity differences in parietal regions, and 9 were bilateral. These features were highly correlated with cognitive measures that are also useful in distinguishing the groups.

Lecithin: absence of neurophysiologic effect in Alzheimer's disease by EEG topography.

Ten patients with Alzheimer's disease participated in a 26-week double-blind trial of lecithin. EEG data were recorded at baseline, after administration of the placebo, and after administration of the drug. Topographic maps of EEG spectra were compared when patients were on and off drugs. A direct comparison of drug and nondrug data was not significant. A second approach, comparing differences between drug and nondrug with differences between the two nondrug conditions, also produced no evidence of a drug treatment effect. The data confirm other reports that lecithin has no effect upon spectrally analyzed EEG activity in Alzheimer's disease.

Neurophysiological heterogeneity and the definition of dyslexia: preliminary evidence for plasticity.

Developments in the field of quantified electroencephalography have enhanced visualization of brain function in the learning disabilities. Optimal utilization of these techniques requires that populations under study be unambiguously defined. Evidence from the literature demonstrates that brain electrical activity of children with reading disability is more extensive and differs from that seen in children with "dyslexia-pure". Preliminary data are presented demonstrating that electrophysiological change seen in children with dyslexia-plus (dyslexia and attentional deficit disorder) could not be predicted by knowledge of electrophysiologic change in children with dyslexia-pure alone and attentional deficit disorder alone. Data from our laboratory are summarized to show that within dyslexia-pure the anomic, dysphonemic and global Denckla subtypes differ electrophysiologically from one another. Of particular interest is the demonstration that regions of electrophysiological difference among these subtypes may reflect compensatory mechanisms rather than pathological change. Finally, a case study is presented demonstrating advantageous effects of remediation upon brain electrical function. As both spontaneous and environmentally induced change in brain function can be documented, developmental dyslexia in its broadest terms appears to represent a more dynamic or plastic process than previously appreciated.

Individualized behavioral and environmental care for the very low birth weight preterm infant at high risk for bronchopulmonary dysplasia: neonatal intensive care unit and developmental outcome.

We hypothesize that the respiratory and functional states of the very low birth weight infant with bronchopulmonary dysplasia can be improved in the neonatal intensive care unit by prevention of inappropriate sensory input. To test this hypothesis, we developed for preterm newborns a behavior observation method that catalogues specific reaction patterns according to putative stress and relaxation behaviors. We then collected behavioral information and heart rate, respiratory rate, and transcutaneous PO2 readings before, during, and after routine care-giving interventions. Eight control and eight experimental infants were selected for study based on the following criteria: birth weight less than 1,250 g, gestational age less than 28 weeks, on the respirator greater than 24 hours in first 48 hours of life at greater than or equal to 0.60 FiO2 for more than two hours during first 48 hours of life. Additionally, the two groups were comparable on other medical and demographic variables, including severity of respiratory status for the first ten days and incidence of intraventricular hemorrhage, patent ductus arteriosus, and socioeconomic status. Systematic observations were conducted on days 10, 20, and 30 after birth and at 36 and 40 weeks postconception. For the intervention infants, our observations were discussed with the infants' primary nurses, and individualized modifications for each infant's care plan were implemented based on these observations. Experimental infants showed significantly briefer stays on the respirator (P less than .01) and in increased FiO2 (P less than .05). Their feeding behavior was normalized significantly earlier (P less than .01). Experimental infants also showed significantly better behavioral regulation scores at 1 month after their mothers' estimated dates of confinement (post-EDC), as measured with the Assessment of Preterm Infants' Behavior, significantly better Mental and Psychomotor Developmental Indices at 3, 6, and 9 months post-EDC, as measured with the Bayley Scales of Infant Development, and significantly better behavioral regulation scores at 9 months post-EDC, as measured in a videotaped play observation. Measurements of weight, height, and head circumference at 3, 6, and 9 months post-EDC showed no differences. All assessments were performed by one of two trained testers not familiar with the goals of the study or the group status of the infant. These results support the hypothesis that very low birth weight preterm babies profit significantly both medically and developmentally from individualized behavioral care in the neonatal intensive care unit.