Enhancing attention in children using an integrated cognitive-physical videogame: A pilot study.

Inattention can negatively impact several aspects of a child's life, including at home and school. Cognitive and physical interventions are two promising non-pharmaceutical approaches used to enhance attention abilities, with combined approaches often being marketed to teachers, therapists, and parents typically without research validation. Here, we assessed the feasibility of incorporating an integrated, cognitive-physical, closed-loop video game (body-brain trainer or 'BBT') as an after-school program, and also evaluated if there were attention benefits following its use. Twenty-two children (7-12 years of age) with a range of attention abilities were recruited to participate in this proof of concept, single-arm, longitudinal study (24 sessions over 8 weeks, ~30 min/day). We interrogated attention abilities through a parent survey of their child's behaviors, in addition to objective performance-based and neural measures of attention. Here we observed 95% compliance as well as, significant improvements on the parent-based reports of inattention and on cognitive tests and neural measures of attention that were comparable in scale to previous work. Exploratory measures of other cognitive control abilities and physical fitness also showed similar improvement, with exploratory evaluation of retained benefits on the primary attention-related outcomes being present 1-year later. Lastly, there was no correlation between the baseline parent-rated inattention score and the improvement on the primary task-based measures of attention, suggesting that intervention-based benefits were not solely attained by those who stood the most to gain. These pilot findings warrant future research to replicate and extend these findings.

Characterizing cognitive control abilities in children with 16p11.2 deletion using adaptive 'video game' technology: a pilot study.

Assessing cognitive abilities in children is challenging for two primary reasons: lack of testing engagement can lead to low testing sensitivity and inherent performance variability. Here we sought to explore whether an engaging, adaptive digital cognitive platform built to look and feel like a video game would reliably measure attention-based abilities in children with and without neurodevelopmental disabilities related to a known genetic condition, 16p11.2 deletion. We assessed 20 children with 16p11.2 deletion, a genetic variation implicated in attention deficit/hyperactivity disorder and autism, as well as 16 siblings without the deletion and 75 neurotypical age-matched children. Deletion carriers showed significantly slower response times and greater response variability when compared with all non-carriers; by comparison, traditional non-adaptive selective attention assessments were unable to discriminate group differences. This phenotypic characterization highlights the potential power of administering tools that integrate adaptive psychophysical mechanics into video-game-style mechanics to achieve robust, reliable measurements.

Children born prematurely have atypical sensory profiles.

OBJECTIVE: To determine if children born prematurely exhibit atypical responses to normally occurring sensory stimuli, as measured by the Sensory Profile. STUDY DESIGN: This is a cross-sectional study of children born at 32 weeks gestation, followed at 1 to 8 years of age. The Sensory Profile questionnaire was completed by each child's primary caregiver. The overall Sensory Profile was considered atypical if any quadrant or section score was >2 s.d. from the mean of the Sensory Profile validation group. Bivariate analyses were performed to determine associations between risk factors for adverse neurodevelopment and overall atypical Sensory Profiles. A section or quadrant was considered atypical if its score was >2 s.d. from the mean. A test of proportions was used to compute observed versus expected scores for each section and quadrant (Sensory Profile scores were based on a normal distribution so one would expect approximately 95% of participants to score within 2 s.d. of the mean). RESULT: Of our 107 participants, 39% had an atypical score in at least one section or quadrant. No specific perinatal or neonatal risk factors were associated with atypical overall Sensory Profiles (P0.05 for all). Children born prematurely were at risk of having atypical scores in the auditory, tactile and vestibular processing sections, and in the four Sensory Profile quadrants (P<0.05). CONCLUSION: Children born prematurely exhibit atypical sensory behaviors on the Sensory Profile. Further investigation to understand the underlying neural mechanisms and to develop effective interventions are critical to support neurodevelopment for these children.

The analytic impact of a reduced centrifugation step on chemistry and immunochemistry assays: an evaluation of the Modular Pre-Analytics.

BACKGROUND: The COBAS 6000 system can be completed by a Modular Pre-Analytics (MPA), an integrated laboratory automation system that streamlines preanalysis. For an optimal throughput, the MPA centrifuges blood collection tubes for 5 min at 1885 × g - a centrifugation time that is not in concordance with the World Health Organization guidelines which suggest centrifugation for 10/15 min at 2000-3000 × g. METHODS: In this study, the analytical outcome of 50 serum and 50 plasma samples centrifuged for 5 or 10 min at 1885 × g was investigated. The study included routine chemistry and immunochemistry assays on the COBAS 6000 and the Minicap capillary electrophoresis. RESULTS: Deming-fit and Bland-Altman plots of the 5-min and 10-min centrifugation steps indicated a significant correlation in serum samples. The lipaemia index in plasma samples centrifuged for 5 min displayed a statistically significant variation when compared with the 10-min centrifugation. CONCLUSIONS: Preanalytical centrifugation can be successfully down-scaled to a duration of 5 min for most routine chemistry and immunochemistry assays in serum and plasma samples. To prevent inaccurate results in plasma samples with an increased lipaemia index from being reported, the laboratory information system was programmed to withhold results above certain lipaemia indices. The presented data support the use of a 5-min centrifugation step to improve turnaround times, thereby meeting one of the desires of the requesting clinicians.

ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.

We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient.

ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal.

INTRODUCTION: We identified a female patient with mental retardation and sensory hyperarousal. She has a de novo paracentric inversion of one X chromosome with completely skewed inactivation of the normal X chromosome. OBJECTIVE: We aimed to identify whether a single gene or gene region caused her cognitive and behavioural impairment and that of others. RESULTS: Fluorescent in situ hybridisation (FISH) showed that the centromeric breakpoint disrupts a single gene: ARHGEF9 (CDC42 guanine nucleotide exchange factor (GEF) 9). The telomeric break lies in a gene poor region. We also found that the levels of the ARHGEF9 transcript from the patient are 10-fold less than those found in control samples. Consequently, we sequenced the coding exons and intron/exon borders of the ARHGEF9 gene in 99 probands from families with X linked mental retardation (XLMR) and 477 mentally retarded males in whom a diagnosis of Fragile X syndrome had been excluded. We did not identify any pathogenic changes; however, we did identify intronic nucleotide changes that might alter splicing. CONCLUSION: ARHGEF9 encodes a RhoGEF family protein: collybistin (hPEM), which is highly expressed in the developing and adult brain. Collybistin can regulate actin cytoskeletal dynamics and may also modulate GABAergic and glycinergic neurotransmission through binding of a scaffolding protein, gephyrin, at the synapse. This potential dual role may explain both the mental retardation and hyperarousal observed in our patient. While ARHGEF9 appears to be an uncommon cause of mental retardation in males, it should be considered in patients with mental retardation and sensory hyperarousal.

MAO activity in serotonergic endings of rat major cerebral arteries.

The present work studies the existence of monoamine oxidase (MAO) activity in serotonergic endings present in rat major cerebral arteries. Enzymatic activity was appraised in vivo by serotonin (5-HT) accumulation or 5-hydroxyindole acetic acid (5-HIAA) disappearance with time after systemic administration of MAO inhibitors. Pargyline (75 mg/Kg, ip) brought about significant 5-HT increase and 5-HIAA decrease in major cerebral arteries 30 and 60 min after its administration. Clorgyline (75 mg/Kg, ip) also induced 5-HT enhancement and 5-HIAA decline in these arteries 30 and 60 min after its injection. However, treatment with deprenyl (75 mg/Kg, ip) only evoked a significant 5-HT increase at 60 min. When either clorgyline (5 mg/Kg, ip) or deprenyl (5 mg/Kg, ip) were administered 5-HT and 5-HIAA levels remained unaffected. Two weeks after performing electrolytical lesion of dorsal raphe nucleus and 60 min after clorgyline (75 mg/Kg, ip) injection 5-HT and 5-HIAA levels appeared significantly reduced in cerebral arteries and striatum when compared to sham-lesioned controls. These results suggest that MAO-A isoform acting on endogenous 5-HT is present in rat major cerebral arteries and is located in nerve endings of fibers arising from dorsal raphe nucleus.

Local treatments of dorsal raphe nucleus induce changes in serotonergic activity in rat major cerebral arteries.

BACKGROUND AND PURPOSE: Rat major cerebral arteries seem to receive serotonergic fibers originating from the dorsal raphe nucleus (DRN), but little is known about their function. The aim of our present work was to establish a functional relationship between this brain stem nucleus and the cerebral blood vessels by studying the effects of several treatments in the DRN on cerebrovascular serotonergic activity. METHODS: Serotonin, clomipramine, 8-OH-DPAT, and WAY-100635 were administered in DRN. A stereotaxically localized electrode allowed the electrical stimulation of this brain stem nucleus. Serotonergic activity was appraised in major cerebral arteries, striatum, and hippocampus from 5-hydroxytryptophan accumulation after aromatic L-amino acid decarboxylase inhibition with NSD-1015. RESULTS: Serotonin significantly decreased serotonergic activity in major cerebral arteries and striatum without affecting it in hippocampus. This reduction was blocked by previous injection of WAY-100635 in DRN. Local administration of 8-OH-DPAT or clomipramine elicited an effect similar to that of serotonin, whereas that of WAY-100635 did not modify serotonergic activity in either of the tissues. Electrical stimulation of DRN significantly increased serotonergic activity in major cerebral arteries and striatum but not in hippocampus. CONCLUSIONS: These results confirm the presence of a serotonergic innervation in rat major cerebral arteries functionally related to DRN. 5-HT(1A) receptor activation partly mediates the action of serotonin in DRN. A serotonergic tone acting on these somatodendritic receptors was not clearly found.

Cervical gangliectomy does not affect in vitro tryptophan hydroxylase activity in rat brain base arteries.

The presence of a serotonergic innervation in rat cerebral arteries of peripheral origin was explored. Superior cervical ganglia removal did not change tryptophan hydroxylase activity measured in cell-free extracts of brain base vessels. A low enzyme activity was detected in the ganglia. These results suggest that rat cerebral arteries do not receive a serotonergic innervation from the superior cervical ganglia.

In vivo tryptophan hydroxylase activity in rat major cerebral arteries is decreased by dorsal raphe nucleus lesions.

The in vivo presence of tryptophan hydroxylase activity in rat major cerebral arteries as well as the possible origin of the structure containing it were explored. Enzyme activity was appraised by accumulation of 5-hydroxytryptophan after inhibition of aromatic L-amino acid decarboxylase. Decarboxylase inhibition evoked a significant increase in 5-hydroxytryptophan levels in rat cerebral arteries, striatum, hippocampus, hypothalamus, and plasma but had no effect on aorta. p-Chlorophenylalanine reduced 5-hydroxytryptophan accumulation in the cerebral vessels and brain nuclei, whereas alpha-methyltyrosine did not modify it except in hypothalamus, where it was enhanced. alpha-Methyltyrosine significantly reduced noradrenaline levels in cerebral arteries and L-dopa accumulation after inhibition of the decarboxylase in striatum. Dorsal raphe nucleus lesioning significantly diminished 5-hydroxytryptophan formation in cerebral arteries, striatum, and hypothalamus, without affecting it in hippocampus. Lesion of median raphe nucleus reduced 5-hydroxytryptophan accumulation in hippocampus and in hypothalamus but not in cerebral blood vessels or striatum. Superior cervical ganglia removal decreased noradrenaline levels in cerebral blood vessels without affecting 5-hydroxytryptophan accumulation. These results indicate the presence of a functionally active tryptophan hydroxylase in rat cerebral arteries associated with fibers originating from dorsal raphe nucleus. This supports that rat major cerebral arteries receive serotonergic innervation from central origin.

Cat cerebral arteries are functionally innervated by serotoninergic fibers from central and peripheral origins.

BACKGROUND AND PURPOSE: Tryptophan hydroxylase activity and responses to tyramine were analyzed in cat cerebral arteries to investigate serotoninergic innervation. METHODS: Enzymatic activity and responses to tyramine were measured in vessels from animals subjected to cervical gangliectomy and dorsal and median raphe nuclei lesions. RESULTS: Tryptophan hydroxylase activity in cat cerebral arteries was reduced after ganglia removal and raphe nuclei destruction. Contractile responses of the middle cerebral artery after gangliectomy were decreased by ketanserine. Dorsal raphe nucleus destruction had a significant effect on the contractile response, whereas median raphe nucleus destruction had only a slight effect. CONCLUSIONS: Cat cerebral arteries receive serotoninergic innervation from central and peripheral origins.

Different influence of superoxide anions and hydrogen peroxide on endothelial function of isolated cat cerebral and pulmonary arteries.

1. Exogenous superoxide dismutase (SOD) or catalase did not modify isolated cat middle cerebral arterial basal tone. Catalase but not SOD reduced ACh relaxation. 2. H2O2 induced endothelium-independent relaxation which was abolished by catalase. 3. 3-Amino-1,2,4-triazole (AT) evoked endothelium-dependent contractions and diminished ACh relaxation. 4. Diethyldithio carbamic acid (DETC) induced endothelium-independent relaxation and did not modify ACh vasodilatation. 5. ACh relaxation of cat isolated pulmonary arteries was unaffected by SOD, catalase or AT, and diminished by DETC. 6. Endothelial catalase but neither SOD nor superoxide anions is involved in EDRF cerebral vasodilatation and H2O2 participates in ACh relaxation. In pulmonary arteries, only endothelial SOD activity plays a role.

Serotonergic activity in rat cerebral arteries depends on dorsal raphe nucleus but not on median raphe nucleus.

The effect of Chlorimipramine and Muscimol on serotonergic activity in rat cerebral arteries and in dorsal and median raphe nuclei were used to study the presence of a serotonergic innervation in the cerebral blood vessels functionally dependent on the brainstem nuclei activity. Serotonergic activity was appraised in rat cerebral arteries from 5-hydroxyindoleacetic acid (5-HIAA) disappearance rate or 5-hydroxytryptophan (5-HTP) accumulation after inhibiting monoamine oxidase (MAO) or aromatic amino acids decarboxylase, respectively. In dorsal and median raphe nuclei the decay with time of 5-HIAA after MAO inhibition was used to estimate serotonergic activity. Chlorimipramine significantly reduced serotonergic activity in cerebral blood vessels and in both raphe nuclei. 5-HIAA basal levels in these blood vessels were not altered by treatment with the drug. Muscimol evoked only a decrease in the serotonergic activity of the median raphe nucleus. These results suggest that rat cerebral arteries receive serotonergic fibers functionally active arising mainly from dorsal raphe nucleus.

Neuropsychological functioning in siblings discordant for schizophrenia and healthy volunteers.

OBJECTIVE: To determine whether schizophrenics and their nonschizophrenic siblings have a similar pattern of neuropsychological deficit when compared with normal controls. DESIGN AND PARTICIPANTS: Fifteen probands with schizophrenia, 16 of their nonschizophrenic siblings, and 31 unrelated, demographically balanced, normal individuals underwent evaluation with a comprehensive neuropsychological test battery. All subjects were screened for history of head injury, neurologic illness, major medical conditions, substance use, and axis I psychiatric disorders other than schizophrenia. Probands underwent evaluation twice: once at intake when half had never received neuroleptic medication and the other half had received none for a minimum of 2 weeks, and again at the 2- to 4-week follow-up, after stabilization with neuroleptic medications. RESULTS: Both schizophrenics and their nonschizophrenic siblings were impaired neuropsychologically compared with normal controls, with the nonschizophrenic siblings' performance intermediate between that of the schizophrenic siblings and the normal controls on all measures of functioning. The shapes of the deficit profiles of schizophrenic patients and their siblings were similar; in patients, verbal memory, abstraction, attention, and language functions were significantly more affected compared with spatial abilities, spatial memory, and sensory-motor functions, with a nonsignificant trend in the same direction in siblings. Cognitive functioning in patients was found to be stable across changes in medication status and clinical state. Four fifths of patients obtained more deviant scores than their nonschizophrenic siblings. Among the sibling group, those with probable and certain diagnoses of schizotypal personality disorder were more impaired compared with those without schizophrenia-spectrum symptoms. CONCLUSION: These results support the hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder. Further work is needed to establish whether particular areas of functioning are selectively impaired in relatives and to determine whether the performance deficits are mediated by structural and/or metabolic disturbances in specific brain regions.

Tryptophan hydroxylase activity in rat brain base arteries related to innervation originating from the dorsal raphe nucleus.

BACKGROUND AND PURPOSE: Tryptophan hydroxylase activity was assayed in cell-free extracts of rat brain base arteries as marker of a serotonergic innervation. METHODS: Estimation of the enzymatic activity was made in untreated male Sprague-Dawley rats (n = 53) and in those who underwent destruction of the dorsal and median raphe nuclei (n = 10). RESULTS: Tryptophan hydroxylase activity was measured in rat cerebral arteries. The time-dependent 5-hydroxytryptophan production was undetectable in the absence of tryptophan or 6-methyltetrahydropterine and in the presence of 6-fluorotryptophan, and it was significantly reduced in the presence of p-chlorophenylalanine. Destruction of the dorsal raphe nucleus but not the median raphe nucleus brought about a significant reduction in enzyme activity. CONCLUSIONS: These results suggest that rat cerebral arteries receive a serotonergic innervation arising from the dorsal raphe nucleus.

[Analysis of antihypertensive effectiveness by means of ambulatory blood pressure monitoring. Usefulness of the Discrete Fourier Transform Model]. / Análisis de la efectividad antihipertensiva mediante el monitoreo ambulatorio de presión arterial. Utilidad del modelo de Transformada de Fourier Discreta.

In order to assess the usefulness of the Discrete Fourier Transform Model (DFT) to evaluate time-course drug effects on hypertensive patients studied with Ambulatory Blood Pressure Monitoring (ABPM) a number of experiments were carried out. A total of 10 mild to moderate hypertensive patients were evaluated under placebo and after 8 weeks of active treatment with Enalapril 20 mg per day using ABPM. Systolic and Diastolic blood pressure (SBP and DBP) were registered every 15 minutes during daytime and every 30 minutes at night. Pressure profiles of each patient were initially smoothed by hourly means. DFT was then applied to these profiles. The minimum number of harmonics necessary to generate a statistically significant fitting of the blood pressure profile, were obtained by residuals analysis (run test and analysis of variance of the mean sum of residual squares with each new harmonic incorporated to the model). A profile of the blood pressure differences (treatment-placebo) with the rough data of each patient was smoothed by hourly means. DFT was applied again on these substraction profiles. To estimate peak and trough drug effects for the blood pressure decrease function, maximum, minimum and inflexion points were calculated defining the following parameters: T peak: time from drug administration to maximum pressure decrease; T late response: time from drug administration to the inflexion point following the last minimum previous to the next dose; BP peak: the maximum blood pressure decrease amplitude; and the slope BP peak/T peak. The stability of the individual circadian rhythm was confirmed for both ABPM controls comparing times of maximum and minimum on the DFT smoothed profiles.(ABSTRACT TRUNCATED AT 250 WORDS)

Analisis de la efectividad antihipertensiva mediante el monitoreo ambulatorio de presion arterial. Utilidad del modelo de Transformada de Fourier Discreta / Analysis of antihypertensive effectiveness by means of ambulatory blood pressure monitoring. Usefulness of the discrete fourier transform model

Se estudiaron 10 pacientes con hipertensión arterial a moderada a quienes se efectuó un monitoreo ambulatorio (MAPA) luego de 30 dias de placebo, y otro al cabo de ocho semanas de tratamiento con una dosis fija de 20 mg de maleato de enalapril. La presión arterial sistólica (PAS) y diastólica (PAD) se registró cada 15 minutos de 07 a 22 hs, y cada 30 minutos de 22 a 07 hs. Los perfiles presores y los perfiles de las diferencias presoras droga-placebo individuales, fueron alisados por los promedios horarios. Luego se aplicó la Transformada de Fourier Discreta (TFD). Se determinó el menor número de armónicas que generan un ajuste estadisticamente significativo por análisis de residuos. En las curvas de diferencias presoras alisadas por TFD, se calcularon máximos, mínimos y puntos de inflexión para determinar: el tiempo de respuesta rápida (intervalo entre toma de la droga y máximo efecto), el tiempo de duración del efecto de la droga (intervalo entre toma de medicación y punto de inflexión, siguiente al último mínimo previo a una nueva dosis) y la pendidente de descenso rápido (cociente entre máximo descenso presor y tiempo de respusta rápida). Dependiendo del paciente, 3 a 5 armónicas en las curvas alisadas por TFD de PAS, PAD y de las diferencias droga-placebo, son suficientes para ajustar los promedios presores horarios. Se confirmó la estabilidad del ritmo circadiano en ambos monitoreos. El efectos se presentó a las 3 hrs (rango: 2 a 5) de toma de dosis; y la duración máxima media del efecto de la medicación fue de 17,6 hs para la PAS y de 18,5 hs para la PAD. Se concluye que las diferencias presoras tratamiento-placebo obtenidas a partir del MAPA y analizadas según el modelo de RFD permiten evaluar los intervalos de tiempo de protección presora asociados a un tratamiento antihipertensivo

Effects of L-arginine analogues in isolated cat cerebral arteries.

The possible contribution of nitric oxide (NO) to the endothelium-dependent relaxation of isolated cat cerebral arteries was studied by examining the effects of the L-arginine (L-ARG) analogues L-canavanine and NG-nitro-L-arginine (L-NOARG) on acetylcholine-induced relaxation. L-canavanine (100 microM) as well as L-NOARG (10 microM) decreased significantly the relaxant response of acetylcholine, their effect being significantly reversed by L-arginine (10 microM) but not by D-arginine (10 microM). In resting conditions, L-NOARG (10 microM) elicited a contraction of 314 +/- 42 mg in arteries endowed with endothelium that was significantly diminished by endothelium removal to 88 +/- 35 mg, and by (10 microM) L-arginine to 135 +/- 54 mg. L-canavanine (100 microM) induced contractions in arteries with and without endothelial cells which were not statistically different. The results suggest that the endothelium of cat cerebral arteries has the ability to synthesize nitric oxide from L-arginine and to release it, even in the absence of a stimulus such as that of acetylcholine. L-NOARG seems to be a specific and powerful inhibitor of nitric oxide synthesis.

Ambulatory blood pressure monitoring and diastolic left ventricular abnormalities in established and borderline hypertension

In order to evaluate left ventricular diastolic function by means of Doppler echocardiography in borderline and established hypertension, identified by office and ABPM, compared with normotensives, 54 subjects: 15 normotensives, 11 borderlines and 28 nontreated mild to moderate essential hypertensives were studied. Age and weight were similar among groups. Established hypertensives showed higher left ventricular mass index (p < 0.05), peak velocity of late left ventricular filling (peak A; p < 0.01), ratio peak A/peak velocity of early ventricular filling, peak E (p < 0.01), velocity time integral of systolic atrial volume (p < 0.001), deceleration half time of peak early diastolic inflow velocity (p < 0.05), left ventricular isovolumic relaxation period (IRP; p < 0.01) than normotensives and lower Doppler indexes of early diastolic left ventricular filling (p < 0.01), peak filling rat normalized to mitral stroke volume (PFRn; p < 0.01) than normotensives. Although borderline hypertensives showed intermediate LVM and Doppler indexes between hypertensives and normotensives only IRP (p < 0.05) and PFRn (p < 0.05) were significant different to normotensives. In conclusion, established hypertension leads to abnormalities in left ventricular diastolic function which can be detected by Doppler echocardiography. In borderline hypertension, the left ventricular diastolic abnormalities are predominantly related to the active process of early diastole. Therefore, these indexes may be early markers of left ventricular dysfunction in hypertension.