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.

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.

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.

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.

Recovery of erythrocyte Na(+)-K(+)-Cl- cotransport activity by enalapril.

We studied total exchangeable sodium, ion transport activity at maximal rate, and erythrocyte Na+ content in response to angiotensin converting enzyme inhibition in mild-to-moderate essential hypertensive patients with normal renal function. Twenty-five patients (mean age 56 years, range 40-62 years) who had abnormal red blood cell Na(+)-K(+)-Cl- cotransport or red blood cell Li(+)-Na+ countertransport were treated with either enalapril (20 mg daily) or hydrochlorothiazide (50 mg daily) during a 30-day period. During the period of enalapril treatment, Na(+)-K+ pump and Na(+)-K(+)-Cl- cotransport increased significantly from 4,282 +/- 255 to 5,236 +/- 325 mumol/l red blood cell/hr (p less than 0.01) and 166 +/- 21 to 220 +/- 24 mumol/l red blood cell/hr (p less than 0.05), respectively. Mean intracellular Na+ content in erythrocytes decreased from 11.4 +/- 0.40 to 10.0 +/- 0.33 mmol/l (p less than 0.01) and exchangeable Na+ from 39.8 +/- 0.6 mmol/kg to 35.6 +/- 0.6 mmol/kg (p less than 0.001). Sodium reduction correlated with the recovery of Na(+)-K(+)-Cl- cotransport activity (r = -0.65, p less than 0.01). During treatment, systolic and diastolic blood pressures were reduced significantly (p less than 0.01). In 12 patients treated with hydrochlorothiazide, Na(+)-K(+)-Cl- cotransport, Na(+)-K+ pump, Na(+)-Li+ countertransport, and Na+ permeability did not change significantly while Na+ content decreased from 11.7 +/- 0.3 to 10.3 +/- 0.2 mmol/l (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term evaluation of cilazapril in severe hypertension. Assessment of left ventricular and renal function.

The effect of cilazapril as monotherapy or in combination with hydrochlorothiazide was assessed in 30 severely hypertensive patients, 23 men and seven women, aged 38 to 68 years, with sitting diastolic blood pressure of more than 115 mmHg. Fifteen patients had left ventricular hypertrophy documented by two-dimensional echo-cardiography. Sitting systolic blood pressure was reduced from 175.8 +/- 2.0 to 143.3 +/- 3.0 mmHg within 25 days of therapy (p less than 0.0001); sitting diastolic blood pressure decreased in the same period from 117.0 +/- 1.0 to 87.8 +/- 2.0 mmHg (p less than 0.0001), whereas heart rate remained unchanged. In 19 patients treated for an average of 48 weeks the therapeutic response was maintained during the long-term period. The mean effective dose was cilazapril 10 mg plus hydrochlorothiazide 12.5 to 25 mg in 90 percent of the patients. Left ventricular mass decreased from 357 +/- 17 to 314 +/- 22 g (nine patients; p less than 0.005) and a correlation (Spearman r = 0.57, p less than 0.01) was found between left ventricular mass and sitting systolic blood pressure before and during treatment. Deceleration half time of peak early diastolic inflow velocity decreased significantly from 128 +/- 9 to 108 +/- 7 msec (p less than 0.05). Glomerular filtration rate and renal blood flow remained within normal limits, whereas renal vascular resistance decreased from 0.16 +/- 0.0 to 0.10 +/- 0.0 resistance units (10 patients; p less than 0.01). Cilazapril in combination with hydrochlorothiazide was effective in the treatment of severe hypertension. Left ventricular hypertrophy regression influenced favorably left ventricular diastolic function in some patients, whereas renal hemodynamics were generally not affected by the therapy.

Role of cardiopulmonary mechanoreceptors in the postural regulation of renin.

To change the stretch on cardiopulmonary mechanoreceptors, large shifts of blood in the capacity space were elicited by tilting and by exerting positive lower body pressure in the tilted position. Twelve volunteers underwent invasive hemodynamic studies and in 10 other subjects cardiac size was determined by radionuclide cardiography. In all 22 subjects tilting caused the expected increase of renin, which was abolished by lower body compression. Decompression caused renin to increase again. Right atrial pressure in invasive studies and end-systolic and end-diastolic counts in noninvasive studies showed a significant and strong negative correlation with renin and norepinephrine levels. Thus, the degree of stretch of the cardiopulmonary mechanoreceptors is a major determinant of reflex regulation of renin release in humans.

Effects of ACE inhibition on renal haemodynamics in essential hypertension and hypertension associated with chronic renal failure.

Angiotensin II has many actions in the kidney, including regulation and distribution of renal circulation and glomerular filtration, as well as effects on mesangial contraction and on the filtration coefficient. The reduction in circulating and intrarenal angiotensin II by angiotensin converting enzyme (ACE) inhibitors in essential hypertension is associated with a significant increase in renal blood flow and a decrease in filtration fraction, without changes in glomerular filtration rate. In addition, administration of ACE inhibitors can reduce proximal sodium reabsorption via changes in peritubular hydrostatic and oncotic forces resulting from the fall in postglomerular capillary resistance. In severe hypertension the state of the renal vasculature does not allow ACE inhibition to induce similar haemodynamic changes and, therefore, it cannot contribute to renal sodium handling that requires the recruitment of alternate mechanisms. In spite of this, ACE inhibitors may exert a protective effect on the renal function of patients with severe hypertension as well as in those with renal impairment, by lowering systemic and, probably, intraglomerular pressure, reducing proteinuria and slowing the progression of renal failure.

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.

Serotonergic innervation of cat cerebral arteries.

5-HT and 5-HIAA were measured in cat cerebral arteries by HPLC. Removal of both superior cervical ganglia or simultaneous lesions of dorsal and central raphe nuclei significantly decreased 5-HT levels but not those of 5-HIAA. This suggests that cat cerebral blood vessels are innervated by serotonergic fibers of different origin.

Lesion of the dorsal raphe nucleus induces supersensitivity to serotonin in isolated cat middle cerebral artery.

Simultaneous lesions of dorsal and median raphe nuclei were induced after 15 days postjunctional supersensitivity to serotonin in isolated segments of cat middle cerebral artery. The same result was obtained when only the dorsal raphe nucleus was destroyed. The lesion of the median raphe nucleus brought about an increased contractile response to serotonin only at the three first doses used. The contractile response to noradrenaline was unaffected by these treatments. These results suggest the existence of a serotonergic innervation of the cat middle cerebral artery whose main origin might be the dorsal raphe nucleus.

The effects of antidepressants on serotonin turnover in discrete regions of rat brain.

Serotonin (5-HT) turnover was measured in hypothalamus, hippocampus, cortex, septum and nucleus caudatus of rats after acute or chronic treatment with antidepressants. Acute chlorimipramine (1.8 -- 16.2 mg/kg i.p.) decreased 5-HT turnover in all the areas tested as measured by the rate of accumulation of 5-hydroxyindoleacetic acid after probenecid, or the rate of accumulation of 5-hydroxytryptophan after decarboxylase inhibition. However, chlorimipramine failed to reduce the rate of 5-HT accumulation after monoamine oxidase inhibition. Chronic chlorimipramine treatment (3 times daily for 2 weeks) did not change the 5-HT turnover. Fluoxetine, which like chlorimipramine specifically blocks 5-HT uptake also decreased 5-HT synthesis. In contrast, no change in 5-HT turnover was observed after desmethylimipramine, amitriptyline, iprindole or amphetamine which affect the catecholaminergic, but not serotoninergic systems.

Indirect adrenergic effect of histamine in cat cerebral arteries.

Histamine (10(-4) M) induced an increase in the tritium outflow from cat cerebral arteries preloaded with 3H-noradrenaline. Pretreatment with reserpine (3 mg/kg, i.p., total dose) or removal of both superior cervical ganglia two weeks before the experiment abolished that increase. The presence of cocaine or diphenhydramine also prevented the rise in tritium efflux induced by histamine. Histamine (10(-8 M to 10(-3) M) elicited dose-dependent contractions in the isolated posterior communicating artery of the cat which were reduced in the presence of diphenhydramine at all doses except the highest three. The addition of phentolamine to the bath decreased the contractile responses at the doses lower than 10(-6) M. Pretreatment with reserpine or removal of both superior cervical ganglia also diminished the responses at doses of histamine below 10(-6) M and 10(-5) M, respectively. When cocaine was added to the bath there was a decrease in the contraction elicited at all doses except the last one. These results suggest the existence of an indirect adrenergic mechanism in the contractile response to histamine in cat cerebral arteries.

Bilateral innervation of the cerebral arteries by the superior cervical ganglion in cats.

The effect of removal of the left superior cervical ganglion on the contractile response to norepinephrine (NE) and 5-hydroxytryptamine (5-HT, serotonin) was studied in isolated segments of the middle cerebral artery (MCA) and posterior communicating artery (PCoA) of the cat. Fifteen days after the excision, each dose of NE elicited a potentiated response in both the MCA and the PCoA, whichever side they originated. By contrast, 5-HT induced enhanced vasoconstriction at each dose only in the MCA and PCoA from the left side. When segments of MCA and PCoA from the right side were challenged against 5-HT, a significantly increased response was found only at the first three doses. On the other hand, the NE content of pools made of MCA, PCoA, and anterior cerebral artery from each side was reduced to the same level on both sides after ganglion removal. These results indicate that the excised superior cervical ganglion innervated the MCA and PCoA from both sides of the circle of Willis.

Measurement of 5-hydroxytryptamine turnover rate in rat cerebral arteries.

Two methods for assessing 5-hydroxytryptamine (5-HT) turnover rate have been tested in the cerebral vessels of the rat. The pretreatment of the animals with benserazide 45 min before death brought about an increase in the levels of 5-hydroxytryptophan (5-HTP). When the MAO inhibitor pargyline was injected and the animals killed at different times, there was an exponential decrease in the concentration of 5-hydroxyindole acetic acid (5-HIAA) with time, whereas the increase in 5-hydroxytryptamine was linear only during the first 30 min, thereafter reaching a plateau. This pattern was similar to that obtained in the caudate nucleus after MAO blockade. In the hippocampus, pargyline induced a lineal accumulation of 5-HT throughout the experiment as well as an exponential decay of the 5-HIAA concentration. These results indicate that the turnover rate of 5-HT can be appraised in the rat cerebral arteries either after the rate of disappearance of 5-HIAA or from the accumulation rate of 5-HTP.

Cocaine-like action of diphenhydramine in cat cerebral arteries.

Diphenhydramine (5.3 X 10(-7) M) significantly reduced the tritium efflux evoked by 10(-7) M tyramine from cat cerebral arteries preloaded with [3H]noradrenaline but not that brought about by 50 mM KCl. These results indicate the ability of diphenhydramine to block the amine neuronal uptake.

Mechanism of the indirect adrenergic effect of histamine in cat cerebral arteries.

KCl (50 mM), tyramine (10(-7) M), and histamine (10(-4) M) induced an increase in tritium release from cat cerebral arteries preincubated with [3H]noradrenaline, this increase being due in part to noradrenaline. When calcium was absent from the superfusion medium, only tyramine (10(-7) M) enhanced the tritium outflow. Colchicine (10(-3) M) partially inhibited the increase in radioactivity brought about by 10(-4) M histamine. KCl (50 mM) also evoked release of radioactivity from cerebral arteries preloaded with [3H]histamine; this release was unaffected by reserpine pretreatment or removal of both superior cervical sympathetic ganglia. Neither tyramine (10(-7) M) nor compound 48/80 (300 micrograms ml-1) altered the spontaneous tritium outflow from cerebral blood vessels preincubated with [3H]histamine. These results suggest that histamine is not accumulated by sympathetic nerve endings and elicits its noradrenaline-releasing effect by means of an exocytotic process.

Indirect adrenergic effect of histamine in human cerebral arteries: influence of post-mortem period.

Histamine (10(-4) M) increased the radioactivity released from human cerebral arteries obtained within 6 h of death and preincubated with [3H]noradrenaline. In the presence of 10(-6) M cocaine or if 7 or more hours had elapsed since death, 10(-4) M histamine was unable to change basal levels of tritium outflow. The radioactivity retained by the tissue was higher when cerebral blood vessels were obtained within a post-mortem period of 6 h. These results suggest that histamine may release noradrenaline from the sympathetic innervation of human cerebral arteries and that the function of this innervation lasts only 6 h after death.

Analysis of the contractile effect of 5-hydroxytryptamine on the isolated posterior communicating artery of the cat.

5-Hydroxytryptamine (5-HT) induced dose-dependent increases in tension on the isolated posterior communicating artery (PCA) of the cat were significantly antagonized by lysergic acid diethylamide (LSD, 6 X 10(-9). In the presence of the phentolamine (10(-6) M) the contraction induced by the two lowest doses of 5-HT was significantly reduced. Pretreatment of the animals with reserpine (3 mg kg-1, i.p., total dose) did not modify the dose-response curve to 5-HT except for the lowest dose. Removal of both superior cervical sympathetic ganglia 15 days before the experiment brought about a significant increase in the vasoconstriction induced by 5-HT at all the doses compared with the control. Cocaine (10(-6) M) induced a significant shift to the left of the dose-response curve to 5-HT but the maximum response was the same as in the control. The augmented response to 5-HT after denervation was partially antagonized by LSD (6 X 10(-9) M) but not by phentolamine (10(-6) M). These results show that the vasoconstriction elicited by 5-HT in the PCA of the cat is mainly due to direct stimulation of tryptaminergic receptors. The participation of an indirect adrenergic component in the contractile effects of 5-HT seems to be negligible.