Neurobiological model of visuo-spatial cognition in young Williams Syndrome children: measures of dorsal-stream and frontal function

We examine hypotheses for the neural basis of the profile of visual cognition in young children with Williams syndrome (WS). These are: (a) that it is a consequence of anomalies in sensory visual processing; (b) that it is a deficit of the dorsal relative to the ventral cortical stream; (c) that it reflects deficit of frontal function, in particular of fronto-parietal interaction; (d) that it is related to impaired function in the right hemisphere relative to the left. The tests reported here are particularly relevant to (b) and (c). They form part of a more extensive programme of investigating visual, visuospatial, and cognitive function in large group of children with WS children, aged 8 months to 15 years. To compare performance across tests, avoiding floor and ceiling effects, we have measured performance in children with WS in terms of the ‘age equivalence’ for typically developing children. In this paper the relation between dorsal and ventral function was tested by motion and form coherence thresholds respectively. We confirm the presence of a subgroup of children with WS who perform particularly poorly on the motion (dorsal) task. However, such performance is also characteristic of normally developingchildren up to 5 years: thus the WS performance may reflect an overall persisting immaturity of visuospatial processing which is particularly evident in the dorsal stream. Looking at the performance on the global coherence tasks of the entire WS group, we find that there is also a subgroup who have both high form and motion coherence thresholds, relative to the performance of children of the same chronological age and verbal age on the BPVS, suggesting a more general global processing deficit. Frontal function was tested by a counterpointing task, ability to retrieve a ball from a ‘detour box’, and the Stroop-like ‘day-night’ task, all of which require inhibition of a familiar response. When considered in relation to overall development as indexed by vocabulary, the day-night task shows little specific impairment, the detour box shows a significant delay relative to controls, and the counterpointing task shows a marked and persistent deficit in many children. We conclude that frontal control processes show most impairment in WS when they are associated with spatially directed responses, reflecting a deficit of fronto-parietal processing. However, children with WS may successfully reduce the effect of this impairment by verbally mediated strategies. On all these tasks we find a range of difficulties across individual children and a small subset of WS who show very good performance, equivalent to chronological age norms of typically developing children. Neurobiological models of visuo-spatial cognition in children with WS p.4 Overall, we conclude that children with WS have specific processing difficulties with tasks involving frontoparietal circuits within the spatial domain. However, some children with WS can achieve similar performance to typically developing children on some tasks involving the dorsal stream, although the strategies and processing may be different in the two groups.

Anatomical study comparing the thickness of the volar and dorsal cortex of cadaveric adult distal radii using digital photography

INTRODUCTION:

Dorsally displaced fractures of the distal radius fractures are one of the commonest in day-to-day practice. There is still no consensus among surgeons regarding the suitability of using volar or the dorsal cortex as basis for internal fixation for dorsally displaced fractures.

BACKGROUND:

We report an anatomical study, which compares the thickness of the volar and dorsal cortices of cadaveric adult radii using digital photography.

RESULTS:

Results of this study show that the volar cortex was statistically, significantly thicker than the dorsal cortex. We believe that the volar cortex may behave as the calcar of the distal radius and hence internal fixation devices applied to the volar cortex may provide a more stable internal fixation compared to those based on the dorsal cortex.

Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader-Willi syndrome

Previous work has suggested that there are specific deficits in dorsal stream processing in a variety of developmental disorders. Prader-Willi syndrome (PWS) is associated with two main genetic subtypes, deletion and disomy. Relative strengths in visual processing are shown in PWS, although these strengths may be specific to the deletion subtype. We investigated visual processing in PWS using an adapted Simon task which contrasted location (dorsal stream) and shape identity (ventral stream) tasks. Compared to a group of typically developing children, children with PWS deletion showed a greater degree of impairment in the dorsal stream task than in the ventral stream task, a pattern similar to that shown in a group of boys with Fragile-X syndrome. When matched on a measure of non-verbal ability, children with PWS disomy showed the opposite pattern with better performance in the location compared to the shape task, although these task performance asymmetries may have been linked to executive control processes. It is proposed that children with PWS deletion show a relative strength in visual processing in the ventral stream along with a specific deficit in dorsal stream processing. In contrast, children with PWS disomy show neither effect. (C) 2009 Published by Elsevier Ltd.

Changes in fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

Fos imaging reveals that lesions of the anterior thalamic nuclei produce widespread limbic hypoactivity in rats

Activity of the immediate early gene c-fos was compared in rats with neurotoxic lesions of the anterior thalamic nuclei and in surgical controls. Fos levels were measured after rats had been placed in a novel room and allowed to run up and down preselected arms of a radial maze. An additional control group showed that in normal rats, this exposure to a novel room leads to a Fos increase in a number of structures, including the anterior thalamic nuclei and hippocampus. In contrast, rats with anterior thalamic lesions were found to have significantly less Fos-positive cells in an array of sites, including the hippocampus (dorsal and ventral), retrosplenial cortex, anterior cingulate cortex, and prelimbic cortex. These results show that anterior thalamic lesions disrupt multiple limbic brain regions, producing hypoactivity in sites associated in rats with spatial memory. Because many of the same sites are implicated in memory processes in humans (e.g., the hippocampus and retrosplenial cortex), this hypoactivity might contribute to diencephalic amnesia.

Evaluation of the antiangiogenic potential of AQ4N.

Purpose: A number of cytotoxic chemotherapy agents tested at low concentrations show antiangiogenic properties with limited cytotoxicity, e.g., cyclophosphamide, tirapazamine, and mitoxantrone. AQ4N is a bioreductive alkylaminoanthraquinone that is cytotoxic when reduced to AQ4; hence, it can be used to target hypoxic tumor cells. AQ4N is structurally similar to mitoxantrone and was evaluated for antiangiogenic properties without the need for bioreduction.

Experimental Design:The effect of AQ4N and fumagillin on human microvascular endothelial cells (HMEC-1) was measured using a variety ofin vitro assays, i.e., 3-(4,5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide, wound scrape, tubule formation, rat aortic ring, and invasion assays. Low-dose AQ4N (20 mg/kg) was also given in vivo to mice bearing a tumor in a dorsal skin flap.

Results:AQ4N (10-11to10-5mol/L) hadno effect on HMEC-1viability. AQ4N (10-9to10-5mol/L) caused a sigmoidal dose-dependent inhibition of endothelial cell migration in the wound scrape model. Fumagillin showed a similar response over a lower dose range (10-13 to 10-9 mol/L); however, the maximal inhibition was less (25% versus 43% for AQ4N). AQ4N inhibited HMEC-1 cell contacts on Matrigel (10-8 to 10-5 mol/L), HMEC-1 cell invasion, and sprouting in rat aorta explants. Immunofluorescence staining with tubulin, vimentim, dynein, and phalloidin revealed that AQ4N caused disruption to the cell cytoskeleton. When AQ4N (20 mg/kg) was given in vivo for 5 days, microvessels disappeared in LNCaP tumors grown in a dorsal skin flap.

Conclusions:This combination of assays has shown that AQ4N possesses antiangiogenic effects in normoxic conditions, which could potentially contribute to antitumor activity

Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats.

The extensive clinical experience of angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists as antihypertensive agents provide numerous examples of anecdotal evidence of improvements in cognition and mood. This study aimed to determine the effect of chronic treatment with the angiotensin converting enzyme inhibitor, perindopril, and the angiotensin AT(1) receptor antagonist, candesartan, on central neurotransmitter levels in the rat. Perindopril (1.0mg/kg/day) or candesartan (10mg/kg/day) was administered via the drinking water at for 1 week, while controls received water alone. At the end of treatment rats were sacrificed, brains removed and discrete regions dissected and analysed for noradrenaline, dopamine and its major metabolites, and serotonin content. As shown previously we found an increase in striatal dopamine levels after perindopril treatment, though this did not extend to the mesolimbic system with neurotransmitter levels unchanged in the hippocampus, nucleus accumbens and frontal cortex. Conversely, candesartan administration produced no change in dopamine, but significant decreases in both DOPAC and HVA in the striatum. In addition chronic candesartan infusion produced a significant increase in the levels of hippocampal noradrenaline and serotonin; and frontal cortex serotonin content. These results demonstrate that while angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists act as antihypertensives by affecting the renin-angiotensin system, they have divergent actions on brain neurochemistry.

Isolation and preliminary biological assessment of AADGAPLIRFamide and SVPGVLRFamide from Caenorhabditis elegans

To date, 9 FMRFamide-related peptides (FaRPs) have been structurally characterised from Caenorhabditis elegans. Radioimmunometrical screening of an ethanolic extract of C. elegans revealed the presence of two additional FaRPs that were purified by reverse-phase HPLC and subjected to Edman degradation analysis and gas-phase sequencing. Unequivocal primary structures for the two FaRPs were determined as Ala-Ala-Asp-Gly-Ala-Pro-Leu-Ile-Arg-Phe-NH2 and Ser-Val-Pro-Gly-Val-Leu-Arg-Phe-NH2. Using MALDI-TOF mass. spectrometry, the molecular masses of the peptides were found to be 1032 Da (MH) and 875 Da (MH)(+), respectively. Two copies of AADGAPLIRFamide are predicted to be encoded on the precursor gene termed flp-13, while one copy of SVPGVLRFamide is located on flp-18. Synthetic replicates of the peptides were tested on Ascaris suum somatic muscle to assess bioactivity. ADDGAPLIRFamide had inhibitory effects on A. suum muscle strips, which occurred over a range of concentrations from a threshold for activity of 10 nM to 10 muM. SVPGVLRFamide was excitatory on A. suum somatic musculature from a threshold concentration for activity of 1 nM to 10 muM. The inhibitory and excitatory effects of AADGAPLIRFamide and SVPGVLRFamide, respectively, were the same for dorsal and ventral muscle strips as well as innervated and denervated preparations, suggesting that these physiological effects are not nerve cord dependent. Addition of ADDGAPLIRFamide (10 muM) to muscle strips preincubated in high-K+ and -Ca2+-free medium resulted in a normal inhibitory response. Peptide addition to muscle strips preincubated in Cl--free medium showed no inhibitory response, suggesting that the inhibitory response of the peptide may be chloride mediated. A normal excitatory response was noted following the addition of 10 muM SVPGVLRFamide to muscle strips preincubated in high-K+, Ca2+- and Cl--free media. (C) 2001 Academic Press.

The sites of neural adaptation induced by resistance training in humans

Although it has long been supposed that resistance training causes adaptive changes in the CNS, the sites and nature of these adaptations have not previously been identified. In order to determine whether the neural adaptations to resistance training occur to a greater extent at cortical or subcortical sites in the CNS, we compared the effects of resistance training on the electromyographic (EMG) responses to transcranial magnetic (TMS) and electrical (TES) stimulation. Motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle of 16 individuals before and after 4 weeks of resistance training for the index finger abductors (n=8), or training involving finger abduction-adduction without external resistance (n=8). TMS was delivered at rest at intensities from 5% below the passive threshold to the maximal output of the stimulator. TMS and TES were also delivered at the active threshold intensity while the participants exerted torques ranging from 5 to 60% of their maximum voluntary contraction (MVC) torque. The average latency of MEPs elicited by TES was significantly shorter than that of TMS MEPs (TES latency=21.5+/-1.4 ms; TMS latency=23.4+/-1.4 ms; P