Multifocal Transcranial Direct Current Stimulation in Primary Progressive Aphasia Does Not Provide a Clinical Benefit Over Speech Therapy

Primary progressive aphasia (PPA) is a group of neurodegenerative disorders including Alzheimer's disease and frontotemporal dementia characterized by language deterioration. Transcranial direct current stimulation (tDCS) is a non-invasive intervention for brain dysfunction.To evaluate the tolerability and efficacy of tDCS combined with speech therapy in the three variants of PPA. We evaluate changes in fMRI activity in a subset of patients.Double-blinded, randomized, cross-over, and sham-controlled tDCS study. 15 patients with PPA were included. Each patient underwent two interventions: a) speech therapy + active tDCS and b) speech therapy + sham tDCS stimulation. A multifocal strategy with anodes placed in the left frontal and parietal regions was used to stimulate the entire language network. Efficacy was evaluated by comparing the results of two independent sets of neuropsychological assessments administered at baseline, immediately after the intervention, and at 1 month and 3 months after the intervention. In a subsample, fMRI scanning was performed before and after each intervention.The interventions were well tolerated. Participants in both arms showed clinical improvement, but no differences were found between active and sham tDCS interventions in any of the evaluations. There were trends toward better outcomes in the active tDCS group for semantic association and reading skills. fMRI identified an activity increase in the right frontal medial cortex and the bilateral paracingulate gyrus after the active tDCS intervention.We did not find differences between active and sham tDCS stimulation in clinical scores of language function in PPA patients

Vascular endothelial growth factor-A165b prevents diabetic neuropathic pain and sensory neuronal degeneration

Diabetic peripheral neuropathy affects up to half of diabetic patients. This neuronal damage leads to sensory disturbances, including allodynia and hyperalgesia. Many growth factors have been suggested as useful treatments for prevention of neurodegeneration, including the vascular endothelial growth factor (VEGF) family. VEGF-A is generated as two alternative splice variant families. The most widely studied isoform, VEGF-A165a is both pro-angiogenic and neuroprotective, but pro-nociceptive and increases vascular permeability in animal models. Streptozotocin (STZ)-induced diabetic rats develop both hyperglycaemia and many of the resulting diabetic complications seen in patients, including peripheral neuropathy. In the present study, we show that the anti-angiogenic VEGF-A splice variant, VEGF-A165b, is also a potential therapeutic for diabetic neuropathy. Seven weeks of VEGF-A165b treatment in diabetic rats reversed enhanced pain behaviour in multiple behavioural paradigms and was neuroprotective, reducing hyperglycaemia-induced activated caspase 3 (AC3) levels in sensory neuronal subsets, epidermal sensory nerve fibre loss and aberrant sciatic nerve morphology. Furthermore, VEGF-A165b inhibited a STZ-induced increase in Evans Blue extravasation in dorsal root ganglia (DRG), saphenous nerve and plantar skin of the hind paw. Increased transient receptor potential ankyrin 1 (TRPA1) channel activity is associated with the onset of diabetic neuropathy. VEGF-A165b also prevented hyperglycaemia-enhanced TRPA1 activity in an in vitro sensory neuronal cell line indicating a novel direct neuronal mechanism that could underlie the anti-nociceptive effect observed in vivo. These results demonstrate that in a model of Type I diabetes VEGF-A165b attenuates altered pain behaviour and prevents neuronal stress, possibly through an effect on TRPA1 activity

A Critical Role of a Cellular Membrane Traffic Protein in Poliovirus RNA Replication

Replication of many RNA viruses is accompanied by extensive remodeling of intracellular membranes. In poliovirus-infected cells, ER and Golgi stacks disappear, while new clusters of vesicle-like structures form sites for viral RNA synthesis. Virus replication is inhibited by brefeldin A (BFA), implicating some components(s) of the cellular secretory pathway in virus growth. Formation of characteristic vesicles induced by expression of viral proteins was not inhibited by BFA, but they were functionally deficient. GBF1, a guanine nucleotide exchange factor for the small cellular GTPases, Arf, is responsible for the sensitivity of virus infection to BFA, and is required for virus replication. Knockdown of GBF1 expression inhibited virus replication, which was rescued by catalytically active protein with an intact N-terminal sequence. We identified a mutation in GBF1 that allows growth of poliovirus in the presence of BFA. Interaction between GBF1 and viral protein 3A determined the outcome of infection in the presence of BFA

Multimessenger NuEM Alerts with AMON

The Astrophysical Multimessenger Observatory Network (AMON), has developed a real-time multi-messenger alert system. The system performs coincidence analyses of datasets from gamma-ray and neutrino detectors, making the Neutrino-Electromagnetic (NuEM) alert channel. For these analyses, AMON takes advantage of sub-threshold events, i.e., events that by themselves are not significant in the individual detectors. The main purpose of this channel is to search for gamma-ray counterparts of neutrino events. We will describe the different analyses that make-up this channel and present a selection of recent results

The somatosensory blink reflex in upper and lower brainstem lesions

The brainstem pathways that mediate the somatosensory blink reflex (SBR) are not completely understood. We hypothesized that the circuits of the SBR might be affected separately from those of the trigeminal blink reflex (TBR). We examined 7 patients with mesencephalic lesions and 8 patients with medullary lesions. The SBR was elicited by median nerve stimulation. The TBR was elicited by supraorbital nerve stimulation. In patients with upper brainstem lesions, the TBR was normal, whereas the SBR was generally abnormal. The SBR was either absent or small and was significantly delayed with respect to control subjects. The opposite was the rule in patients with lower brainstem lesions who had delayed or absent TBR and no abnormal findings in the SBR. The SBR is mediated through circuits in the upper brainstem. Study of the SBR can be helpful in the neurophysiological assessment of patients with mesencephalic lesions

Morphometry of dermal nerve fibers in human skin

Objective: We aimed to assess the innervation density of dermal nerves in human skin biopsies by bright-field immunohistochemistry. Methods: The size of dermal area where nerve length was quantified was validated in 30 skin biopsy sections (5 controls and 5 patients with small-fiber neuropathy [SFN]). It was obtained dividing an area of 200-mu m depth from the dermal-epidermal junction into 4 equal portions. The length of dermal nerves (DNFL) was measured into 150 sections (25 controls and 25 patients with SFN) and values per millimeter of epidermis (DNFL/mm) and dermal area (DNFL/mm(2)) were obtained. Age-and gender-matched normative values of intraepidermal nerve fiber (IENF) density were used as gold standard to calculate the performance of dermal nerve morphometry. Results: Patients showed significantly lower DNFL (1.96 mm +/- 0.96 SD), DNFL/mm (0.65 +/- 0.29 SD), and DNFL/mm(2) (3.75 +/- 1.7 SD) than controls (DNFL 3.52 mm +/- 1.31 SD, 5th percentile 2.05; DNFL/mm 1.25 +/- 0.39, 5th percentile 0.71; DNFL/mm(2) 7.07 +/- 2.41 SD, 5th percentile 3.95). Sensitivity, specificity, and percentage of individuals correctly classified were 75.8%, 73.9%, and 74.8% for DNFL, 75%, 80%, and 77.7% for DNFL/mm, and 75.8%, 80.2%, and 78.1% for DNFL/mm(2). Receiver operator characteristic area analysis confirmed the excellent discrimination (0.8-0.9) between patients and controls. Dermal nerve morphometry significantly correlated with IENF density. Spearman rank correlation demonstrated good agreement for interobserver analysis (0.87-0.89), and between DNFL and IENF densities (0.71-0.73; p <0.0001). Conclusions: We provided a reliable method to quantify the innervation density of dermal nerves that might improve the diagnostic yield of skin biopsy. Neurology (R) 2011;77:242-24

Effects of postural and voluntary muscle contraction on modulation of the soleus H reflex by transcranial magnetic stimulation

Modulation of spinal reflexes depends largely on the integrity of the corticospinal tract. A useful method to document the influence of descending tracts on reflexes is to examine the effects of transcranial magnetic stimulation (TMS) on the soleus H reflex elicited by posterior tibial nerve electrical stimuli (PTS). In 12 healthy volunteers, we investigated how postural or voluntary muscle contraction modified such descending modulation. We first characterized the effects of TMS at 95 % of motor threshold for leg responses on the H reflex elicited by a preceding PTS at inter-stimuli intervals (ISIs) between 0 and 120 ms at rest and, then, during voluntary plantar flexion (pf), dorsal flexion (df), and standing still (ss). During pf, there was an increase in the facilitation of the H reflex at ISIs 0-20 ms. During df, there were no effects of TMS on the H reflex. During ss, there was inhibition at ISIs 40-60 ms. Our observations suggest that muscle contraction prevails over the baseline effects of TMS on the soleus H reflex. While contraction of the antagonist (df) suppressed most of the effects, contraction of the agonist had different effects depending on the type of activity (pf or ss). The characterization of the interaction between descending corticospinal volleys and segmental peripheral inputs provides useful information on motor control for physiological research and further understanding of the effects of spinal cord lesions