Priming Pharyngeal Motor Cortex by Repeated Paired Associative Stimulation: Implications for Dysphagia Neurorehabilitation

Background. Several stimulation parameters can influence the neurophysiological and behavioral effects of paired associative stimulation (PAS), a neurostimulation paradigm that repeatedly pairs a peripheral electrical with a central cortical (transcranial magnetic stimulation [TMS]) stimulus. This also appears to be the case when PAS is applied to the pharyngeal motor cortex (MI), with some variability in excitatory responses, questioning its translation into a useful therapy for patients with brain injury. Objective. To investigate whether repeated PAS in both “responders” and “nonresponders” could enhance cortical excitability in pharyngeal MI more robustly. Methods. Based on their responses after single PAS, healthy participants were stratified into 2 groups of “responders” and “nonresponders” and underwent 2 periods (60 minutes inter-PAS interval) of active and sham PAS in a randomized order. Neurophysiological measurements with single TMS pulses from pharyngeal motor representation were collected up to 90 minutes after the second PAS period. Results. Repeated PAS increased cortical excitability up to 95% at 60 minutes following the second PAS in both the “responders” and “nonresponders.” Moreover, cortical excitability in the “nonresponders” was significantly different after repeated PAS compared with single and sham application (P = .02; z = −2.2). Conclusions. Double dose PAS switched “nonresponders” to “responders.” These results are important for PAS application to dysphagic stroke patients who do not initially respond to a single application

Limb Heaviness: A Perceptual Phenomenon Associated With Poststroke Fatigue?

Poststroke fatigue and limb heaviness are 2 perceptual problems that commonly occur after stroke. Previous work suggests that poststroke fatigue may be related to altered sensorimotor processing whereas limb heaviness is often considered an association of muscle weakness. To address the hypothesis that the perception of limb heaviness may also be a problem of altered sensorimotor control, we investigated whether it was more closely related to poststroke fatigue or muscle weakness. In 69 chronic stroke survivors, we found that those with high perceived limb heaviness (31 individuals) also reported significantly higher levels of fatigue (4.8/7) than those with no perceived limb heaviness (38 individuals, fatigue score = 2.68/7), but there was no difference in weakness between the 2 groups. This intriguing finding is discussed in relation to effort perception and sensory processing. The association between limb heaviness and poststroke fatigue and a dissociation from muscle weakness gives rise to the hypothesis that limb heaviness maybe a centrally arising sensorimotor disorder

Frequency-dependent modulation of cerebellar excitability during the application of non-invasive alternating current stimulation

Background: it is well-known that the cerebellum is critical for the integrity of motor and cognitive actions. Applying non-invasive brain stimulation techniques over this region results in neurophysiological and behavioural changes, which have been associated with the modulation of cerebellar-cerebral cortex connectivity. Here, we investigated whether online application of cerebellar transcranial alternating current stimulation (tACS) results in changes to this pathway. Methods: thirteen healthy individuals participated in two sessions of cerebellar tACS delivered at different frequencies (5Hz and 50Hz). We used transcranial magnetic stimulation to measure cerebellar-motor cortex (M1) inhibition (CBI), short-intracortical inhibition (SICI) and short-afferent inhibition (SAI) before, during and after the application of tACS. Results: we found that CBI was specifically strengthened during the application of 5Hz cerebellar tACS. No changes were detected immediately following the application of 5Hz stimulation, nor at any time point with 50Hz stimulation. We also found no changes to M1 intracortical circuits (i.e. SICI) or sensorimotor interaction (i.e. SAI), indicating that the effects of 5Hz tACS over the cerebellum are site-specific. Conclusions: cerebellar tACS can modulate cerebellar excitability in a time- and frequency-dependent manner. Additionally, cerebellar tACS does not appear to induce any long-lasting effects (i.e. plasticity), suggesting that stimulation enhances oscillations within the cerebellum only throughout the stimulation period. As such, cerebellar tACS may have significant implications for diseases manifesting with abnormal cerebellar oscillatory activity and also for future behavioural studies

Searching for "monogenic diabetes" in dogs using a candidate gene approach

BACKGROUND: Canine diabetes is a common endocrine disorder with an estimated breed-related prevalence ranging from 0.005% to 1.5% in pet dogs. Increased prevalence in some breeds suggests that diabetes in dogs is influenced by genetic factors and similarities between canine and human diabetes phenotypes suggest that the same genes might be associated with disease susceptibility in both species. Between 1-5% of human diabetes cases result from mutations in a single gene, including maturity onset diabetes of the adult (MODY) and neonatal diabetes mellitus (NDM). It is not clear whether monogenic forms of diabetes exist within some dog breeds. Identification of forms of canine monogenic diabetes could help to resolve the heterogeneity of the condition and lead to development of breed-specific genetic tests for diabetes susceptibility. RESULTS: Seventeen dog breeds were screened for single nucleotide polymorphisms (SNPs) in eighteen genes that have been associated with human MODY/NDM. Six SNP associations were found from five genes, with one gene (ZFP57) being associated in two different breeds. CONCLUSIONS: Some of the genes that have been associated with susceptibility to MODY and NDM in humans appear to also be associated with canine diabetes, although the limited number of associations identified in this study indicates canine diabetes is a heterogeneous condition and is most likely to be a polygenic trait in most dog breeds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/2052-6687-1-8) contains supplementary material, which is available to authorized users

The Unusual Linear Plasmid Generating Systems of Prokaryotes

Linear DNA is vulnerable to exonuclease degradation and suffers from genetic loss due to the end replication problem. Eukaryotes overcome these problems by locating repetitive telomere sequences at the end of each chromosome. In humans and other vertebrates this noncoding terminal sequence is repeated between hundreds and thousands of times, ensuring important genetic information is protected. In most prokaryotes, the end-replication problem is solved by utilizing circular DNA molecules as chromosomes. However, some phage and bacteria do store genetic information in linear constructs, and the ends of these structures form either invertrons or hairpin telomeres. Hairpin telomere formation is catalyzed by a protelomerase, a unique protein that modifies DNA by a two-step transesterification reaction, proceeding via a covalent protein bound intermediate. The specifics of this mechanism are largely unknown and conflicting data suggests variations occur between different systems. These proteins, and the DNA constructs they produce, have valuable applications in the biotechnology industry. They are also an essential component of some human pathogens, an increased understanding of how they operate is therefore of fundamental importance. Although this review will focus on phage encoded protelomerase, protelomerases found from Agrobacterium and Borellia will be discussed in terms of mechanism of action

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Signaling in The Prefrontal Cortex Modulates Cued Fear Learning, But Not Spatial Working Memory, in Female Rats

A genetic polymorphism within the gene encoding the pituitary adenylate cyclase- activating polypeptide (PACAP) receptor type I (PAC1R) has recently been associated with hyper-reactivity to threat-related cues in women, but not men, with post-traumatic stress disorder (PTSD). PACAP is a highly conserved peptide, whose role in mediating adaptive physiological stress responses is well established. Far less is understood about the contribution of PACAP signaling in emotional learning and memory, particularly the encoding of fear to discrete cues. Moreover, a neurobiological substrate that may account for the observed link between PAC1R and PTSD in women, but not men, has yet to be identified. Sex differences in PACAP signaling during emotional learning could provide novel targets for the treatment of PTSD. Here we investigated the contribution of PAC1R signaling within the prefrontal cortex to the acquisition of cued fear in female and male rats. We used a variant of fear conditioning called trace fear conditioning, which requires sustained attention to fear cues and depends on working-memory like neuronal activity within the prefrontal cortex. We found that cued fear learning, but not spatial working memory, was impaired by administration of a PAC1R antagonist directly into the prelimbic area of the prefrontal cortex. This effect was specific to females. We also found that levels of mRNA for the PAC1R receptor in the prelimbic cortex were greater in females compared with males, and were highest during and immediately following the proestrus stage of the estrous cycle. Together, these results demonstrate a sex-specific role of PAC1R signaling in learning about threat-related cues

Cooperatively breeding cottontop tamarins (Saguinus oedipus) do not donate rewards to their long-term mates

This study tested the hypothesis that cooperative breeding facilitates the emergence of prosocial behavior by presenting cottontop tamarins (Saguinus oedipus) with the option to provide food rewards to pair-bonded mates. In Experiment 1, tamarins could provide rewards to mates at no additional cost while obtaining rewards for themselves. Contrary to the hypothesis, tamarins did not demonstrate a preference to donate rewards, behaving similar to chimpanzees in previous studies. In Experiment 2, the authors eliminated rewards for the donor for a stricter test of prosocial behavior, while reducing separation distress and food preoccupation. Again, the authors found no evidence for a donation preference. Furthermore, tamarins were significantly less likely to deliver rewards to mates when the mate displayed interest in the reward. The results of this study contrast with those recently reported for cooperatively breeding common marmosets, and indicate that prosocial preferences in a food donation task do not emerge in all cooperative breeders. In previous studies, cottontop tamarins have cooperated and reciprocated to obtain food rewards; the current findings sharpen understanding of the boundaries of cottontop tamarins’ food-provisioning behavior

Cerebellar Theta-Burst Stimulation Impairs Memory Consolidation in Eyeblink Classical Conditioning

Associative learning of sensorimotor contingences, as it occurs in eyeblink classical conditioning (EBCC), is known to involve the cerebellum, but its mechanism remains controversial. EBCC involves a sequence of learning processes which are thought to occur in the cerebellar cortex and deep cerebellar nuclei. Recently, the extinction phase of EBCC has been shown to be modulated after one week by cerebellar continuous theta-burst stimulation (cTBS). Here, we asked whether cerebellar cTBS could affect retention and reacquisition of conditioned responses (CRs) tested immediately after conditioning. We also investigated a possible lateralized cerebellar control of EBCC by applying cTBS on both the right and left cerebellar hemispheres. Both right and left cerebellar cTBSs induced a statistically significant impairment in retention and new acquisition of conditioned responses (CRs), the disruption effect being marginally more effective when the left cerebellar hemisphere was stimulated. These data support a model in which cTBS impairs retention and reacquisition of CR in the cerebellum, possibly by interfering with the transfer of memory to the deep cerebellar nuclei

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects