Representations of time in human frontoparietal cortex

Precise time estimation is crucial in perception, action and social interaction. Previous neuroimaging studies in humans indicate that perceptual timing tasks involve multiple brain regions; however, whether the representation of time is localized or distributed in the brain remains elusive. Using ultra-high-field functional magnetic resonance imaging combined with multivariate pattern analyses, we show that duration information is decoded in multiple brain areas, including the bilateral parietal cortex, right inferior frontal gyrus and, albeit less clearly, the medial frontal cortex. Individual differences in the duration judgment accuracy were positively correlated with the decoding accuracy of duration in the right parietal cortex, suggesting that individuals with a better timing performance represent duration information in a more distinctive manner. Our study demonstrates that although time representation is widely distributed across frontoparietal regions, neural populations in the right parietal cortex play a crucial role in time estimation

Falls and falls efficacy: the role of sustained attention in older adults

<p>Abstract</p> <p>Background</p> <p>Previous evidence indicates that older people allocate more of their attentional resources toward their gait and that the attention-related changes that occur during aging increase the risk of falls. The aim of this study was to investigate whether performance and variability in sustained attention is associated with falls and falls efficacy in older adults.</p> <p>Methods</p> <p>458 community-dwelling adults aged ≥ 60 years underwent a comprehensive geriatric assessment. Mean and variability of reaction time (RT), commission errors and omission errors were recorded during a fixed version of the Sustained Attention to Response Task (SART). RT variability was decomposed using the Fast Fourier Transform (FFT) procedure, to help characterise variability associated with the arousal and vigilance aspects of sustained attention.</p> <p>The number of self-reported falls in the previous twelve months, and falls efficacy (Modified Falls Efficacy Scale) were also recorded.</p> <p>Results</p> <p>Significant increases in the mean and variability of reaction time on the SART were significantly associated with both falls (p < 0.01) and reduced falls efficacy (p < 0.05) in older adults. An increase in omission errors was also associated with falls (p < 0.01) and reduced falls efficacy (p < 0.05). Upon controlling for age and gender affects, logistic regression modelling revealed that increasing variability associated with the vigilance (top-down) aspect of sustained attention was a retrospective predictor of falling (p < 0.01, OR = 1.14, 95% CI: 1.03 - 1.26) in the previous year and was weakly correlated with reduced falls efficacy in non-fallers (p = 0.07).</p> <p>Conclusions</p> <p>Greater variability in sustained attention is strongly correlated with retrospective falls and to a lesser degree with reduced falls efficacy. This cognitive measure may provide a novel and valuable biomarker for falls in older adults, potentially allowing for early detection and the implementation of preventative intervention strategies.</p

A putative relay circuit providing low-threshold mechanoreceptive input to lamina I projection neurons via vertical cells in lamina II of the rat dorsal horn

Background: Lamina I projection neurons respond to painful stimuli, and some are also activated by touch or hair movement. Neuropathic pain resulting from peripheral nerve damage is often associated with tactile allodynia (touch-evoked pain), and this may result from increased responsiveness of lamina I projection neurons to non-noxious mechanical stimuli. It is thought that polysynaptic pathways involving excitatory interneurons can transmit tactile inputs to lamina I projection neurons, but that these are normally suppressed by inhibitory interneurons. Vertical cells in lamina II provide a potential route through which tactile stimuli can activate lamina I projection neurons, since their dendrites extend into the region where tactile afferents terminate, while their axons can innervate the projection cells. The aim of this study was to determine whether vertical cell dendrites were contacted by the central terminals of low-threshold mechanoreceptive primary afferents. Results: We initially demonstrated contacts between dendritic spines of vertical cells that had been recorded in spinal cord slices and axonal boutons containing the vesicular glutamate transporter 1 (VGLUT1), which is expressed by myelinated low-threshold mechanoreceptive afferents. To confirm that the VGLUT1 boutons included primary afferents, we then examined vertical cells recorded in rats that had received injections of cholera toxin B subunit (CTb) into the sciatic nerve. We found that over half of the VGLUT1 boutons contacting the vertical cells were CTb-immunoreactive, indicating that they were of primary afferent origin. Conclusions: These results show that vertical cell dendritic spines are frequently contacted by the central terminals of myelinated low-threshold mechanoreceptive afferents. Since dendritic spines are associated with excitatory synapses, it is likely that most of these contacts were synaptic. Vertical cells in lamina II are therefore a potential route through which tactile afferents can activate lamina I projection neurons, and this pathway could play a role in tactile allodynia

Neuronal circuitry for pain processing in the dorsal horn

Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region

Intentional Binding Is Driven by the Mere Presence of an Action and Not by Motor Prediction

Intentional binding refers to the fact that when a voluntary action produces a sensory outcome, action and outcome are perceived as being closer together in time. This phenomenon is often attributed, at least partially, to predictive motor mechanisms. However, previous studies failed to unequivocally attribute intentional binding to these mechanisms, since the contrasts that have been used to demonstrate intentional binding covered not only one but two processes: temporal control and motor identity prediction. In the present study we aimed to isolate the respective role of each of these processes in the emergence of intentional binding of action-effects. The results show that motor identity prediction does not modulate intentional binding of action-effects. Our findings cast doubts on the assumption that intentional binding of action effects is linked to internal forward predictive process

Using time perception to explore implicit sensitivity to emotional stimuli in autism spectrum disorder

Establishing whether implicit responses to emotional cues are intact in autism spectrum disorder (ASD) is fundamental to ascertaining why their emotional understanding is compromised. We used a temporal bisection task to assess for responsiveness to face and wildlife images that varied in emotional salience. There were no significant differences between an adult ASD and comparison group, with both showing implicit overestimation of emotional stimuli. Further, there was no correlation between overestimation of emotional stimuli and autistic traits in undergraduate students. These data do not suggest a fundamental insensitivity to the arousing content of emotional images in ASD, or in individuals with a high degree of autistic traits. The findings have implications for understanding how emotional stimuli are processed in ASD

Glycine Inhibitory Dysfunction Turns Touch into Pain through PKCgamma Interneurons

Dynamic mechanical allodynia is a widespread and intractable symptom of neuropathic pain for which there is a lack of effective therapy. During tactile allodynia, activation of the sensory fibers which normally detect touch elicits pain. Here we provide a new behavioral investigation into the dynamic component of tactile allodynia that developed in rats after segmental removal of glycine inhibition. Using in vivo electrophysiological recordings, we show that in this condition innocuous mechanical stimuli could activate superficial dorsal horn nociceptive specific neurons. These neurons do not normally respond to touch. We anatomically show that the activation was mediated through a local circuit involving neurons expressing the gamma isoform of protein kinase C (PKCγ). Selective inhibition of PKCγ as well as selective blockade of glutamate NMDA receptors in the superficial dorsal horn prevented both activation of the circuit and allodynia. Thus, our data demonstrates that a normally inactive circuit in the dorsal horn can be recruited to convert touch into pain. It also provides evidence that glycine inhibitory dysfunction gates tactile input to nociceptive specific neurons through PKCγ-dependent activation of a local, excitatory, NMDA receptor-dependent, circuit. As a consequence of these findings, we suggest that pharmacological inhibition of PKCγ might provide a new tool for alleviating allodynia in the clinical setting

Cell line-dependent variability in HIV activation employing DNMT inhibitors

Long-lived reservoirs of Human Immunodeficiency Virus (HIV) latently infected cells present the main barrier to a cure for HIV infection. Much interest has focused on identifying strategies to activate HIV, which would be used together with antiretrovirals to attack reservoirs. Several HIV activating agents, including Tumor Necrosis Factor alpha (TNFα) and other agents that activate via NF-kB are not fully effective in all latent infection models due to epigenetic restrictions, such as DNA methylation and the state of histone acetylation. DNA methyltransferases (DNMT) inhibitors like 5-aza-2'deoxycytidine (Aza-CdR) and histone deacetylase (HDAC) inhibitors like Trichostatin A (TSA) have been proposed as agents to enhance reactivation and have shown activity in model systems. However, it is not clear how the activities of DNMT and HDAC inhibitors range across different latently infected cell lines, potential models for the many different latently infected cells within an HIV patient. We determined HIV activation following treatment with TNFα, TSA and Aza-CdR across a range of well known latently infected cell lines. We assessed the activity of these compounds in four different Jurkat T cell-derived J-Lat cell lines (6.3, 8.4, 9.2 and 10.6), which have a latent HIV provirus in which GFP replaces Nef coding sequence, and ACH-2 and J1.1 (T cell-derived), and U1 (promonocyte-derived) cell lines with full-length provirus. We found that Aza-CdR plus TNFα activated HIV at least twice as well as TNFα alone for almost all J-Lat cells, as previously described, but not for J-Lat 10.6, in which TNFα plus Aza-CdR moderately decreased activation compared to TNFα alone. Surprisingly, a much greater reduction of TNFα-stimulated activation with Aza-CdR was detected for ACH-2, J1.1 and U1 cells. Reaching the highest reduction in U1 cells with a 75% reduction. Interestingly, Aza-CdR not only decreased TNFα induction of HIV expression in certain cell lines, but also decreased activation by TSA. Since DNMT inhibitors reduce the activity of provirus activators in some HIV latently infected cell lines the use of epigenetic modifying agents may need to be carefully optimized if they are to find clinical utility in therapies aimed at attacking latent HIV reservoirs

Acute and Chronic Effects of Particles on Hospital Admissions in New-England

Background: Many studies have reported significant associations between exposure to $PM_{2.5}$ and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of $PM_{2.5}$ monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias. Methods Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of $PM_{2.5}$ exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term $PM_{2.5}$ exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk. Results: We observed associations between both short-term and long-term exposure to $PM_{2.5}$ and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every10-µg/m$^3$ increase in short-term $PM_{2.5}$ exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every10-µg/m$^3$ increase in long-term $PM_{2.5}$ exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75). Conclusions: As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models