Optical cuff for optogenetic control of the peripheral nervous system

OBJECTIVE: Nerves in the peripheral nervous system (PNS) contain axons with specific motor, somatosensory and autonomic functions. Optogenetics offers an efficient approach to selectively activate axons within the nerve. However, the heterogeneous nature of nerves and their tortuous route through the body create a challenging environment to reliably implant a light delivery interface. APPROACH: Here, we propose an optical peripheral nerve interface – an optocuff -, so that optogenetic modulation of peripheral nerves become possible in freely behaving mice. MAIN RESULTS: Using this optocuff, we demonstrate orderly recruitment of motor units with epineural optical stimulation of genetically targeted sciatic nerve axons, both in anaesthetized and in awake, freely behaving animals. Behavioural experiments and histology show the optocuff does not damage the nerve thus is suitable for long-term experiments. SIGNIFICANCE: These results suggest that the soft optocuff might be a straightforward and efficient tool to support more extensive study of the PNS using optogenetics

Extensions and degenerations of spectral triples

For a unital C*-algebra A, which is equipped with a spectral triple and an extension T of A by the compacts, we construct a family of spectral triples associated to T and depending on the two positive parameters (s,t). Using Rieffel's notation of quantum Gromov-Hausdorff distance between compact quantum metric spaces it is possible to define a metric on this family of spectral triples, and we show that the distance between a pair of spectral triples varies continuously with respect to the parameters. It turns out that a spectral triple associated to the unitarization of the algebra of compact operators is obtained under the limit - in this metric - for (s,1) -> (0, 1), while the basic spectral triple, associated to A, is obtained from this family under a sort of a dual limiting process for (1, t) -> (1, 0). We show that our constructions will provide families of spectral triples for the unitarized compacts and for the Podles sphere. In the case of the compacts we investigate to which extent our proposed spectral triple satisfies Connes' 7 axioms for noncommutative geometry.Comment: 40 pages. Addedd in ver. 2: Examples for the compacts and the Podle`s sphere plus comments on the relations to matricial quantum metrics. In ver.3 the word "deformations" in the original title has changed to "degenerations" and some illustrative remarks on this aspect are adde

Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.</p> <p>Methods</p> <p>Subjects in Cohort 1 (HC = 368; CFS = 203) completed questionnaires about many diverse symptoms by giving nominal (yes/no) answers. Cohort 2 (HC = 21; CFS = 67) had more focused evaluations. They scored symptom severities on 0 to 4 anchored ordinal scales, and had structured headache evaluations. All subjects had history and physical examinations; assessments for exclusion criteria; questionnaires about CFS related symptoms (0 to 4 scale), Multidimensional Fatigue Inventory (MFI) and Medical Outcome Survey Short Form 36 (MOS SF-36).</p> <p>Results</p> <p>Demographics, trends for the number of diffuse "functional" symptoms present, and severity of CFS case designation criteria symptoms were equivalent between CFS subjects in Cohorts 1 and 2. HC had significantly fewer symptoms, lower MFI and higher SF-36 domain scores than CFS in both cohorts. Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC. The CFS group had migraine without aura (60%; MO; CFS+MO), with aura (24%; CFS+MA), tension headaches only (12%), or no headaches (4%). Co-morbid tension and migraine headaches were found in 67% of CFS. CFS+MA had higher severity scores than CFS+MO for the sum of scores for poor memory, dizziness, balance, and numbness ("Neuro-construct", p = 0.002) and perceived heart rhythm disturbances, palpitations and noncardiac chest pain ("Cardio-construct"; p = 0.045, t-tests after Bonferroni corrections). CFS+MO subjects had lower pressure-induced pain thresholds (2.36 kg [1.95-2.78; 95% C.I.] n = 40) and a higher prevalence of fibromyalgia (47%; 1990 criteria) compared to HC (5.23 kg [3.95-6.52] n = 20; and 0%, respectively). Sumatriptan was beneficial for 13 out of 14 newly diagnosed CFS migraine subjects.</p> <p>Conclusions</p> <p>CFS subjects had higher prevalences of MO and MA than HC, suggesting that mechanisms of migraine pathogenesis such as central sensitization may contribute to CFS pathophysiology.</p> <p>Clinical Trial Registration</p> <p>Georgetown University IRB # 2006-481</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00810329">NCT00810329</a></p

Cognitive effects of transcranial direct current stimulation combined with working memory training in fibromyalgia: a randomized clinical trial

Cognitive dysfunction in fibromyalgia has been reported, especially memory. Anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) has been effective in enhancing this function. We tested the effects of eight sessions of tDCS and cognitive training on immediate and delayed memory, verbal fluency and working memory and its association with brain-derived neurotrophic factor (BDNF) levels. Forty females with fibromyalgia were randomized to receive eight sessions of active or sham tDCS. Anodal stimulation (2 mA) was applied over the DLPFC and online combined with a working memory training (WMT) for 20 minutes. Pre and post-treatment neurocognitive tests were administered. Data analysis on deltas considering years of education and BDNF as covariates, indicated active-tDCS + WMT significantly increased immediate memory indexed by Rey Auditory Verbal Learning Test score when compared to sham. This effect was dependent on basal BDNF levels. In addition, the model showed active stimulation increased orthographic and semantic verbal fluency scores (Controlled Oral Word Association Test) and short-term memory (Forward Digit Span). The combination of both techniques seemed to produce effects on specific cognitive functions related to short-term and long-term episodic memory and executive functions, which has clinical relevance for top-down treatment approaches in FM.financiamento: This research was supported by grants and material support from the following Brazilian agencies: Committee for the Development of Higher Education Personnel - CAPES - PNPD/CAPES and material support. National Council for Scientific and Technological Development - CNPq (grants to Dr. I.L.S. Torres, Dr. W. Caumo). Postgraduate Program in Medical Sciences at the School of Medicine of the Federal University of Rio Grande do Sul (material support). Postgraduate Research Group at the Hospital de Clinicas de Porto Alegre - FIPE HCPA (material support). Foundations for Support of Research at Rio Grande do Sul (FAPERGS) (material support)

The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input

Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino–supraspinal–spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting 72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin

EP₂ receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis

Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis

Risk factors for moderate and severe persistent pain in patients undergoing total knee and hip arthroplasty : a prospective predictive study

Persistent post-surgical pain (PPSP) is a major clinical problem with significant individual, social and health care costs. The aim of this study was to examine the joint role of demographic, clinical and psychological risk factors in the development of moderate and severe PPSP after Total Knee and Hip Arthroplasty (TKA and THA, respectively). This was a prospective study wherein a consecutive sample of 92 patients were assessed 24 hours before (T1), 48 hours after (T2) and 4-6 months (T3) after surgery. Hierarchical logistic regression analyses were performed to identify predictors of moderate and severe levels of PPSP. Four to six months after TKA and THA, 54 patients (58.7%) reported none or mild pain (Numerical Rating Scale: NRS 3). In the final multivariate hierarchical logistic regression analyses, illness representations concerning the condition leading to surgery (osteoarthritis), such as a chronic timeline perception of the disease, emerged as a significant predictor of PPSP. Additionally, post-surgical anxiety also showed a predictive role in the development of PPSP. Pre-surgical pain was the most significant clinical predictive factor and, as expected, undergoing TKA was associated with greater odds of PPSP development than THA. The findings on PPSP predictors after major joint arthroplasties can guide clinical practice in terms of considering cognitive and emotional factors, together with clinical factors, in planning acute pain management before and after surgery.This work was supported by a Project grant (PTDC/SAU-NEU/108557/2008) and by a PhD grant (SFRH/BD/36368/2007) from the Portuguese Foundation of Science and Technology, COMPETE and FEDER. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Specific treatment of problems of the spine (STOPS): design of a randomised controlled trial comparing specific physiotherapy versus advice for people with subacute low back disorders

<p>Abstract</p> <p>Background</p> <p>Low back disorders are a common and costly cause of pain and activity limitation in adults. Few treatment options have demonstrated clinically meaningful benefits apart from advice which is recommended in all international guidelines. Clinical heterogeneity of participants in clinical trials is hypothesised as reducing the likelihood of demonstrating treatment effects, and sampling of more homogenous subgroups is recommended. We propose five subgroups that allow the delivery of specific physiotherapy treatment targeting the pathoanatomical, neurophysiological and psychosocial components of low back disorders. The aim of this article is to describe the methodology of a randomised controlled trial comparing specific physiotherapy treatment to advice for people classified into five subacute low back disorder subgroups.</p> <p>Methods/Design</p> <p>A multi-centre parallel group randomised controlled trial is proposed. A minimum of 250 participants with subacute (6 weeks to 6 months) low back pain and/or referred leg pain will be classified into one of five subgroups and then randomly allocated to receive either physiotherapy advice (2 sessions over 10 weeks) or specific physiotherapy treatment (10 sessions over 10 weeks) tailored according to the subgroup of the participant. Outcomes will be assessed at 5 weeks, 10 weeks, 6 months and 12 months following randomisation. Primary outcomes will be activity limitation measured with a modified Oswestry Disability Index as well as leg and back pain intensity measured on separate 0-10 Numerical Rating Scales. Secondary outcomes will include a 7-point global rating of change scale, satisfaction with physiotherapy treatment, satisfaction with treatment results, the Sciatica Frequency and Bothersomeness Scale, quality of life (EuroQol-5D), interference with work, and psychosocial risk factors (Orebro Musculoskeletal Pain Questionnaire). Adverse events and co-interventions will also be measured. Data will be analysed according to intention to treat principles, using linear mixed models for continuous outcomes, Mann Whitney U tests for ordinal outcomes, and Chi-square, risk ratios and risk differences for dichotomous outcomes.</p> <p>Discussion</p> <p>This trial will determine the difference in outcomes between specific physiotherapy treatment tailored to each of the five subgroups versus advice which is recommended in guidelines as a suitable treatment for most people with a low back disorder.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12609000834257.aspx">ACTRN12609000834257</a>.</p

Descending controls modulate inflammatory joint pain and regulate CXC chemokine and iNOS expression in the dorsal horn.

Descending control of nociceptive processing, by pathways originating in the rostral ventromedial medulla (RVM) and terminating in the dorsal horn, contributes to behavioural hypersensitivity in a number of pain models. Two facilitatory pathways have been identified and are characterized by serotonin (5-HT) content or expression of the mu opiate receptor. Here we investigated the contribution of these pathways to inflammatory joint pain behaviour and gene expression changes in the dorsal horn