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Objectives Peripheral neuropathy ranks among the most common dose-limiting and disabling side-effect of oxaliplatin (OXA)-based chemotherapy. The aim of this prospective, multicentre study was to define early clinical and neurophysiological markers that may help to identify patients at risk of developing severe, treatment emergent, cumulative OXA-induced peripheral neuropathy (OXAIPN). Methods 200 colorectal cancer patients, scheduled to receive OXA-based chemotherapy, were prospectively followed. Detailed neurological assessment employing the clinical Total Neuropathy Score (TNSc), oncological rating scales (National Common Institute-Common Toxicity Criteria V.3) and nerve conduction studies (NCS) were performed at baseline, mid-treatment and at the end of chemotherapy. Symptoms of OXA-induced acute neurotoxicity were systematically recorded. Results According to TNSc, 36 (18%) patients developed grade 3 OXAIPN. These patients were predominantly men (p=0.005), presented a significant decrease in all NCS (p<0.001), reported more acute neuropathic symptoms (p<0.001) and received higher OXA cumulative dose (p=0.003). Multivariate analysis showed that three variables obtained at intermediate follow-up, namely, the number of acute symptoms (OR 1.9; CI 95% 1.2 to 3.2; p=0.012) and the >30% decrease in sensory nerve action potential amplitude from the baseline value in radial (OR 41.4; CI 95% 4.98 to 343.1; p=0.001) and dorsal sural nerves (OR 24.96; CI 95% 2.6 to 239.4; p=0.005) were independently associated with the risk of developing severe OXAIPN. Conclusions High-grade OXA neurotoxicity can be predicted by clinical and neurophysiological information obtained at mid-treatment. Neurological assessment of acute neuropathy symptoms and radial and dorsal sural nerves NCS should be carefully monitored to predict and hopefully prevent the induction of severe OXAIPN.

BackgroundTo evaluate the efficacy of rituximab in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients not responding to conventional immune therapies.MethodsAn open-label, prospective exploratory study was conducted with intravenous rituximab on 17 CIDP patients who had not responded to at least two first-line therapies. The primary endpoint was to determine the proportion of patients who showed improvement 6 months after rituximab therapy. The percentage of responders to rituximab, along with a 95% CI, was reported and compared with the 30% response rate after other immunosuppressive drugs previously documented in the literature.Results13 of the 17 treated patients (76.5%) showed improvement at 6 months (95% CI 50.1 to 93.2). Among the 14 patients who completed the 12-month follow-up (2 were lost to follow-up after showing improvement at months 8 and 10, and 1 deteriorated at 6 months), 13 (92.9%) demonstrated improvement at 12 months (95% CI 66.1 to 99.8). Nerve conduction parameters improved by at least 20% in two nerves in 6 out of 15 (40%) patients at 6 months and in 7 out of 13 (53.9%) at 12 months. None of the treated patients withdrew from the study due to side effects. There was a significant reduction of circulating CD19+ cells 15 days, 2, 6 and 12 months after treatment.ConclusionRituximab seems to be a safe therapy in most patients with CIDP not responding to conventional immune therapies. The high percentage of patients who improved in this study suggests a possible positive effect of rituximab which is worth investigating in future randomised controlled clinical trials.Trial registration numberNCT05877040.

Charcot–Marie–Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2–16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number 12606000481572. 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1·7 m/s, 95% CI −0·1 to 3·4; p=0·06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached. University of Sydney Research and Development Scheme; National Health and Medical Research Council of Australia; James N Kirby Foundation; New South Wales Podiatrists Registration Board; Australian Podiatry Education and Research Foundation; Charcot–Marie–Tooth Association of Australia.

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R dlDRN neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4R dlDRN signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders. Neuronal signaling has an important role in the regulation of energy expenditure and body weight, however, the underlying mechanisms are incompletely understood. Here, the authors report a AgRP-MC4R-serotonin expressing neuronal circuit that regulate energy expenditure without affecting feeding.

The biomedical sciences have recently undergone revolutionary change, due to the ability to digitize and store large data sets. In neuroscience, the data sources include measurements of neural activity measured using electrode arrays, EEG and MEG, brain imaging data from PET, fMRI, and optical imaging methods. Analysis, visualization, and management of these time series data sets is a growing field of research that has become increasingly important both for experimentalists and theorists interested in brain function. The first part of the book contains a set of chapters which provide non-technical conceptual background to the subject. Salient features include the adoption of an active perspective of the nervous system, an emphasis on function, and a brief survey of different theoretical accounts in neuroscience. The second part is the longest in the book, and contains a refresher course in mathematics and statistics leading up to time series analysis techniques. The third part contains applications of data analysis techniques to the range of data sources indicated above, and the fourth part contains special topics.

A large body of evidence suggests that repetitive transcranial magnetic stimulation (rTMS) is clinically effective in treating neuropsychiatric disorders and multiple sessions are commonly used. However, it is unknown whether multiple sessions of rTMS improve cognitive control, which is a function of the neural circuitry of the left dorsolateral prefrontal cortex (DLPFC)-cingulate cortex in healthy individuals. In addition, it is still unclear which stages of neural processing are altered by rTMS. In this study, we investigated the effects of high-frequency rTMS on cognitive control and explored the time course changes of cognitive processing after rTMS using event-related potentials (ERPs). For seven consecutive days, 25 young healthy participants underwent one 10-Hz rTMS session per day in which stimulation was applied over the left DLPFC, and a homogeneous participant group of 25 individuals received a sham rTMS treatment. A Stroop task was performed, and an electroencephalogram (EEG) was recorded. The results revealed that multiple sessions of rTMS can decrease reaction time (RTs) under both congruent and incongruent conditions and also increased the amplitudes of both N2 and N450 compared with sham rTMS. The negative correlations between the mean amplitudes of both N2 and N450 and the RTs were found, however, the latter correlation were restricted to incongruent trials and the correlation was enhanced significantly by rTMS. This observation supports the view that high-frequency rTMS over the left DLPFC can not only recruit more neural resources from the prefrontal cortex by inducing an electrophysiologically excitatory effect but also enhance efficiency of resources to deploy for conflict resolution during multiple stages of cognitive control processing in healthy young people.

ObjectiveTo evaluate the clinical and pathological correlations characterising each clinical subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).MethodsWe assessed 106 consecutive patients who had CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria and had been referred for sural nerve biopsy. Patients with anti-neurofascin 155, anti-contactin 1 and anti-LM1 antibodies were excluded.Results55 patients were classified as having typical CIDP. Regarding atypical CIDP, the multifocal acquired demyelinating sensory and motor (MADSAM) (n=15), distal acquired demyelinating symmetric (DADS) (n=16) and pure sensory (n=15) forms were major subtypes, while the pure motor (n=4) and focal (n=1) forms were rare. Nerve conduction studies revealed that distal motor latencies and F-wave latencies were markedly prolonged in the typical CIDP group but relatively preserved in the MADSAM group. Motor conduction velocity was conspicuously slowed in the DADS group, and distal motor latencies were markedly prolonged in the pure sensory group. Sural nerve biopsy specimens from patients with MADSAM, DADS and pure sensory type tended to show extreme variation in myelinated fibre density among fascicles due to focal myelinated fibre loss or onion-bulb formation, whereas patients with typical CIDP tended to show mild fascicular variation. Epineurial lymphocytic infiltration was conspicuous in cases with marked fascicular variation in myelinated fibre density.ConclusionsPreferential involvement of distal and proximal segments and uniform pathological features in typical CIDP indicate a role of humoral factors at sites where the blood–nerve barrier is deficient. By contrast, focal lesions in MADSAM, DADS and pure sensory forms may share neuropathic mechanisms primarily affecting the nerve trunk.

ObjectiveThe objective of this study was to elucidate the natural history of late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) in non-endemic areas.MethodsThe authors retrospectively assessed the development of major clinical landmarks and abnormalities of nerve conduction and cardiac examination indices in 50 patients with an age of onset older than 50 years and no relationship to endemic foci.ResultsOnce the neuropathic process was initiated, sensory and motor symptoms of both the upper and lower extremities appeared within a period of one and a half years. Digestive and orthostatic symptoms also tended to occur in the early phase of the disease, whereas urinary symptoms appeared in the middle of the disease progress. Along with pain in the extremities, these symptoms progressed over time and significantly disturbed the quality of life during the late phase of the disease, resulting in the need for wheelchair use. Although cardiomyopathy became clinically apparent only in the late phase of the disease, it was found to be the major cause of death. The mean duration of the disease onset to death was 7.3 years. Although values at the time of diagnosis were extremely variable, serial measurements of electrophysiological indices, the cardiothoracic ratio and interventricular septum thickness indicated a steady exacerbation in these outcomes among patients within a span of a couple of years.ConclusionsThe ages of onset of each clinical landmark were extremely variable between patients. However, once an initial symptom appeared, the chronological sequence of other clinical landmarks tended to be uniform, occurring within a relatively short time span.

Abstract BACKGROUND Patients with severe cubital tunnel syndrome often have poor functional recovery with conventional surgical treatment. Postsurgical electrical stimulation (PES) has been shown to enhance axonal regeneration in animal and human studies. OBJECTIVE To determine if PES following surgery for severe cubital tunnel syndrome would result in better outcomes compared to surgery alone. METHODS Patients with severe cubital tunnel syndrome in this randomized, double-blind, placebo-controlled trial were randomized in a 1:2 ratio to the control or stimulation groups. Control patients received cubital tunnel surgery and sham stimulation, whereas patients in the stimulation group received 1-h of 20 Hz PES following surgery. Patients were assessed by a blinded evaluator annually for 3 yr. The primary outcome was motor unit number estimation (MUNE) and secondary outcomes were grip and key pinch strength and McGowan grade and compound muscle action potential. RESULTS A total of 31 patients were enrolled: 11 received surgery alone and 20 received surgery and PES. Three years following surgery, MUNE was significantly higher in the PES group (176 ± 23, mean + SE) compared to controls (88 ± 11, P < .05). The mean gain in key pinch strength in the PES group was almost 3 times greater than in the controls (P < .05). Similarly, other functional and physiological outcomes showed significantly greater improvements in the PES group. CONCLUSION PES enhanced muscle reinnervation and functional recovery following surgery for severe cubital tunnel syndrome. It may be a clinically useful adjunct to surgery for severe ulnar neuropathy, in which functional recovery with conventional treatment is often suboptimal. Graphical Abstract Graphical Abstract