Lesion of the Cerebellar Noradrenergic Innervation Enhances the Harmaline-Induced Tremor in Rats

Abnormal synchronous activation of the glutamatergic olivo-cerebellar pathway has been suggested to be crucial for the harmaline-induced tremor. The cerebellum receives two catecholaminergic pathways: the dopaminergic pathway arising from the ventral tegmental area/substantia nigra pars compacta, and the noradrenergic one from the locus coeruleus. The aim of the present study was to examine a contribution of the cerebellar catecholaminergic innervations to the harmaline-induced tremor in rats. Rats were injected bilaterally into the cerebellar vermis with 6-hydroxydopamine (6-OHDA; 8 μg/0.5 μl) either alone or this treatment was preceded (30 min earlier) by desipramine (15 mg/kg ip). Harmaline was administered to animals in doses of 7.5 or 15 mg/kg ip. Tremor of forelimbs was measured as a number of episodes during a 90-min observation. Rats were killed by decapitation 30 or 120 min after harmaline treatment. The levels of dopamine, noradrenaline, serotonin, and their metabolites were measured by HPLC in the cerebellum, substantia nigra, caudate–putamen, and frontal cortex. 6-OHDA injected alone enhanced the harmaline-induced tremor. Furthermore, it decreased the noradrenaline level by ca. 40–80% in the cerebellum and increased the levels of serotonin and 5-HIAA in the caudate–putamen and frontal cortex in untreated and/or harmaline-treated animals. When 6-OHDA treatment was preceded by desipramine, it decreased dopaminergic transmission in some regions of the cerebellum while inducing its compensatory activation in others. The latter lesion did not markedly influence the tremor induced by harmaline. The present study indicates that noradrenergic innervation of the cerebellum interacts with cerebral serotonergic systems and plays an inhibitory role in the harmaline-induced tremor

Comparative analysis of bones, mites, soil chemistry, nematodes and soil micro-Eukaryotes from a suspected homicide to estimate the post-mortem interval

Criminal investigations of suspected murder cases require estimating the post-mortem interval (PMI, or time after death) which is challenging for longer periods. Here we present the case of human remains found in a Swiss forest. We have used a multidisciplinary approach involving the analysis of bones, soil chemical characteristics, mites and nematodes (by microscopy) and micro-Eukaryotes (by Illumina high throughput sequencing). We analysed soil samples collected beneath the remains of the head, upper and lower body and “control” samples taken a few meters away. The PMI estimated on hair 14C-data via bomb peak radiocarbon dating gave a time range of 1 to 2 years before the finding of the remains on site. Cluster analyses for chemical constituents, nematodes, mites and micro- Eukaryotes revealed two clusters 1) head and upper body and 2) lower body and controls. From mite evidence, we conclude that the body was likely to have been brought to the site after death. However, chemical analyses, nematode community analyses and the analyses of micro-Eukaryotes indicate that decomposition took place at least partly on site. This study illustrates the usefulness of combining several lines of evidence for the study of homicide cases to better calibrate PMI inference tools

Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018)

A group of European experts reappraised the guidelines on the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) previously published in 2014 [Lefaucheur et al., Clin Neurophysiol 2014;125:2150-206]. These updated recommendations take into account all rTMS publications, including data prior to 2014, as well as currently reviewed literature until the end of 2018. Level A evidence (definite efficacy) was reached for: high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the painful side for neuropathic pain; HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC) using a figure-of-8 or a H1-coil for depression; low-frequency (LF) rTMS of contralesional M1 for hand motor recovery in the post-acute stage of stroke. Level B evidence (probable efficacy) was reached for: HF-rTMS of the left M1 or DLPFC for improving quality of life or pain, respectively, in fibromyalgia; HF-rTMS of bilateral M1 regions or the left DLPFC for improving motor impairment or depression, respectively, in Parkinson's disease; HF-rTMS of ipsilesional M1 for promoting motor recovery at the post-acute stage of stroke; intermittent theta burst stimulation targeted to the leg motor cortex for lower limb spasticity in multiple sclerosis; HF-rTMS of the right DLPFC in posttraumatic stress disorder; LF-rTMS of the right inferior frontal gyrus in chronic post-stroke non-fluent aphasia; LF-rTMS of the right DLPFC in depression; and bihemispheric stimulation of the DLPFC combining right-sided LF-rTMS (or continuous theta burst stimulation) and left-sided HF-rTMS (or intermittent theta burst stimulation) in depression. Level A/B evidence is not reached concerning efficacy of rTMS in any other condition. The current recommendations are based on the differences reached in therapeutic efficacy of real vs. sham rTMS protocols, replicated in a sufficient number of independent studies. This does not mean that the benefit produced by rTMS inevitably reaches a level of clinical relevance

Neurostimulation, doping, and the spirit of sport

There is increasing interest in using neuro-stimulation devices to achieve an ergogenic effect in elite athletes. Although the World Anti-Doping Authority (WADA) does not currently prohibit neuro-stimulation techniques, a number of researchers have called on WADA to consider its position on this issue. Focusing on trans-cranial direct current stimulation (tDCS) as a case study of an imminent so-called ‘neuro-doping’ intervention, we argue that the emerging evidence suggests that tDCS may meet WADA’s own criteria (pertaining to safety, performance-enhancing effect, and incompatibility with the ‘spirit of sport’) for a method’s inclusion on its list of prohibited substances and methods. We begin by surveying WADA’s general approach to doping, and highlight important limitations to the current evidence base regarding the performance-enhancing effect of pharmacological doping substances. We then review the current evidence base for the safety and efficacy of tDCS, and argue that despite significant shortcomings, it may be sufficient for WADA to consider prohibiting tDCS, in light of the comparable flaws in the evidence base for pharmacological doping substances. In the second half of the paper, we argue that the question of whether WADA ought to ban tDCS turns significantly on the question of whether it is compatible with the ‘spirit of sport’ criterion. We critique some of the previously published positions on this, and advocate our own sport-specific and application-specific approach. Despite these arguments, we finally conclude by suggesting that tDCS ought to be monitored rather than prohibited due to compelling non-ideal considerations

Recent trends in the use of electrical neuromodulation in Parkinson's disease

Purpose of Review: This review aims to survey recent trends in electrical forms of neuromodulation, with a specific application to Parkinson’s disease (PD). Emerging trends are identified, highlighting synergies in state-of-the-art neuromodulation strategies, with directions for future improvements in stimulation efficacy suggested. Recent Findings: Deep brain stimulation remains the most common and effective form of electrical stimulation for the treatment of PD. Evidence suggests that transcranial direct current stimulation (tDCS) most likely impacts the motor symptoms of the disease, with the most prominent results relating to rehabilitation. However, utility is limited due to its weak effects and high variability, with medication state a key confound for efficacy level. Recent innovations in transcranial alternating current stimulation (tACS) offer new areas for investigation. Summary: Our understanding of the mechanistic foundations of electrical current stimulation is advancing and as it does so, trends emerge which steer future clinical trials towards greater efficacy

The effects of rTMS on impulsivity in normal adults: a systematic review and meta-analysis

Background: Impulsivity is a multi-dimensional construct that is regarded as a symptom of many psychiatric disorders. Harm resulting from impulsive behaviour can be substantial for the individuals concerned, people around them and the society they live in. Therefore, the importance of developing therapeutic interventions to target impulsivity is paramount. Aims and methods: We conducted a systematic review and meta-analysis of the literature from AMED, Embase, Medline, and PsycINFO databases on the use of repetitive transcranial magnetic stimulation (rTMS) in healthy adults to modulate different subdomains (motor, temporal and reflection) of impulsivity. Results: The results indicated that rTMS has distinct effects on different impulsivity subdomains. It has a significant, albeit small, effect on modulating motor impulsivity (g = 0.30, 95% CI, 0.17 to 0.43, p < .001) and a moderate effect on temporal impulsivity (g = 0.59, 95% CI, 0.32 to 0.86, p < .001). Subgroup analyses (e.g., excitatory vs. inhibitory rTMS, conventional rTMS vs. theta burst stimulation, analyses by stimulation sites, and type of outcome measure used) identified key parameters associated with the effects of rTMS on motor and temporal impulsivity. Age, sex, stimulation intensity and the number of pulses were not significant moderators for effects of rTMS on motor impulsivity. Due to lack of sufficient data to inform a meta-analysis, it has not been possible to assess the effects of rTMS on reflection impulsivity. Conclusions: The present findings provide preliminary evidence that rTMS can be used to modulate motor and temporal impulsivity in healthy individuals. Further studies are required to extend the use of rTMS to modulate impulsivity in those at most risk of engaging in harmful behaviour as a result of impulsivity, such as patients with offending histories and those with a history of self-harming behaviour