Chronic High-frequency Stimulation of the Subthalamic Nucleus Induces a Sustained Inhibition of Serotonergic System via Loss of Cell Phenotype

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard treatment in Parkinson’s disease (PD). However, in a considerable number of patients debilitating psychiatric side-effects occur. Recent research has revealed that external stimuli can alter the neurotransmitters’ homeostasis in neurons, which is known as “neurotransmitter respecification”. Herein, we addressed if neurotransmitter respecification could be a mechanism by which DBS suppresses the serotonergic function in the dorsal raphe nucleus (DRN) leading to mood changes. We infused transgenic 5-HT-Cre (ePet-cre) mice with AAV viruses to achieve targeted expression of eYFP and the genetically encoded calcium indicator GCaMP6s in the DRN prior to methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. Mice received bilateral DBS electrodes in the STN and an optic fiber in the DRN for Ca2+ photometry. MPTP treated mice demonstrated behavioral and histological PD phenotype, whereas all STN-DBS animals exhibited an increased immobility time in the forced swim test, reduced Ca2+ activity, and loss of TPH2 expression in the DRN. Given the prominent role of Ca2+ transients in mediating neurotransmitter respecification, these results suggest a chronic loss of serotonergic phenotype in the DRN following STN-DBS. These findings indicate that loss of 5-HT cell phenotype may underlie the unwanted depressive symptoms following STN-DBS.

Priming of central- and peripheral mechanisms with heat and cutaneous capsaicin facilitates secondary hyperalgesia to high frequency electrical stimulation

Heat/capsaicin sensitization and electrical high frequency stimulation (HFS) are well known model of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45 °C heat stimulation for 5 min followed by a topical capsaicin patch (4x4 cm) for 30 minutes on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS+HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS) and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pinprick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pinprick stimulation (difference from baseline and control area) was observed in the HFS+HEAT/CAPS session than in the HFS session 20 and 30 minutes after HFS. Furthermore, sensitivity was increased after HFS+HEAT/CAPS compared to after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central- and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS.

The effect of observational learning on the development of central sensitization

Watching other people in pain may affect one’s own experience of pain. It is unknown whether it can also modulate secondary mechanical hypersensitivity. We have addressed this question in two experiments in healthy human volunteers. In experiment 1 we tested, on a large sample (N=83), five videos of a model demonstrating high or low pain during high frequency stimulation (HFS) of the skin, a procedure known to induce secondary mechanical hypersensitivity. The aim was to select the two videos rated with the highest and lowest expected pain and fear (high pain and low pain videos). Morevoer, we have explored the correlation between empathy and fear scores. In experiment 2 (N=44), two groups of participants were randomly allocated to watching either the low or the high pain video, and subsequently underwent HFS. The high pain video group reported increased pain during HFS. The two groups differed in the magnitude of secondary mechanical hypersensitivity after HFS, but the unpleasantness scores for mechanical stimulation after HFS, as well as spread of hyperalgesia were not statistically different. Empathy scores correlated positively with fear reports in experiment 1 but not experiment 2. Unexpectedly, we found higher scores of fear of pain for the high pain video only in experiment 1. In summary, observational learning of a model demonstrating high pain seems to have a stastistically significant but small effect on pinprick hypersensitivity. Its operating mechanisms remain partially elusive.

Serendipitous Stimulation of Nucleus Basalis of Meynert—The Effect of Unintentional, Long-Term High-Frequency Stimulation on Cognition in Parkinson’s Disease

There is a growing interest in deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) as a potential therapeutic modality for Parkinson’s disease dementia (PDD). Low-frequency stimulation has yielded encouraging results in individual patients; however, these are not yet sustained in larger studies. With the aim to expand the understanding of NBM-DBS, we share our experience with serendipitous NBM-DBS in patients treated with DBS of the internal Globus pallidus (GPi) for Parkinson’s disease. Since NBM is anatomically located ventral to GPi, several GPi-treated patients appeared to have the distal contact of DBS-electrode(s) positioned in the NBM. We hypothesized that unintentional high-frequency NBM-DBS over a period of one year would result in the opposite effect of low-frequency NBM-stimulation and cause cognitive decline. We studied a cohort of 33 patients with bilateral high-frequency DBS in the GPi for Parkinson’s disease, of which twelve were unintentionally co-stimulated in NBM. The subgroups of unintentional unilateral (N = 7) and bilateral NBM-DBS (N = 5) were compared to the control group of bilateral GPi-DBS (N = 11). Here, we show that unintentional high-frequency NBM-DBS did not cause a significantly faster decline in cognitive function. Further research is warranted for characterizing the therapeutic role of NBM-DBS.

Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.

Effects of methamphetamine-induced neurotoxicity on striatal long-term potentiation

Rationale Methamphetamine (METH) exposure is associated with damage to central monoamine systems, particularly dopamine signaling. Rodent models of such damage have revealed a decrease in the amplitude of phasic dopamine signals and significant striatal dysfunction, including changes in the molecular, system, and behavioral functions of the striatum. Dopamine signaling through D1 receptors promotes corticostriatal long-term potentiation (LTP), a critical substrate of these striatal functions. Objectives Therefore, the purpose of this study was to determine if METH-induced dopamine neurotoxicity would impair D1 receptor-dependent striatal LTP in mice. Methods Mice were treated with a METH binge regimen (4 × 10 mg/kg d,l-methamphetamine, s.c.) that recapitulates all of the known METH-induced neurotoxic effects observed in humans, including dopamine toxicity. Three weeks later, acute brain slices containing either the dorsomedial striatum (DMS) or dorsolateral striatum (DLS) were prepared, and plasticity was assessed using white matter, high-frequency stimulation (HFS), and striatal extracellular electrophysiology. Results Under these conditions, LTP was induced in brain slices containing the DMS from saline-pretreated mice, but not mice with METH-induced neurotoxicity. Furthermore, the LTP observed in DMS slices from saline-pretreated mice was blocked by the dopamine D1 receptor antagonist SCH23390, indicating that this LTP is dopamine D1 receptor-dependent. Finally, acute in vivo treatment of METH-pretreated mice with bupropion (50 mg/kg, i.p.) promoted LTP in DMS slices. Conclusions Together, these studies demonstrate that METH-induced neurotoxicity impairs dopamine D1 receptor-dependent LTP within the DMS and that the FDA-approved drug bupropion restores induction of striatal LTP in mice with METH-induced dopamine neurotoxicity.

Drop jumps versus sled towing and their effects on repeated sprint ability in young basketball players

Background The aim of the investigation was to compare the occurrence of post-activation performance enhancement (PAPE) after drop jumps, or heavy sled towing, and the subsequent effect on repeated sprint ability (RSA). Methods Ten young basketball players (17 ± 1 yrs) performed, in randomized order, RSA test with changes of direction after a standardized warm up followed by drop jumps, heavy sled towing, or no exercise (control condition). Neuromuscular assessments composed of two maximal voluntary contractions of the knee extensors, peripheral nerve stimulation, and surface electromyography (EMG), responses were recorded before and immediately after the RSA. The EMG signal of leg muscles during sprinting were also recorded as well as the blood lactate concentration. Results The drop jumps improved the RSA mean time (P = 0.033), total time (P = 0.031), and slowest time (P = 0.029) compared to control condition, while heavy sled towing did not change RSA outcomes (P > 0.05). All conditions exhibited a decrease of doublet high frequency stimulation force (pre-post measurement) (P = 0.023) and voluntary activation (P = 0.041), evidencing the occurrence from peripheral and central components of fatigue after RSA, respectively, but no difference was evident between-conditions. There was a significantly greater EMG activity during sprints for the biceps femoris after drop jumps, only when compared to control condition (P = 0.013). Conclusion Repeated drop jumps were effective to induce PAPE in the form of RSA, while heavy sled towing had no effect on RSA performance in young basketball players. Furthermore, both conditioning activities exhibited similar levels of fatigue following the RSA protocol. Thus, drop jumps may be used as an alternative to induce PAPE and thus improve performance during sprints in young male basketball players.

In the back of your mind: Cortical mapping of tactile and proprioceptive paraspinal afferent inputs

Persistent pain alters brain-body representations, highlighting their potential pathological significance. In chronic low back pain (LBP), sparse evidence points towards a shift of the cortical representation of sensory afferents of the back. However, systematic investigations of the cortical representation of tactile and proprioceptive paraspinal afferents along the thoracolumbar axis are lacking. Detailed cortical maps of paraspinal afferent input might be crucial to further explore potential relationships between brain changes and the development and maintenance of chronic LBP. We therefore validated a novel and functional magnetic resonance imaging- (fMRI-)compatible method of mapping cortical representations of tactile and proprioceptive afferents of the back, using pneumatic vibrotactile stimulation ("pneuVID") at varying frequencies and paraspinal locations, in conjunction with high-resolution fMRI. We hypothesised that: (i) high (80 Hz) frequency stimulation would lead to increased postural sway compared to low (20 Hz) stimulation, due to differential evoked mechanoreceptor contributions to postural control (proprioceptive vs tactile); and (ii) that high (80 Hz) versus low (20 Hz) frequency stimulation would be associated with neuronal activity in distinct primary somatosensory (S1) and motor (M1) cortical targets of tactile and proprioceptive afferents (N=15, healthy volunteers). Additionally, we expected neural representations to vary spatially along the thoracolumbar axis. We found significant differences between neural representations of low and high frequency stimulation and between representations of thoracic and lumbar paraspinal locations, in several bilateral sensorimotor cortical regions. Proprioceptive (80 Hz) stimulation preferentially activated sub-regions S1 3a and M1 4p, while tactile (20 Hz) stimulation was more encoded in S1 3b and M1 4a. Moreover, in S1, lower back proprioceptive stimulation activated dorsal-posterior representations, compared to ventral-anterior representations activated by upper back stimulation. As per our hypotheses, we found distinct sensorimotor cortical tactile and proprioceptive representations, with the latter displaying clear topographic differences between the upper and lower back. This thus represents the first behavioural and neurobiological validation of the novel pneuVID method for stimulating muscle spindles and mapping cortical representations of paraspinal afferents. Future investigations of detailed cortical maps will be of major importance in elucidating the role of cortical reorganization in the pathophysiology of chronic LBP.

Impairments of Long-Term Synaptic Plasticity in the Hippocampus of Young Rats during the Latent Phase of the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) causes persistent abnormalities in the functioning of neuronal networks, often resulting in worsening epileptic seizures. Many details of cellular and molecular mechanisms of seizure-induced changes are still unknown. The lithium–pilocarpine model of epilepsy in rats reproduces many features of human temporal lobe epilepsy. In this work, using the lithium–pilocarpine model in three-week-old rats, we examined the morphological and electrophysiological changes in the hippocampus within a week following pilocarpine-induced seizures. We found that almost a third of the neurons in the hippocampus and dentate gyrus died on the first day, but this was not accompanied by impaired synaptic plasticity at that time. A diminished long-term potentiation (LTP) was observed following three days, and the negative effect of SE on plasticity increased one week later, being accompanied by astrogliosis. The attenuation of LTP was caused by the weakening of N-methyl-D-aspartate receptor (NMDAR)-dependent signaling. NMDAR-current was more than two-fold weaker during high-frequency stimulation in the post-SE rats than in the control group. Application of glial transmitter D-serine, a coagonist of NMDARs, allows the enhancement of the NMDAR-dependent current and the restoration of LTP. These results suggest that the disorder of neuron–astrocyte interactions plays a critical role in the impairment of synaptic plasticity.