RESUMEN
Transcranial direct current stimulation (tDCS) induces polarity-dependent neuroplasticity: with conventional protocols, anodal tDCS results in excitability enhancement while cathodal stimulation reduces excitability. However, partially non-linear responses are observed with increased stimulation intensity and/or duration. Cathodal tDCS with 2 mA for 20 min reverses the excitability-diminishing plasticity induced by stimulation with 1 mA into excitation, while cathodal tDCS with 3 mA again results in excitability diminution. Since tDCS generates NMDA receptor-dependent neuroplasticity, such non-linearity could be explained by different levels of calcium concentration changes, which have been demonstrated in animal models to control for the directionality of plasticity. In this study, we tested the calcium dependency of non-linear cortical plasticity induced by cathodal tDCS in human subjects in a placebo controlled, double-blind and randomized design. The calcium channel blocker flunarizine was applied in low (2.5 mg), medium (5 mg) or high (10 mg) dosages before 20 min cathodal motor cortex tDCS with 3 mA in 12 young healthy subjects. After-effects of stimulation were monitored with TMS-induced motor evoked potentials (MEPs) until 2 h after stimulation. The results show that motor cortical excitability-diminishing after-effects of stimulation were unchanged, diminished, or converted to excitability enhancement with low, medium and high dosages of flunarizine. These results suggest a calcium-dependency of the directionality of tDCS-induced neuroplasticity, which may have relevant implications for future basic and clinical research.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/fisiología , Potenciales Evocados Motores/fisiología , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Estimulación Transcraneal de Corriente Directa/métodos , Adulto , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Electrodos , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Estimulación Transcraneal de Corriente Directa/instrumentación , Adulto JovenRESUMEN
NEW FINDINGS: What is the central question of the study? What are the effects of caffeine on neuromuscular function in a non-fatigued state and during fatiguing exercise? What is the main finding and its importance? In a non-fatigued state, caffeine decreased the duration of the silent period evoked by transcranial magnetic stimulation. Caffeine-induced reduction of inhibitory mechanisms in the central nervous system before exercise was associated with an increased performance. Individuals who benefit from caffeine ingestion may experience lower perception of effort during exercise and an accelerated recovery of M-wave amplitude postfatigue. This study elucidates the mechanisms of action of caffeine and demonstrates that inter-individual variability of its effects on neuromuscular function is a fruitful area for further work. ABSTRACT: Caffeine enhances exercise performance, but its mechanisms of action remain unclear. In this study, we investigated its effects on neuromuscular function in a non-fatigued state and during fatiguing exercise. Eighteen men participated in this randomized, double-blind, placebo-controlled crossover trial. Baseline measures included plantarflexion force, drop jump, squat jump, voluntary activation of triceps surae muscle, soleus muscle contractile properties, M-wave, α-motoneuron excitability (H-reflex), corticospinal excitability, short-interval intracortical inhibition, intracortical facilitation, silent period evoked by transcranial magnetic stimulation (SP) and plasma potassium and caffeine concentrations. Immediately after baseline testing, participants ingested caffeine (6 mg·kg-1 ) or placebo. After a 1-h rest, baseline measures were repeated, followed by a fatiguing stretch-shortening cycle exercise (sets of 40 bilateral rebound jumps on a sledge apparatus) until task failure. Neuromuscular testing was carried out throughout the fatigue protocol and afterwards. Caffeine enhanced drop jump height (by 4.2%) and decreased the SP (by 12.6%) in a non-fatigued state. A caffeine-related decrease in SP and short-interval intracortical inhibition before the fatiguing activity was associated with an increased time to task failure. The participants who benefitted from an improved performance on the caffeine day reported a significantly lower sense of effort during exercise and had an accelerated postexercise recovery of M-wave amplitude. Caffeine modulates inhibitory mechanisms of the CNS, recovery of M-wave amplitude and perception of effort. This study lays the groundwork for future examinations of differences in caffeine-induced neuromuscular changes between those who are deemed to benefit from caffeine ingestion and those who are not.
Asunto(s)
Cafeína/administración & dosificación , Ejercicio Físico/fisiología , Fatiga Muscular/efectos de los fármacos , Fármacos Neuromusculares/administración & dosificación , Adulto , Método Doble Ciego , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Reflejo H/efectos de los fármacos , Reflejo H/fisiología , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/fisiología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Fatiga Muscular/fisiología , Postura/fisiología , Estimulación Magnética Transcraneal/métodosAsunto(s)
Cafeína/farmacología , Café , Potenciales Evocados Motores/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Estimulación Transcraneal de Corriente Directa , Adulto , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Corteza Motora/fisiología , Adulto JovenRESUMEN
Taurine (TAU) is one of the most abundant amino acids in the brain. It has many important physiological functions. The effects of TAU supplementation on brain function need to be further characterized in humans. The purpose of this study was to investigate whether a single dose of Taurine (TAU) intake would modulate corticospinal excitability and post-exercise facilitation (PEF) of the motor evoked potentials (MEP).
Asunto(s)
Excitabilidad Cortical/efectos de los fármacos , Excitabilidad Cortical/fisiología , Ejercicio Físico/fisiología , Taurina/farmacología , Estimulación Magnética Transcraneal , Adulto , Análisis de Varianza , Estudios Cruzados , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , HumanosRESUMEN
KEY POINTS: Nicotine (NIC) modulates cognition and memory function by targeting the nicotinic ACh receptor and releasing different transmitter systems postsynaptically. With both NIC-generated mechanisms, calcium influx and calcium permeability can be regulated, which is a key requirement for the induction of long-term potentiation, comprising the physiological basis of learning and memory function. We attempt to unmask the underlying mechanism of nicotinic effects on anodal transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity based on the hypothesis of calcium-dependency. Abolished tDCS-induced neuroplasticity as a result of NIC administration is reversed by calcium channel blockade with flunarizine in a dose-dependent manner. The results of the present study suggest that there is a dose determination of NIC/NIC agonists in therapeutical settings when treating cognitive dysfunction, which partially explains the heterogeneous results on cognition observed in subjects in different experimental settings. ABSTRACT: Nicotine (NIC) modulates neuroplasticity and improves cognitive performance in animals and humans mainly by increased calcium permeability and modulation of diverse transmitter systems. NIC administration impairs calcium-dependent plasticity induced by non-invasive brain stimulation with transcranial direct current stimulation (tDCS) in non-smoking participants probably as a result of intracellular calcium overflow. To test this hypothesis, we analysed the effect of calcium channel blockade with flunarizine (FLU) on anodal tDCS-induced cortical excitability changes in healthy non-smokers under NIC. We applied anodal tDCS combined with NIC patch and FLU at three different doses (2.5, 5 and 10 mg) or with placebo medication. NIC abolished anodal tDCS-induced neuroplasticity. Under medium dosage (but not under low and high dosage) of FLU combined with NIC, plasticity was re-established. For FLU alone, the lowest dosage weakened long-term potentiation (LTP)-like plasticity, whereas the highest dosage again abolished tDCS-induced plasticity. The medium dosage turned LTP-like plasticity in long-term depression-like plasticity. The results of the present study suggest a key role of calcium influx and calcium levels in nicotinic effects on LTP-like plasticity in humans. This knowledge might be relevant for the development of new therapeutic strategies in cognitive dysfunction.
Asunto(s)
Calcio/metabolismo , Potenciales Evocados Motores/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nicotina/farmacología , Estimulación Transcraneal de Corriente Directa , Adulto , Femenino , Humanos , Masculino , Plasticidad Neuronal/fisiología , Agonistas Nicotínicos/farmacología , Adulto JovenRESUMEN
BACKGROUND: Autoimmune neuropathies are common PNS disorders and effective treatment is challenging. Environmental influence and dietary components are known to affect the course of autoimmune diseases. Capsaicin as pungent component of chili-peppers is common in human nutrition. An influence of capsaicin on autoimmune diseases has been postulated. METHODS: We tested capsaicin in the animal model of experimental autoimmune neuritis (EAN) in Lewis rat. Rats were immunized with P2-peptide and were treated with capsaicin in different preventive settings. Electrophysiological, histological, and molecular biological analyses of the sciatic nerve were performed to analyze T-cell and macrophage cell count, TRPV1, and cytokine expression. Moreover, FACS analyses including the intestinal immune system were executed. RESULTS: We observed an immunomodulatory effect of an early preventive diet-concept, where a physiological dosage of oral capsaicin was given 10 days before immunization in EAN. A reduced inflammation of the sciatic nerve was significant detectable clinically, electrophysiologically (CMAPs reduced in control group p < 0.01; increase of nerve conduction blocks in control group p < 0.05), histologically (significant reduction of T-cells, macrophages and demyelination), and at cytokine level. In contrast, this therapeutic effect was missing with capsaicin given from the day of immunization onwards. As possible underlying mechanism, we were able to show changes in the expression of the capsaicin receptor in the sciatic nerve and the small intestine, as well as altered immune cell populations in the small intestine. CONCLUSION: This is the first report about the immunomodulatory effect of the common nutrient, capsaicin, in an experimental model for autoimmune neuropathies.
Asunto(s)
Capsaicina/uso terapéutico , Dieta/métodos , Neuritis Autoinmune Experimental/dietoterapia , Animales , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Modelos Animales de Enfermedad , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Adyuvante de Freund/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Conducción Nerviosa/efectos de los fármacos , Neuritis Autoinmune Experimental/patología , Neuritis Autoinmune Experimental/fisiopatología , Ratas , Ratas Endogámicas Lew , Proteínas S100/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Nervio Ciático/patología , Linfocitos T/efectos de los fármacos , Canales Catiónicos TRPV/metabolismoRESUMEN
OBJECTIVE: To evaluate the changes in glutamate/GABA balance of intracortical excitability produced by ketamine, delivered at subanaesthetic dose to treat patients with complex regional pain syndrome (CRPS). METHODS: In 19 patients with CRPS, we assessed the effect of a 5-day ketamine protocol on various clinical aspects, including pain and depression, and on cortical excitability parameters provided by transcranial magnetic stimulation testing. RESULTS: The rest motor threshold (RMT) and the amplitude of the motor evoked potentials at 120% of RMT were not modified after ketamine therapy. In contrast, ketamine reduced intracortical facilitation (ICF) in both hemispheres and increased short-interval intracortical inhibition (SICI), which was defective at baseline only in the hemisphere corresponding to the painful side. These changes positively correlated with pain relief. CONCLUSION: This study shows for the first time that the remarkable analgesic effects produced by ketamine in CRPS patients is associated with cortical excitability changes in favour of an enhanced GABAergic transmission in the hemisphere corresponding to the painful side and an overall reduction of excitability in the contralateral hemisphere. SIGNIFICANCE: Analgesic effects of ketamine cannot be resumed to its classical antigutamatergic action related to N-methyl-d-aspartate receptor blockade.
Asunto(s)
Analgésicos/uso terapéutico , Corteza Cerebral/efectos de los fármacos , Síndromes de Dolor Regional Complejo/tratamiento farmacológico , Excitabilidad Cortical/efectos de los fármacos , Ácido Glutámico/metabolismo , Ketamina/uso terapéutico , Ácido gamma-Aminobutírico/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Analgésicos/farmacología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Síndromes de Dolor Regional Complejo/metabolismo , Síndromes de Dolor Regional Complejo/fisiopatología , Excitabilidad Cortical/fisiología , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Humanos , Ketamina/farmacología , Masculino , Persona de Mediana Edad , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Hypericum perforatum (HYP) extract is one of the most commonly used complementary alternative medicines (CAMs) for the treatment of mild-to-moderate depression. Non-invasive brain stimulation protocols can be used to investigate the effect of psychoactive substances on the human brain. In this study, we explored the effect of a single dose of HYP extract (WS 5570) intake on corticospinal excitability and plasticity in humans. METHODS: Twenty-eight healthy subjects were required to intake 900 mg of either HYP extract or placebo. Cortical excitability was assessed using single and paired transcranial magnetic stimulation (TMS). The electrophysiological parameters of motor threshold, recruitment of motor-evoked potentials (MEPs), cortical silent period (CSP), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were tested before and 2 and 5 h after the oral intake. Spinal and neuromuscular excitability and peripheral nerve excitability were measured by F response and M-wave. Cortical plasticity was induced using transcranial direct current stimulation (tDCS). Subjects received either HYP extract or placebo before anodal and cathodal tDCS of the primary motor cortex. Plasticity was assessed by MEP amplitudes. RESULTS: HYP extract reversed cathodal tDCS-induced long-term depression (LTD)-like plasticity into facilitation, as compared to placebo. HYP extract did not have a significant effect on anodal tDCS-induced plasticity and TMS measures of motor cortex and spinal/neuromuscular excitability. CONCLUSIONS: Our findings suggest that a single oral dose of HYP extract modulates cortical plasticity in healthy subjects and provide new insight into its possible mechanism of action in humans.
Asunto(s)
Potenciales Evocados Motores/efectos de los fármacos , Hypericum , Corteza Motora/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Extractos Vegetales/farmacología , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Estimulación Transcraneal de Corriente Directa , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
BACKGROUND: Valeriana officinalis extract (VE) is a popular herbal medicine used for the treatment of anxiety and sleep disorders. Although the anxiolytic and sedative effects are mainly attributed to the modulation of GABA-ergic transmission, the mechanism of action has not been fully investigated in humans. Noninvasive brain stimulation protocols can be used to elucidate the mechanisms of action of psychoactive substances at the cortical level in humans. In this study, we investigated the effects of a single dose of VE on cortical excitability as assessed with transcranial magnetic stimulation (TMS). METHODS: Fifteen healthy volunteers participated in a double-blind, randomized, cross-over, placebo-controlled study. Subjects were required to take either 900 mg of VE (valerenic acid 0.8%) or placebo (an equal dose of vitamin E). Motor cortex excitability was studied by single and paired TMS before and at 1 h and 6 h after the oral administration. Cortical excitability was assessed using different TMS parameters: resting motor threshold, motor-evoked potential amplitude, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation. Furthermore, we assessed sensorimotor integration by short-latency and long-latency afferent inhibition. RESULTS: We found a significant reduction in ICF, without any significant changes in other TMS measures of motor cortex excitability. The amount of ICF returned to baseline value 6 h after the intake of the VE. CONCLUSION: A single oral dose of VE modulates intracortical facilitatory circuits. Our results in healthy subjects could be predictive markers of treatment response in patients and further support the use of pharmaco-TMS to investigate the neuropsychiatric effects of herbal therapies in humans.
Asunto(s)
Potenciales Evocados Motores/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Raíces de Plantas/química , Valeriana/química , Adulto , Método Doble Ciego , Electromiografía , Femenino , Humanos , Masculino , Corteza Motora/fisiología , Estimulación Magnética Transcraneal , Adulto JovenRESUMEN
Nicotine modulates neuroplasticity and improves cognitive functions in animals and humans. In the brain of smoking individuals, calcium-dependent plasticity induced by non-invasive brain stimulation methods such as transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) is impaired by nicotine withdrawal, but partially re-established after nicotine re-administration. In order to investigate the underlying mechanism further, we tested the impact of the α4ß2-nicotinic receptor partial agonist varenicline on focal and non-focal plasticity in smokers during nicotine withdrawal, induced by PAS and tDCS, respectively. We administered low (0.3 mg) and high (1.0 mg) single doses of varenicline or placebo medication before stimulation over the left motor cortex of 20 healthy smokers under nicotine withdrawal. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor evoked potential amplitudes for 36 hours after plasticity induction. Stimulation-induced plasticity was absent under placebo medication, whereas it was present in all conditions under high dose. Low dose restituted only tDCS-induced non-focal plasticity, producing no significant impact on focal plasticity. High dose varenicline also prolonged inhibitory plasticity. These results are comparable to the impact of nicotine on withdrawal-related impaired plasticity in smokers and suggest that α4ß2 nicotinic receptors are relevantly involved in plasticity deficits and restitution in smokers.
Asunto(s)
Fumar Cigarrillos/fisiopatología , Plasticidad Neuronal/efectos de los fármacos , Nicotina/efectos adversos , Agonistas Nicotínicos/administración & dosificación , Receptores Nicotínicos/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Vareniclina/administración & dosificación , Adulto , Fumar Cigarrillos/efectos adversos , Estimulación Eléctrica , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiopatología , Estimulación Transcraneal de Corriente Directa , Adulto JovenRESUMEN
We investigated the effect of 4-aminopyridine (4-AP) on experimental autoimmune neuritis (EAN) using a 4-AP-treated group in which 4-AP was administered in the diet, and a control group (n=10 per group). Electrophysiological and pathological assessment was performed in the sciatic nerve. The EAN clinical scores were significantly lower in the 4-AP-treated group than in the control group (p<0.05). The motor conductance velocity two weeks post-immunization was significantly higher in the 4-AP-treated group (p<0.05). Finally, 4-AP did not lead to pathological changes. Thus, 4-AP might be a potential therapeutic agent in demyelinating neuropathy.
Asunto(s)
4-Aminopiridina/uso terapéutico , Neuritis Autoinmune Experimental/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/uso terapéutico , 4-Aminopiridina/farmacología , Animales , Modelos Animales de Enfermedad , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Adyuvante de Freund/toxicidad , Masculino , Proteínas de la Mielina/toxicidad , Conducción Nerviosa/efectos de los fármacos , Neuritis Autoinmune Experimental/inducido químicamente , Neuritis Autoinmune Experimental/inmunología , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Endogámicas Lew , Estadísticas no Paramétricas , Vacunación/efectos adversosRESUMEN
BACKGROUND: 4-Aminopyridine (4-AP) is a Food and Drug Administration-approved drug to improve motor function in people with multiple sclerosis. Preliminary results suggest the drug may act on intact neural circuits and not just on demyelinated ones. OBJECTIVE: To determine if 4-AP at clinically relevant levels alters the excitability of intact motor circuits. METHODS: In anesthetized rats, electrodes were placed over motor cortex and the dorsal cervical spinal cord for electrical stimulation, and electromyogram electrodes were inserted into biceps muscle to measure responses. The motor responses to brain and spinal cord stimulation were measured before and for 5 hours after 4-AP administration both in uninjured rats and rats with a cut lesion of the pyramidal tract. Blood was collected at the same time as electrophysiology to determine drug plasma concentration with a goal of 20 to 100 ng/mL. RESULTS: We first determined that a bolus infusion of 0.32 mg/kg 4-AP was optimal: it produced on average 61.5 ± 1.8 ng/mL over the 5 hours after infusion. This dose of 4-AP increased responses to spinal cord stimulation by 1.3-fold in uninjured rats and 3-fold in rats with pyramidal tract lesion. Responses to cortical stimulation also increased by 2-fold in uninjured rats and up to 4-fold in the injured. CONCLUSION: Clinically relevant levels of 4-AP strongly augment physiological responses in intact circuits, an effect that was more robust after partial injury, demonstrating its broad potential in treating central nervous system injuries.
Asunto(s)
4-Aminopiridina/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Médula Cervical/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Tractos Piramidales/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , 4-Aminopiridina/sangre , 4-Aminopiridina/farmacocinética , Animales , Fármacos del Sistema Nervioso Central/sangre , Fármacos del Sistema Nervioso Central/farmacocinética , Médula Cervical/lesiones , Médula Cervical/fisiología , Médula Cervical/fisiopatología , Evaluación Preclínica de Medicamentos , Estimulación Eléctrica , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Miembro Anterior/efectos de los fármacos , Miembro Anterior/fisiología , Miembro Anterior/fisiopatología , Microelectrodos , Corteza Motora/fisiología , Corteza Motora/fisiopatología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Músculo Esquelético/fisiopatología , Tractos Piramidales/lesiones , Tractos Piramidales/fisiología , Tractos Piramidales/fisiopatología , Distribución Aleatoria , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/fisiopatologíaRESUMEN
The impact of nicotine (NIC) on plasticity is thought to be primarily determined via calcium channel properties of nicotinic receptor subtypes, and glutamatergic plasticity is likewise calcium-dependent. Therefore glutamatergic plasticity is likely modulated by the impact of nicotinic receptor-dependent neuronal calcium influx. We tested this hypothesis for transcranial direct current stimulation (tDCS)-induced long-term potentiation-like plasticity, which is abolished by NIC in nonsmokers. To reduce calcium influx under NIC, we blocked N-methyl-d-aspartate (NMDA) receptors. We applied anodal tDCS combined with 15 mg NIC patches and the NMDA-receptor antagonist dextromethorphan (DMO) in 3 different doses (50, 100, and 150 mg) or placebo medication. Corticospinal excitability was monitored by single-pulse transcranial magnetic stimulation-induced motor-evoked potential amplitudes after plasticity induction. NIC abolished anodal tDCS-induced motor cortex excitability enhancement, which was restituted under medium dosage of DMO. Low-dosage DMO did not affect the impact of NIC on tDCS-induced plasticity and high-dosage DMO abolished plasticity. For DMO alone, the low dosage had no effect, but medium and high dosages abolished tDCS-induced plasticity. These results enhance our knowledge about the proposed calcium-dependent impact of NIC on plasticity in humans and might be relevant for the development of novel nicotinic treatments for cognitive dysfunction.
Asunto(s)
Dextrometorfano/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Plasticidad Neuronal/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Estimulación Transcraneal de Corriente Directa , Adulto , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Factores de TiempoRESUMEN
Activity-dependent changes of postsynaptic Ca2+-concentration are influenced by a variety of different Ca2+-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca2+-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). Although, surprisingly, static corticospinal excitability was increased by the combination of DXM and NDP, PAS-induced facilitation was blocked. TBS-induced facilitation of corticospinal excitability, which has previously been shown to be turned into depression by L-type VGCC blocker NDP (Wankerl K, Weise D, Gentner R, Rumpf J, Classen J. 2010. L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci. 30(18):6197-6204.), was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS-induced plasticity may point to an important role of backpropagating action potentials in PAS-induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity.
Asunto(s)
Canales de Calcio Tipo L/metabolismo , Canales de Calcio Tipo T/metabolismo , Corteza Motora/fisiología , Plasticidad Neuronal/fisiología , Estimulación Magnética Transcraneal/métodos , Adolescente , Adulto , Bloqueadores de los Canales de Calcio/farmacología , Electromiografía , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Mano/fisiología , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Plasticidad Neuronal/efectos de los fármacos , Tractos Piramidales/efectos de los fármacos , Tractos Piramidales/metabolismo , Receptores AMPA/antagonistas & inhibidores , Receptores AMPA/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex®) has been recently approved for the management of treatment-resistant multiple sclerosis (MS) spasticity. Although the symptomatic relief of Sativex® on MS-spasticity has been consistently demonstrated, the pathogenetic implications remain unclear and the few electrophysiological studies performed to address this topic yielded controversial results. We therefore aimed to investigate the mechanisms underpinning the modulation of spastic hypertonia by Sativex®, at both central and spinal levels, through an extensive neurophysiological battery in patients with MS. METHODS: Nineteen MS patients with treatment-resistant spasticity were recruited. Before and after 4weeks of treatment with Sativex® patients were clinically assessed with the Modified Ashworth Scale (MAS) and underwent a large neurophysiological protocol targeting measures of excitability and inhibition at both cortical [e.g., intracortical facilitation (ICF), short (SICI) and long (LICI) intracortical inhibition, cortical silent period (CSP)] and spinal level [e.g., H-reflex, H/M ratio and recovery curve of the H-reflex (HRC)]. A group of 19 healthy subjects served as controls. RESULTS: A significant reduction of the MAS score after 4weeks of Sativex® treatment was detected. Before treatment, an increase in the late facilitatory phase of HRC was recorded in patients compared to the control group, that normalised post treatment. At central level, SICI and LICI were significantly higher in patients compared to healthy subjects. After therapy, a significant strengthening of inhibition (e.g. reduced LICI) and a non-significant facilitation (e.g. marginally increased ICF) occurred, suggesting a modulatory effect of Sativex® on different pathways, predominantly of inhibitory type. Sativex® treatment was well tolerated, with only 3 patients complaining about dizziness and bitter taste in their mouth. DISCUSSION: Our results confirm the clinical benefit of Sativex® on spastic hypertonia and demonstrate that it might modulate both cortical and spinal circuits, arguably in terms of both excitation and inhibition. We suggest that the clinical benefit was likely related to a net increase of inhibition at cortical level that, in turn, might have influenced spinal excitability.
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Esclerosis Múltiple/tratamiento farmacológico , Espasticidad Muscular/tratamiento farmacológico , Fármacos Neuromusculares/administración & dosificación , Extractos Vegetales/administración & dosificación , Adulto , Anciano , Cannabidiol , Moduladores de Receptores de Cannabinoides/administración & dosificación , Evaluación de la Discapacidad , Dronabinol , Combinación de Medicamentos , Potenciales Evocados Motores/efectos de los fármacos , Femenino , Estudios de Seguimiento , Reflejo H/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatología , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Rociadores Nasales , Vaporizadores Orales , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Inhibition is considered a key mechanism in schizophrenia. Short-latency intracortical inhibition (SICI) in the motor cortex is reduced in schizophrenia and is considered to reflect locally deficient γ-aminobutyric acid (GABA)-ergic modulation. However, it remains unclear how SICI is modulated during motor inhibition and how it relates to neural processing in other cortical areas. Here we studied motor inhibition Stop signal task (SST) in stabilized patients with schizophrenia (N = 28), healthy siblings (N = 21) and healthy controls (n = 31) matched in general cognitive status and educational level. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) were used to investigate neural correlates of motor inhibition. SST performance was similar in patients and controls. SICI was modulated by the task as expected in healthy controls and siblings but was reduced in patients with schizophrenia during inhibition despite equivalent motor inhibition performance. fMRI showed greater prefrontal and premotor activation during motor inhibition in schizophrenia. Task-related modulation of SICI was higher in subjects who showed less inhibition-related activity in pre-supplementary motor area (SMA) and cingulate motor area. An exploratory genetic analysis of selected markers of inhibition (GABRB2, GAD1, GRM1, and GRM3) did not explain task-related differences in SICI or cortical activation. In conclusion, this multimodal study provides direct evidence of a task-related deficiency in SICI modulation in schizophrenia likely reflecting deficient GABA-A related processing in motor cortex. Compensatory activation of premotor areas may explain similar motor inhibition in patients despite local deficits in intracortical processing. Task-related modulation of SICI may serve as a useful non-invasive GABAergic marker in development of therapeutic strategies in schizophrenia.
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Corteza Motora/fisiopatología , Esquizofrenia/fisiopatología , Adulto , Antipsicóticos/uso terapéutico , Mapeo Encefálico , Electromiografía/métodos , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Corteza Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Esquizofrenia/tratamiento farmacológico , Estimulación Magnética Transcraneal/métodos , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Chemical stimulation of the swallowing network with carbonation and citric acid has been investigated, showing potential benefits on swallowing of dysphagic patients. Despite this, the underlying mechanisms for these effects are not fully understood. Here we investigated the effects of 5 ml liquid bolus swallows of carbonated, citric acid, and still water on a swallowing reaction-time tasks paradigm in 16 healthy adults (8 male, mean age 33 ± 3.7 yr, protocol 1). We then investigated the net effects of "sensory bolus interventions" (40 repeated swallows every 15 s) of the three different liquid boluses on corticobulbar excitability, as examined with single-pulse transcranial magnetic stimulation (TMS) in 16 participants (8 female, mean age 33 ± 3.7 yr, protocol 2). The findings showed that a larger number of correctly timed swallows (within a predetermined time window) was accomplished mainly with carbonated liquids (z = -2.04, P = 0.04 vs. still water, protocol 1). Both carbonated and citric acid liquid interventions with 40 swallows increased corticobulbar excitability of the stronger pharyngeal projection, suggesting a similar modulatory pathway for the effects on swallowing. However, carbonation showed superiority (P = 0.04, F = 4.75, 2-way ANOVA), with the changes lasting up to 60 min following the intervention. These results hold significance for future further and in-depth physiological investigations of the differences between different stimuli on swallowing neural network.
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Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Agua Carbonatada/administración & dosificación , Corteza Motora/efectos de los fármacos , Corteza Motora/fisiología , Faringe/efectos de los fármacos , Faringe/fisiología , Adulto , Ácido Cítrico/administración & dosificación , Potenciales Evocados Motores/efectos de los fármacos , Potenciales Evocados Motores/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Adulto JovenRESUMEN
Despite the proven efficacy of Sativex(®) (9-delta-tetrahydrocannabinol plus cannabidiol) oromucosal spray in reducing spasticity symptoms in multiple sclerosis (MS), little is known about the neurophysiological correlates of such effects. The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity (H/M ratio) and corticospinal excitability in patients with progressive MS. This was a randomized, double-blind, placebo-controlled, crossover study. Consecutive subjects with progressive MS and lower limb spasticity referred to our center were randomized to 4 weeks' treatment (including 2 weeks' titration) with Sativex or placebo, with crossover after a 2-week washout. Clinical and neurophysiological measures (H/M ratio and cortical excitability) of spasticity were assessed. The H/M ratio was the primary outcome, with sample size calculation of 40 patients. Of 44 recruited patients, 34 were analyzed due to 6 drop-outs and 4 exclusions, which lowered the power of the study to show differences between treatments. Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response. Response on the modified Ashworth scale (at least 20 % improvement) was significantly more frequent after Sativex than placebo (50 vs 23.5 %; p = 0.041; McNemar). Side effects did not differ significantly according to treatment. Our findings confirm the clinical benefit of Sativex on MS spasticity. The lack of corresponding changes in corticospinal excitability and on the monosynaptic component, of the stretch reflex, although in a limited sample size, points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS.
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Corteza Cerebral/efectos de los fármacos , Potenciales Evocados Motores/efectos de los fármacos , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Espasticidad Muscular/tratamiento farmacológico , Evaluación de Resultado en la Atención de Salud , Extractos Vegetales/farmacología , Adulto , Cannabidiol , Estudios Cruzados , Método Doble Ciego , Dronabinol , Combinación de Medicamentos , Estimulación Eléctrica , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/complicaciones , Espasticidad Muscular/etiología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/efectos adversos , Índice de Severidad de la Enfermedad , Estimulación Magnética TranscranealRESUMEN
PURPOSE: Recently, we have shown that the combination of mouth rinsing and ingesting a bitter-tasting quinine solution immediately prior to the performance of a maximal 30-s cycling sprint significantly improves mean and peak power output. This ergogenic effect was proposed to be related to the activation of the corticomotor pathway by afferent taste signals originating from bitter taste receptors in the oral cavity. The aim of the present study was to use single-pulse transcranial magnetic stimulation to investigate whether mouth rinsing and ingestion of a bitter quinine solution increases corticomotor excitability. METHODS: A series of 10 motor-evoked potentials (MEPs) were recorded from the relaxed first dorsal interosseus muscle in 16 male competitive cyclists immediately before and after they rinsed their mouth for 10 s and then ingested either a 2 mM bitter quinine solution or plain water. RESULTS: Mean MEP amplitude was significantly increased in response to quinine administration by 16% (p < 0.05), with no evidence of a time-dependent effect over the 10 pulses. Mean MEP amplitude also increased by 10% in response to water administration (p < 0.05), though this increase was significantly smaller than the response to quinine (p < 0.05). CONCLUSIONS: We conclude that the activation of bitter taste receptors in the oral cavity and upper gastrointestinal tract has the capacity to increase corticomotor excitability in male competitive cyclists.
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Potenciales Evocados Motores/efectos de los fármacos , Corteza Motora/fisiología , Relajantes Musculares Centrales/farmacología , Músculo Esquelético/fisiología , Quinina/farmacología , Adulto , Rendimiento Atlético , Ingestión de Alimentos , Humanos , Masculino , Antisépticos Bucales/química , Antisépticos Bucales/farmacología , Relajantes Musculares Centrales/administración & dosificación , Quinina/administración & dosificación , Gusto , Estimulación Magnética TranscranealRESUMEN
BACKGROUND: Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI in patients treated with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or are related to clozapine treatment. METHODS: TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine. RESULTS: CSP was significantly longer after 6 weeks of treatment with clozapine (p=0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p>0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p>0.05). CONCLUSIONS: This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABAB mediated inhibitory neurotransmission. Potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia.