Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an ""induction phase"" of 5 daily sessions followed by a ""maintenance phase"" of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability. Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new therapeutic option in patients with fibromyalgia. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Interhemispheric Asymmetry of Corticomotor Excitability After Chronic Cerebellar Infarcts

Early after stroke, there is loss of intracortical facilitation (ICF) and increase in short-interval intracortical inhibition (SICI) in the primary motor cortex (M1) contralateral to a cerebellar infarct. Our goal was to investigate intracortical M1 function in the chronic stage following cerebellar infarcts (> 4 months). We measured resting motor threshold (rMT), SICI, ICF, and ratios between motor-evoked potential amplitudes (MEP) and supramaximal M response amplitudes (MEP/M; %), after transcranial magnetic stimulation was applied to the M1 contralateral (M1(contralesional)) and ipsilateral (M1(ipsilesional)) to the cerebellar infarct in patients and to both M1s of healthy age-matched volunteers. SICI was decreased in M1(contralesional) compared to M1(ipsilesional) in the patient group in the absence of side-to-side differences in controls. There were no significant interhemispheric or between-group differences in rMT, ICF, or MEP/M (%). Our results document disinhibition of M1(contralesional) in the chronic phase after cerebellar stroke.

Alteration of cortical excitability in patients with fibromyalgia

We assessed cortical excitability and intracortical modulation systematically, by transcranial magnetic stimulation (TMS) of the motor cortex, in patients with fibromyalgia. In total 46 female patients with fibromyalgia and 21 normal female subjects, matched for age, were included in this study. TMS was applied to the hand motor area of both hemispheres and motor evoked potentials (MEPs) were recorded for the first interosseous muscle of the contralateral hand. Single-pulse stimulation was used for measurements of the rest motor threshold (RMT) and suprathreshold MEP. Paired-pulse stimulation was used to assess short intracortical inhibition (SICI) and intracortical facilitation (ICF). Putative correlations were sought between changes in electrophysiological parameters and major clinical features of fibromyalgia, such as pain, fatigue, anxiety, depression and catastrophizing. The RMT on both sides was significantly increased in patients with fibromyalgia and suprathreshold MEP was significantly decreased bilaterally. However, these alterations, suggesting a global decrease in corticospinal excitability, were not correlated with clinical features. Patients with fibromyalgia also had lower ICF and SICI on both sides, than controls, these lower values being correlated with fatigue, catastrophizing and depression. These neurophysiological alterations were not linked to medication, as similar changes were observed in patients with or without psychotropic treatment. In conclusion, fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome. Our data add to the growing body of evidence for objective and quantifiable changes in brain function in fibromyalgia. (C) 2010 International Association for the Study of Pain. Published by Elsevier B. V. All rights reserved.

Inhibitory network interactions shape the auditory processing of natural communication signals in the songbird auditory forebrain

The role of GABA in the central processing of complex auditory signals is not fully understood. We have studied the involvement of GABA(A)-mediated inhibition in the processing of birdsong, a learned vocal communication signal requiring intact hearing for its development and maintenance. We focused on caudomedial nidopallium (NCM), an area analogous to parts of the mammalian auditory cortex with selective responses to birdsong. We present evidence that GABA(A)-mediated inhibition plays a pronounced role in NCM`s auditory processing of birdsong. Using immunocytochemistry, we show that approximately half of NCM`s neurons are GABAergic. Whole cell patch-clamp recordings in a slice preparation demonstrate that, at rest, spontaneously active GABAergic synapses inhibit excitatory inputs onto NCM neurons via GABA(A) receptors. Multi-electrode electrophysiological recordings in awake birds show that local blockade of GABA(A)-mediated inhibition in NCM markedly affects the temporal pattern of song-evoked responses in NCM without modifications in frequency tuning. Surprisingly, this blockade increases the phasic and largely suppresses the tonic response component, reflecting dynamic relationships of inhibitory networks that could include disinhibition. Thus processing of learned natural communication sounds in songbirds, and possibly other vocal learners, may depend on complex interactions of inhibitory networks.

Phasic modulation of corticomotor excitability during passive movement of the upper limb: effects of movement frequency and muscle specificity

Modulations in the excitability of spinal reflex pathways during passive rhythmic movements of the lower limb have been demonstrated by a number of previous studies [4]. Less emphasis has been placed on the role of supraspinal pathways during passive movement, and on tasks involving the upper limb. In the present study, transcranial magnetic stimulation (TMS) was delivered to subjects while undergoing passive flexion-extension movements of the contralateral wrist. Motor evoked potentials (MEPs) of flexor carpi radialis (FCR) and abductor pollicus brevis (APB) muscles were recorded. Stimuli were delivered in eight phases of the movement cycle during three different frequencies of movement. Evidence of marked modulations in pathway excitability was found in the MEP amplitudes of the FCR muscle, with responses inhibited and facilitated from static values in the extension and flexion phases, respectively. The results indicated that at higher frequencies of movement there was greater modulation in pathway excitability. Paired-pulse TMS (sub-threshold conditioning) at short interstimulus intervals revealed modulations in the extent of inhibition in MEP amplitude at high movement frequencies. In the APE muscle, there was some evidence of phasic modulations of response amplitude, although the effects were less marked than those observed in FCR. It is speculated that these modulatory effects are mediated via Ia afferent pathways and arise as a consequence of the induced forearm muscle shortening and lengthening. Although the level at which this input influences the corticomotoneuronal pathway is difficult to discern, a contribution from cortical regions is suggested. (C) 2001 Published by Elsevier Science B.V.

Intrahemispheric dysfunction in primary motor cortex without corpus callosum: a transcranial magnetic stimulation study

Affiliation: Département de Psychologie, Université de Montréal

Effets de la vibration des muscles sur les mécanismes neuronaux et la fonction du membre supérieur et inférieur des personnes ayant une hémiparésie chronique

Cette thèse vise à répondre à trois questions fondamentales: 1) La diminution de l’excitabilité corticospinale et le manque d’inhibition intracorticale observés suite à la stimulation magnétique transcrânienne (SMT) du cortex moteur de la main atteinte de sujets hémiparétiques sont-ils aussi présents suite à la SMT du cortex moteur de la jambe atteinte? 2) Est-ce que les altérations dans l’excitabilité corticomotrice sont corrélées aux déficits et incapacités motrices des personnes ayant subi un accident vasculaire cérébral depuis plus de 6 mois? 3) La vibration musculaire, étant la source d’une forte afférence sensorielle, peut-elle moduler l’excitabilité corticomotrice et améliorer la performance motrice de ces personnes? Premièrement, afin d’appuyer notre choix d’intervention et d’évaluer le potentiel de la vibration mécanique locale pour favoriser la réadaptation des personnes ayant une atteinte neurologique, nous avons réalisé une révision en profondeur de ses applications et intérêts cliniques à partir d’informations trouvées dans la littérature scientifique (article 1). La quantité importante d’information sur les effets physiologiques de la vibration contraste avec la pauvreté des études qui ont évalué son effet thérapeutique. Nous avons trouvé que, malgré le manque d’études, les résultats sur son utilisation sont encourageants et positifs et aucun effet adverse n’a été rapporté. Dans les trois autres articles qui composent cette thèse, l’excitabilité des circuits corticospinaux et intracorticaux a été étudiée chez 27 sujets hémiparétiques et 20 sujets sains sans atteintes neurologiques. Les fonctions sensorimotrices ont aussi été évaluées par des tests cliniques valides et fidèles. Tel qu’observé à la main chez les sujets hémiparétiques, nous avons trouvé, par rapport aux sujets sains, une diminution de l’excitabilité corticospinale ainsi qu’un manque d’inhibition intracorticale suite à la SMT du cortex moteur de la jambe atteinte (article 2). Les sujets hémiparétiques ont également montré un manque de focus de la commande motrice lors de l’activation volontaire des fléchisseurs plantaires. Ceci était caractérisé par une augmentation de l’excitabilité nerveuse des muscles agonistes, mais aussi généralisée aux synergistes et même aux antagonistes. De plus, ces altérations ont été corrélées aux déficits moteurs au membre parétique. Le but principal de cette thèse était de tester les effets potentiels de la vibration des muscles de la main (article 3) et de la cuisse (article 4) sur les mécanismes neuronaux qui contrôlent ces muscles. Nous avons trouvé que la vibration augmente l’amplitude de la réponse motrice des muscles vibrés, même chez des personnes n’ayant pas de réponse motrice au repos ou lors d’une contraction volontaire. La vibration a également diminué l’inhibition intracorticale enregistrée au quadriceps parétique (muscle vibré). La diminution n’a cependant pas été significative au niveau de la main. Finalement, lors d’un devis d’investigation croisé, la vibration de la main ou de la jambe parétique a résulté en une amélioration spécifique de la dextérité manuelle ou de la coordination de la jambe, respectivement. Au membre inférieur, la vibration du quadriceps a également diminuée la spasticité des patients. Les résultats obtenus dans cette thèse sont très prometteurs pour la rééducation de la personne hémiparétique car avec une seule séance de vibration, nous avons obtenu des améliorations neurophysiologiques et cliniques.

Le GABA comme marqueur de récupération suite à une commotion cérébrale dans le sport ?

L’association démontrée récemment entre les commotions cérébrales dans le sport et le développement possible de maladies neurodégénératives a suggéré la possibilité que des altérations persistantes soient présentes dans le cerveau de l’athlète commotionné. En fait, des altérations neurophysiologiques ont récemment été révélées au sein du cortex moteur primaire (M1) d’athlètes ayant un historique de commotions via la stimulation magnétique transcrânienne (SMT). Plus précisément, la période silencieuse corticale (PSC), une mesure d’inhibition liée aux récepteurs GABAB, était anormalement élevée, et cette hyper-inhibition était présente jusqu’à 30 ans post-commotion. La PSC, et possiblement le GABA, pourraient donc s’avérer des marqueurs objectifs des effets persistants de la commotion cérébrale. Toutefois, aucune étude à ce jour n’a directement évalué les niveaux de GABA chez l’athlète commotionné. Ainsi, les études cliniques et méthodologiques composant le présent ouvrage comportent deux objectifs principaux: (1) déterminer si l’inhibition excessive (GABA et PSC) est un marqueur des effets persistants de la commotion cérébrale; (2) déterminer s’il est possible de moduler l’inhibition intracorticale de façon non-invasive dans l’optique de développer de futurs avenues de traitements. L’article 1 révèle une préservation des systèmes sensorimoteurs, somatosensoriels et de l’inhibition liée au GABAA chez un groupe d’athlètes universitaires asymptomatiques ayant subi de multiples commotions cérébrales en comparaison avec des athlètes sans historique connu de commotion cérébrale. Cependant, une atteinte spécifique des mesures liées au système inhibiteur associé aux récepteurs GABAB est révélée chez les athlètes commotionnés en moyenne 24 mois post-commotion. Dans l’article 2, aucune atteinte des mesures SMT liées au système inhibiteur n’est révélée en moyenne 41 mois après la dernière commotion cérébrale chez un groupe d’athlètes asymptomatiques ayant subi 1 à 5 commotions cérébrales. Bien qu’aucune différence entre les groupes n’est obtenue quant aux concentrations de GABA et de glutamate dans M1 via la spectroscopie par résonance magnétique (SRM), des corrélations différentielles suggèrent la présence d’un déséquilibre métabolique entre le GABA et le glutamate chez les athlètes commotionnés. L’article 3 a démontré, chez des individus en bonne santé, un lien entre la PSC et la transmission glutamatergique, ainsi que le GABA et le glutamate. Ces résultats suggèrent que la PSC ne reflète pas directement les concentrations du GABA mesurées par la SRM, mais qu’un lien étroit entre la GABA et le glutamate est présent. L’article 4 a démontré la possibilité de moduler la PSC avec la stimulation électrique transcrânienne à courant direct (SÉTcd) anodale chez des individus en santé, suggérant l’existence d’un potentiel thérapeutique lié à l’utilisation de cette technique. L’article 5 a illustré un protocole d’évaluation des effets métaboliques de la SÉTcd bilatérale. Dans l’article 6, aucune modulation des systèmes GABAergiques révélées par la SMT et la SRM n’est obtenue suite à l’utilisation de ce protocole auprès d’individus en santé. Cet article révèle également que la SÉTcd anodale n’engendre pas de modulation significative du GABA et du glutamate. En somme, les études incluent dans le présent ouvrage ont permis d’approfondir les connaissances sur les effets neurophysiologiques et métaboliques des commotions cérébrales, mais également sur le mécanisme d’action des diverses méthodologies utilisées.

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: Influence of theta burst stimulation priming

Background Conventional protocols of high-frequency repetitive transcranial magnetic stimulation (rTMS) delivered to M1 can produce analgesia. Theta burst stimulation (TBS), a novel rTMS paradigm, is thought to produce greater changes in M1 excitability than conventional protocols. After a preliminary experiment showing no analgesic effect of continuous or intermittent TBS trains (cTBS or iTBS) delivered to M1 as single procedures, we used TBS to prime a subsequent session of conventional 10?Hz-rTMS. Methods In 14 patients with chronic refractory neuropathic pain, navigated rTMS was targeted over M1 hand region, contralateral to painful side. Analgesic effects were daily assessed on a visual analogue scale for the week after each 10?Hz-rTMS session, preceded or not by TBS priming. In an additional experiment, the effects on cortical excitability parameters provided by single- and paired-pulse TMS paradigms were studied. Results Pain level was reduced after any type of rTMS procedure compared to baseline, but iTBS priming produced greater analgesia than the other protocols. Regarding motor cortex excitability changes, the analgesic effects were associated with an increase in intracortical inhibition, whatever the type of stimulation, primed or non-primed. Conclusions The present results show that the analgesic effects of conventional 10?Hz-rTMS delivered to M1 can be enhanced by TBS priming, at least using iTBS. Interestingly, the application of cTBS and iTBS did not produce opposite modulations, unlike previously reported in other systems. It remains to be determined whether the interest of TBS priming is to generate a simple additive effect or a more specific process of cortical plasticity.

Increased variability of motor cortical excitability to transcranial magnetic stimulation in migraine: a new clue to an old enigma

Increased, decreased or normal excitability to transcranial magnetic stimulation (TMS) has been reported in the motor (M1) and visual cortices of patients with migraine. Light deprivation (LD) has been reported to modulate M1 excitability in control subjects (CS). Still, effects of LD on M1 excitability compared to exposure to environmental light exposure (EL) had not been previously described in patients with migraine (MP). To further our knowledge about differences between CS and MP, regarding M1 excitability and effects of LD on M1 excitability, we opted for a novel approach by extending measurement conditions. We measured motor thresholds (MTs) to TMS, short-interval intracortical inhibition, and ratios between motor-evoked potential amplitudes and supramaximal M responses in MP and CS on two different days, before and after LD or EL. Motor thresholds significantly increased in MP in LD and EL sessions, and remained stable in CS. There were no significant between-group differences in other measures of TMS. Short-term variation of MTs was greater in MP compared to CS. Fluctuation in excitability over hours or days in MP is an issue that, until now, has been relatively neglected. The results presented here will help to reconcile conflicting observations.

Abnormality of motor cortex excitability in peripherally induced dystonia

It is widely accepted that peripheral trauma such as soft tissue injuries can trigger dystonia, although little is known about the underlying mechanism. Because peripheral injury only rarely appears to elicit dystonia, a predisposing vulnerability in cortical motor areas might play a role. Using single and paired-pulse pulse transcranial magnetic stimulation, we evaluated motor cortex excitability of a hand muscle in a patient with peripherally induced foot dystonia, in her brother with craniocervical dystonia, and in her unaffected sister, and compared their results to those from a group of normal subjects. In the patient with peripherally induced dystonia, we found a paradoxical intracortical facilitation at short interstimulus intervals of 3 and 5 milliseconds, at which regular intracortical inhibition (ICI) occurred in healthy subjects. These findings suggest that the foot dystonia may have been precipitated as the result of a preexisting abnormality of motor cortex excitability. Furthermore, the abnormality of ICI in her brother and sister indicates that altered motor excitability may be a hereditary predisposition. The study demonstrates that the paired-pulse technique is a useful tool to assess individual vulnerability, which can be particularly relevant when the causal association between trauma and dystonia is less evident.

Inhibition of motor cortex excitability with 15 Hz transcranial alternating current stimulation (tACS)

There remains a lack of solid evidence showing whether transcranial stimulation with weak alternating current (transcranial alternating current stimulation, tACS) can in fact induce significant neurophysiological effects. Previously, a study in which tACS was applied for 2 and 5 min with current density = 0.16-0.25 A/m(2) was unable to show robust effects on cortical excitability. Here we applied tACS at a significantly higher current density (0.80 A/m(2)) for a considerably longer duration (20 min) and were indeed able to demonstrate measurable changes to cortical excitability. Our results show that active 15 Hz tACS of the motor cortex (electrodes placed at C3 and C4) significantly diminished the amplitude of motor evoked potentials and decreased intracortical facilitation (ICF) as compared to baseline and sham stimulation. In addition, we show that our method of sham tACS is a reliable control condition. These results support the notion that AC stimulation with weak currents can induce significant changes in brain excitability; in this case, 15 Hz tACS led to a pattern of inhibition of cortical excitability. We propose that tACS may have a dampening effect on cortical networks and perhaps interfere with the temporal and spatial summation of weak subthreshold electric potentials. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Ikkε Is Key To Induction Of Insulin Resistance In The Hypothalamus, And Its Inhibition Reverses Obesity.

IKK epsilon (IKKε) is induced by the activation of nuclear factor-κB (NF-κB). Whole-body IKKε knockout mice on a high-fat diet (HFD) were protected from insulin resistance and showed altered energy balance. We demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice with CAYMAN10576 or small interfering RNA decreased NF-κB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser307) phosphorylation and insulin and leptin resistance by an improvement of the IR/IRS-1/Akt and JAK2/STAT3 pathways in the hypothalamus. These improvements were independent of body weight and food intake. Increased insulin and leptin action/signaling in the hypothalamus may contribute to a decrease in adiposity and hypophagia and an enhancement of energy expenditure accompanied by lower NPY and increased POMC mRNA levels. Improvement of hypothalamic insulin action decreases fasting glycemia, glycemia after pyruvate injection, and PEPCK protein expression in the liver of HFD-fed and db/db mice, suggesting a reduction in hepatic glucose production. We suggest that IKKε may be a key inflammatory mediator in the hypothalamus of obese mice, and its hypothalamic inhibition improves energy and glucose metabolism.

Fatty Acid Synthase Inhibitors Induce Apoptosis In Non-tumorigenic Melan-a Cells Associated With Inhibition Of Mitochondrial Respiration.

The metabolic enzyme fatty acid synthase (FASN) is responsible for the endogenous synthesis of palmitate, a saturated long-chain fatty acid. In contrast to most normal tissues, a variety of human cancers overexpress FASN. One such cancer is cutaneous melanoma, in which the level of FASN expression is associated with tumor invasion and poor prognosis. We previously reported that two FASN inhibitors, cerulenin and orlistat, induce apoptosis in B16-F10 mouse melanoma cells via the intrinsic apoptosis pathway. Here, we investigated the effects of these inhibitors on non-tumorigenic melan-a cells. Cerulenin and orlistat treatments were found to induce apoptosis and decrease cell proliferation, in addition to inducing the release of mitochondrial cytochrome c and activating caspases-9 and -3. Transfection with FASN siRNA did not result in apoptosis. Mass spectrometry analysis demonstrated that treatment with the FASN inhibitors did not alter either the mitochondrial free fatty acid content or composition. This result suggests that cerulenin- and orlistat-induced apoptosis events are independent of FASN inhibition. Analysis of the energy-linked functions of melan-a mitochondria demonstrated the inhibition of respiration, followed by a significant decrease in mitochondrial membrane potential (ΔΨm) and the stimulation of superoxide anion generation. The inhibition of NADH-linked substrate oxidation was approximately 40% and 61% for cerulenin and orlistat treatments, respectively, and the inhibition of succinate oxidation was approximately 46% and 52%, respectively. In contrast, no significant inhibition occurred when respiration was supported by the complex IV substrate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). The protection conferred by the free radical scavenger N-acetyl-cysteine indicates that the FASN inhibitors induced apoptosis through an oxidative stress-associated mechanism. In combination, the present results demonstrate that cerulenin and orlistat induce apoptosis in non-tumorigenic cells via mitochondrial dysfunction, independent of FASN inhibition.

Effects Of Partial Inhibition Of Respiratory Complex I On H2o 2 Production By Isolated Brain Mitochondria In Different Respiratory States.

The aim of this work was to characterize the effects of partial inhibition of respiratory complex I by rotenone on H2O2 production by isolated rat brain mitochondria in different respiratory states. Flow cytometric analysis of membrane potential in isolated mitochondria indicated that rotenone leads to uniform respiratory inhibition when added to a suspension of mitochondria. When mitochondria were incubated in the presence of a low concentration of rotenone (10 nm) and NADH-linked substrates, oxygen consumption was reduced from 45.9 ± 1.0 to 26.4 ± 2.6 nmol O2 mg(-1) min(-1) and from 7.8 ± 0.3 to 6.3 ± 0.3 nmol O2 mg(-1) min(-1) in respiratory states 3 (ADP-stimulated respiration) and 4 (resting respiration), respectively. Under these conditions, mitochondrial H2O2 production was stimulated from 12.2 ± 1.1 to 21.0 ± 1.2 pmol H2O2 mg(-1) min(-1) and 56.5 ± 4.7 to 95.0 ± 11.1 pmol H2O2 mg(-1) min(-1) in respiratory states 3 and 4, respectively. Similar results were observed when comparing mitochondrial preparations enriched with synaptic or nonsynaptic mitochondria or when 1-methyl-4-phenylpyridinium ion (MPP(+)) was used as a respiratory complex I inhibitor. Rotenone-stimulated H2O2 production in respiratory states 3 and 4 was associated with a high reduction state of endogenous nicotinamide nucleotides. In succinate-supported mitochondrial respiration, where most of the mitochondrial H2O2 production relies on electron backflow from complex II to complex I, low rotenone concentrations inhibited H2O2 production. Rotenone had no effect on mitochondrial elimination of micromolar concentrations of H2O2. The present results support the conclusion that partial complex I inhibition may result in mitochondrial energy crisis and oxidative stress, the former being predominant under oxidative phosphorylation and the latter under resting respiration conditions.