Alaa Mhalla

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

&NA; 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. The analgesic effects induced by repetitive transcranial magnetic stimulation of the motor cortex can be maintained over 6 months in patients with fibromyalgia, using monthly stimulation.

Alteration of cortical excitability in patients with fibromyalgia.

&NA; 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.

Neuropharmacological basis of rTMS-induced analgesia: The role of endogenous opioids

&NA; We investigated the role of endogenous opioid systems in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). We compared the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation before and after naloxone or placebo treatment, in a randomized, double‐blind crossover design, in healthy volunteers. Three groups of 12 volunteers were selected at random and given active stimulation (frequency 10 Hz, at 80% motor threshold intensity, 1500 pulses per session) of the right M1, active stimulation of the right DLPFC, or sham stimulation, during two experimental sessions 2 weeks apart. Cold pain thresholds and the intensity of pain induced by a series of fixed‐temperature cold stimuli (5, 10, and 15 °C) were used to evaluate the analgesic effects of rTMS. Measurements were made at the left thenar eminence, before and 1 hour after the intravenous injection of naloxone (bolus of 0.1 mg/kg followed by a continuous infusion of 0.1 mg/kg/h until the end of rTMS) or placebo (saline). Naloxone injection significantly decreased the analgesic effects of M1 stimulation, but did not change the effects of rTMS of the DLPFC or sham rTMS. This study demonstrates, for the first time, the involvement of endogenous opioid systems in rTMS‐induced analgesia. The differential effects of naloxone on M1 and DLPFC stimulation suggest that the analgesic effects induced by the stimulation of these 2 cortical sites are mediated by different mechanisms. Endogenous opioids are shown to be involved in the analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex.

Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers

ABSTRACT We investigated the analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) in two models of experimental pain in healthy volunteers. Two studies were carried out in parallel in two groups of 26 paid healthy volunteers. The effects of active or sham rTMS (frequency, 10 Hz; intensity, 80% resting motor threshold) applied to the right M1 or DLPFC were compared in a double‐blind randomized cross‐over design. In the first series of experiments, we analyzed the effects of rTMS on thermal (heat and cold) detection and pain thresholds measured on both hands and the left foot, by standardized quantitative sensory testing methods. In the second series of experiments, we measured the effects of M1 or DLPFC rTMS on the threshold and recruitment curves of the RIII nociceptive reflex evoked by ipsilateral electrical stimulation of the sural nerve and recorded on the biceps femoris of both lower limbs. In both studies, measurements were taken before and up to 60 min after the end of rTMS. Active rTMS of both M1 and DLPFC significantly increased the thermal pain thresholds, measured for both hands and the left foot, this effect being most marked for cold pain. These effects, which lasted at least 1 h after rTMS, were selective because they were not associated with changes in non‐painful thermal sensations. By contrast, the second study showed that rTMS of M1 or DLPFC had no significant effect on the threshold or recruitment curve of the nociceptive flexion RIII reflex. Our findings demonstrate that unilateral rTMS of M1 or DLPFC induces diffuse and selective analgesic effects in healthy volunteers. The lack of effect on the RIII reflex suggests that such analgesic effects may not depend on the activation of descending inhibitory systems.

Repetitive transcranial magnetic stimulation induced analgesia depends on N-methyl-D-aspartate glutamate receptors.

Summary The analgesic effects induced by repetitive transcranial stimulation of the primary motor cortex or dorsolateral prefrontal cortex are significantly decreased by ketamine administration. ABSTRACT We investigated the role of glutamate N‐methyl‐d‐aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double‐blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10 Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10‐minute bolus followed by continuous infusion of 6 &mgr;g/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor‐evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS‐induced analgesia. Ketamine injection significantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not influenced by rTMS following the administration of either saline or ketamine. Thus, rTMS‐induced analgesia depends on glutamate NMDA receptors and may involve long‐term potentiation‐like mechanisms.

Unilateral repetitive transcranial magnetic stimulation of the motor cortex does not affect cognition in patients with fibromyalgia.

Repetitive transcranial magnetic stimulation (rTMS) induces changes in neuronal activity that may affect cognition. We assessed cognitive functions, in patients with fibromyalgia participating in a sham-controlled randomized trial of rTMS for pain management. We randomly assigned 38 non depressed fibromyalgia patients (American College of Rheumatology criteria) to the active (n = 20) and sham (n = 18) rTMS treatment groups, in a double-blind manner. rTMS was applied to the left primary motor cortex (10 Hz at 80% of rest motor threshold). Neuropsychological tests were performed immediately before stimulation, to evaluate episodic memory, selective and divided attention and executive functions at baseline, week 3 (after 7 rTMS sessions) and week 11 (after 11 rTMS sessions). The actively treated and sham-treated groups were similar in terms of clinical and neuropsychological variables at baseline. No difference in overall neuropsychological performance with respect to baseline was found between these two groups, but a significant improvement over time was observed in the rTMS group, for several measurements of attention/executive function (the Symbol Digit Modalities Test and the Stroop Color Word Test). Unilateral rTMS of the motor cortex over a three-month period did not modify cognitive functions in patients with chronic pain. rTMS may have mild beneficial cognitive effects, but confirmation is required in larger groups of patients.

P11-26 Long term analgesic efficacy of transcranial magnetic stimulation of the motor cortex in patients with fibromyalgia

Results: Significant reduction of the SICI and decrease of the rMT were observed in patients with NPH compared to young control subjects and age-matched patients with peripheral neuropathy. At baseline, these changes were not correlated with severity of walking disturbances. However, there was a significant relationship between enhancement of the SICI and improvement of the motor performance following ventricular shunting. Conclusion: The results of this study suggest that NPH affects corticospinal excitability causing a disinhibition of the motor cortex.

P20-26 Neuropharmacological basis of repetitive transcranial magnetic stimulation (rTMS) induced analgesia: the role of endogenous opioids

Background: It has been shown that rTMS to the primary motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) can reduce pain in experimental models in healthy subjects. The mechanisms may depend on the activation of pain modulation systems. Due to the major role of endogenous opioids systems (EOS) in pain modulation, we hypothesized that EOS are involved in the analgesic action of rTMS. Methods: To investigate the role of EOS in rTMS-induced analgesia, we compared the analgesic effects of M1 or DLPFC stimulation before and after naloxone or placebo, using a randomized double-blind design. Twelve healthy volunteers were randomly assigned to three groups and received either active stimulation of the right M1, active stimulation of the right DLPFC (frequency 10 Hz, 80% of the motor threshold, 1500 pulses/session) or sham stimulation, during two experimental sessions within two weeks interval. Based on our previous results showing that rTMS acts preferentially on cold pain [1], measurements of cold pain thresholds were used to evaluate the analgesic effects of rTMS. During each session, cold pain thresholds were measured on the left thenar eminence before and one hour after iv injection of naloxone or saline (bolus of 0.1 mg/kg then continuous infusion of 0.1 mg/kg/h up to the end of rTMS). Results: Compared with the sham stimulation, both the stimulation of M1 and DLPFC induced a significant decrease in cold pain (i.e. analgesia) after saline injection. Naloxone significantly reduced the analgesic effects of M1, but not of DLPFC stimulation. Conclusions: We showed for the first time that EOS are involved in the analgesic effects of rTMS. The differential effects of naloxone on M1 and DLPFC stimulation indicate that, despite their apparent similarity, the analgesic effects evoked by stimulation of these cortical sites involve distinct mechanisms.

512 ALTERATION OF CORTICAL EXCITABILITY IN PATIENTS OF FIBROMYALGIA

fibromyalgia in these patients can easily be misdiagnosed and mistreated. Case report: We report a 47-year-old female patient with primary progressive multiple sclerosis (PPMS) who presented with widespread musculoskeletal pain since 6 months. At first, she was complaining for low back pain, fatigue and muscle pain after exertion. For the last 5 months reported pain in her neck, shoulders and arms with gnawing sensation and pain in her knees, legs and feet with a burning-aching sensation. Stiffness was almost present every day. Additionally, the pain awakened the patient frequently at night. Her neurological examination revealed otherwise only a mild gait disturbance. The diagnosis of fibromyalgia was then considered possible, since it requires a history of at least 3 months of widespread pain, and tenderness in at least 11 of 18 tenderpoint sites. The patient was administered duloxetine in up to 60mg daily and pregabalin in up to 150mg daily and showed great improvement 3 weeks after initiation of treatment. Discussion and Conclusions: Despite the fact that clinical manifestations such as pain, stiffness and fatigue are common in patients with MS, the possibility of another cause must always be taken into consideration, especially if the symptoms cannot be easily attributed to the lesions of MS.

948 INTERACTION BETWEEN APATHY AND MENTAL FLEXIBILITY ON PAIN COPING STRATEGIES IN FIBROMYALGIA (FM)

Aim of study: To examine the influence of apathy (reduction of voluntary behaviours sustained by a lack of motivation not attributable to diminished level of consciousness, cognitive impairment or emotional distress) on cognitive functions in the FM patients. Methods: Thirty-nine consecutive FM women (age: 50.1±9.9, disease duration: 9.8±8.9) were evaluated by the Auditory Verbal Learning Test (learning), Trail Making Test A (focused attention) and B (mental flexibility) and Stroop Color Word Test (SCWT, selective attention, mental flexibility). They also completed the chronic pain acceptance questionnaire (CPAQ); survey of pain attitudes (SOPA-B) and multidimensional pain coping strategic questionnaire (MLPC). Apathy was measured by the Starkstein’s scale. Results: 54% of the patients had signs of mild to moderate apathy (mean: 18.5±5.5). The apathy score was correlated to the Trail Making Test B only. There were no differences between the patients with and without apathy on cognitive tests. The apathy score was also correlated to the CPAQ, MLPC and SOPA-B. Finally, the Trail Making Test B was related with the CPAQ and SOPA-B, and the SCWT with the SOPA-B. Conclusion: Apathy appears to have a little impact on cognitive functions in FM patients. But, its influence on pain coping strategies may be more important. Furthermore, flexibility seems to be implicated in pain coping strategies. Apathy and flexibility should be considered as they could interfere with successful clinical management. Because of apathy or inflexibility, dysfunctional behaviours persist despite their disabling effects.