Visually induced analgesia during face or limb stimulation in healthy and migraine subjects.

BACKGROUND: Visually induced analgesia (VIA) defines a phenomenon in which viewing one's own body part during its painful stimulation decreases the perception of pain. VIA occurs during direct vision of the stimulated body part and also when seeing it reflected in a mirror. To the best of our knowledge, VIA has not been studied in the trigeminal area, where it could be relevant for the control of headache. SUBJECTS AND METHODS: We used heat stimuli (53°C) to induce pain in the right forehead or wrist in 11 healthy subjects (HSs) and 14 female migraine without aura (MO) patients between attacks. The subjects rated pain on a visual analog scale (VAS) and underwent contact heat-evoked potential (CHEP) recordings (five sequential blocks of four responses) with or without observation of their face/wrist in a mirror. RESULTS: During wrist stimulation, amplitude of the first block of P1-P2 components of CHEPs decreased compared to that in the control recording when HSs were seeing their wrist reflected in the mirror (p = 0.036; Z = 2.08); however, this was not found in MO patients. In the latter, the VAS pain score increased viewing the reflected wrist (p = 0.049; Z = 1.96). Seeing their forehead reflected in the mirror induced a significant increase in N2 latency of CHEPs in HSs, as well as an amplitude reduction in the first block of P1-P2 components of CHEPs both in HSs (p = 0.007; Z = 2.69) and MO patients (p = 0.035; Z = 2.10). Visualizing the body part did not modify habituation of CHEP amplitudes over the five blocks of averaged responses, neither during wrist nor during forehead stimulation. CONCLUSION: This study adds to the available knowledge on VIA and demonstrates this phenomenon for painful stimuli in the trigeminal area, as long as CHEPs are used as indices of central pain processing. In migraine patients during interictal periods, VIA assessed with CHEPs is within normal limits in the face but absent at the wrist, possibly reflecting dysfunctioning of extracephalic pain control.

Correlation between deep brain stimulation effects on freezing of gait and audio-spinal reflex.

OBJECTIVE: A network of cortical, subcortical and brainstem structures might be involved in freezing of gait (FOG). Subthalamic nucleus (STN) deep brain stimulation (DBS) could modulate this network. The audio-spinal reflex (ASR), reduced in PD, but increased by treatment, can be used to further investigate that locomotor network. The aim of this study is to find whether a correlation exists between ASR and FOG in PD patients under DBS. METHODS: In 14 PD patients with STN DBS and previous FOG, ASR was recorded, with DBS switched on and off. We also assessed FOG Questionnaire (FOGQ) and Unified Parkinson's Disease Rating Scale (UPDRS) Part III. RESULTS: Switching "on" DBS increased ASR amplitude (+ 33.2% with DBS ON, p = 0.048). We also found a significant inverse correlation between FOGQ and modulation of ASR by DBS (r = -0.59, r2 = 0.35, p < 0.05). CONCLUSIONS: This study shows that the incremental effect of DBS on ASR is greater in PD patients with less severe FOG. SIGNIFICANCE: This study shows a link between electrophysiological and clinical data about gait control. It might contribute to better understand why some DBS patients report heavy FOG and others do not. ASR might be used to evaluate or maybe predict the effect of stimulation parameters changes on FOG.

Cerebral metabolism before and after external trigeminal nerve stimulation in episodic migraine.

Background and aim A recent sham-controlled trial showed that external trigeminal nerve stimulation (eTNS) is effective in episodic migraine (MO) prevention. However, its mechanism of action remains unknown. We performed 18-fluorodeoxyglucose positron emission tomography (FDG-PET) to evaluate brain metabolic changes before and after eTNS in episodic migraineurs. Methods Twenty-eight individuals were recruited: 14 with MO and 20 healthy volunteers (HVs). HVs underwent a single FDG-PET, whereas patients were scanned at baseline, directly after a first prolonged session of eTNS (Cefaly®) and after three months of treatment (uncontrolled study). Results The frequency of migraine attacks significantly decreased in compliant patients ( N = 10). Baseline FDG-PET revealed a significant hypometabolism in fronto-temporal areas, especially in the orbitofrontal (OFC) and rostral anterior cingulate cortices (rACC) in MO patients. This hypometabolism was reduced after three months of eTNS treatment. Conclusion Our study shows that metabolic activity of OFC and rACC, which are pivotal areas in central pain and behaviour control, is decreased in migraine. This hypometabolism is reduced after three months of eTNS. eTNS might thus exert its beneficial effects via slow neuromodulation of central pain-controlling areas, a mechanism also previously reported in chronic migraine and cluster headache after percutaneous occipital nerve stimulation. However, this finding needs to be confirmed by further studies using a sham condition.

Effects of visual cortex activation on the nociceptive blink reflex in healthy subjects.

Bright light can cause excessive visual discomfort, referred to as photophobia. The precise mechanisms linking luminance to the trigeminal nociceptive system supposed to mediate this discomfort are not known. To address this issue in healthy human subjects we modulated differentially visual cortex activity by repetitive transcranial magnetic stimulation (rTMS) or flash light stimulation, and studied the effect on supraorbital pain thresholds and the nociceptive-specific blink reflex (nBR). Low frequency rTMS that inhibits the underlying cortex, significantly decreased pain thresholds, increased the 1st nBR block ipsi- and contralaterally and potentiated habituation contralaterally. After high frequency or sham rTMS over the visual cortex, and rMS over the right greater occipital nerve we found no significant change. By contrast, excitatory flash light stimulation increased pain thresholds, decreased the 1st nBR block of ipsi- and contralaterally and increased habituation contralaterally. Our data demonstrate in healthy subjects a functional relation between the visual cortex and the trigeminal nociceptive system, as assessed by the nociceptive blink reflex. The results argue in favour of a top-down inhibitory pathway from the visual areas to trigemino-cervical nociceptors. We postulate that in normal conditions this visuo-trigeminal inhibitory pathway may avoid disturbance of vision by too frequent blinking and that hypoactivity of the visual cortex for pathological reasons may promote headache and photophobia.

Transcranial Direct Current Stimulation (tDCS) of the visual cortex: a proof-of-concept study based on interictal electrophysiological abnormalities in migraine.

BACKGROUND: Preventive pharmacotherapy for migraine is not satisfactory because of the low efficacy/tolerability ratio of many available drugs. Novel and more efficient preventive strategies are therefore warranted. Abnormal excitability of cortical areas appears to play a pivotal role in migraine pathophysiology. Transcranial direct current stimulation (tDCS) is a non-invasive and safe technique that is able to durably modulate the activity of the underlying cerebral cortex, and is being tested in various medical indications. The results of small open studies using tDCS in migraine prophylaxis are conflicting, possibly because the optimal stimulation settings and the brain targets were not well chosen. We have previously shown that the cerebral cortex, especially the visual cortex, is hyperresponsive in migraine patients between attacks and provided evidence from evoked potential studies that this is due to a decreased cortical preactivation level. If one accepts this concept, anodal tDCS over the visual cortex may have therapeutic potentials in migraine prevention, as it is able to increase neuronal firing. OBJECTIVE: To study the effects of anodal tDCS on visual cortex activity in healthy volunteers (HV) and episodic migraine without aura patients (MoA), and its potentials for migraine prevention. METHODS: We recorded pattern-reversal visual evoked potentials (VEP) before and after a 15-min session of anodal tDCS over the visual cortex in 11 HV and 13 MoA interictally. Then 10 MoA patients reporting at least 4 attacks/month subsequently participated in a therapeutic study, and received 2 similar sessions of tDCS per week for 8 weeks as migraine preventive therapy. RESULTS: In HV as well as in MoA, anodal tDCS transiently increased habituation of the VEP N1P1 component. VEP amplitudes were not modified by tDCS. Preventive treatment with anodal tDCS turned out to be beneficial in MoA: migraine attack frequency, migraine days, attack duration and acute medication intake significantly decreased during the treatment period compared to pre-treatment baseline (all p < 0.05), and this benefit persisted on average 4.8 weeks after the end of tDCS. CONCLUSIONS: Anodal tDCS over the visual cortex is thus able to increase habituation to repetitive visual stimuli in healthy volunteers and in episodic migraineurs, who on average lack habituation interictally. Moreover, 2 weekly sessions of anodal tDCS had a significant preventive anti- migraine effect, proofing the concept that the low preactivation level of the visual cortex in migraine patients can be corrected by an activating neurostimulation. The therapeutic results indicate that a larger sham-controlled trial using the same tDCS protocol is worthwhile.

Abnormal corticospinal excitability in patients with disorders of consciousness.

BACKGROUND: Transcranial magnetic stimulation (TMS) has been frequently used to explore changes in the human motor cortex in different conditions, while the extent of motor cortex reorganization in patients in vegetative state (VS) (now known as unresponsive wakefulness syndrome, UWS) and minimally conscious (MCS) states due to severe brain damage remains largely unknown. OBJECTIVE/HYPOTHESIS: It was hypothesized that cortical motor excitability would be decreased and would correlate to the level of consciousness in patients with disorders of consciousness. METHODS: Corticospinal excitability was assessed in 47 patients (24 VS/UWS and 23 MCS) and 14 healthy controls. The test parameters included maximal peak-to-peak M-wave (Mmax), F-wave persistence, peripheral and central motor conduction times, sensory (SEP) and motor evoked (MEP) potential latencies and amplitudes, resting motor threshold (RMT), stimulus/response curves, and short latency afferent inhibition (SAI). TMS measurements were correlated to the level of consciousness (assessed using the Coma Recovery Scale-Revised). RESULTS: On average, the patient group had lower Mmax, lower MEP and SEP amplitudes, higher RMTs, narrower stimulus/response curves, and reduced SAI compared to the healthy controls (P < 0.05). The SAI alterations were correlated to the level of consciousness (P < 0.05). CONCLUSIONS: The findings demonstrated the impairment of the cortical inhibitory circuits in patients with disorders of consciousness. Moreover, the significant relationship was found between cortical inhibition and clinical consciousness dysfunction.

Effects of repetitive transcranial magnetic stimulation on somatosensory evoked potentials and high frequency oscillations in migraine.

BACKGROUND: In previous studies we found that high-frequency somatosensory oscillations (HFOs) reflecting thalamo-cortical activation were decreased in migraineurs between attacks and that high-frequency repetitive transcranial magnetic stimulation (rTMS) was able to normalize the habituation deficit of visual evoked potentials (VEPs). Here we study the effects of activating (10 Hz) or inhibiting (1 Hz) rTMS on conventional low-frequency (LF) and high-frequency somatosensory evoked potentials (SSEPs). SUBJECTS AND METHODS: rTMS was applied on the motor cortex of 13 healthy volunteers (HVs) and 13 migraine without aura (MO) patients. We measured N20-P25 LF-SSEP amplitude and habituation, and maximal peak-to-peak amplitude of early and late HFOs before and after rTMS. RESULTS: In HVs, 1 Hz rTMS significantly reduced the amplitude of the first LF-SSEP block and its habituation. In MO patients, 10 Hz rTMS increased the amplitude of the first block and induced habituation. Ten Hz rTMS produced an increase of late HFO in both groups, but more interestingly, in MO patients also significantly increased the early HFOs, which are reduced at baseline compared to those of HVs. CONCLUSIONS: These data confirm for SSEP that excitatory rTMS can normalize habituation in migraine patients and show that this is accompanied by early an HFO increase, which is thought to reflect thalamo-cortical activity. Taken together with similar effects we observed for VEPs, this finding supports the hypothesis that dysfunctioning thalamo-cortical loops may be responsible for the interictal habituation deficit in migraine.

Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials.

Nitroglycerin (NTG), a NO donor, induces an attack in migraine patients approximately 4-6 h after administration. The causative mechanisms are not known, but the long delay leaves room for a central effect, such as a change in neuronal excitability and synaptic transmission of various CNS areas involved in pain and behaviour including trigeminal nucleus caudalis and monoaminergic brain stem nuclei. To explore the central action of NTG, we have studied its effects on amplitude and habituation of the nociceptive blink reflex (nBR) and the visual evoked potential (VEP) before, 1 h and 4 h after administration of NTG (1.2 mg sublingual) or placebo (vehicle sublingual) in two groups of 10 healthy volunteers. We found a significant decrease in nBR pain and reflex thresholds both 1 and 4 h post-NTG. At the 4 h time point R2 latency was shorter (p=0.04) and R2 response area increased (p<0.01) after NTG but not after placebo. Habituation tended to become more pronounced after both NTG and placebo administration. There was a significant amplitude increase in the 5th VEP block (p=0.03) at 1h after NTG and in the 1st block (p=0.04) at 4 h. VEP habituation was replaced by potentiation at both delays after NTG; the change in habituation slope was significant at 1h (p=0.02). There were no significant VEP changes in subjects who received sublingual placebo. In conclusion, we found that in healthy subjects sublingual NTG, but not its vehicle, induces changes in a trigeminal nociceptive reflex and an evoked cortical response which are comparable to those found immediately before and during an attack of migraine. These changes could be relevant for the attack-triggering effect of NTG in migraineurs.

Performances in cerebellar and neuromuscular transmission tests are correlated in migraine with aura.

In previous studies, we described subclinical abnormalities of neuromuscular transmission and cerebellar functions in migraineurs. The aim of this study was to search if these two functions are correlated in the same patient. Thirteen migraineurs [five without aura (MO) and eight with aura (MA)] underwent both stimulation-SFEMG and 3D-movement analysis. Single fiber EMG (SFEMG) results were expressed as the "mean value of consecutive differences" (mean MCD). Precision of arm-reaching movements (measured with an infrared optoelectronic tracking system) was expressed as the average deviation in the horizontal plane. Median values of mean MCD and mean horizontal deviation were not different between MO and MA. However, in MA, but not in MO, both variables were positively correlated. Thus, we conclude that neuromuscular transmission and cerebellar functions are correlated in the same patient when affected by migraine with aura. We suggest that this correlation might be due to a common molecular abnormality.

Occipital nerve stimulation for drug-resistant chronic cluster headache: a prospective pilot study.

BACKGROUND: Drug-resistant chronic cluster headache (drCCH) is a devastating disorder for which various destructive procedures have been tried unsuccessfully. Occipital nerve stimulation (ONS) is a new, safe strategy for intractable headaches. We undertook a prospective pilot trial of ONS in drCCH to assess clinical efficacy and pain perception. METHODS: Eight patients with drCCH had a suboccipital neurostimulator implanted on the side of the headache and were asked to record details of frequency, intensity, and symptomatic treatment for their attacks in a diary before and after continuous ONS. To detect changes in cephalic and extracephalic pain processing we measured electrical and pressure pain thresholds and the nociceptive blink reflex. FINDINGS: Two patients were pain free after a follow-up of 16 and 22 months; one of them still had occasional autonomic attacks. Three patients had around a 90% reduction in attack frequency. Two patients, one of whom had had the implant for only 3 months, had improvement of around 40%. Mean follow-up was 15.1 months (SD 9.5, range 3-22). Intensity of attacks tends to decrease earlier than frequency during ONS and, on average, is improved by 50% in remaining attacks. All but one patient were able to substantially reduce their preventive drug treatment. Interruption of ONS by switching off the stimulator or because of an empty battery was followed within days by recurrence and increase of attacks in all improved patients. ONS did not significantly modify pain thresholds. The amplitude of the nociceptive blink reflex increased with longer durations of ONS. There were no serious adverse events. INTERPRETATION: ONS could be an efficient treatment for drCCH and could be safer than deep hypothalamic stimulation. The delay of 2 months or more between implantation and significant clinical improvement suggests that the procedure acts via slow neuromodulatory processes at the level of upper brain stem or diencephalic centres.

Nociceptive blink reflex and visual evoked potential habituations are correlated in migraine.

BACKGROUND: Lack of habituation, as reported in migraine patients between attacks for evoked cortical responses, was also recently found for the nociceptive blink reflex (nBR) mediated by brainstem neurons. It is not known if both brain stem and cortical habituation deficits are correlated in the same patient, which would favor a common underlying mechanism. OBJECTIVE: To search for intraindividual correlations between habituation of pattern reversal-visual evoked potentials and that of the nociception-specific blink reflex in migraineurs and in healthy volunteers (HV). METHODS: We recorded 15 HV and 15 migraine without aura patients between attacks. Habituation for visual evoked potentials was measured by comparing the N1-P1 amplitude change (%) between the first and sixth block of 100 sequential averaged responses. Habituation for the nBR was defined as the percentage change of the R2 response area between the 1st and 10th block of five averaged EMG responses, elicited by stimulating the right side every 2 minutes for 32 minutes. We also calculated the slope of N1-P1 amplitude and R2 response area changes from the first to the last response and the correlation with attack frequency. RESULTS: A significant habituation deficit in both cortical and brain stem evoked activity characterized on average the group of migraineurs compared to controls. In migraine patients, but not in HV, we found a significant positive correlation between habituation of pattern reversal-visual evoked potentials and that of the nociception-specific blink reflex both for the degree of habituation between first and last blocks of averagings (r = 0.703; P = .003) and for the habituation slope (r = 0.751; P = .001). Moreover, nBR habituation was positively correlated with attack frequency (r = 0.548; P = .034). CONCLUSION: The positive correlation between visual evoked potential and nBR habituations is consistent with the idea that in migraine the same neurobiological dysfunction might be responsible for the habituation deficit both in cortex and brain stem. As nBR habituation increases with attack frequency, its interictal deficit is unlikely to be due to trigeminal sensitization.

Somatosensory evoked high-frequency oscillations reflecting thalamo-cortical activity are decreased in migraine patients between attacks.

A deficit of habituation in cortical information processing, including somatosensory evoked potentials (SSEPs), is the most consistent neurophysiological abnormality in migraine patients between attacks. To explore further the mechanisms underlying this interictal neural dysfunction, we have studied the high-frequency oscillations (HFOs) embedded in SSEPs because they are thought to reflect spike activity in thalamo-cortical cholinergic fibres (early HFOs) and in cortical inhibitory GABAergic interneurons (late HFOs). Untreated migraine patients with (MA) and without (MO) aura were recorded during (n = 13: nine MO, four MA) and between attacks (n = 29: 14 MO, 15 MA) and compared with healthy volunteers. SSEPs were filtered off-line (digital band-pass between 450 and 750 Hz) to extract the two HFO bursts from the broad-band contralateral N20 somatosensory cortical response obtained by median nerve stimulation. In both migraine groups, amplitudes and latencies of conventional broad-band SSEPs recorded interictally from cervical and parietal active electrodes were not significantly different from those found in healthy volunteers. In contrast, maximum peak-to-peak amplitude and area under the rectified curve of the early HFO burst were significantly smaller in both MA and MO patients than in healthy volunteers. There was no significant difference in the later HFO burst between migraineurs and healthy volunteers. During attacks, all electrophysiological measurements in migraineurs were similar to those found in healthy volunteers. Thalamo-cortical activation, as reflected by the early SSEP HFO burst, may thus be reduced in migraine interictally, but normalizes during an attack, whereas intracortical inhibition, as indexed by the late HFO burst, is normal at any time. This supports the hypothesis that the habituation deficit in migraineurs is due to a reduced pre-activation level of sensory cortices and not to increased cortical excitability or reduced intracortical inhibition.

Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation.

OBJECTIVE: Focal transcranial magnetic stimulation was used to test prospectively corticospinal excitability changes and reorganization of first dorsal interosseous (FDI) motor cortical representation in 31 patients who experienced a first ischemic stroke in the middle cerebral artery territory. All had severe hand palsy at onset. METHODS: Patients were assessed clinically with the Medical Research Council, Rankin, the National Institutes of Health stroke scales and Barthel Index at days 1, 8, 30, 90, 180 and 360 after stroke. The following parameters of FDI motor evoked potential (MEPS) to focal transcranial magnetic stimulation were measured at the same delays: motor threshold, MEP amplitude, excitable cortical area, hot spot and center of gravity of FDI motor maps on affected and unaffected hemispheres. Correlations were sought between clinical and electrophysiological parameters. RESULTS: In patients whose affected motor cortex remained excitable at day 1, motor thresholds were not significantly different between sides and were similar to those of controls. Persistence of MEP on the affected side at day 1 was a strong predictor of good recovery. If present at day 1, MEPs recorded in affected FDI were significantly smaller than of the opposite side or in normals and progressively recovered up to day 360. In these patients, area of excitable cortex remained stable throughout the entire study. At day 1, amplitudes of MEPs obtained in unaffected FDI were significantly larger than later. Between days 1 and 360, we observed a significant displacement of center of gravity of motor maps towards more frontal regions on the affected side while no change was noted on the unaffected side. CONCLUSIONS: Our data confirm the early prognosis value of transcranial magnetic stimulation in stroke. They indicate that the brain insult induces a transient hyperexcitability of the unaffected motor cortex. The evolution of FDI motor maps along the course of recovery mostly reflect corticospinal excitability changes but might also reveal some degree of brain plasticity. Most modifications observed occurred within 3 months of stroke onset.

Effects of repetitive transcranial magnetic stimulation on visual evoked potentials: new insights in healthy subjects.

In a previous comparative study with migraineurs, we found in 24 normal subjects that the amplitude of the pattern-reversal visual evoked potential (PR-VEP) in the first block of 100 responses and its habituation over 6 sequential blocks were significantly decreased after 1 Hz repetitive transcranial magnetic stimulation (rTMS), while 10 Hz rTMS had no significant effect. We report here our results on the reproducibility of the rTMS effect studied in ten of these subjects by repeating the recordings for each frequency three times on different days. We have also reanalysed the data obtained in 24 normal subjects, looking separately at the results in those stimulated at an intensity equal to phosphene threshold (group 1; n=14) and those stimulated at 110% of motor threshold because of unelicitable phosphenes (group 2; n=10). We finally determined the precise duration of the rTMS effect. Despite some interindividual variability, the effects of both rTMS frequencies on first block amplitude, habituation between first and sixth block and habituation slope over the six blocks were highly reproducible. The only difference between the two groups of subjects was the effect of 1 Hz rTMS on the second measured PR-VEP component. Whereas first block amplitude of the first P1-N1 component and habituation were decreased in both groups, such a decrease was found for the second P1-N2 component only in group 1 stimulated at phosphene threshold. The dishabituation of the N1-P1 component after 1 Hz rTMS was maximal at 15 min, but lasted up to 33 min, while that of P1-N2 disappeared after 3 min. There was a non-significant trend ( p=0.06) for a reduction of first block amplitude after 10 Hz rTMS in the total group of subjects, but no effect on habituation. The inhibitory effect of 1 Hz rTMS, which reduces in healthy controls both first block PR-VEP amplitude and habituation, probably by decreasing the preactivation excitability level of the underlying visual cortex, is thus reproducible and long lasting. Long trains of 10 Hz rTMS tend to attenuate reproducibly the cortical preactivation level in normal subjects, but they do not affect habituation at all, which contrasts with their effect in migraineurs, in whom, as previously reported, they significantly correct the habituation deficit. The absence of an effect of 1 Hz rTMS on PR-VEP P1-N2 in subjects stimulated at 110% of motor threshold may be explained by the deeper anatomical location of the cortical generators of this component and the lower stimulation intensity used. Taken together our results confirm that the effect of rTMS on the underlying cortex depends on several variables such as frequency, intensity and level of cortical preactivation.

Single motor axon conduction velocities of human upper and lower limb motor units. A study with transcranial electrical stimulation.

OBJECTIVES: To calculate conduction velocities (CV) of single motor axons innervating hand, forearm and leg muscles, weak anodal electrical transcranial stimuli were used and single motor unit potentials were recorded in 17 normal subjects. METHODS: The central motor conduction time and neuromuscular transmission delay were subtracted from the latency of unit response to cortical stimulation and single motor axon CV were calculated. RESULTS: In extensor indicis proprius (EIP) units, CV ranged from 30.3 to 76.1m/s (mean: 51.3 +/- 7.1m/s, 139 units). In first dorsal interosseous (FDI), they ranged from 45.1 to 66.2m/s (mean: 54.6 +/- 2.6m/s, 88 units). In tibialis anterior (TA), velocities ranged from 27.8 to 55.9m/s (mean: 41.3 +/- 7.5m/s, 123 units). In FDI units, velocities were compared with those obtained with the F-wave method (range: 50.3-64.5m/s, mean: 58.1 +/- 2.0m/s). CONCLUSIONS: Compared with previously published values, the present method gives better access to slow-conducting units, first recruited by transcranial stimulation and voluntary effort. The spectrum of individual CV was much broader for EIP and TA than for FDI. A linear decline of maximal CV with age was observed, while minimal CV were not affected, suggesting that aging causes a selective loss of the fastest-conducting units.