Magnetic suppression of perceptual accuracy is not reduced in episodic migraine without aura

Background

Altered cortical excitability is thought to be part of migraine pathophysiology. Reduced magnetic suppression of perceptual accuracy (MSPA) has been found in episodic migraine with aura and in chronic migraine, and has been interpreted as reduced inhibition of the occipital cortex in these migraine subtypes. Results are less clear for episodic migraine without aura. In the present study we compared MSPA between 24 healthy controls and 22 interictally measured episodic migraine patients without aura. In addition, we investigated test-retest reliability in 33 subjects (24 controls, 9 migraine).

Findings

Visual accuracy was assessed by letter recognition and modulated by transcranial magnetic stimulation delivered to the occipital cortex at different intervals to the letter presentation (40, 100 and 190 ms). The results confirm suppression of visual accuracy at the 100 ms interval (p < 0.001), but there were no significant group differences (percentage of correctly recognized letters, control: 36.1 ± 36.2; migraine: 44.0 ± 32.3, p = 0.44). Controls and migraine patients were pooled for assessment of test-retest reliability (n = 33). Levels of suppression at 100 ms were similar at test (percentage of correctly recognized letters: 42.3 ± 32.6) and retest (41.9 ± 33.8, p = 0.90) and test-retest correlations were good (r = 0.82, p < 0.001).

Conclusions

The results demonstrate that occipital cortex inhibition as assessed with MSPA is not reduced in episodic migraine without aura. This suggests a larger role of occipital cortex excitability in episodic migraine with aura and in chronic migraine compared to episodic migraine without aura. Test-retest reliability of MSPA was good.     

Cortical inhibition is reduced in chronic and episodic migraine and demonstrates a spectrum of illness

BACKGROUND: The pathophysiological relationship between episodic migraine and chronic migraine is not fully understood. We aimed to examine transcranial magnetic stimulation (TMS) indices of cortical excitability in patients with episodic migraine (EM) and probable chronic migraine (PCM), and matched controls. METHODS: Cortical excitability was assessed at baseline with two well-established methods: phosphene thresholds (PT) and magnetic suppression of perceptual accuracy (MSPA) profiles. Five EM patients, five PCM patients, and five normal controls participated in the main study. In addition, two patients were reassessed after 30 days of treatment with topiramate. RESULTS: Both PT and MPSA measures were consistent in indicating a continuum of excitability across the three groups: PCM patients had the highest excitability, followed by EM, then controls. In the two treated patients MPSA profiles appeared to normalize at a 100 mg dosage. CONCLUSIONS: Patients with PCM appear to be characterized by very high cortical excitability. This may contribute to their greatly increased attack frequency. TMS-based methods will be important for future research examining the evolution of chronic migraine from episodic migraine over time.     

Objective assessment of cortical excitability in migraine with and without aura

Recent progress in the genetics of migraine has refocused attention on cortical dysfunction as an important component of the pathophysiology of this disorder. In previous work, we have demonstrated functional changes in the visual cortex of migraine patients, using an objective transcranial magnetic stimulation technique, termed magnetic suppression of perceptual accuracy (MSPA). This study aimed to replicate previous findings in migraine with aura (MA) and to use the technique to examine migraine without aura (MoA). Eight MA patients, 14 MoA patients and 13 migraine-free controls participated. MSPA assessments were undertaken using a standardized protocol in which computer-presented letter targets were followed at a variable delay interval by a single magnetic pulse delivered over the occiput. MSPA performance is expressed as a profile of response accuracy across target-pulse delay intervals. The profiles of migraine-free controls exhibited a normal U-shape. MA patients had significantly shallower profiles, showing little or no suppression at intermediate delay intervals. MoA patients had profiles that were similar to controls. Recent animal evidence strongly indicates that the U-shape of the normal MSPA function is caused by preferential activation of inhibitory neurons. Shallower MPSA profiles in MA patients are therefore likely to indicate a functional hyperexcitability caused by impaired inhibition. The finding of normal MPSA profiles in MoA patients is novel and will require further investigation.     

Cyclical changes of cortical excitability and metaplasticity in migraine: Evidence from a repetitive transcranial magnetic stimulation study

The primary brain dysfunctions leading to the onset of a migraine attack remain largely unknown. Other important open questions concern the mechanisms of initiation, continuation, and termination of migraine pain, and the changes in brain function underlying migraine transformation. Brief trains of high-frequency repetitive transcranial magnetic stimulation (rTMS), when applied to the primary motor cortex at suprathreshold intensity (?120% of resting motor threshold [RMT]), elicit in healthy subjects a progressive, glutamate-dependent facilitation of the motor evoked potentials (MEP). Conversely, in conditions of increased cortical excitability, the rTMS trains induce inhibitory MEP responses likely mediated by cortical homeostatic mechanisms. We enrolled 66 migraine-without-aura patients, 48 migraine-with-aura patients, 14 patients affected by chronic migraine (CM), and 20 healthy controls. We assessed motor cortical response to 5-Hz rTMS trains of 10 stimuli given at 120% RMT. Patients with episodic migraine were studied in different phases of the migraine cycle: interictal, preictal, ictal, and postictal states. Results showed a facilitatory MEP response during the trains in patients evaluated in the preictal phase, whereas inhibitory responses were observed during and after a migraine attack, as well as in CM patients. In the interictal phase, different responses were observed, depending on attack frequency: facilitation in patients with low and inhibition in those with high attack recurrence. Our findings suggest that changes in cortical excitability and fluctuations in the threshold for inhibitory metaplasticity underlie the migraine attack recurrence, and could be involved in the process of migraine transformation.     

Assessing cortical excitability in migraine: reliability of magnetic suppression of perceptual accuracy technique over time

OBJECTIVES: To examine test-retest reliability of magnetic suppression of perceptual accuracy (MSPA) prior to its use as a marker of cortical excitability in a trial of migraine prophylactic agents. BACKGROUND: MSPA is a relatively novel avenue of research in headache, providing an opportunity to study cortical responsiveness objectively and noninvasively. However, little is known about the reliability of magnetic stimulation protocols such as MSPA in longitudinal research designs. METHODS: We tested 10 healthy headache-free volunteers who had no family history of migraine. In 54 trials, they were briefly presented different three-letter combinations, flashed on a computer screen for 24 ms (target). After a brief interval, each target was followed by a single magnetic pulse through a 90-mm circular coil centered 7 cm above inion in the midline. The interval between target and magnetic pulse was systematically varied. Volunteers were requested to report as many letters as they had possibly identified. After 2 weeks, all volunteers were retested using identical methods. RESULTS: MSPA performance is expressed as a profile of response accuracy (ie, percentage of correctly identified letters) across target-pulse intervals. Profiles were characteristic of normal headache-free subjects at the first test. Analysis of variance revealed no significant difference in profiles between test and retest (F= 2.05; P= .136): the retest profiles are almost coincidental with the test profiles. CONCLUSIONS: MSPA is a safe and objective measure of cortical excitability, which is reliable over time. MSPA, therefore, shows excellent promise as a biological marker of cortical response in trials of migraine prophylactics.     

Cortical inhibition and habituation to evoked potentials: relevance for pathophysiology of migraine

Dysfunction of neuronal cortical excitability has been supposed to play an important role in etiopathogenesis of migraine. Neurophysiological techniques like evoked potentials (EP) and in the last years non-invasive brain stimulation techniques like transcranial magnetic stimulation (TMS) and transcranial direct current stimulation gave important contribution to understanding of such issue highlighting possible mechanisms of cortical dysfunctions in migraine. EP studies showed impaired habituation to repeated sensorial stimulation and this abnormality was confirmed across all sensorial modalities, making defective habituation a neurophysiological hallmark of the disease. TMS was employed to test more directly cortical excitability in visual cortex and then also in motor cortex. Contradictory results have been reported pointing towards hyperexcitability or on the contrary to reduced preactivation of sensory cortex in migraine. Other experimental evidence speaks in favour of impairment of inhibitory circuits and analogies have been proposed between migraine and conditions of sensory deafferentation in which down-regulation of GABA circuits is considered the more relevant pathophysiological mechanism. Whatever the mechanism involved, it has been found that repeated sessions of high-frequency rTMS trains that have been shown to up-regulate inhibitory circuits could persistently normalize habituation in migraine. This could give interesting insight into pathophysiology establishing a link between cortical inhibition and habituation and opening also new treatment strategies in migraine.     

Motor cortex excitability in patients with migraine with aura and hemiplegic migraine

We studied the excitability of the motor cortex using transcranial magnetic stimulation (TMS) in 12 patients with migraine with aura (MA) and nine patients with familial hemiplegic migraine (FHM). Motor thresholds at rest, the duration of the cortical and peripheral silent period and intracortical inhibition and facilitation using paired-pulse TMS at intervals of 2 to 15 ms were measured with patients free of attacks for at least 48 h. In contrast to previous reports we could not find any significant differences between patient groups and compared to controls (n=17) in the parameters tested. The results suggest that there are no interictal changes of excitability of the motor cortex in migraine. This study does not support the concept of general cortical hyperexcitability in migraine secondary to a genetic predisposition or a structural alteration of inhibitory interneurones in the cortex due to repeated parenchymal insults during attacks.     

Transcranial direct current stimulation reveals inhibitory deficiency in migraine

The issue of interictal excitability of cortical neurons in migraine patients is controversial: some studies have reported hypo-, others hyperexcitability. The aim of the present study was to observe the dynamics of this basic interictal state by further modulating the excitability level of the visual cortex using transcranial direct current stimulation (tDCS) in migraineurs with and without aura. In healthy subjects anodal tDCS decreases, cathodal stimulation increases transcranial magnetic stimulation (TMS)-elicited phosphene thresholds (PT), which is suggested as a representative value of visual cortex excitability. Compared with healthy controls, migraine patients tended to show lower baseline PT values, but this decrease failed to reach statistical significance. Anodal stimulation decreased phosphene threshold in migraineurs similarly to controls, having a larger effect in migraineurs with aura. Cathodal stimulation had no significant effect in the patient groups. This result strengthens the notion of deficient inhibitory processes in the cortex of migraineurs, which is selectively revealed by activity-modulating cortical input.     

Cortical Excitability in Chronic Migraine

A proportion of episodic migraine patients experiences a progressive increase in attack frequency leading to chronic migraine (CM). The most frequent external factor that leads to headache chronification is medication overuse. The neurobiological bases of headache chronification and of the vicious circle of medication overconsumption are not completely elucidated. More recently, the same neurophysiological methods used to study episodic migraine were applied to CM and medication-overuse headache (MOH). Studies of cortical responsivity tend overall to indicate an increase in excitability, in particular of somatosensory and visual cortices, reflected by increased amplitude of evoked responses, decreased activity of inhibitory cortical interneurons reflected in the smaller magnetic suppression of perceptual accuracy, and, at least for visual responses, an increase in habituation. In MOH, overconsumption of triptans or NSAIDs influences cortical excitability differently. Generalized central sensitization is suggested to play an important role in the pathophysiology of headache chronification.     

Visual Cortex Excitability in Migraine With and Without Aura

OBJECTIVES: Previous research using transcranial magnetic stimulation has produced equivocal findings concerning thresholds for the generation of visual phosphenes in migraine with aura. These studies were methodologically varied and did not systematically address cortical excitability in migraine without aura. We therefore studied magnetophosphene thresholds in both migraine with aura and migraine without aura compared with headache-free controls. METHODS: Sixteen subjects with migraine with aura and 12 subjects with migraine without aura were studied and compared with 16 sex- and age-matched controls. Using a standardized transcranial magnetic stimulation protocol of the occipital cortex, we assessed the threshold stimulation intensity at which subjects just perceived phosphenes via a method of alternating course and fine-tuning of stimulator output. RESULTS: There were no significant differences across groups in the proportion of subjects seeing phosphenes. However, the mean threshold at which phosphenes were reported was significantly lower in both migraine groups (migraine with aura=47%, migraine without aura=46%) than in controls (66%). Moreover, there was no significant correlation between individual phosphene threshold and the time interval to the closest migraine attack. CONCLUSION: Our findings confirm that the occipital cortex is hyperexcitable in the migraine interictum, both in migraine with and without aura.     

Intracortical inhibition and facilitation in migraine--a transcranial magnetic stimulation study

OBJECTIVE: Migraine is a disease of altered cortical excitability between attacks. However, the mechanisms of abnormal excitability in migraine are insufficiently investigated. Hence, the aim of the study was to investigate intracortical inhibition/facilitation of the motor circuit in migraine. METHODS: Sixteen women suffering from migraine without aura and 15 healthy women were investigated using a suprathreshold transcranial magnetic stimulation (TMS) in the paired-pulse paradigm with long interstimulus intervals (ISI = 20, 60, 120 ms) and measurement of the cortical silent period. RESULTS: We found no differences for the cortical silent period and for the long intracortical inhibition between the groups. Concerning intracortical facilitation, this ability was significantly more pronounced in patients suffering from migraine compared with healthy controls. CONCLUSION: Migraineurs produce an increased intracortical facilitation. The results may be discussed in line of glutamatergic mechanisms in migraine, which could be related to altered facilitation.     

Visual cortex excitability in migraine evaluated by single and paired magnetic stimuli

OBJECTIVE: To determine the excitability of the visual cortex by phosphene thresholds (PT) in patients with migraine using transcranial magnetic stimulation (TMS) with single- and paired-pulses. METHODS: Nineteen patients with migraine with aura (MWA), 19 patients with migraine without aura (MWoA), and 22 control subjects were included. Patients were free from preventive anti-migraine treatment and were investigated within 3 days before or after an acute migraine attack. In each subject, PT were assessed by single-pulse and paired-pulse TMS with an interstimulus interval of 50 ms. RESULTS: The main effect of diagnosis indicated that mean PT were significantly lower in migraine patients than in control subjects (P = .001). Using single-pulse TMS, mean PT tended to be lower in MWoA-patients (57.7 +/- 11.8%) compared with control subjects (64.4 +/- 10.5%) (P = .064). In MWA-patients, mean PT (53.1 +/- 5.7%) were significantly lower compared with controls (P < .001). Using TMS with paired pulses, mean PT were significantly reduced in MWoA-patients (40.3 +/- 4.9%, P = .017) as well as in MWA-patients (39.6 +/- 4.2%, P = .005) compared with controls (44.6 +/- 6.0%). The main effect of stimulation type indicated that mean PT were lower determined with paired-pulse stimulation than with single pulses (P < .001). CONCLUSIONS: PT are reduced in patients with migraine in the interictal state suggesting an increased excitability of visual cortical areas. Compared with single-pulse TMS, paired-pulse magnetic stimulation is more efficient to elicit phosphenes. This technique provides the opportunity to evaluate visual cortex excitability with lower stimulus intensities and less discomfort.     

Multisensorial Perception in Chronic Migraine and the Role of Medication Overuse

Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by 2 or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (ie, fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine (CM) patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in CM patients (n = 63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (P < .0001). Triptan MOH patients (n = 23) presented significantly less fission effects than other CM groups (P = .008). This exploratory study suggests that CM – both with and without medication overuse – is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI.PerspectiveThis observational study shows reduced susceptibility to the SIFI in CM, confirming and extending previous results in episodic migraine. MOH contributes to this phenomenon, especially in case of triptans.     

Effects of topiramate on migraine frequency and cortical excitability in patients with frequent migraine

We studied the excitability of the visual and motor cortex in 36 patients with frequent migraine without aura (30 women, mean age 38.6 ± 10.0 years) before and after treatment with topiramate (100 mg/day) using transcranial magnetic stimulation. Treatment with topiramate resulted in reduction of both headache frequency (12.0 ± 1.3 to 5.8 ± 3.2 migraine days per month; P  = 0.004) and cortical excitability: motor cortex thresholds increased on the right side from 43.8 ± 7.5% to 47.7 ± 9.2% ( P  = 0.049) and on the left side from 43.4 ± 7.0% to 47.2 ± 9.6% ( P  = 0.047), and phosphene thresholds increased from 58.9 ± 11.1% to 71.2 ± 11.2% ( P  = 0.0001). Reduction of headache frequency correlated inversely with an increase of visual thresholds and did not correlate with motor thresholds. The effect of topiramate in migraine prevention is complex and can not be explained simply by inhibition of cortical excitability.     

Shortened cortical silent period in facial muscles of patients with migraine

Despite intensive neurophysiological research, evidence is lacking to show whether abnormal cortical excitability in migraine reflects a primary cortical disturbance or reduced control by thalamo-cortical loops. One way to contribute to the scientific discussion on this topic is to deliver transcranial magnetic stimulation (TMS) and test the cortical silent period (SP) recorded in facial muscles. The facial-muscle SP is a purely cortical phenomenon that reflects the excitability of inhibitory interneurons, and can disclose changes in cortical inhibition even in patients without documented primary lesions of the motor cortices. To test the interictal excitability of cortical motor inhibitory interneurons in migraine, we investigated the facial-SP in patients with migraine with and without aura between attacks. In 26 patients and 15 age-matched controls, high-intensity magnetic stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction. Electromyographic responses were recorded from surface electrodes placed over the subjects' perioral muscles. Facial SPs were significantly shorter in patients than in controls. The SP shortening provides neurophysiological evidence showing hypoexcitability of cortical inhibitory neurons in patients with migraine between attacks. Despite a possible primary deficit of cortical inhibitory interneurons in migraine, we favor the interpretation of a secondary disfacilitation by hypoactive thalamo-cortical loops. Based on this interpretation, the interictal reduced cortical inhibition documented by the shortened SP could be considered the motor counterpart of the reduced preactivation excitability level in the sensory cortices purported to explain why cortical evoked responses habituate poorly in patients with migraine.     

The cortical silent period is shortened in migraine with aura

OBJECTIVES: Central neuronal hyperexcitability may be the physiological disturbance that predisposes subjects to migraine attacks. To test this hypothesis, we studied the cortical stimulation silent period (CSSP) elicited by transcranial magnetic stimulation (TMS), which is in part a measure of central inhibition of motor pathways in migraine with aura (MwA) patients and normal controls. METHODS: In nine MwA patients (mean age 35.9 +/- 7) and 9 controls (mean age 37.6 +/- 7), we carried out transcranial stimulation using a 95 mm circular coil and Caldwell MES 10 stimulator to determine resting motor threshold (MT) for bilateral FDI muscles. All subjects performed isometric voluntary contraction of bilateral FDI maintained at 20% of maximal effort, during which we measured bilateral CSSP at (i) the stimulus intensity (SI) determined for the MT and (ii) an SI of 1.5 x MT. RESULTS: Although the mean MT was higher in MwA compared with controls (63.1 +/- 14.4 vs 58.1 +/- 8.9), the difference was not significant. At an SI of 1.5 x MT the mean CSSP did not differ between the groups (MwA 141.7 +/- 31.9 vs controls 162.4 +/- 36.6). At the SI of the MT, however, the CSSP was shorter in MwA patients than in controls (62.9 +/- 27.3 vs 106.3 +/- 19.6, p = 0.001). There was an inverse correlation between the duration of CSSP and an increased frequency of headache (p = 0.02). CONCLUSIONS: The shortened CSSP that we measured in MWA patients compared to normal with low intensity magnetic stimulation suggests reduced central inhibition resulting in increased excitability of cortical neurons in migraine subjects. The association of CSSP reduction with increased frequency of migraine is further suggestive that brain excitability is the basis of susceptibility to migraine attacks.     

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex

Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308-5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning.     

The occipital cortex is hyperexcitable in migraine: experimental evidence

OBJECTIVES: Threshold for generation of magnetophosphenes has been reported to be lower in migraine. We compared the threshold for eliciting phosphenes by transcranial magnetic stimulation and the ability to visually trigger headache in a select group of individuals with migraine with and without aura to normal controls. METHODS: Transcranial magnetic stimulation was performed using the Cadwell MES-10 stimulator. A circular coil, 9.5 cm in diameter, was applied to the occipital scalp (7 cm above the inion). Stimulator intensity was increased in 10% increments until subjects reported visual phenomena or 100% intensity was reached. Stimulator intensity was then fine-tuned to determine the threshold at which phosphenes were seen. In the same subjects, visual stimulation was given in 3.0 T MRI and if a headache occurred the response was recorded. RESULTS: Fifteen subjects with migraine were compared to 8 controls. A significant proportion of the migraineurs (86.7%) developed phosphenes compared to the controls (25%) (P = .006). The probability of triggering a headache was also higher in the migraineurs (53%); no headache was triggered in the controls (P = .019). A significant correlation was found between the threshold for phosphenes on transcranial magnetic stimulation and visually triggered headache (P = .002). When only migraine was considered, there was again a significant trend (P = .084). CONCLUSIONS: There is a difference in threshold for excitability of occipital cortex in migraineurs and controls. The hyperexcitable visual cortex in migraine is predisposed to visually triggered headache.     

Cortical dysbalance in the brain in migraineurs--hyperexcitability as the result of sensitisation?

A cortical dysbalance has a pivotal role in the pathophysiology of migraine. Numerous electrophysiological and transcranial magnetic stimulation (TMS) studies have investigated the interictal excitability level in migraineurs and have shown a consistent lack of habituation during repetitive stimulation. There is some controversy in the current literature over whether this deficit is based on a lowered or an elevated preactivation level. However, the current discussion may be misguided. It seems that multiple external and intrinsic factors influence the level of cortical excitability and the frequency and intensity of attacks: Habituation is specific neither to migraine nor even to pain; the same phenomenon is found in tinnitus patients, for example. Cortical hyperexcitability is presumably the result of chronicity and the concomitant central sensitisation process.     

Kortikale Dysbalance des Migränikerhirns – Hyperexzitabilität als Folge einer Sensitisierung?

A cortical dysbalance has a pivotal role in the pathophysiology of migraine. Numerous electrophysiological and transcranial magnetic stimulation (TMS) studies have investigated the interictal excitability level in migraineurs and have shown a consistent lack of habituation during repetitive stimulation. There is some controversy in the current literature over whether this deficit is based on a lowered or an elevated preactivation level. However, the current discussion may be misguided. It seems that multiple external and intrinsic factors influence the level of cortical excitability and the frequency and intensity of attacks: Habituation is specific neither to migraine nor even to pain; the same phenomenon is found in tinnitus patients, for example. Cortical hyperexcitability is presumably the result of chronicity and the concomitant central sensitisation process.