Petter Moe Omland

Visual Evoked Potentials in Interictal Migraine: No Confirmation of Abnormal Habituation

We intended to study the effect of check size on visual evoked potential habituation in interictal migraine, using the faster 3 per second reversal rate and an improved analytic procedure with block‐number blinding.

The effect of sleep restriction on laser evoked potentials, thermal sensory and pain thresholds and suprathreshold pain in healthy subjects

OBJECTIVE Sleep restriction seems to change our experience of pain and reduce laser evoked potential (LEP) amplitudes. However, although LEP-habituation abnormalities have been described in painful conditions with comorbid sleep impairment, no study has previously measured the effect of sleep restriction on LEP-habituation, pain thresholds, and suprathreshold pain. METHOD Sixteen males and seventeen females (aged 18-31years) were randomly assigned to either two nights of delayed bedtime and four hours sleep (partial sleep deprivation) or nine hours sleep. The study subjects slept at home, and the sleep was measured with actigraphy both nights and polysomnography the last night. LEP, thermal thresholds and suprathreshold pain ratings were obtained the day before and the day after intervention. The investigator was blinded. ANOVA was used to evaluate the interaction between sleep restriction and day for each pain-related variable. RESULTS LEP-amplitude decreased after sleep restriction (interaction p=0.02) compared to subjects randomized to nine hours sleep. LEP-habituation was similar in both groups. Thenar cold pain threshold decreased after sleep restriction (interaction p=0.009). Supra-threshold heat pain rating increased temporarily 10s after stimulus onset after sleep restriction (interaction p=0.01), while it did not change after nine hours sleep. CONCLUSION Sleep restriction reduced the CNS response to pain, while some of the subjective pain measures indicated hyperalgesia. SIGNIFICANCE Since LEP-amplitude is known to reflect both CNS-pain-specific processing and cognitive attentive processing, our results suggest that hyperalgesia after sleep restriction might partly be caused by a reduction in cortical cognitive or perceptual mechanisms, rather than sensory amplification.

Does pain sensitivity change by migraine phase? A blinded longitudinal study:

Objective Studies suggest that pain thresholds may be altered before and during migraine headaches, but it is still debated if a central or peripheral dysfunction is responsible for the onset of pain in migraine. The present blinded longitudinal study explores alterations in thermal pain thresholds and suprathreshold heat pain scores before, during, and after headache. Methods We measured pain thresholds to cold and heat, and pain scores to 30 seconds of suprathreshold heat four times in 49 migraineurs and once in 31 controls. Sessions in migraineurs were categorized by migraine diaries as interictal, preictal (≤one day before attack), ictal or postictal (≤one day after attack). Results Trigeminal cold pain thresholds were decreased (p = 0.014) and pain scores increased (p = 0.031) in the ictal compared to the interictal phase. Initial pain scores were decreased (p < 0.029), and the temporal profile showed less adaptation (p < 0.020) in the preictal compared to the interictal phase. Hand cold pain thresholds were decreased in interictal migraineurs compared to controls (p < 0.019). Conclusion Preictal heat hypoalgesia and reduced adaptation was followed by ictal trigeminal cold suballodynia and heat hyperalgesia. Our results support that cyclic alterations of pain perception occur late in the prodromal phase before headache. Further longitudinal investigation of how pain physiology changes within the migraine cycle is important to gain a more complete understanding of the pathogenic mechanisms behind the migraine attack.

Non-invasive cortical modulation of experimental pain in migraine.

OBJECTIVE To test the hypothesis that secondary somatosensory cortex (S2) is involved in the migraine pathogenesis, by exploring the effect of navigated repetitive transcranial magnetic stimulation (rTMS) to S2 on thermal perception and pain. METHODS In this blinded sham-controlled case-control study of 26 interictal migraineurs and 31 controls, we measured thermal detection and pain thresholds on the hand and forehead, and pain ratings to heat stimulation on the forearm and temple, after real and sham 10Hz rTMS. RESULTS rTMS increased cold and heat pain thresholds in controls as compared to interictal migraineurs (p<0.026). rTMS decreased forehead and arm pain ratings (p<0.005) and increased hand cool detection thresholds (p<0.005) in both interictal migraineurs and controls. CONCLUSIONS The effects of rTMS to S2 on thermal pain measures differed significantly between migraine and control subjects, although the effects were generally low in magnitude and not present in pain ratings. However, the lack of cold and heat pain threshold increase in migraineurs may reflect a hypofunction of inhibitory pain modulation mechanisms. SIGNIFICANCE The expected rTMS-induced cold and heat hypoalgesia was not found among migraineurs, possibly a reflection of reduced intracortical inhibition.

Neurophysiology of Migraine

Migraine is a recurrent ictal headache disorder accompanied by multisensory symptoms and pain-free interictal periods of variable length between attacks. During the last few decades, many research groups have used a variety of neurophysiological techniques to search for biomarkers of subtle CNS – factors that may predispose individuals to migraine attacks. Researchers have demonstrated significant changes in bioelectrical activity in the brains of migraineurs that change during the migraine cycle, although controversy remain regarding the reliability, effect size and utility of several findings. Notably, various abnormalities of spinal, brainstem and cortical responsivity to external innocuous or noxious stimuli have been described in several migraine groups by several research teams.

Habituation of laser-evoked potentials by migraine phase: a blinded longitudinal study

BackgroundMigraineurs seem to have cyclic variations in cortical excitability in several neurophysiological modalities. Laser-evoked potentials (LEP) are of particular interest in migraine because LEP specifically targets pain pathways, and studies have reported different LEP-changes both between and during headaches. Our primary aim was to explore potential cyclic variations in LEP amplitude and habituation in more detail with a blinded longitudinal study design.MethodsWe compared N1 and N2P2 amplitudes and habituation between two blocks of laser stimulations to the dorsal hand, obtained from 49 migraineurs with four sessions each. We used migraine diaries to categorize sessions as interictal (> one day from previous and to next attack), preictal (< one day before the attack), ictal or postictal (< one day after the attack). Also, we compared 29 interictal recordings from the first session to 30 controls.ResultsN1 and N2P2 amplitudes and habituation did not differ between preictal, interictal and postictal phase sessions, except for a post hoc contrast that showed deficient ictal habituation of N1. Habituation is present and similar in migraineurs in the interictal phase and controls.ConclusionsHand-evoked LEP amplitudes and habituation were mainly invariable between migraine phases, but this matter needs further study. Because hand-evoked LEP-habituation was similar in migraineurs and controls, the present findings contradict several previous LEP studies. Pain-evoked cerebral responses are normal and show normal habituation in migraine.

Reduced motor cortical inhibition in migraine: A blinded transcranial magnetic stimulation study

OBJECTIVE To investigate motor cortical excitability, inhibition, and facilitation with navigated transcranial magnetic stimulation (TMS) in migraine in a blinded cross-sectional study. METHODS Resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were compared in 27 interictal migraineurs and 33 controls. 24 female interictal migraineurs and 27 female controls were compared in subgroup analyses. Seven preictal migraineurs were also compared to the interictal group in a hypothesis-generating analysis. Investigators were blinded for diagnosis during recording and analysis of data. RESULTS SICI was decreased in interictal migraineurs when compared to healthy controls (p=0.013), CSP was shortened in female interictal migraineurs (p=0.041). ICF was decreased in preictal compared to interictal migraineurs (p=0.023). RMT and ICF were not different between interictal migraineurs and controls. CONCLUSION Cortical inhibition was decreased in migraineurs between attacks, primarily in a female subgroup, indicating an importance of altered cortical inhibition in migraine. SIGNIFICANCE Previous studies on motor cortical excitability in migraineurs have yielded varying results. This relatively large and blinded study provides support for altered cortical inhibition in migraine. Measuring intracortical facilitation in the period preceding migraine attacks may be of interest for future studies.

EHMTI-0319. TMS-measured cortical excitability do not change by migraine phase: a blinded longitudinal study

Many migraineurs have increased sensitivity to light, sounds, odours or sensory stimuli, particularly in the premonitory phase and during the headache attack. These symptoms may be caused by alterations in cortical excitability. Transcranial magnetic stimulation (TMS) measurements of cortical excitability in migraineurs have yielded conflicting results, possibly due to large interindividual differences, different procedures and lack of blinding.

Visual and auditory cortical evoked potentials in interictal episodic migraine: The predictive value of a proposed diagnostic test should always be corrected for prevalence

It is important to take disease prevalence within the target population (pre-test probability) correctly into account. Authors, referees and editors should be aware of this to prevent the publication of erroneous results. Ambrosini et al. (2) have replied to our letter (3) regarding their recent publication (4), and they still claim that the combination of visual evoked potentials (VEP) and intensity dependent auditory evoked potentials (IDAP) have a high diagnostic value in migraine. However, recalculation based on the sensitivity and specificity reported by Ambrosini et al. (3), and the expected population-prevalence equal to 15% for migraine, yields disappointingly low PPV for VEP, IDAP and the combinations of IDAP and VEP (Table 1). Indeed, the PPV of an abnormality of at least one of VEP and IDAP is only 30.7%, far below the 94.1% value given by Ambrosini et al. A PPV of 94.1 % would require considerably higher sensitivity and specificity than those reported by Ambrosini et al. Ambrosini et al. also suggest that regional differences in solar radiation could be of importance in migraine (2). This hypothesis should be investigated with rigorous methods. We contend that matched

Re: Visual and auditory cortical evoked potentials in interictal episodic migraine: An audit on 624 patients from three centres.

To the Editor, In a recent publication, Ambrosini et al. (1) investigated the diagnostic value of visual and intensity dependent auditory evoked potentials (VEP and IDAP) in migraine. They concluded that these tests had insufficient diagnostic efficacy alone, but a good efficacy when combined. This conclusion is based on a positive predictive value (PPV) of 94.1% and diagnostic accuracy of 81.1%. However, these values are misleading, because the authors have not taken pretest probability into account. The pretest probability in the group tested with both VEP and IDAP was 86.5%, and a positive test increased the probability of disease by only 7.6 percentage points. A pretest probability (or migraine prevalence) of 15%, relevant for screening, reduces PPV and diagnostic accuracy to 30.7% and 69.2% respectively. The authors are in general too optimistic when interpreting their results. For instance, they describe a diagnostic accuracy of 54.3% for IDAP as ‘‘moderate to fair’’. This is only 4.3 percentage points better than the 50% that is expected from chance alone. Also, unpublished accuracy estimates from our own database of blinded VEP-studies show values close to 50%. Hence, we agree with Ambrosini et. al. (1) on this point; VEP habituation is not useful in differentiating migraineurs from headache-free controls. There are also other methodological limitations in the present multicentre study: (1) 87 % of the examinations were performed in one centre, the centres did not use the same VEP protocol, IDAP was only recorded in one centre, age and sex distributions were different in migraine and control groups, blinding during data recording was not applied and exclusions were not reported. These limitations may have an impact on results, as we have discussed previously (2). In addition, the study is retrospective, and the authors provide little information about how the subjects were recruited. The authors argue that VEP and IDAP could be useful in uncertain headache cases, based on the usual comparison of controls who obviously do not have the disease with migraineurs who obviously do. However, sensitivity and specificity will likely be even lower within a clinical context characterised by diagnostic uncertainty (3). Lijmer et al. (4) found that diagnostic performance of a test will be severely overestimated if a diseased population is compared to healthy controls, probably because cases that are difficult to diagnose are omitted from casecontrol studies. In contrast, we recommend performing blinded cohort studies, preferably a multicentre study, within a clinically-relevant study population, e.g. comparing migraine with tension-type headache. Although the concept of habituation is still of considerable scientific interest for several sensory and motor modalities in migraine, we have to conclude that the data presented by Ambrosini et. al. (1) suggests that the real diagnostic value of VEP and IDAP is very low. We therefore believe that uncertain headache cases should not be referred to VEP and IDAP. The proposed practice will waste time and resources, and it may also result in an incorrect diagnosis.