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We investigated whether the stimulation frequency (SF), the pain phases, and different diagnoses of trigeminal autonomic cephalalgias (TACs) may influence the habituation to pain. We studied the habituation of the nociceptive blink reflex R2 responses at different SFs (.05, .1, .2, .3, .5, and 1 Hz), in 28 episodic cluster headache (ECH) patients, 16 during and 12 outside the bout; they were compared with 16 episodic paroxysmal hemicrania (EPH) during the bout and 21 healthy subjects. We delivered 26 electrical stimuli and subdivided stimuli 2 to 26 in 5 blocks of 5 responses for each SF. Habituation values for each SF were expressed as the percentages of the mean area value of second through fifth blocks with respect to the first one. A significant lower mean percentage decrease of the R2 area across all blocks was found at .2 to 1 Hz SF during ECH, outside of the ECH, and EPH compared with healthy subjects. We showed a common frequency-dependent deficit of habituation of trigeminal nociceptive responses at higher SFs in ECH and EPH patients, independently from the disease phase. This abnormal temporal pattern of pain processing may suggest a trait-dependent dysfunction of some underlying pain-related subcortical structures, rather than a state-dependent functional abnormality due to the recurrence of the headache attacks during the active period.Perspective: TACs showed a frequency-related defective habituation of nociceptive trigeminal responses at the higher SFs, irrespectively of the diagnosis and/or the disease phase. We showed that the clinical similarities in the different subtypes of TACs are in parallel with a trait-dependent dysfunction in pain processing. [ABSTRACT FROM AUTHOR]

Objective To study the influence of the migraine aura on the trigeminal nociception, we investigated the habituation of the nociceptive blink reflex (nBR) R2 responses in aura with migraine headache (AwMH) and comparatively in migraine without aura (MWoA) and healthy subjects (HS). Background A clear deficit of habituation in trigeminal nociceptive responses has been documented in MWoA; however, similar data in MWA are lacking. Methods Seventeen AwMH, 29 MWoA, and 30 HS were enrolled and a nonrandomized clinical neurophysiological study examining nBR habituation by clinical diagnosis was devised. We delivered a series of 26 electrical stimuli, at different stimulation frequencies (SF) (0.05, 0.1, 0.2, 0.3, 0.5, and 1 Hz), subsequently subdivided in five blocks of five responses for each SF. The mean area values of the second to the fifth block expressed as the percentage of the mean area value of the first block were taken as an index of habituation for each SF. Results A significant lower mean percentage decrease of the R2 area across all blocks was found at 1, 0.5, 0.3, and 0.2 Hz SF in MWoA and at 0.3 and 0.2 Hz SF in AwMH, when compared to HS. In the most representative fifth block of responses, we found in MWoA vs HS at 1 Hz, 57.0 ± 27.8 vs 30.6 ± 12.0; at 0.5 Hz, 54.8 ± 26.1 vs 32.51 ± 17.7; at 0.3 Hz, 44.7 ± 21.6 vs 27.6 ± 13.2; at 0.2 Hz, 61.3 ± 29.5 vs 32.6 ± 18.0, and in AwMH vs HS at 0.3 Hz, 52.7 ± 24.7 vs 27.6 ± 13.2; at 0.2 Hz, 69.3 ± 38.6 vs 32.6 ± 18.0 as mean ± SD of the R2 area percentage of the first block, respectively. Interestingly, AwMH subjects did not show differences in mean percentage decrease of the R2 area at 1 and 0.5 Hz SF when compared to HS. No differences between groups were found at 0.1 and 0.05 Hz SF. Conclusions We demonstrated in AwMH a deficit of habituation of the nBR R2 responses after repeated stimulations, although less pronounced than that observed in MWoA of comparable clinical severity. We hypothesize that AwMH and MWoA share some pathogenetic aspects, and also that migraine aura physiopathology may play a modulating role on the excitability of the nociceptive trigeminal pathways. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Electrical stimulation of the supraorbital trigeminal nerve branch induces trigeminocervical reflex responses (TCRs) in the neck muscles. The purpose of this study was to elicit more nociceptive TCR responses through preferential activation of the nociceptive afferents with a concentric surface electrode. Methods: We recorded TCRs in 10 healthy subjects using both a standard (sTCR) and a nociceptive (nTCR) concentric surface electrode. We compared the baseline parameters, stimulus intensity/response, recovery, and habituation curves recorded for the two types of electrode, and assessed the effects of local anaesthesia. Results: Compared with the sTCRs, nTCRs showed a significantly longer latency of the late reflex component, as well as lower pain and higher reflex thresholds. They also showed a different recovery cycle and stimulus intensity/response curve, but similar habituation rate. Local anaesthesia attenuated by 85% the late reflex response to stimulation by the concentric electrode, and by only 15% the response to standard electrode stimulation. Conclusions: The differences observed stimulating with these two electrode types may be due to their different activation of the afferent fibres. Significance: If this study were extended to patients affected by primary headaches, TCR monitoring could emerge as a sensitive tool for detecting changes in nociceptive transmission at the level of trigeminocervical complex. [ABSTRACT FROM AUTHOR]

Abstract: We investigated changes in visual cortex excitability by analyzing visual evoked potential (VEP) habituation in healthy subjects during tonic pain evoked by the cold-pressor test (CPT). We tested VEP amplitude habituation (slope of the linear regression line for N1-P1 amplitude from the 1st to 6th block of 100 sweeps) in 19 healthy volunteers during 4 experimental conditions: baseline; no-pain (hand held in warm water, 25°C); pain (hand held in cold water, 2–4°C); and the after-effects of tonic pain. During baseline and no-pain sessions, VEPs habituated normally across the 6 consecutive blocks (mean slope –.28 and –.18%), whereas during pain and its after-effects they failed to decrease (0%, and –.11%). Tonic pain induced by the CPT abolishes normal VEP habituation and the lack of habituation persists after the CPT is stopped. Tonic pain probably abolishes VEP habituation by acting on brainstem neural structures which modulate thalamo-cortical activation thereby changing visual cortex excitability. Perspective: This study shows that tonic pain alters visual cortex excitability, a brain region unrelated to pain processing. These changes probably reflect defensive strategies against pain. Extending the study from healthy volunteers to patients with migraine between attacks would offer the opportunity to investigate visual cortical excitability under conditions when baseline habituation is absent. [Copyright &y& Elsevier]

Background: It is unclear whether cortical hyperexcitability in chronic migraine with medication overuse headache (CM-MOH) is due to increased thalamocortical drive or aberrant cortical inhibitory mechanisms. Methods: Somatosensory evoked potentials (SSEP) were performed by electrical stimulation of the median nerve (M), ulnar nerve (U) and simultaneous stimulation of both nerves (MU) in 27 patients with CM-MOH and, for comparison, in 23 healthy volunteers (HVs) of a comparable age distribution. We calculated the degree of cortical lateral inhibition using the formula: 100 – [MU/(M + U) × 100] and the level of thalamocortical activation by analyzing the high frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. Results: Compared to HV, CM-MOH patients showed higher lateral inhibition (CM-MOH 52.2% ± 15.4 vs. HV 40.4% ± 13.3; p = 0.005), which positively correlated with monthly headache days, and greater amplitude of pre-synaptic HFOs (p = 0.010) but normal post-synaptic HFOs (p = 0.122). Conclusion: Our findings suggest that central neuronal circuits are highly sensitized in CM-MOH patients, at both thalamocortical and cortical levels. The observed changes could be due to the combination of dysfunctional central pain control mechanisms, hypersensitivity and hyperresponsiveness directly linked to the chronic intake of acute migraine drugs. [ABSTRACT FROM AUTHOR]

Objectives: It is unclear whether the electrophysiological effects of erenumab, a monoclonal antibody against the calcitonin gene-related peptide receptor, occur only at the periphery of the trigeminal system or centrally and at the cortical level. Methods: We prospectively enrolled 20 patients with migraine who had failed at least two preventative treatments. We measured the nociceptive blink reflex and non-noxious somatosensory evoked potentials in all participants. The area under the curve and habituation of the second polysynaptic nociceptive blink reflex component (R2) as well as the amplitude and habituation of somatosensory evoked potentials N20-P25 were measured. Electrophysiological data were collected at baseline (T0), 28 days (T1), and 56 days (T2) before each injection of erenumab (70 mg). Results: Erenumab reduced the patients' mean monthly headache days, headache intensity, and acute medication intake considerably at T1 and T2 (all p < 0.05). The nociceptive blink reflex area under the curve was considerably lower at T1 and T2 than at baseline without changing the habituation slope. At T2, there was a significant increase in the delayed somatosensory evoked potentials amplitude reduction (habituation) but not in the initial cortical activation. Conclusion: Our findings showed that erenumab, in addition to its well-known peripheral effects, can induce central effects earlier in the brainstem and later in the cortex. We cannot rule out whether these results are due to a direct effect of erenumab on the central nervous system or an indirect effect secondary to peripheral drug modulation. [ABSTRACT FROM AUTHOR]

Background: Merging of sensory information is a crucial process for adapting the behaviour to the environment in all species. It is not known if this multisensory integration might be dysfunctioning interictally in migraine without aura, where sensory stimuli of various modalities are processed abnormally when delivered separately. To investigate this question, we compared the effects of a concomitant visual stimulation on conventional low-frequency somatosensory evoked potentials and embedded high-frequency oscillations between migraine patients and healthy volunteers. Methods: We recorded somatosensory evoked potentials in 19 healthy volunteers and in 19 interictal migraine without aura patients before, during, and 5 min after (T2) simultaneous synchronous pattern-reversal visual stimulation. At each time point, we measured amplitude and habituation of the N20-P25 low-frequency-somatosensory evoked potentials component and maximal peak-to-peak amplitude of early and late bursts of high-frequency oscillations. Results: In healthy volunteers, the bimodal stimulation significantly reduced low-frequency-somatosensory evoked potentials habituation and tended to reduce early high-frequency oscillations that reflect thalamocortical activity. By contrast, in migraine without aura patients, bimodal stimulation significantly increased low-frequency-somatosensory evoked potentials habituation and early high-frequency oscillations. At T2, all visual stimulation-induced changes of somatosensory processing had vanished. Conclusion: These results suggest a malfunctioning multisensory integration process, which could be favoured by an abnormal excitability level of thalamo-cortical loops. [ABSTRACT FROM AUTHOR]

Abstract: A common experimental neurophysiological method to study synaptic plasticity is pairing activity of somatosensory afferents and motor cortical circuits, so-called paired associative stimulation (PAS). Dysfunctional inhibitory and excitatory PAS mechanisms within the sensorimotor system were described in patients with migraine without aura (MO) between attacks. We have recently observed that the same bidirectional PAS rules also apply to the visual system. Here, we have tested whether dysfunctioning associative plasticity might characterize the visual system of patients with MO. In 14 patients with MO between attacks and in 15 healthy volunteers, we performed a previously validated visual PAS (vPAS) protocol by coupling 90 black-and-white checkerboard reversals with low-frequency transcranial magnetic stimulation pulses over the occipital cortex at 2 interstimulus intervals of -25/+25 ms around the visual-evoked potential (VEP) P1 latency. We recorded VEPs (600 sweeps) before, immediately after, and 10 min after each vPAS session. We analysed VEP N1-P1 amplitude and delayed habituation. Although vPAS-25 significantly enhanced and vPAS + 25 reduced VEP amplitude habituation in healthy volunteers, the same protocols did not significantly change VEP amplitude habituation in MO between attacks. We provide evidence for lack of habituation enhancing and habituation suppressing visual PAS mechanisms within the visual system in interictal migraine. This finding, in combination with those previously obtained studying the sensorimotor system, leads us to argue that migraine disease-related dysrhythmic thalamocortical activity prevents the occurrence of physiological bidirectional synaptic plasticity induced by vPAS. [ABSTRACT FROM AUTHOR]

The article discusses a study which concludes that the predisposition and recurrence of episodic cluster headache (ECH) is attributed to the malfunctioning of the posterior hypothalamus and of the nociceptive processing and the sensitization of the trigeminal pain system resulting in the descending aminergic controls. It is mentioned that lateralized pathological abnormalities were observed in the nociceptive-specific blink reflex (BR) in the ECH patients.