Asymmetrical reduction of the nociceptive flexion reflex threshold in cluster headache

The nociceptive flexion reflex (NFR) of the lower limbs (RIII reflex) was examined bilaterally in 54 cluster headache (CH) patients suffering from episodic CH (ECH) and chronic CH (CCH). Fifteen ECH patients were examined in both remission and active phases. The RIII reflex threshold (Tr) and the threshold of pain sensation (Tp) were significantly reduced on the symptomatic side in patients with episodic CH during the bout. During the active phase of episodic CH an inverse correlation was found between the severity of CH (ratio: number of cluster periods/years of illness duration) and the Tp, which may suggest a role for secondary central sensitization in pain pathways. The lower Tr and Tp on the symptomatic side is in keeping with previous observations exploring pain mechanisms using different methods (i.e. corneal reflex, pain pressure threshold). On the whole, these data tie in with the view of an impairment of the pain control system, which parallels the periodicity of the disorder in the episodic form.     

The trigemino-pupillary response in cluster headache

Central impairment of the integrative neural systems controlling vegetative function and pain perception has been demonstrated in cluster headache (CH). Recently, we described the human pupillary response (trigeminal reflex) to quantified (painless and painful) corneal stimulation with a combined neurophysiological and pharmacological technique. In this study, the trigeminal reflex was evaluated in 26 subjects with episodic cluster headache. During the active phase of the disease, on the side of the pain we observed reduced mydriasis to electrical stimuli with an intensity equal to the corneal reflex threshold, and on both sides to stimuli with intensity that equalled the pain threshold. No difference was found when amplitude of the miotic phase was compared in the different groups. These suggest disordered pupillary activation in response to pain, probably sympathetic in origin, which is bilateral, detectable also during the remission phase and which cannot be explained simply by the antidromic release of pain-related peptides.     

Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache

BACKGROUND: Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. OBJECTIVES: To explore whether circadian failure of the pain control system may exist in cluster headache. METHODS: The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. RESULTS: In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. CONCLUSIONS: Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.     

Facilitated temporal processing of pain and defective supraspinal control of pain in cluster headache

In cluster headache (CH), pathogenesis has been emphasized the role of the posterior hypothalamus. It is part of a supraspinal network involved in the descending control of pain, including the diffuse noxious inhibitory control (DNIC), which in turn modulates the pain processing. We hypothesized that CH during the active phase facilitated temporal pain processing supported by abnormal functioning of the DNIC. We studied the functional activity of the DNIC by evaluating the effect of the cold pressor test (CPT) on the temporal summation threshold (TST) of the nociceptive withdrawal reflex. Ten subjects with episodic CH (2 women, 8 men) and 10 healthy subjects were recruited. Each subject underwent neurophysiological evaluation (nociceptive withdrawal reflex TST and related painful sensation) at baseline, then before (control session), during (pain session), and 5 min after (aftereffect) the CPT (immersing hand in a 4 °C water bath for 4–5 min). Patients had been studied during both the active and remission phases. During the active phase, CH revealed a significant facilitation in temporal processing of pain stimuli (reduction of TST), which reverted during the remission phase. The CPT activating the DNIC did not produce any significant inhibitory effect of pain responses in CH during the active phase, whereas it induced a clear inhibition during the remission phase. We hypothesized that in CH, a dysfunction of the supraspinal control of pain related to the clinical activity of the disease, possibly supported by an abnormal hypothalamic function, leads to a facilitation in pain processing and a predisposition to pain attacks.     

Pupil responsiveness in cluster headache: A dynamic TV pupillometric evaluation

In this study the variations in pupil diameter induced by different stimuli (dark-light adaptation, light reflex, electric stimulation of the sural nerve) were investigated in episodic (in the active or remission phases) and in chronic cluster headache (CH) patients. Pupil size monitoring was performed with a monocular, infrared TV pupillometer, and sural nerve stimuli were applied after the pain threshold had been measured as the flexion reflex threshold of the biceps femoris muscle (RIII reflex). The results were compared with those obtained in patients with "peripheral" (third neuron) Horner's syndrome and in healthy sex- and age-matched controls. On the symptomatic side we found an impairment of pupil response to light flashes and nociceptive stimuli; similar findings were sometimes evident on the pain-free side, too. These results substantiate previous observations that in cluster headache a dysfunction of the integrative central nervous system pathways also exists intercritically and mostly bilaterally, involving both autonomic regulation and pain perception mechanisms.     

Neurophysiological Studies in Chronic Paroxysmal Hemicrania and Hemicrania Continua

SYNOPSIS
To explore the possible involvement of the pain control system, pain pressure threshold (PPT), nociceptive flexion reflex (RIll), blink and corneal reflexes have been studied for pain perception assessment in 12 patients with chronic paroxysmal hemicrania (CPH) and 12 patients with hemicrania continua (HC). PPT was found to be reduced in HC and CPH when separately compared to controls. In addition, a significant reduction of subjective pain perception (Tp) which was most marked on the symptomatic side, has been demonstrated after sural nerve stimulation in CPH. The RIll reflex threshold on the symptomatic side was significantly reduced when patients were compared to controls, No major differences between CPH and HC as regards blink reflex latencies were found; nor was any such difference observed when comparing the two headache groups to controls. The corneal reflex thresholds were found significantly reduced bilaterally in CPH, irrespective of whether the treatment was given or not.     

Trigemino-cervical reflex abnormalities in patients with migraine and cluster headache

BACKGROUND: Head pain arises within the trigeminal nociceptive system. Current theories propose that the trigeminal system is intimately involved in the pathogenesis of migraine. Short-latency responses can be recorded in sternocleidomastoid muscles after stimulation of the trigeminal nerve (trigemino-cervical reflex). This brainstem reflex could be a suitable method to evaluate the trigeminal system in migraine and CH. OBJECTIVE: The aim of the present study was to further elucidate the pathophysiology of migraine and cluster headache (CH) with special reference to the involvement of the central trigeminal system in the different forms of primary headache. METHODS: The trigemino-cervical reflex was investigated in 15 healthy subjects, in 15 patients having migraine with aura, in 15 patients with migraine without aura, and in 10 patients with CH. RESULTS: Significant abnormalities were observed in a great number of patients with both types of migraine and CH during the headache attacks, but only in migraine patients during the interictal period. The alterations are bilateral in migraine, unilateral in CH. CONCLUSIONS: Our results further support the relevance of brainstem mechanisms in the pathogenesis of migraine rather than of CH. These data, taken together with that from experimental head pain and functional imaging studies, demonstrate that primary headache syndromes may be distinguished on a functional basis by areas of activation specific to the clinical syndrome.     

Mutation analysis of the CACNA1A calcium channel subunit gene in 27 patients with sporadic hemiplegic migraine.

Int J Psychophysiol . 2002 Jun;44(3):239-249
The modulation of trigeminal reflex excitability in migraine patients was evaluated during the asymptomatic phase by studying the effects of attention, habituation and preconditioning stimulus on the R2 and R3 components of the blink reflex (BR). Fifty patients suffering from migraine without aura, 20 affected by migraine with aura and 35 sex- and age-matched controls were selected. In subgroups of migraine with-aura and without-aura patients, and normal controls, the blink reflex was elicited during different cognitive situations: (a) spontaneous mental activity; (b) stimulus anticipation; (c) recognition of target numbers. In the remaining subjects, R2 and R3 habituation was evaluated by repetitive stimulation at 1, 5, 10, 15, 20, 25 and 30 s intervals. The R2 and R3 recovery curves were also computed. A reduced R3 threshold with a normal pain threshold was found in migraine with-aura and without-aura patients; the R3 component was not significantly correlated with the pain thresholds in patients and controls. The R2 and R3 components were less influenced by the warning of the stimulus in migraine without-aura and migraine with-aura patients, in comparison with the control group. A slight increase of both R2 and R3 recovery after preconditioning stimulus was also observed in migraine patients, probably caused by a phenomenon of trigeminal hyperexcitability persisting after the last attack. The abnormal BR modulation by alerting expresses in migraine a dysfunction of adaptation capacity to environmental conditions, probably predisposing to migraine.
Comment: Further physiologic and functional evidence for the interictal hyperexcitability of neurons in patients with migraine, in this case trigeminal neurons involved in the blink reflex. SJT     

Sumatriptan and corneal reflexes in headache-free migraine patients: a randomized and placebo-controlled crossover study

A temporary sensitization of central trigeminal neurones in migraine patients during acute attacks has been described in previous studies using the electrically evoked nociceptive blink reflex. The cornea is innervated by small myelinated A-delta and unmyelinated C-fibres only. Stimulation with air puffs activates peripheral nociceptors and allows the investigation of peripheral trigeminal nerve structures. Our objective was to investigate whether corneal reflex examinations with air puff stimulation detect abnormalities in migraineurs during their pain-free interval and if the corneal reflex may be modulated by the administration of an oral triptan. After validation of the nociceptive air puff technique by investigating the corneal reflexes before and after a local anaesthesia of the cornea, we recorded corneal reflexes in 25 migraineurs during their pain-free period and 25 healthy controls before and after the oral administration of 100 mg sumatriptan in a randomized, placebo-controlled, crossover study. Baseline response areas under the curve (AUCs) and latencies of the R2 components of the corneal reflexes did not show any significant differences between patients and controls. Patients did not show any significant differences regarding their headache and non-headache side. The use of an oral triptan had no significant influence on latencies or AUCs in both patients and controls. Our data suggest that there is no facilitation of the trigeminal system in the headache-free interval among patients with migraine. The stable corneal reflexes after the oral administration of 100 mg sumatriptan suggest that there was no inhibition of the trigeminal system, both in patients during their headache-free period and in healthy controls.     

The blink reflex in chronic cluster headache: a comparison with migraine patients suffering from unilateral pain

Objective. To evaluate the blink reflex (BR) in chronic cluster headache (CH) patients. Design. The elecrophysiological data were collected in during the headache-free phase. Setting. Headache patients were recruited from outpatients seen for the first time at the First Neurologic Clinic of Bari University. Patients and participants. Ten CH patients, 19 migraine without aura patients with strictly unilateral headache (MwoA) and 18 normal controls were selected. Measurements and results. The BR procedure was applied. In CH, a significant R2 duration increase was found on the symptomatic side in comparison with MwoA and controls. In both patient groups an early appearance of the R3 component was bilaterally clear. Conclusions. The BR findings confirm the central genesis of CH. The R3 abnormalities suggest a basic dysfunction of the Central control on the trigeminal nociceptive circuits. The R2 involvement on the symptomatic side indicates a unilateral facilitation of the trigeminal-facial connections persisting after the CH bout. Received: 3 January 2000, Accepted in revised form: 2 November 2000     

Substance P mechanism in cluster headache: Evaluation in plasma and cerebrospinal fluid

Substance P (SP), present in sensory afferent neurons, seems to process nociceptive information in the trigeminal system. SP, released from peripheral trigeminal endings, causes typical cluster headache (CH) signs, e.g. vasodilatation, conjunctival and nasal edema and miosis. Opiates and somatostatin (SRIF), both active in relieving CH attack, inhibit SP release from the central and peripheral trigeminal system. In the present study, plasma and cerebrospinal fluid (CSF), SP-like immunoreactivity (SPLI) and enkephalinase activity (EKA), and plasma SRIF-like immunoreactivity (SRIFLI) have been evaluated during spontaneous and histamine induced attacks in the cluster phase. During the histamine provoked attacks, CSF SPLI and plasma SRIFLI and EKA were unchanged, while plasma SPLI decreased significantly. During spontaneously occurring attacks, plasma SRIFLI was found to be unmodified and a significant lowering of SPLI was detected when compared with controls. Moreover, both during and between attacks in the cluster phase, plasma EKA was increased in comparison with the values in controls. It remains to be seen whether variations of plasma SPLI and EKA levels play a role in the CH mechanism.     

Electrophysiological evidence for trigeminal neuron sensitization in patients with migraine.

Neurosci Lett . 2002 Jan 14;317(3):135-138
The electrically elicited corneal reflex is a useful tool for exploring the trigeminal system in humans and it may provide additional evidence pointing to a dysfunction of this system in migrainous patients. Tactile perception, corneal reflex and pain thresholds were studied in 48 migraine without aura patients during pain-free periods and compared with those observed in 24 controls. Twenty-eight of the patients had strictly unilateral headache, while the other 20 had bilateral or side-shifting pain during attacks. Both migraine subgroups (bilateral and unilateral) showed significantly lower thresholds compared with controls. The lowest values were observed on the symptomatic side of unilateral migraine patients. These findings suggest that sensorimotor mechanisms and/or pain control systems at the trigeminal level are impaired in migraine. The bilateral location of these abnormalities seems to point to a centrally located dysfunction.
Comment: This is an important paper which describes a noninvasive method of studying sensorimotor/pain control mechanism in humans. This approach may help in the development of potential prophylactic agents, to establish likely clinically effective doses and duration of treatments in small-scale phase II trials, before exposing larger numbers of subjects to potentially ineffective doses in phase III trials. DSM     

Comparative study of perceived pain and nociceptive flexion reflex in man

The purpose of this study was to compare the amplitude of the flexion reflex of the biceps femoris muscle (BF) with the intensity of the painful sensation elicited by a nociceptive stimulation resulting from application of a constant-current either on the sural nerve or on the skin in its distal receptive field. Experiments were carried out on 15 normal volunteers.It was observed that: (1) Stimulation of the sural nerve (either on or through the skin) elicits two different reflex responses in the BF: the first (RII) is of short latency, low threshold and corresponds to a tactile reflex. The second (RIII) is of longer latency and higher threshold, and corresponds to a nociceptive reflex. The threshold of RIII was found to be the threshold of a pain sensation. (2) Stimulation of the skin elicits only a late nociceptive (RIII) response in the BF. The threshold of this response was also found to be that of pain. (3) The thresholds of both pain and RIII were found to be higher for sural nerve stimulation (10 mA) than for cutaneous stimulation (5 mA).It was suggested that the large diameter cutaneous fibers could have an inhibitory effect on both pain and the nociceptive reflex. This was supported by the results obtained during a selective ischemic block of the largest diameter fibers in the sural nerve, when a 10 mA stimulation was applied to the nerve. In this case, a decrease of the RII reflex was observed in BF, together with an increase of both RIII and pain sensation. Functional implications of these results are discussed.     

Bilateral asymmetry of cerebral blood velocity in cluster headache

In this study, 69 episodic cluster headache (CH) patients (40 in the active phase, 29 in remission period) underwent a complete TCD examination in order to verify the relationship between cerebral blood velocities (CBVs) and the clinical profile of the disease. Fifteen patients were examined during both phases, while 7 were monitored during a spontaneous attack. Sixty-three healthy sex and age-matched controls were also studied. We measured widespread, asymmetric CBV activation during the active phase, bilaterally in the anterior circulation and also in the posterior circulation. A relative reduction of CBV on the anterior cerebral artery pain side, also during remission, suggests a relationship between local vasodilation and the autonomic symptoms ipsilateral to pain during CH attacks.     

The effect of multiple stimuli on the modulation of the 'nociceptive' blink reflex

The 'nociceptive' blink reflex is a method of examining human trigeminal pain pathways. We explored temporal summation of this reflex by using a train of pulses, rather than a single pulse, and remote activation of diffuse noxious inhibitory control (DNIC), to improve reliability, flexibility and nociceptive specificity of this technique. The R2 component of the nociceptive blink reflex response (nR2) was assessed in 28 healthy volunteers using between 1 and 7 pulses per stimulus train (inter-pulse interval 5 ms). The effect of DNIC on single-, double-, and triple-pulse nR2 was investigated. Compared to single pulses, double and triple pulses increased the sensation of pain, reduced the tactile and pain thresholds, and facilitated the blink reflex responses (reduced onset latency, increased magnitude and persistence of nR2). The maximal reflex facilitation was achieved using a triple pulse. Higher pulse numbers had no additional facilitatory effect. Activation of the DNIC system using heterotopic pain suppressed the nR2 evoked by double and triple stimulation by 16 and 42%, respectively, but not the nR2 from a single pulse. Stimulation with double and triple pulses may be more suitable to study influences on nociceptive pathways than single pulses and may widen the methodological flexibility of the nociceptive blink reflex technique. This technique may be useful in studying the trigeminal nociceptive system with particular reference to primary headache disorders and their neuropharmacology.     

Pain pressure threshold in cluster headache patients

Pain perception threshold (PFT) in the head was assessed with a pressure algometer in 58 cluster headache (CH) patients (52M, 6F; 41 episodic and 17 chronic). Fourteen patients in cluster period were retested in remission. Thresholds were assessed at 10 symmetrical points on each side of the head and at the deltoid. Compared with controls ( n = 80), CH patients had lower PPT in the head and in the deltoid. PPT was lower on the symptomatic side than on the non-symptomatic side in patients with episodic CH during a cluster period ( p <0.001) and in patients with chronic CH ( p <0.05). This pattern was more evident during a cluster period than during remission ( p <0.05). A reduced PPT did not correlate with illness duration and pain side. The lowest PPT mean values were found at the anterior and intermediate levels of the temporal muscle on the symptomatic side. These results imply a central mechanism underlying the pathogenesis of CH.     

Trait- and Frequency-Dependent Dysfunctional Habituation to Trigeminal Nociceptive Stimulation in Trigeminal Autonomic Cephalalgias

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.

Psychophysical and cerebral responses to heat stimulation in patients with central pain, painless central sensory loss, and in healthy persons

Patients with central pain (CP) typically have chronic pain within an area of reduced pain and temperature sensation, suggesting an impairment of endogenous pain modulation mechanisms. We tested the hypothesis that some brain structures normally activated by cutaneous heat stimulation would be hyperresponsive among patients with CP but not among patients with a central nervous system lesion causing a loss of heat or nociceptive sensation with no pain (NP). We used H₂¹⁵O positron emission tomography to measure, in 15 healthy control participants, 10 NP patients, and 10 CP patients, increases in regional cerebral blood flow among volumes of interest (VOI) from the resting (no stimulus) condition during bilateral contact heat stimulation at heat detection, heat pain threshold, and heat pain tolerance levels. Both patient groups had a reduced perception of heat intensity and unpleasantness on the clinically affected side and a bilateral impairment of heat detection. Compared with the HC group, both NP and CP patients had more hyperactive and hypoactive VOI in the resting state and more hyperresponsive and hyporesponsive VOI during heat stimulation. Compared with NP patients, CP patients had more hyperresponsive VOI in the intralaminar thalamus and sensory-motor cortex during heat stimulation. Our results show that focal CNS lesions produce bilateral sensory deficits and widespread changes in the nociceptive excitability of the brain. The increased nociceptive excitability within the intralaminar thalamus and sensory-motor cortex of our sample of CP patients suggests an underlying pathophysiology for the pain in some central pain syndromes.     

Quantification and immunocytochemical characteristics of trigeminal ganglion neurons projecting to the cornea: Effect of corneal wounding

The number and immunocytochemical characteristics of trigeminal ganglion neurons providing sensory innervation to the cornea were studied in the mouse. Corneal neurons were retrogradely labelled with fluorogold placed on the cornea after removal of the epithelium with n-heptanol. Corneal neurons were counted, sized and characterized immunocytochemically with antisera against substance P (SP), calcitonin gene-related peptide (CGRP), calbindin, calretinin, and with a monoclonal antibody (RT97) against neurofilament proteins. A total of 258 corneal neurons were counted, most of them located in the ophthalmic division of the trigeminal ganglion. They represent only a small fraction (1.3%) of the population of trigeminal ganglion neurons. More than 70% of corneal neurons were classified as ‘small dark’ according to their cell body area and the absence of immunoreactivity to RT97. A low percentage of corneal neurons, usually large in size, contained calcium binding proteins. Fifty-eight percent of the corneal neurons were immunoreactive to CGRP, and 20% to SP Corneal wounding with NaOH, which affects stromal nerve trunk, did not modify the total number of corneal neurons or their neuropeptide content. However, this increased the total number of calbindin-positive and decreased the RT97-positive neurons. Thus, unlike in other nociceptive neurons, peripheral axotomy did not modify the SP/CGRP content of corneal neurons. Trigeminal ganglion neurons projecting to the cornea are similar in size and neuropeptide content to nociceptive neurons of other territories. Their number is high in relation to the corneal surface, thus confirming that the cornea has a large nociceptive representation in the trigeminal ganglion.