Chirp stimulation: H-response short and dynamic.

BACKGROUND: Migraine patients have an increased photic-driving response. This 'H-response' (HR) has potential diagnostic value but it is time consuming. AIM: The aim of the study was to establish a fast and standardized test for the study of migraine biology and treatment. METHODS: We studied 11 migraine patients and 11 matched control participants. We used stroboscope flashes with a 'chirp'-like linear frequency-increase from 10 to 40 Hz. EEG was recorded from occipital electrodes. Power spectral density was calculated for the stimulus response and corrected for baseline. An HR-estimator was calculated as the average power between 18 and 26 Hz in the stimulation-frequency window. RESULTS: There was a significant difference for single (p < 0.05) and for 10 averaged recordings (p < 0.01) between migraineurs and controls, and a high inter-test reliability (Cronbach's alpha = 0.94). CONCLUSION: Chirp-like stimulation to study the H-response is reliable and efficient and might therefore have a potential for acute interventional studies in migraine research.

Spinal cord stimulation in cluster headache.

Neurostimulation techniques for the treatment of primary headache syndromes, particularly for chronic cluster headache (CCH), have received much interest in the recent years. Occipital nerve stimulation (ONS) has yielded favourable clinical results, and is becoming a routine treatment for refractory chronic cluster headache in specialized centres. Meanwhile, other promising techniques, such as spinal cord stimulation (SCS) or sphenopalatine ganglion stimulation, are emerging. This article reviews the current state of clinical research for neurostimulation techniques for chronic cluster headache, and particularly the pros and cons of SCS and ONS.

Spinal cord stimulation in cluster headache.

Neurostimulation techniques for the treatment of primary headache syndromes, particularly for chronic cluster headache (CCH), have received much interest in the recent years. Occipital nerve stimulation (ONS) has yielded favourable clinical results, and is becoming a routine treatment for refractory chronic cluster headache in specialized centres. Meanwhile, other promising techniques, such as spinal cord stimulation (SCS) or sphenopalatine ganglion stimulation, are emerging. This article reviews the current state of clinical research for neurostimulation techniques for chronic cluster headache, and particularly the pros and cons of SCS and ONS.

Cerebellar and cerebral autoregulation in migraine.

BACKGROUND AND PURPOSE: Silent ischemic brain lesions frequently occur in migraine with aura and are most often located in cerebellar border zones. This may imply an impairment of cerebellar blood flow autoregulation. This study investigated the characteristics of interictal cerebellar autoregulation in migraine with and without aura. METHODS: Thirty-four patients (n=17, migraine without aura; n=17, migraine with aura) and 35 age- and sex-matched controls were studied. Triple simultaneous transcranial Doppler monitoring of one posterior inferior cerebellar artery, right posterior cerebral artery, and left middle cerebral artery was performed. Autoregulation dynamics were assessed from spontaneous blood pressure fluctuations (correlation coefficient index Dx) and from respiratory-induced 0.1-Hz blood pressure oscillations (phase and gain). RESULTS: Compared with controls, the autoregulatory index Dx was higher (indicating less autoregulation) in the posterior inferior cerebellar artery (P=0.0062) and middle cerebral artery (P=0.0078) in migraine with aura, but not in migraine without aura. Phase and gain did not significantly differ between migraine patients and controls. No significant associations of autoregulation with clinical factors were found, including frequency of migraine attacks and orthostatic intolerance. CONCLUSIONS: This first-time analysis of cerebellar autoregulation in migraine did not show a specific cerebellar dysautoregulation in the interictal period. More static autoregulatory properties (index Dx) are, however, impaired in persons with migraine with aura both in the cerebellar and anterior circulation. The cerebellar predilection of ischemic lesions in migraine with aura might be a combination of altered autoregulation and additional factors, such as the end artery cerebellar angioarchitecture.

Habituation of the nociceptive blink reflex in episodic and chronic cluster headache.

BACKGROUND: Analysis of habituation patterns in patients with primary headache disorders allows the detection of changes to the excitability level of the trigeminal nociceptive system. Previous studies demonstrated a habituation deficit to painful stimuli in migraine and it was suggested that similar observations could be made in cluster headache (CH). METHODS: Habituation of the "nociceptive" blink reflex (nBR) (R2 response) was studied in 66 CH patients (18 episodic CH inside bout, 28 episodic CH outside bout, 20 chronic CH) as well as in 30 healthy controls in a case-control study design. RESULTS: Habituation behaviour was similar in CH and healthy controls as well as in CH subtypes. No side-to-side differences of habituation between headache side and non-headache side were detected. CONCLUSION: Our results did not detect an altered habituation in CH patients. Despite clinical similarities, migraine and CH seem not to share the same pathophysiological mechanisms in this regard.

High cervical spinal cord stimulation for chronic cluster headache.

BACKGROUND: Cluster headache (CH) is the most painful and debilitating primary headache syndrome. Conventional treatment combines acute and prophylactic drugs. Also with maximal therapy a substantial proportion of patients do not experience a meaningful prevention or pain relief. Recent case series and early trials have suggested that occipital nerve stimulation can be very effective in the management of intractable CH. METHODS: Seven patients with medically intractable chronic cluster headache were implanted with high cervical epidural electrodes. After a median test phase of 10 days (range 4-19 days) an impulse generator was implanted subcutaneously. Mean follow up was 23 months (median 12 months, range 3-78 months). RESULTS: All patients showed significant treatment effects. In all patients, improvement occurred immediately after electrode implantation. The mean attack frequency decreased, as well as the mean duration and intensity of attacks. Also, depression, anxiety, and pain-related impairment scores decreased and medication intake was markedly reduced. CONCLUSIONS: In this prospective series, high cervical spinal cord stimulation shows an effect size equal or larger than occipital nerve stimulation with immediate onset after surgery and may serve as a valuable additional treatment option of intractable cluster headache in the future.

Nociceptive blink reflex and pain-related evoked potentials in hypnic headache.

BACKGROUND: Central facilitation of trigeminal pain processing and deficient habituation was observed in different headache and facial pain disorders. This overactivation seems to be primarily associated with chronic pain states. OBJECTIVE: To investigate the function of the trigeminal nociceptive system in patients with hypnic headache (HH). METHODS: Fifteen HH patients according International Classification of Headache Disorders II criteria and 15 age- and gender-matched healthy controls were investigated using the nociceptive blink reflex (nBR) and trigeminal pain-related evoked potentials (PREP). RESULTS: nBR and PREP responses showed no significant differences comparing HH patients and healthy controls. Moreover, no habituation deficit was detected in HH patients. CONCLUSION: Central facilitation and change in habituation do not seem to be a crucial part in the pathophysiology of HH despite the chronic nature of this disease. Facilitation or habituation deficit does not seem to be exclusively related to chronic pain disorders in general. Further research is needed to illuminate the pathophysiology of HH.

Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Prednisone is commonly used for initial short-term therapy of episodic cluster headaches before preventive medication such as verapamil becomes effective, but this strategy has not been tested in large randomised trials. We aimed to access the safety and efficacy of this treatment approach. METHODS: This study was a multicentre, randomised, double-blind, placebo-controlled trial done in ten specialised headache centres in Germany. Patients with episodic cluster headaches who were aged between 18 and 65 years and within a current pain episode for not more than 30 days, received 100 mg oral prednisone for 5 days followed by tapering of 20 mg every 3 days, or matching placebo (17 days total exposure). All patients received oral verapamil for long-term prevention, starting with 40 mg three times daily and increasing to 120 mg three times daily by day 19; patients then continued with verapamil 120 mg throughout the study. Randomisation was computer-generated at a 1:1 ratio by use of an interactive web-response system, with stratification according to age, sex, and participating site. Participants, investigators, and those assessing outcomes were unaware of treatment allocation. The primary endpoint was the mean number of attacks within the first week of treatment with prednisone compared with placebo. An attack was defined as a unilateral headache with moderate-to-severe intensity of at least five on a numerical rating scale. All efficacy and safety analyses were done in the modified intention-to-treat (mITT) population, which consisted of all patients who had been randomly assigned to a trial group and received at least one dose of prednisone or placebo. The study was stopped early due to slow recruitment and expired funding. The study was registered with EudraCT (2011-006204-13) and with the German Clinical Trials Register (DRKS00004716). FINDINGS: Between April 5, 2013, and Jan 11, 2018, 118 patients were enrolled in the study. Two patients dropped out immediately and 116 patients were randomly assigned (57 patients to prednisone and 59 patients to placebo); 109 patients were included in the mITT analysis (53 patients assigned to prednisone and 56 patients assigned to placebo). Participants in the prednisone group had a mean of 7·1 (SD 6·5) attacks within the first week compared with 9·5 (6·0) attacks in the placebo group (difference -2·4 attacks, 95% CI -4·8 to -0·03; p=0·002). Two serious adverse events occurred, both in the placebo group (inguinal hernia and severe deterioration of cluster headache). A total of 270 adverse events were observed: in the prednisone group, 37 (71%) of 52 patients reported 135 adverse events (most common were headache, palpitations, dizziness, and nausea) and in the placebo group, 39 (71%) of 55 patients had 135 adverse events (most common were nausea, dizziness, and headache). INTERPRETATION: Oral prednisone was an effective short-term preventive therapy in our population of patients with episodic cluster headache. Our findings support the use of prednisone as a first-line treatment in parallel to the up-titration of verapamil, although the efficacy of prednisone alongside other long-term prevention requires additional investigation. FUNDING: German Federal Ministry for Education and Research.

Is Mindfulness-Based Stress Reduction a Promising and Feasible Intervention for Patients Suffering from Migraine? A Randomized Controlled Pilot Trial.

AIM: We performed a pilot study in order to evaluate the feasibility and to estimate effect sizes of mindfulness-based stress reduction (MBSR) in a sample of patients suffering from migraine. METHOD: Migraine patients (n = 62, mean age 44 years, 92% female) were randomly allocated to either MBSR or an active control intervention based on progressive muscle relaxation and psychoeducation. The primary outcome was the number of migraine days per month assessed by headache diaries covering one month before and one month after the intervention. Secondary outcomes included functional impairment, use of medication, psychological symptoms, quality of life, pain acceptance, pain self-efficacy, pain perception and self-attributed mindfulness. To measure feasibility, questionnaires assessing study compliance and contentment were administered. RESULTS: The primary outcome migraine frequency showed no significant group difference. Compared to the control group, the MBSR group showed greater improvements in variables of psychological symptoms, pain self-efficacy and sensory pain perception. Within the MBSR condition, all variables showed significant improvements over the course span with effect sizes ranging from d = 0.37 to 0.81, apart from the primary outcome (27% reduction in migraine days, p = 0.07). Compliance and contentment rates were good, supporting the feasibility of the MBSR intervention. CONCLUSION: Overall, participants in the MBSR group showed more adaptive coping strategies and decreased levels of psychological impairment compared to the control group, indicating a reduced impact of migraine on their everyday lives. It is concluded that this feasibility study demonstrates the ability of mindfulness-based interventions to reduce suffering in patients with migraine.

Temporal summation of trigeminal pain in human anterior cingulate cortex.

Temporal summation of nociceptive inputs in trigeminal networks can induce central sensitization and maintain chronic pain. We combined functional magnetic resonance imaging and electrically evoked pain-related potentials (PREP) in healthy human subjects to identify brain regions involved in temporal summation of nociceptive inputs. We stimulated the skin innervated by the ophthalmic division of the trigeminal nerve with trains of three, seven and eleven similar nociceptive pulses, while recording evoked hemodynamic or electrical brain responses. We found that PREP amplitudes and pain ratings increased in parallel with increasing train length. Strikingly, only hemodynamic responses in the posterior part of the anterior cingulate cortex (pACC) scaled with individual pain ratings on a verbal rating scale (VRS) and electrically evoked responses (i.e., PREP amplitudes for the three train lengths). These findings indicate that pACC codes temporal summation of trigeminal nociception and in this regard may be important for the development of central sensitization observed in chronic head and facial pain.

Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy.

The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine-guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.

Practical management of medication-overuse headache.

Epidemiological studies suggest that medication-overuse as defined by the International Headache Society is extremely common in patients with chronic daily headache. If all medication-overuse produces medication-overuse headache (MOH) in headache patients, it would be the third most frequent form of headache, after tension-type headache and migraine. Treatment of MOH is hindered by the absence of placebo-controlled, double-blind, randomised clinical trials. Nevertheless, several headache centers worldwide have developed expertise in the treatment of this syndrome, and have been quite successful. Here, we summarize available data on MOH, including clinical features, drugs used in withdrawal, as well as withdrawal strategies that have been described in the literature. We also include a detailed description of an in-patient and out-patient withdrawal procedure, reflecting personal experience and opinion of the authors.

P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine?

The discovery of mis-sense mutations in the alpha1A subunit of the P/Q-type calcium channel in patients with familial hemiplegic migraine indicates the potential involvement of dysfunctional ion channels in migraine. The periaqueductal gray (PAG) region of the brainstem modulates craniovascular nociception and, through its role in the descending pain modulation system, may contribute to migraine pathophysiology. In this study we sought to investigate the possible link between the genetic mutations found in migraineurs and the PAG as a modulator of craniovascular nociception. We microinjected the P/Q-type calcium-channel blocker omega-agatoxin IVA into the rat ventrolateral PAG (vlPAG). We examined its effect on the nociceptive transmission of second-order neurons recorded in the trigeminal nucleus caudalis and activated by stimulation of the parietal dura mater. After injection of agatoxin into the vlPAG (n = 20) responses to dural stimulation were facilitated by 143% (p < 0.0001) for Adelta-fiber activity and 180% for C-fiber activity (p < 0.05). Similarly, spontaneous background activity increased by 163% (p < 0.0001). These results demonstrate that P/Q-type calcium channels in the PAG play a role in modulating trigeminal nociception and suggest a role for dysfunctional P/Q-type calcium channels in migraine pathophysiology.

A positron emission tomographic study in spontaneous migraine.

BACKGROUND: Functional brain imaging in acute migraine has proved challenging because of the logistic problems associated with an episodic condition. Since the seminal observation of brainstem activation in migraine, there has been only a single case substantiating this finding. OBJECTIVE: To test the hypothesis that brainstem activation could be detected in migraine and to refine the anatomic localization with higher-resolution positron emission tomography than previously used. DESIGN: Using positron emission tomography with radioactive water (H(2)15O), we studied acute migraine attacks occurring spontaneously. Five patients underwent imaging in ictal and interictal states, and the differences were analyzed by means of statistical parametric mapping. SETTING: Tertiary referral center. PATIENTS: Six volunteers with episodic migraine were recruited from advertisements in migraine newsletters. One patient was excluded because of use of preventive medication. MAIN OUTCOME MEASURE: Brainstem activation during migraine state vs interictal state. RESULTS: Two patients had a typical migrainous aura before the onset of the headache. All of the attacks studied fulfilled standard diagnostic criteria for migraine. Comparing the migraine scans with interictal scans, there was significant activation in the dorsal pons, lateralized to the left (small volume correction, P = .003). Activation was also seen in the right anterior cingulate, posterior cingulate, cerebellum, thalamus, insula, prefrontal cortex, and temporal lobes. There was an area of deactivation in the migraine phase also located in the pons, lateralized to the right. CONCLUSIONS: Our findings provide clear evidence of dorsal pontine activation in migraine and reinforce the view that migraine is a subcortical disorder modulating afferent neural traffic.

Is the R3 component of the human blink reflex nociceptive in origin?

The R3 component of the blink reflex can reproducibly be evoked by noxious stimulation but can probably also be elicited by innocuous stimuli. This study was conducted to investigate the contribution of nociceptive A delta and C fibers to the generation of the electrically evoked R3 blink reflex. Electrical thresholds for detection, pain and all blink reflex components were determined and the modulatory effects of local anesthesia were investigated. The electrical R3 threshold of 4.6 +/- 0.5 mA (mean +/- SE) corresponded to 2.9 times the detection threshold and to 0.35 times the pain threshold. The R3 threshold was significantly below the pain threshold. Under local anesthesia of the supraorbital skin with a complete loss of warm and cold sensation, a loss of pinprick sensation, but a normal detection of tactile stimuli, the electrical pain threshold increased, all other thresholds remained unchanged. Under local anesthesia none of the reflex components were significantly reduced. Cutaneous A beta fibers and nociceptive A delta fibers, but not unmyelinated C fibers, contribute to the generation of the electrically evoked R3 component. According to the recruitment order in peripheral sensory nerves the electrical threshold of the R3 is mainly determined by activation of A beta fibers. Thus, it can not be assumed that the electrically evoked R3 is an adequate model to investigate nociceptive processing.

Symptomatic migraine and sensitization of trigeminal nociception associated with contralateral pontine cavernoma.

A 38-year-old woman is described with symptomatic strictly right-sided migraine associated with a pontine cavernoma affecting the contralateral (left) nucleus raphe magnus. A persistent facilitation of the right-sided trigeminal nociception was detected interictally using the 'nociception specific' blink reflex, which was more pronounced during the acute attack. This case shows for the first time, an impairment of the anti-nociceptive brainstem nuclei and the facilitation of the trigeminal nociception in the same subject, thus providing further evidence for the key role of the brainstem raphe nuclei in the pathophysiology of migraine.

The role of histamine in dural vessel dilation.

The pain of migraine is often throbbing suggesting an important role for the cranial blood vessels and their innervation by the trigeminal nerve. It is proposed that clinically effective anti-migraine compounds, such as 5-HT(1B/1D) agonists, have actions that include inhibiting calcitonin gene-related peptide (CGRP) release from trigeminal nerves. Human studies suggest that histamine can induce migraine possibly by activating nitric oxide (NO) synthase to promote endogenous NO production. The present studies investigated the effect of histamine and its antagonists on the cranial blood vessels using intravital microscopy to assess directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. Histamine infusion caused immediate and reproducible dilation of meningeal blood vessels (103.5+/-6%; n=40) that could be blocked by H(1)- (mepyramine) and H(2) (famotidine)-receptor antagonists (P<0.05), as well as a nitric oxide synthase inhibitor (N(G)-nitro-L-arginine methylester; P<0.05). Neurogenic dural vasodilation was not inhibited by H(2)-receptor antagonists, but was significantly inhibited by a H(1)-receptor antagonist at the high dose of 10 mg/kg. The present studies demonstrate that histamine is likely to activate NO synthase to promote NO production. There is also evidence that H(1)-receptors may be present on trigeminal neurones as the H(1)-receptor antagonist inhibited neurogenic vasodilation, albeit at a large dose.

The effect of anti-migraine compounds on nitric oxide-induced dilation of dural meningeal vessels.

Migraine is characteristically accompanied by a throbbing quality of head pain thought to involve trigeminovascular afferents. Administration of nitric oxide (NO) donors provides the most reliable model of migraine induction in humans. The present studies used intravital microscopy to monitor the effect of local meningeal nerve stimulation and NO on dural blood vessels and any modulation of that effect by anti-migraine compounds. NO caused an immediate and reproducible dilation of meningeal blood vessels that was partially blocked by sumatriptan and indomethacin, while flunarizine and histamine H(1) and H(2) receptor antagonists were unable to block the dilation. Indomethacin also inhibited the neurogenic dilation while flunarizine did not. The present studies demonstrate that NO is unlikely to interact with histamine to produce its dilatory response. Sumatriptan and indomethacin inhibit the NO response by inhibiting trigeminal activation and calcitonin gene-related peptide (CGRP) release. Flunarizine does not modify either the neurogenic vasodilator response or the NO meningeal dilator response at least acutely.

Sensory information processing may be neuroenergetically more demanding in migraine patients.

Electrophysiological studies of stimulus-evoked brain activation suggest that sensory processing in migraine patients is abnormal between attacks. The main findings are increased amplitudes and decreased habituation of cortical evoked potentials. Recent findings in healthy individuals showed that evoked potentials result mainly from phase resetting of background electroencephalographic activity. We recorded single trial visual evoked potentials during repetitive visual stimulation in migraine patients and healthy controls and analyzed these in the frequency domain for amplitude and phase. Increases in visual evoked potential amplitudes in migraine patients are explained almost entirely by increases in local amplitude, rather than increases in phase synchrony across trials. As amplitude modulation is generally considered more energy demanding than phase synchronization, this may explain the increased vulnerability of migraine patients to sensory stressors and the effectiveness of drugs that reduce evoked potential amplitudes or enhance aerobic energy metabolism.

A randomized controlled trial of intranasal ketamine in migraine with prolonged aura.

OBJECTIVE: The aim of our study was to test the hypothesis that ketamine would affect aura in a randomized controlled double-blind trial, and thus to provide direct evidence for the role of glutamatergic transmission in human aura. METHODS: We performed a double-blinded, randomized parallel-group controlled study investigating the effect of 25 mg intranasal ketamine on migraine with prolonged aura in 30 migraineurs using 2 mg intranasal midazolam as an active control. Each subject recorded data from 3 episodes of migraine. RESULTS: Eighteen subjects completed the study. Ketamine reduced the severity (p = 0.032) but not duration of aura in this group, whereas midazolam had no effect. CONCLUSIONS: These data provide translational evidence for the potential importance of glutamatergic mechanisms in migraine aura and offer a pharmacologic parallel between animal experimental work on cortical spreading depression and the clinical problem. CLASSIFICATION OF EVIDENCE: This study provides class III evidence that intranasal ketamine is effective in reducing aura severity in patients with migraine with prolonged aura.