Central effects of erenumab in migraine patients: An event-related functional imaging study.

OBJECTIVE: To determine whether erenumab, a new monoclonal antibody to the calcitonin gene-related peptide (CGRP) receptor, exerts functional central effects in migraineurs by performing functional imaging scans on patients treated with erenumab. METHODS: We conducted an fMRI study on 27 patients with migraine using a well-established trigeminal nociceptive paradigm, examining patients before and 2 weeks after administration of the CGRP receptor antibody erenumab 70 mg. RESULTS: Comparing both visit days in all patients (n = 27) revealed that erenumab leads to a decrease in activation in the right thalamus (i.e., contralateral to the stimulated side), right middle temporal gyrus, right lingual gyrus, left operculum, and several clusters on both sides of the cerebellum. Furthermore, when responders (n = 9) and nonresponders (n = 8) of the respective same headache state were compared, we found a significant reduction of hypothalamic activation after the administration of erenumab in responders only (t = 4.78; contrast estimate 29.79 [90% confidence interval 19.53-40.05]). This finding of reduced hypothalamic activation was confirmed when absolute headache days was used as a regressor. INTERPRETATION: These findings suggest that erenumab may not be an exclusively peripheral migraine treatment but has additional central effects. Whether this is due to secondary changes after peripheral modulation of sensory input or indeed represents a direct central mode of action is discussed.

Phase dependent hypothalamic activation following trigeminal input in cluster headache.

BACKGROUND: Task-free imaging approaches using PET have shown the posterior hypothalamus to be specifically activated during but not outside cluster headache attacks. Evidence from task related functional imaging approaches however is scarce. METHODS: Twenty-one inactive cluster headache patients (episodic cluster headache out of bout), 16 active cluster headache patients (10 episodic cluster headache in bout, 6 chronic cluster headache) and 18 control participants underwent high resolution brainstem functional magnetic resonance imaging of trigeminal nociception using gaseous ammonia as a painful stimulus. RESULTS: Following trigeminonociceptive stimulation with ammonia there was a significantly stronger activation within the posterior hypothalamus in episodic cluster headache patients out of bout when compared to controls. When contrasting estimates of the pain contrast, active cluster headache patients where in between the two other groups but did not differ significantly from either. CONCLUSION: The posterior hypothalamus might thus be hyperexcitable in cluster headache patients outside the bout while excitability to external nociceptive stimuli decreases during in bout periods, probably due to frequent hypothalamic activation and possible neurotransmitter exhaustion during cluster attacks.

Longitudinal Neuroimaging over 30 Days: Temporal Characteristics of Migraine.

OBJECTIVE: Although migraine is defined by the headache and headache-associated symptoms, the true beginning of a migraine attack lies in the premonitory phase. To understand the generation of attacks, one needs to investigate the phase before headache starts. The premonitory phase of migraine is characterized by a well-described complex of symptoms. Its duration, however, is not clearly defined, and there are no biomarkers to help define when this phase starts. METHODS: Here, we used functional magnetic resonance imaging (MRI) to elucidate the duration of the premonitory phase in spontaneous human migraine attacks. Because migraine attacks are hardly predictable and thereby the premonitory phase is difficult to catch, we scanned 9 patients daily over a minimum period of 30 days using a well-established paradigm for functional MRI of trigeminal nociception. RESULTS: Seven patients were included in the analysis, thus providing cumulative data of 27 spontaneous human migraine attacks including scans before, during, and after migraine pain as well as interictal scans. As a response to painful trigeminal stimulation, activation of the hypothalamus was present within the last 48 hours before headache onset but not earlier. INTERPRETATION: Using hypothalamic activation as a potential marker for the premonitory phase of migraine in this unique dataset, our data corroborated a duration of 48 hours for the premonitory phase of migraine. We suggest applying this time criterion in future studies when focusing on this phase of the migraine cycle. ANN NEUROL 2020;87:646-651.

Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: An fMRI study.

OBJECTIVE: The trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex. METHODS: Twenty-one healthy participants were included in a 2-day, randomized, single-blind, within-subject design. The reflex was activated inside the MRI scanner using kinetic oscillation stimulation placed in the left nostril, resulting in an increase in lacrimation. After the first fMRI session, the participants received either sham vagus nerve stimulation or nVNS outside the scanner and underwent a subsequent fMRI session. RESULTS: nVNS prompted an increase in activation of the left pontine nucleus and a decreased activation of the right parahippocampal gyrus. Psychophysiologic interaction analyses revealed an increased functional connectivity between the left pontine nucleus and the right hypothalamus and a decreased functional connectivity between the right parahippocampal gyrus and the bilateral spinal trigeminal nuclei (sTN). CONCLUSIONS: These findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

Hypothalamic activation discriminates painful and non-painful initiation of the trigeminal autonomic reflex - an fMRI study.

BACKGROUND: The role of the trigeminal autonomic reflex in headache syndromes, such as cluster headache, is undisputed but sparsely investigated. The aim of the present study was therefore, to identify neural correlates that play a role in the initiation of the trigeminal autonomic reflex. We further aimed to discriminate between components of the reflex that are involved in nociceptive compared to non-nociceptive processing. METHODS: Kinetic Oscillation Stimulation (KOS) in the left nostril was applied in order to provoke autonomic symptoms (e.g. lacrimation) via the trigeminal autonomic reflex in 26 healthy participants using functional magnetic resonance imaging. Unpleasantness and painfulness were assessed on a visual analog scale (VAS), in order to assess the quality of the stimulus (e.g. pain or no pain). RESULTS: During non-painful activation, specific regions involved in the trigeminal autonomic reflex became activated, including several brainstem nuclei but also cerebellar and bilateral insular regions. However, when the input leading to activation of the trigeminal autonomic reflex was perceived as painful, activation of the anterior hypothalamus, the locus coeruleus (LC), the ventral posteriomedial nucleus of the thalamus (VPM), as well as an activation of ipsilateral insular regions, was observed. CONCLUSION: Our results suggest the anterior hypothalamus, besides the thalamus and specific brain stem regions, play a significant role in networks that mediate autonomic output (e.g. lacrimation) following trigeminal input, but only if the trigeminal system is activated by a stimulus comprising a painful component.

Hypothalamic regulation of headache and migraine.

BACKGROUND: The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine. FINDINGS: This has been intensely discussed in the last decades and the advent of modern imaging studies refined the involvement of rostral parts of the pons in acute migraine attacks, but more importantly suggested a predominant role of the hypothalamus and alterations in hypothalamic functional connectivity shortly before the beginning of migraine headaches. This was shown in the NO-triggered and also in the preictal stage of native human migraine attacks. Another headache type that is clinically even more suggestive of hypothalamic involvement is cluster headache, and indeed a structure in close proximity to the hypothalamus has been identified to play a crucial role in attack generation. CONCLUSION: It is very likely that spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in susceptibility thresholds that ultimately start but also terminate headache attacks. We will review clinical and neuroscience evidence that puts the hypothalamus in the center of scientific attention when attack generation is discussed.

Neuromodulation for the treatment of primary headache syndromes.

INTRODUCTION: Neuromodulation techniques play an increasing role in the treatment of primary headaches. While initially reserved for refractory cases they are now increasingly taken into consideration in earlier treatment phases and in non-refractory situations. One of the main reasons for this paradigm shift is that most neuromodulation techniques are better tolerated as compared to the majority of pharmacological approaches. However, these techniques have their limitations that should be considered. Areas covered: The review provides an overview of the available techniques and their therapeutic rationale as well as on the evidence for their efficacy and their limitations. The review covers these aspects for non-invasive vagal nerve stimulation, sphenopalatine ganglion stimulation, external trigeminal nerve stimulation, occipital nerve stimulation as well as single-pulse and repetitive-pulse transcranial magnetic stimulation. Expert commentary: Most of the evidence is based on open-label studies. Sham devices used in controlled studies remain problematic as they either do not produce the paresthesias perceived during stimulation or induce some degree of stimulation. Invasive techniques require a surgical intervention with all the potential complications that may arise. In summary, some of the techniques provide an effective expansion of available treatment options but their indication should be thoroughly evaluated before treatment is considered.

Cluster headache.

Cluster headache is an excruciating, strictly one-sided pain syndrome with attacks that last between 15 minutes and 180 minutes and that are accompanied by marked ipsilateral cranial autonomic symptoms, such as lacrimation and conjunctival injection. The pain is so severe that female patients describe each attack as worse than childbirth. The past decade has seen remarkable progress in the understanding of the pathophysiological background of cluster headache and has implicated the brain, particularly the hypothalamus, as the generator of both the pain and the autonomic symptoms. Anatomical connections between the hypothalamus and the trigeminovascular system, as well as the parasympathetic nervous system, have also been implicated in cluster headache pathophysiology. The diagnosis of cluster headache involves excluding other primary headaches and secondary headaches and is based primarily on the patient's symptoms. Remarkable progress has been achieved in developing effective treatment options for single cluster attacks and in developing preventive measures, which include pharmacological therapies and neuromodulation.

Sphenopalatine ganglion stimulation for cluster headache, results from a large, open-label European registry.

BACKGROUND: Cluster headache (CH) is a disabling primary headache disorder characterized by severe periorbital pain. A subset of patients does not respond to established pharmacological therapy. This study examines outcomes of a cohort of mainly chronic CH patients treated with sphenopalatine ganglion (SPG) stimulation. METHODS: Patients were followed in an open-label prospective study for 12 months. Ninety-seven CH patients (88 chronic, 9 episodic) underwent trans-oral insertion of a microstimulator targeting the SPG. Patients recorded stimulation effect prospectively for individual attacks. Frequency, use of preventive and acute medications, headache impact (HIT-6) and quality of life measures (SF-36v2) were monitored at clinic visits. Per protocol, frequency responders experienced ≥ 50% reduction in attack frequency and acute responders treated ≥ 50% of attacks. HIT-6 responders experienced an improvement ≥ 2.3 units and SF-36 responders ≥ 4 units vs. baseline. RESULTS: Eighty-five patients (78 chronic, 7 episodic) remained implanted and were evaluated for effectiveness at 12 months. In total, 68% of all patients were responders, 55% of chronic patients were frequency responders and 32% of all patients were acute responders. 67% of patients using acute treatments were able to reduce the use of these by 52% and 74% of chronic patients were able to stop, reduce or remain off all preventive medications. 59% of all patients were HIT-6 responders, 67% were SF-36 responders. CONCLUSIONS: This open-label registry corroborates that SPG stimulation is an effective therapy for CH patients providing therapeutic benefits and improvements in use of medication as well as headache impact and quality of life.

The enigma of site of action of migraine preventives: no effect of metoprolol on trigeminal pain processing in patients and healthy controls.

BACKGROUND: Beta-blockers are a first choice migraine preventive medication. So far it is unknown how they exert their therapeutic effect in migraine. To this end we examined the neural effect of metoprolol on trigeminal pain processing in 19 migraine patients and 26 healthy controls. All participants underwent functional magnetic resonance imaging (fMRI) during trigeminal pain twice: Healthy subjects took part in a placebo-controlled, randomized and double-blind study, receiving a single dose of metoprolol and placebo. Patients were examined with a baseline scan before starting the preventive medication and 3 months later whilst treated with metoprolol. RESULTS: Mean pain intensity ratings were not significantly altered under metoprolol. Functional imaging revealed no significant differences in nociceptive processing in both groups. Contrary to earlier findings from animal studies, we did not find an effect of metoprolol on the thalamus in either group. However, using a more liberal and exploratory threshold, hypothalamic activity was slightly increased under metoprolol in patients and migraineurs. CONCLUSIONS: No significant effect of metoprolol on trigeminal pain processing was observed, suggesting a peripheral effect of metoprolol. Exploratory analyses revealed slightly enhanced hypothalamic activity under metoprolol in both groups. Given the emerging role of the hypothalamus in migraine attack generation, these data need further examination.

Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration.

Migraine is the sixth most common cause of disability in the world. Preventive migraine treatment is used to reduce frequency, severity and duration of attacks and therefore lightens the burden on the patients' quality of life and reduces disability. Topiramate is one of the preventive migraine treatments of proven efficacy. The mechanism of action underlying the preventive effect of topiramate in migraine remains largely unknown. Using functional magnetic resonance imaging (fMRI) we examined the central effects of a single dose of topiramate (100mg) on trigeminal pain in humans, compared to placebo (mannitol). In this prospective, within subject, randomized, placebo-controlled and double-blind study, 23 healthy participants received a standardized nociceptive trigeminal stimulation and control stimuli whilst being in the scanner. No differences in the subjective intensity ratings of the painful stimuli were observed between topiramate and placebo sessions. In contrast, topiramate significantly decreased the activity in the thalamus and other pain processing areas. Additionally, topiramate increased functional coupling between the thalamus and several brain regions such as the bilateral precuneus, posterior cingulate cortex and secondary somatosensory cortex. These data suggest that topiramate exhibits modulating effects on nociceptive processing in thalamo-cortical networks during trigeminal pain and that the preventive effect of topiramate on frequent migraine is probably mediated by an effect on thalamo-cortical networks.

Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging.

Due to the clinical picture and also based on early imaging data (Weiller et al. Nat Med 1:658-660, 1995), the brainstem and midbrain structures have been intensely discussed as possible driving or generating structures in migraine. The fact that the brainstem activation persisted after treatment makes it unlikely that this activation was only due to increased activity of the endogenous anti-nociceptive system. It was consequently (and somewhat simplifying) coined the "migraine generator". Since then several studies have focussed on this region when investigating episodic, but also chronic migraine. Denuelle et al. were the first to not only demonstrate significant activations in the midbrain and pons but also in the hypothalamus, which, just like the brainstem activation in the first study, persisted after headache relief with sumatriptan. Expanding these studies into f-MRI studies, refined the involvement of rostral parts of the pons in acute migraine attacks. However, they also focused on the preictal stage of NO-triggered and native human migraine attacks and suggested a predominant role of the hypothalamus shortly before the beginning of migraine headaches as well as alterations in hypothalamic functional connectivity. Additionally, changes in resting-state functional connectivity of the dorsal pons and the hypothalamus in interictal migraineurs has recently been found. The pathophysiology and genesis of migraine attacks is probably not just the result of one single "brainstem generator". Spontaneous oscillations of complex networks involving the hypothalamus, brainstem, and dopaminergic networks lead to changes in activity in certain subcortical and brainstem areas, thus changing susceptibility thresholds and not only starting but also terminating headache attacks.

Hypothalamus as a mediator of chronic migraine: Evidence from high-resolution fMRI.

OBJECTIVE: To identify pathophysiologic mechanisms of migraine chronification using a recently standardized protocol for high-resolution brainstem imaging of trigeminal nociceptive stimulation. METHODS: Eighteen episodic migraineurs (EMs), 17 chronic migraineurs (CMs), and 19 healthy controls (HCs) underwent painful ammonia stimulation of the left nostril in a 3T MRI scanner. Functional images were acquired with a brainstem-optimized protocol for high-resolution echo-planar imaging. RESULTS: We detected a significantly stronger activation of the anterior right hypothalamus in CMs compared to HCs. To exclude the headache as a prime mediator of the hypothalamic activations, we compared all migraineurs with headaches (EMs and CMs) with all migraineurs without headaches (EMs and CMs) and HCs in a second analysis and found a more posterior region of the hypothalamus to be more activated bilaterally during headaches. CONCLUSIONS: Our data corroborate the fact that the hypothalamus plays a crucial role in the pathophysiology of migraine chronification and acute pain stage of migraineurs. While the more posterior part of the hypothalamus seems to be important for the acute pain stage, the more anterior part seems to play an important role in attack generation and migraine chronification.

Of generators, networks and migraine attacks.

PURPOSE OF REVIEW: One of the most discussed topics in migraine pathophysiology is where migraine attacks originate. Although recent evidence suggests central attack generating loci, there is an ongoing debate about the involved centres of the brain and brainstem. RECENT FINDINGS: Recent neuroimaging studies focussing on the preictal stage of migraine attacks suggest a predominant role of the hypothalamus and its functional connectivity shortly before the beginning of migraine headaches. In interictal migraineurs, changes in resting state functional connectivity of the dorsal pons and the hypothalamus have been found. SUMMARY: Based on the clinical presentation of the premonitory phase of migraine, the hypothalamus and changes within the dopaminergic system have been discussed as likely candidates for attack generation. Neuroimaging studies however suggested the dorsal pons as attack generator. Taking into account the recent findings of hypothalamic involvement and changing connectivity in the preictal stage, the available evidence suggests that the idea of a single migraine generator within the human brain is probably too simplistic. More likely, spontaneous oscillations of complex networks lead to activity changes in certain subcortical and brainstem areas. This in turn might constitute functional changes of descending pain-modulating pathways, and thus the generation of migraine pain.

Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache.

Objectives The sphenopalatine ganglion (SPG) plays a pivotal role in cluster headache (CH) pathophysiology as the major efferent parasympathetic relay. We evaluated the long-term effectiveness of SPG stimulation in medically refractory, chronic CH patients. Methods Thirty-three patients were enrolled in an open-label follow-up study of the original Pathway CH-1 study, and participated through 24 months post-insertion of a microstimulator. Response to therapy was defined as acute effectiveness in ≥ 50% of attacks or a ≥ 50% reduction in attack frequency versus baseline. Results In total, 5956 attacks (180.5 ± 344.8, range 2-1581 per patient) were evaluated. At 24 months, 45% ( n = 15) of patients were acute responders. Among acute responders, a total of 4340 attacks had been treated, and in 78% of these, effective therapy was achieved using only SPG stimulation (relief from moderate or greater pain or freedom from mild pain or greater). A frequency response was observed in 33% ( n = 11) of patients with a mean reduction of attack frequency of 83% versus baseline. In total, 61% (20/33) of all patients were either acute or frequency responders or both. The majority maintained their therapeutic response through the 24-month evaluation. Conclusions In the population of disabled, medically refractory chronic CH patients treated in this study, SPG stimulation is an effective acute therapy in 45% of patients, offering sustained effectiveness over 24 months of observation. In addition, a maintained, clinically relevant reduction of attack frequency was observed in a third of patients. These long-term data provide support for the use of SPG stimulation for disabled patients and should be considered after medical treatments fail, are not tolerated or are inconvenient for the patients.

Cluster headache attack remission with sphenopalatine ganglion stimulation: experiences in chronic cluster headache patients through 24 months.

BACKGROUND: Cluster headache (CH) is a debilitating headache disorder with severe consequences for patient quality of life. On-demand neuromodulation targeting the sphenopalatine ganglion (SPG) is effective in treating the acute pain and a subgroup of patients experience a decreased frequency of CH attacks. METHODS: We monitored self-reported attack frequency, headache disability, and medication intake in 33 patients with medically refractory, chronic CH (CCH) in an open label follow-up study of the original Pathway CH-1 study. Patients were followed for at least 24 months (average 750 ± 34 days, range 699-847) after insertion of an SPG microstimulator. Remission periods (attack-free periods exceeding one month, per the ICHD 3 (beta) definition) occurring during the 24-month study period were characterized. Attack frequency, acute effectiveness, medication usage, and questionnaire data were collected at regular clinic visits. The time point "after remission" was defined as the first visit after the end of the remission period. RESULTS: Thirty percent (10/33) of enrolled patients experienced at least one period of complete attack remission. All remission periods followed the start of SPG stimulation, with the first period beginning 134 ± 86 (range 21-272) days after initiation of stimulation. On average, each patient's longest remission period lasted 149 ± 97 (range 62-322) days. The ability to treat acute attacks before and after remission was similar (37 % ± 25 % before, 49 % ± 32 % after; p = 0.2188). Post-remission headache disability (HIT-6) was significantly improved versus baseline (67.7 ± 6.0 before, 55.2 ± 11.4 after; p = 0.0118). Six of the 10 remission patients experienced clinical improvements in their preventive medication use. At 24 months post insertion headache disability improvements remained and patient satisfaction measures were positive in 100 % (10/10). CONCLUSIONS: In this population of 33 refractory CCH patients, in addition to providing the ability to treat acute attacks, neuromodulation of the SPG induced periods of remission from cluster attacks in a subset of these. Some patients experiencing remission were also able to reduce or stop their preventive medication and remissions were accompanied by an improvement in headache disability.

The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks.

Functional imaging using positron emission tomography and later functional magnetic resonance imaging revealed a particular brainstem area that is believed to be specifically activated in migraine during, but not outside of the attack, and consequently has been coined the 'migraine generator'. However, the pathophysiological concept behind this term is not undisputed and typical migraine premonitory symptoms such as fatigue and yawning, but also a typical association of attacks to circadian and menstrual cycles, all make the hypothalamus a possible regulating region of migraine attacks. Neuroimaging studies investigating native human migraine attacks however are scarce and for methodological but also clinical reasons there are currently no studies investigating the last 24 h before headache onset. Here we report a migraine patient who had magnetic resonance imaging every day for 30 days, always in the morning, to cover, using functional imaging, a whole month and three complete, untreated migraine attacks. We found that hypothalamic activity as a response to trigeminal nociceptive stimulation is altered during the 24 h prior to pain onset, i.e. increases towards the next migraine attack. More importantly, the hypothalamus shows altered functional coupling with the spinal trigeminal nuclei and the region of the migraine generator, i.e. the dorsal rostral pons during the preictal day and the pain phase of native human migraine attacks. These data suggest that although the brainstem is highly linked to the migraine biology, the real driver of attacks might be the functional changes in hypothalamo-brainstem connectivity.

Cost-effectiveness of stimulation of the sphenopalatine ganglion (SPG) for the treatment of chronic cluster headache: a model-based analysis based on the Pathway CH-1 study.

BACKGROUND: In the recent Pathway CH-1 study, on-demand stimulation of the sphenopalatine ganglion (SPG) by means of an implantable neurostimulation system was proven to be a safe and effective therapy for the treatment of chronic cluster headache. Our objective was to assess the cost-effectiveness of SPG stimulation in the German healthcare system when compared to medical management. METHODS: Clinical data from the Pathway CH-1 study were used as input for a model-based projection of the cost-effectiveness of SPG stimulation through 5 years. Medical management as the comparator treatment was modeled on the basis of clinical events observed during the baseline period of CH-1. The costs of treatment were derived from a previously published cluster headache costing study and 2014 medication, neurostimulator, and procedure costs. We computed the 5-year incremental cost-effectiveness ratio (ICER) in euros per quality-adjusted life year (QALY), with costs and effects discounted at 3 % per year. RESULTS: SPG stimulation was projected to add 0.325 QALYs over the study period, while adding €889 in cost, resulting in a 5-year ICER of €2,736 per QALY gained. Longer follow-up periods, higher baseline attack frequency, and higher utilization of attack-aborting medications led to overall cost savings. SPG stimulation was found either cost-effective or cost-saving across all scenarios investigated in sensitivity analyses. CONCLUSIONS: Our model-based analysis suggests that SPG stimulation for the treatment of chronic cluster headache, under the assumption of sustained therapy effectiveness, leads to meaningful gains in health-related quality of life and is a cost-effective treatment strategy in the German healthcare system.

Triptan-induced disruption of trigemino-cortical connectivity.

OBJECTIVE: The 5-HT1B/D agonists (triptans) are specific headache medications that have no effect on pain as such. Although they are routinely used in the treatment of acute migraine attacks, the underlying mechanisms of action are still a matter of debate. METHODS: Forty-three healthy participants underwent fMRI while receiving trigemino-nociceptive stimulation and control stimuli in a standardized fMRI paradigm. Using a crossover, double-blind, placebo-controlled design, 21 participants (10 women, mean age 26.9, range 20-37 years) received sumatriptan and 22 participants (11 women, mean age 25.5, range 22-32 years) received acetylsalicylic acid (ASA). Administration of medication and saline was randomized between participants of each group resulting in half of the participants receiving saline and the other half receiving the respective medication during the first fMRI data acquisition. RESULTS: While mean pain intensity ratings did not differ significantly between control and medication nor between medications, we found a significant blood oxygen level-dependent signal increase in the trigeminal nuclei and the thalamus after sumatriptan treatment compared with placebo or ASA. In addition, we specifically looked for the pharmacologic modulation of functional coupling between trigeminal nuclei and higher brain areas, i.e., trigemino-cortical pathways, and found a strong coupling during the saline condition, which was altered by sumatriptan but not after ASA administration. CONCLUSION: These data suggest that a specific functional inhibition of trigemino-cortical projections is one of the reasons that triptans, unlike pain killers, act highly specifically on headache and migraine but not pain as such.

Value of intra- and post-operative cone beam computed tomography (CBCT) for positioning control of a sphenopalatine ganglion neurostimulator in patients with chronic cluster headache.

INTRODUCTION: The objective of this study was to determine whether postoperative control of the neurostimulator placement within the pterygopalatine fossa (PPF) by means of 3-dimensional (3D) cone beam computed tomography (CBCT) was of therapeutic relevance compared to intraoperative CBCT imaging alone. MATERIAL AND METHODS: Immediately after implantation of the sphenopalatine ganglion (SPG) neurostimulator, intraoperative CBCT datasets were generated in order to visualize the position of the probe within the PPF. Postoperatively, all patients received a CBCT for comparison with intraoperatively acquired radiographs. RESULTS: Twenty-four patients with cluster headache (CH) received an SPG neurostimulator. In 4 patients, postoperative CBCT images detected misplacement not found in intraoperative CBCT. In 3 cases, electrode tips were misplaced into the maxillary sinus and in 1 case into the apex of the PPF superior to the suspected location of the SPG. Immediate revision with successful repositioning within 3 days was done in 2 patients and a deferred reimplantation in 1 patient within 6 months. One patient declined revision. CONCLUSION: We were able to demonstrate the clinical value of postoperative dental CBCT imaging with a wide region of interest (ROI) due to a superior image quality compared with that achieved with intraoperative medical CBCT. Although intraoperative 3D CBCT imaging of electrode placement is helpful in the acute surgical setting, resolution is, at present, too low to safely exclude misplacement, especially in the maxillary sinus. High-resolution postoperative dental CBCT allows rapid detection and revision of electrode misplacement, thereby avoiding readmission and recurrent tissue trauma.