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Fundamental to the concept of idiopathic or primary headache, including migraine, tension-type headache and cluster headache, is the currently accepted view that these conditions are due to abnormal brain function with completely normal brain structure 1 . Cluster headache is one such idiopathic headache with many similarities to migraine, including normal brain structure on magnetic resonance imaging and abnormal function in the hypothalamic grey matter by positron emission tomography 2 . Given the consistency of the positron emission tomography findings with the clinical presentation, we sought to assess whether the brains of such patients were structurally normal. We used voxel-based morphometry, an objective and automated method of analyzing changes in brain structure, to study the structure of the brains of patients with cluster headache. We found a co-localization of structural changes and changes in local brain activity with positron emission tomography in the same area of the brain in the same patients. The results indicate that the current view of the neurobiology of cluster headache requires complete revision and that this periodic headache is associated with a hitherto unrecognized brain abnormality in the hypothalamic region. We believe that voxel-based morphometry has the potential to change in the most fundamental way our concept of primary headache disorders, requiring a radical reappraisal of the tenet of structural normality.

Background. Tinnitus and headache are frequent disorders. Here, we aimed to investigate whether the occurrence of headache among tinnitus patients is purely coincidental or whether tinnitus and headache are pathophysiologically linked. We investigated a large sample of patients with tinnitus and headache to estimate prevalence rates of different headache forms, to determine the relationship between tinnitus laterality and headache laterality, and to explore the relationship between tinnitus and headache over time. Method. Patients who presented at a tertiary referral center because of tinnitus and reported comorbid headache were asked to complete validated questionnaires to determine the prevalence of migraine and tension-type headache and to assess tinnitus severity. In addition, several questions about the relationship between headache and tinnitus were asked. Results. Datasets of 193 patients with tinnitus and headache were analysed. 44.6% suffered from migraine, 13% from tension-type headache, and 5.7% from both. Headache laterality was significantly related to tinnitus laterality and in the majority of patients fluctuations in symptom severity of tinnitus and headache were interrelated. Conclusion. These findings suggest a significant relationship between tinnitus and headache laterality and symptom interaction over time and argue against a purely coincidental cooccurrence of tinnitus and headache. Both disorders may be linked by common pathophysiological mechanisms.

The aim of this study was to determine the relationship of high daily monosodium glutamate (MSG) consumption with glutamate concentrations in jaw muscle, saliva, and serum, and muscle pain sensitivity in healthy participants. A randomized, double-blinded, placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity. In five contiguous experimental daily sessions, 32 healthy participants drank MSG (150 mg/kg) or NaCl (24 mg/kg) diluted with a 400 mL soda. The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma samples on the first and last days. Saliva glutamate concentration was assessed every day. Pressure pain threshold, pressure pain tolerance, autonomic parameters (heart rate, systolic and diastolic blood pressures) and reported side effects also were assessed. No significant change was noted in the baseline concentration of glutamate in the masseter muscle, blood, or saliva, but the peak concentration in the masseter muscle increased significantly between day 1 and 5. A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed, as well as a significantly higher frequency of reports of nausea and headache in the MSG group. No robust effect of MSG on muscle sensitivity was found. Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man. •Baseline glutamate level in the masseter did not very significantly through 5 d.•Peak concentration in the masseter increased significantly between day 1 and 5.•No robust effect of monosodium glutamate on muscle sensitivity was found.•There was a significantly higher frequency of reports of nausea and headache in the monosodium glutamate group.

Abstract Medication overuse headache (MOH) is a prevalent secondary headache, bringing heavy economic burden and neuropsychological damage. Neuroimaging studies on the disease reported divergent results. To merge the reported neuroimaging alterations in MOH patients and explore a pathophysiological mechanism of this disorder. A meta-analytic activation likelihood estimation (ALE) analysis method was used. We systematically searched English and Chinese databases for both morphological and functional neuroimaging studies published before Nov 18, 2021. Reported altered brain regions and the stereotactic coordinates of their peaks were extracted and pooled by GingerALE using Gaussian probability distribution into brain maps, illustrating converged regions of alteration among studies. We identified 927 articles, of which five studies on gray matter changes, using voxel-based morphometry (VBM) were eventually included for ALE analysis, with 344 subjects and 54 coordinates put into GingerALE. No functional magnetic resonance imaging (fMRI) or positron emission topography (PET) studies were included for pooling. Compared with healthy controls (HCs), MOH featured increased gray matter density in midbrain, striatum, cingulate, inferior parietal cortex and cerebellum (P < 0.001 uncorrected), whereas decreased gray matter density in orbitofrontal cortex (P < 0.05, family-wise error), frontal, insular and parietal cortices (P < 0.001 uncorrected). Withdrawal of analgesics led to decreased gray matter density in superior temporal gyrus, cuneus, midbrain and cerebellum (P < 0.001 uncorrected). This meta-analysis confirmed that medication overuse headache is associated with morphologic alteration in the reward system, the prefrontal cortex and a reversible modification in the pain network. Further functional imaging paradigms and longitudinal studies are required for a more definite conclusion and a causal mechanism.

Pain is a common complication in patients with cystic fibrosis (CF) and is associated with shorter survival. We evaluated the impact of osteopathic manipulative treatment (OMT) on pain in adults with CF. A pilot multicenter randomized controlled trial was conducted with three parallel arms: OMT (group A, 16 patients), sham OMT (sham treatment, group B, 8 patients) and no treatment (group C, 8 patients). Medical investigators and patients were double-blind to treatment for groups A and B, who received OMT or sham OMT monthly for 6 months. Pain was rated as a composite of its intensity and duration over the previous month. The evolution of chest/back pain after 6 months was compared between group A and groups B+C combined (control group). The evolution of cervical pain, headache and quality of life (QOL) were similarly evaluated. There was no statistically significant difference between the treatment and control groups in the decrease of chest/back pain (difference = -2.20 IC95% [-4.81; 0.42], p = 0.098); also, group A did not differ from group B. However, chest/back pain decreased more in groups A (p = 0.002) and B (p = 0.006) than in group C. Cervical pain, headache and QOL scores did not differ between the treatment and control groups. This pilot study demonstrated the feasibility of evaluating the efficacy of OMT to treat the pain of patients with CF. The lack of difference between the group treated with OMT and the control group may be due to the small number of patients included in this trial, which also precludes any definitive conclusion about the greater decrease of pain in patients receiving OMT or sham OMT than in those with no intervention. ClinicalTrials.gov NCT01293019.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

BackgroundPostdural puncture headache (PDPH) is a relatively common acute complication that occurs following regional anesthesia and is among the clinical features of secondary intracranial hypotension syndrome (IHS).The aim of this study was to document the radiological findings specific to PDPH with brain MRI and to determine whether these findings differed from those described in the third edition of the International Headache Society’s International Classification of Headache Disorders (ICHD-3).MethodsThirty patients who were diagnosed with PDPH based on the ICHD-3 clinical criteria were enrolled in the study and signed the informed consent form approved by our hospital ethics committee. Their symptoms were recorded and they underwent brain MRI before and after the administration of a gadolinium-based contrast agent within 48–72 hours after the onset of their orthostatic headache.ResultsAll patients with PDPH presented with MRI features of pachymeningeal enhancement. The thickness of the pachymeningeal enhancement varied from 0.6 mm to 4.1 mm, with a mean of 1.6 mm+0.8.No cases of brain sagging were observed. 4 of the 30 patients presented with intracranial subdural fluid collections, 7 presented with pneumocephalus and 7 pituitary gland enlargement.ConclusionsThe radiological characteristics of IHS and PDPH are most likely the result of compensatory mechanisms in response to decreased cerebrospinal fluid pressure. The acute nature of PDPH probably causes its radiological MRI characteristics to differ from those of IHS, given that no brain sagging could be demonstrated.

Headache is very frequent in multiple sclerosis. However, the question whether headache is just coincidental or may be secondary due to inflammatory cerebral multiple sclerosis lesions is yet to be clarified. This study intended to evaluate the distribution of cerebral lesion sites and the potential presence of specific lesion clusters in patients with multiple sclerosis and comorbid headache using voxel-based lesion symptom mapping (VLSM). Patients with multiple sclerosis and headache were prospectively identified and included in a university neurological center between 2017 and 2023. Only patients with headache onset after first manifestation of multiple sclerosis were included. Demographic and clinical data were assessed, and lesion volumes calculated. Cerebral lesion sites were correlated voxel-wise with presence and absence of headache using non-parametric permutation testing. A cohort of multiple sclerosis patients served as controls for the VLSM-analysis. 48 multiple sclerosis patients with headache were included, as well as 92 controls without headache. Of the 48 patients with headache, 39 (81%) were female and nine (19%) were male. Mean age was significantly higher in headache patients than in controls (51 + / − 11 vs. 42 + / − 11 years, p < 0.05). EDSS, disease duration and lesion volumes did not significantly differ between both groups. Lesion overlap of all patients demonstrated a distribution of white matter lesions consistently in all subcortical brain areas. The VLSM-analysis showed associations between headache and lesion clusters in the left insula, left hippocampus and right thalamus. In our study, multiple sclerosis lesions in the left insula, left hippocampus and right thalamus were associated with headache in multiple sclerosis patients. The data therefore indicates that headache in multiple sclerosis may, in a proportion of patients, result from lesions in the central nervous systems’ pain processing network. Trial registration : No. 93_17 B, Ethics committee of the University Hospital Erlangen-Nürnberg.

Previous MR studies have established that bilateral transverse sinus stenosis (BTSS) predicts idiopathic intracranial hypertension without papilledema (IIHWOP) in migraine. However, it is uncertain whether BTSS identifies IIHWOP in patients with chronic tension-type headache (CTTH): using cerebral MR venography this study aimed to address this question. In a prospective study from February 2002 to December 2006, 198 consecutive patients with CTTH underwent MR venography. Of these patients, 58 underwent lumbar puncture to measure cerebrospinal fluid (CSF) pressure. MR venography and lumbar puncture were also performed in 45 agematched control subjects. BTSS was considered present when the signal flow was poor or lacking (flow gap) in the mid-lateral portion of both transverse sinuses. IIHWOP was diagnosed if the patient met the diagnostic criteria for idiopathic intracranial hypertension and did not have papilledema. Among the 198 patients with CTTH who underwent MR venography, 18 (9%) had BTSS. Thirteen of these 18 patients with BTSS underwent lumbar puncture, and nine (69.2%) had IIHWOP. CSF opening pressure was normal in all 45 patients as well as in all 45 controls with normal MR venography. These data suggest that BTSS on MR venography is associated with increased intracranial pressure in the absence of papilledema in patients with headache mimicking CTTH.

Background Neuroimaging studies have shown that hypothalamic/thalamic nuclei and other distant brain regions belonging to complex cerebral networks are involved in cluster headache (CH). However, the exact relationship between these areas, which may be dependent or independent, remains to be understood. We investigated differences in resting-state functional connectivity (FC) between brain networks and its relationship with the microstructure of the hypothalamus and thalamus in patients with episodic CH outside attacks and healthy controls (HCs). Methods We collected 3T MRI data from 26 patients with CH during the in-bout period outside the attacks and compared them with data from 20 HCs. From resting-state data we derived independent component (IC) networks. We calculated the fractional anisotropy (FA) and mean (MD), axial (AD), and radial (RD) diffusivity values of the hypothalamus and bilateral thalami and correlated them with resting-state IC Z-scores and CH clinical features. Results Patients with CH had less FC between the salience network (SN) and left executive control network (ECN) than HCs, but more FC between the default mode network and right ECN. Patients with CH showed lower FA and higher MD microstructural hypothalamic metrics than HCs. Patients with CH had a higher bilateral FA metric in the thalamus than HCs. The AD and RD diffusivity metrics of the hypothalamus were positively correlated with the disease history duration. We found no correlations between the hypothalamic and thalamic diffusivity metrics and the FC of the cortical networks. Conclusion Our findings presented the possibility of a correlation between the FC of the SN and the inability to switch between internalizing and externalizing brain activity during demanding cognitive tasks, such as recurring headaches. Moreover, we found differences in the thalamic and hypothalamic microstructures that may independently contribute to the pathophysiology of CH. These differences may reflect changes in directional organization, cell size, and density.