The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI).
The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients\' clinical characteristics and neuropsychological evaluations.
Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016).
Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

BACKGROUND: The brain functional network topology in new daily persistent headache (NDPH) is not well understood. In this study, we aim to assess the cortical functional network topological characteristics of NDPH using non-invasive neural signal recordings.
METHODS: Resting-state magnetoencephalography (MEG) was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 35 patients with NDPH and 40 healthy controls (HCs). Their structural data were collected by 3T MRI. Functional connectivity (FC) of neural networks from 1 to 80 Hz frequency ranges was analyzed with topographic patterns and calculated network topological parameters with graph theory.
RESULTS: In the delta (1-4 Hz) and beta (13-30 Hz) bands, the lateral occipital cortex and superior frontal gyrus FC were increased in NDPH groups compared to HCs. Graph theory analysis revealed that the NDPH had significantly increased global efficiency in the delta band and decreased nodal clustering coefficient (left medial orbitofrontal cortex) in the theta (4-8 Hz) band. The clinical characteristics had a significant correlation with network topological parameters. Age at onset of patients showed a positive correlation with global efficiency in the delta band. The degree of depression of patients showed a negative correlation with the nodal clustering coefficient (left medial orbitofrontal cortex) in the theta band.
CONCLUSIONS: The FC and topology of NDPH in brain networks may be altered, potentially leading to cortical hyperexcitability. Moreover, medial orbitofrontal cortex is involved in the pathophysiological mechanism of depression in patients with NDPH. Increased FC observed in the lateral occipital cortex and superior frontal gyrus during resting-state MEG could serve as one of the imaging characteristics associated with NDPH.

BACKGROUND: New daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS).
METHODS: Twenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis.
RESULTS: Significantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96).
CONCLUSIONS: The results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

To investigate the glymphatic function in patients with new daily persistent headache (NDPH) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method.
NDPH, a rare and treatment-refractory primary headache disorder, is poorly understood. There is limited evidence to suggest that headaches are associated with glymphatic dysfunction. Thus far, no studies have evaluated glymphatic function in patients with NDPH.
In this cross-sectional study conducted in the Headache Center of Beijing Tiantan Hospital, patients with NDPH and healthy controls were enrolled. All participants underwent brain magnetic resonance imaging examinations. Clinical characteristics and neuropsychological evaluation were examined in patients with NDPH. ALPS indexes for both hemispheres were measured to determine the glymphatic system function in patients with NDPH and healthy controls.
In total, 27 patients with NDPH (14 males, 13 females; age [mean ± standard deviation (SD)]: 36.6 ± 20.6) and 33 healthy controls (15 males, 18 females; age [mean ± SD]: 36.0 ± 10.8) were included in the analysis. No significant differences between groups were observed in the left ALPS index (1.583 ± 0.182 vs. 1.586 ± 0.175, mean difference = 0.003, 95% confidence interval [CI] of difference = -0.089 to 0.096, p = 0.942), or right ALPS index (1.578 ± 0.230 vs. 1.559 ± 0.206, mean difference = -0.027, 95% CI of difference = -0.132 to 0.094, p = 0.738). Additionally, ALPS indexes were not correlated with clinical characteristics or neuropsychiatric scores.
No glymphatic dysfunction was detected in patients with NDPH by means of the ALPS method. Additional studies with larger samples are needed to confirm these preliminary findings and improve the understanding of glymphatic function in NDPH.

BACKGROUND: New daily persistent headache (NDPH) is a rare but debilitating primary headache disorder that poses a significant burden on individuals and society. Despite its clinical importance, the underlying pathophysiological mechanisms of NDPH remain unclear. In this study, we aimed to investigate the brain structural changes and neural activity patterns in patients with NDPH using multimodal brain imaging analysis of structural magnetic resonance imaging (sMRI) combined with magnetoencephalography (MEG).
METHODS: Twenty-eight patients with NDPH and 37 healthy controls (HCs) were recruited for this study, and their structural and resting-state data were collected by 3.0 Tesla MRI and MEG. We analyzed the brain morphology using voxel-based morphometry and source-based morphometry. In each brain region, MEG sensor signals from 1 to 200 Hz were analyzed using an adapted version of Welch\'s method. MEG source localization was conducted using the dynamic statistical parametric mapping, and the difference of source distribution between patients with NDPH and HCs was examined.
RESULTS: Our results revealed significant differences in the regional grey matter volume, cortical thickness, and cortical surface area between the two groups. Specifically, compared with HCs, patients with NDPH showed a significant decrease in cortical thickness of the left rostral cortex in the middle frontal gyrus, decreased cortical surface area of the left fusiform gyrus, decreased grey matter volume of the left superior frontal gyrus and the left middle frontal gyrus, and increased grey matter volume of the left calcarine. Furthermore, the power of the whole brain, bilateral frontal lobes, and right temporal lobe in the NDPH group were higher than that in HCs in the ripple frequency band (80-200 Hz). Functional and structural analysis suggested that there were structural changes and abnormal high frequency cortical activity in both frontal and temporal lobes in patients with NDPH.
CONCLUSIONS: Our findings indicated that patients with NDPH have abnormalities in brain morphology, such as cortical area, cortical thickness, and grey matter volume, accompanied by abnormal cortical neural activity. Brain structural changes in the frontotemporal cortex and abnormalities in cortical ripple activity may be involved in the pathogenesis of NDPH.

OBJECTIVE: The pathogenesis of new daily persistent headache (NDPH) is not fully understood. We aim to map aberrant functional connectivity (FC) in patients with NDPH using resting-state functional magnetic resonance imaging (MRI).
METHODS: Brain structural and functional MRI data were acquired from 29 patients with NDPH and 37 well-matched healthy controls (HCs) in this cross-sectional study. Region of interest (ROI) based analysis was used to compare FC between patients and HCs, with 116 brain regions in the automated anatomical labeling (AAL) atlas were defined as seeds. The correlations between aberrant FC and patients\' clinical characteristics, and neuropsychological evaluation were also investigated.
RESULTS: Compared with HCs, patients with NDPH showed increased FC in the left inferior occipital gyrus, right thalamus and decreased FC in right lingual gyrus, left superior occipital gyrus, right middle occipital gyrus, left inferior occipital gyrus, right inferior occipital gyrus, right fusiform gyrus, left postcentral gyrus, right postcentral gyrus, right thalamus and right superior temporal gyrus. There were no correlation between FC of these brain regions and clinical characteristics, neuropsychological evaluation after Bonferroni correction (p > 0.05/266).
CONCLUSIONS: Patients with NDPH showed aberrant FC in multiple brain regions involved in perception and regulation of emotion and pain.
BACKGROUND: ClinicalTrials.gov Identifier: NCT05334927.

BACKGROUND: New daily persistent headache (NPDH) is a rare primary headache that is highly disabling. The pathophysiology of NDPH is still unclear, and we aimed to reveal the underlying mechanism of NDPH through functional magnetic resonance imaging (fMRI) analysis.
METHODS: In this cross-sectional study, thirty patients with NDPH and 30 healthy controls (HCs) were recruited. The blood oxygen level-dependent (BOLD) sequences of all participants were obtained using the GE 3.0 T system. We performed ReHo, ALFF (conventional band: 0.01-0.08 Hz, slow-5: 0.01-0.027 Hz, slow-4: 0.027-0.073 Hz) and seed-based to the whole brain functional connectivity (FC) analysis in the NDPH and HC groups. The sex difference analysis of ReHo, ALFF, and FC values was conducted in the NDPH group. We also conducted Pearson\'s correlation analysis between ReHo, ALFF, FC values and clinical characteristics (pain intensity, disease duration, HIT-6, GAD-7, PHQ-9, and PSQI scores).
RESULTS: Both increased ReHo (PFWE-corr = 0.012) and ALFF values (0.01-0.08 Hz, PFWE-corr = 0.009; 0.027-0.073 Hz, PFWE-corr =0.044) of the left middle occipital gyrus (MOG_L) were found in the NDPH group compared to the HC group. There was no significant difference in FC maps between the two groups. Compared to the HC group, no difference was found in ReHo (p = 0.284), ALFF (p = 0.246), and FC (p = 0.118) z scores of the MOG_L in the NDPH group. There was also no sex difference in ReHo (p = 0.288), ALFF (p = 0.859), or FC z score (p = 0.118) of the MOG_L in patients with NDPH. There was no correlation between ReHo, ALFF, FC z scores and clinical characteristics after Bonferroni correction (p < 0.05/18).
CONCLUSIONS: Patients with NDPH may have abnormal activation of the visual system. Abnormal visual activation may occur mainly in higher frequency band of the classical band. No sex differences in brain activity were found in patients with NDPH.

OBJECTIVE: New daily persistent headache (NDPH) and chronic migraine (CM) are two different types of headaches that might involve vascular dysregulation. There is still a lack of clarity about altered brain perfusion in NDPH and CM. This study aimed to investigate the cerebral perfusion variances of NDPH and CM using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI).
METHODS: Fifteen patients with NDPH, 18 patients with CM, and 15 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL-MRI to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The automated anatomical labeling atlas 3 (AAL3) was used to parcellate 170 brain regions. The CBF and aCBV values in each brain region were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed.
RESULTS: Compared with HC participants, patients with NDPH were found to have decreased CBF and aCBV values in multiple regions in the right hemisphere, including the right posterior orbital gyrus (OFCpost.R), right middle occipital gyrus (MOG.R), and ventral anterior nucleus of right thalamus (tVA.R), while patients with CM showed increased CBF and aCBV values presenting in the ventral lateral nucleus of left thalamus (tVL.L) and right thalamus (tVL.R) compared with HCs (all p < 0.05). In patients with NDPH, after age and sex adjustment, the increased aCBV values of IFGorb. R were positively correlated with GAD-7 scores; and the increased CBF and aCBV values of tVA.R were positively correlated with disease duration.
CONCLUSIONS: The multi-delay pCASL technique can detect cerebral perfusion variation in patients with NDPH and CM. The cerebral perfusion changes may suggest different variations between NDPH and CM, which might provide hemodynamic evidence of these two types of primary headaches.

New daily persistent headache is described as an enigmatic condition with daily headache from onset. It has posed challenges diagnostically and therapeutically.Methods: We conducted a study of patients referred to headache services based in Central and North-East London, United Kingdom, meeting the International Classificaiton of Headache Disorders - 3 criteria for New daily persistent headache. Information on demographics, phenotype and treatment responses were collected. The syndrome of the daily headache was also classified according any other ICHD-3-defined syndrome.Results: Of 162 patients, females comprised 68.5% with median age of onset 35 years. The daily headache experienced was chronic migraine in 89.7% and tension-type headache in 8.8%. Thunderclap-onset New daily persistent headache occurred in 14.8%. More than one headache syndrome was experienced in 15.4%, including cough, hypnic, sexual and stabbing headache. All aura types were experienced, most commonly brainstem aura in 39%. Prior headache was reported 53.7%. A persisting sub-form was present in 51.2%, relapsing remitting in 12.3% and 14.0% reported improvement; 19.8% were lost to follow-up. Only 11.1% reported an antecedent trigger. The most common premorbid disorders were psychiatric in 35.7%. A fifth improved on preventative medication, most commonly amitriptyline, propranolol and topiramate.Conclusion: Our cohort of New daily persistent headache is consistent with a mode of onset of migraine and tension-type headache which occurs in predisposed individuals.

OBJECTIVE: To analyze the clinical features of new daily persistent headache (NDPH) in the neurological outpatient clinic of a tertiary hospital in China.
METHODS: A cross-sectional survey was conducted between July and December 2011 in the First Affiliated Hospital of Chongqing Medical University. All consecutive patients who cited headache as their chief complaint were asked to participate in a face-to-face interview by a qualified headache specialist through a detailed headache questionnaire, and the diagnosis of NDPH was according to the modified version criteria of the International Classification of Headache Disorders.
RESULTS: A total of 38 were diagnosed as NDPH among 1219 patients with headache, including 20 women and 18 men. The mean age was 42.1 years. The duration of headache ranged from 3 months to 30 years. Headache location was bilateral in 84.2% of the patients. The intensity of pain was mainly described as mild and moderate. Nausea occurred in 21.1% of the patients, vomiting in 5.3%, photophobia in 15.8%, phonophobia in 10.5%, and vertigo in 18.4%. Seventy-nine percent of the patients were able to pinpoint the exact month when their headache started. Trigger factors were noted in 47.4% of the patients, which consisted of stressful life events, flu-like illnesses, surgeries, and some other reasons. Twenty-six patients were able to be followed up by telephone, and 16 had good outcomes.
CONCLUSIONS: NDPH is underrecognized in China. This study outlines the clinical features of patients with NDPH in a tertiary outpatient population. Better education among physicians is needed urgently so as to improve the diagnosis and treatment of NDPH.