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MRI-based analysis of the microstructure of the thalamus and hypothalamus and functional connectivity between cortical networks in episodic cluster headache

The Journal of Headache and Pain volume 26, Article number: 12 (2025) Cite this article

Abstract

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.

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Introduction

Cluster headache (CH) attacks are characterized by severe stabbing pain along the sensory distribution territory of the trigeminal nerve and activation of the parasympathetic reflex, with the resulting autonomic manifestations ipsilateral to the side of the pain [1]. Comprehending the biology of CH might clarify misconceptions arising from the social and physical constraints imposed by the recurrent pain sickness [2]. Numerous clinical and experimental studies have emphasized the key role of the hypothalamus in the pathophysiology of CH [3]. Of the various nuclei that make up the hypothalamus, the suprachiasmatic nucleus located anteriorly (known as the master clock) is assumed to play a major role in this context, partially because of its connection to brainstem reticular formation and the trigeminal system [3]. Invasive deep inhibitory stimulation of the posterior hypothalamus can plastically reduce the recurrence of CH attacks, highlighting the possibility that more subregions of the hypothalamus may be involved [4]. However, several other brain areas outside the hypothalamus have been identified as sites of abnormality in CH in both structure and function [5].

In a whole-brain diffusion tensor imaging (DTI) 1.5T MRI study, compared with healthy participants, patients with in-bout episodic CH (eCH) under prophylactic medications, showed regionally higher absolute (radial and mean) diffusivities in the left medial frontal gyrus and sub-gyrus and lower absolute (axial, radial, and mean) diffusivities in the right parahippocampal gyrus of the limbic lobe, all areas previously involved in pain modulation [6]. Furthermore, the investigation employing probabilistic fiber tractography demonstrated the presence of highly consistent and direct anatomical connections between all regions exhibiting alterations in diffusivity indices and the ipsilateral hypothalamus [6]. In addition, another 1.5T MRI study showed that compared with healthy controls, the mean fractional anisotropy of the right amygdala, mean axial and mean diffusivity of the right caudate nucleus, and radial diffusivity of the right pallidum were higher in patients with CH; however, the mean anisotropy of the right pallidum was lower [7]. Nevertheless, none of these DTI investigations specifically focused their analyses on the hypothalamic region of interest while employing a more detailed 3T scan in medication-free patients.

In addition to structural MRI findings, multiple studies conducted on patients with eCH, both in- and out-of-bout, have revealed abnormal functional connectivity between the hypothalamus and various brain regions associated with the processing of salient information. These regions include the prefrontal cortex, anterior cingulate cortex, contralateral thalamus, ipsilateral basal ganglia, insula, and the cerebellar hemispheres [8,9,10,11,12,13,14]. These different and sometimes non-adjacent regions of the brain may work in coordination and form brain networks. Inside and outside cluster bout, a decreased resting-state functional coactivation was detected between the hypothalamus (ipsilateral and contralateral to the headache) and the salience network (SN) [12]. The authors interpret their results as due to a malfunctioning central pathway for pain modulation and dysregulation of the autonomic nervous system. A model to differentiate between CH and migraine found that the most significant MRI characteristics indicated crucial involvement of the thalamus. Specifically, patients with CH in the out of the bout phase exhibit reduced functional connectivity between the left thalamus and parietal brain regions, such as the precuneus and angular gyrus [15]. A more recent study showed reduced FC (functional connectivity) between bilateral thalamus and SN in patients with CH compared with healthy controls, regardless of the side of pain [16].

However, in most of the abovementioned studies, patients with eCH were receiving one or several prophylactic medications at the time of scanning, which may have altered the course of the disease and led to biased results. The aim of our study was to analyze hypothalamic and thalamic microstructures and simultaneously identify independent network abnormalities using functional MRI (fMRI) in patients with eCH who were not on prophylactic medications at the time of scanning during the bout outside the attacks. We use this multimodal approach because contemporary models of human brain organization demonstrate that anatomical architecture significantly impacts brain function, reflecting multisynaptic interactions within intricate large-scale multidimensional networks [17]. Consequently, functional brain features cannot be directly assessed from structural data but must be inferred by statistical models of various complexity, as employed in our study [18]. We have already utilized that approach in the investigation of migraine pathophysiology [19,20,21,22,23,24]. We hypothesized that the microstructural metrics of the thalamus and hypothalamus, along with the functional connectivity between cortical networks, may be concurrently altered during the bout, outside of attacks, and associated with the clinical features of eCH patients.

Methods

Participants

Twenty-six patients with eCH (ICHD III code 3.1.1 [1]) and strictly unilateral pain (15 of the right side) attending the Headache Centers of Rome (directed by Prof. Vittorio Di Piero) and Latina (directed by Prof. Gianluca Coppola) were recruited. Patients were scanned during the in-bouts period outside of the attacks. Other primary or secondary headache types were excluded by clinical and/or instrumental evaluation, as appropriate. We collected information on various patient clinical characteristics at the time of either the screening visit or the day of the scanning session, including daily attack frequency, mean severity of headache attacks (0–10), duration of the attacks (hours), and duration of history of eCH (years). The exclusion criteria were severe systemic or neurological/neuro-ophthalmological diseases or psychiatric disorders. Patients with eCH and a family history of migraine (1st -degree relatives) were also excluded. No preventive drugs were permitted during the 3 months preceding the observations in eCH. For comparison, 20 healthy controls (HCs) of comparable age and sex distributions were recruited from among medical students and healthcare professionals. They were devoid of any overt medical conditions, personal or family history of primary headaches or epilepsy, or regular drug intake.

None of the enrolled participants experienced sleep deprivation or alcohol ingestion on the day preceding the recordings. Caffeinated beverages were not allowed on the day of the recording. All the participants provided written informed consent to participate in the study, which was approved by the local ethics committee (N° 0295/2023). The study complied with the principles of the Declaration of Helsinki for Human Experimentation.

MRI data acquisition

MRI data were obtained using a Siemens 3T Verio scanner with a 12-channel head coil. Structural anatomic scans were performed using a T1-weighted sagittal magnetization-prepared rapid gradient echo (MPRAGE) series (TR: 1900 ms, TE: 2.93 ms, 176 sagittal slices, 0.508 × 0.508 × 1 mm3 voxels). We acquired an interleaved double-echo Turbo Spin Echo sequence proton density and T2-weighted images (repetition time: 3320ms, echo time: 10/103ms, matrix: 384 × 384, field of view: 220 mm, slice thickness: 4 mm, gap: 1.2 mm, 50 axial slices). fMRI data were obtained using T2*-weighted echo-planar imaging (TR, 3000 ms; TE, 30 ms; 40 axial slices, 3.906 × 3.906 × 3 mm; 150 volumes). Functional resting scans lasted for 7 min and 30 s. During these sessions, the participants were instructed to relax, avoid motion, and keep their eyes closed, but not fall asleep. Upon completion of the scanning, all participants indicated that they had not fallen asleep during the resting-state fMRI procedure.

DTI images were obtained with a single-shot echo-planar image sequence with the following parameters: repetition time (TR) = 12,200 ms, echo time (TE) = 94 ms, field of view (FOV) = 192 mm x 192 mm, matrix = 96 × 96, 2 mm x 2 mm in-plane resolution, slice thickness = 2 mm, 72 continuous axial slices with no gap, 1 volume anterior to posterior (AP) phase of encoding direction b = 0 s/mm2, b = 1000 s/mm2, and 30 diffusion directions were isotropically distributed on a sphere where one direction lacked diffusion weighting resulting in 31 volumes of the AP phase of encoding direction and 1 volume posterior to anterior (PA) phase of encoding direction b = 0.

fMRI preprocessing and data analysis

Data pre-processing was performed using SPM12 software (http://www.fil.ion.ucl.ac.uk/spm/) implemented in MATLAB (version R2016b, MathWorks, Inc., Natick, MA, USA). The data were realigned to the first volume to correct for head motion using a 6-parameter rigid body process and resliced using cubic spline interpolation. Moreover, in order to check motion, we calculated framewise displacement (FD), based on participants’ root mean square values (RMS) [25], and their contrast was not statistically significant (HCs: 0.0323 ± 0.0374, CH patients: 0.0484 ± 0.0333, p = 0.86 unpaired 2-sample t-test).

Structural (T1–MPRAGE) and functional data were co-registered for each participant. All participant’s f-MRI images were normalized by means of SPM12 default parameters (normalise est & wri functions). The normalization procedure transformed the structural and realigned EPI images into a standard stereotactic space based on Talairach and Tournoux [26], which was resampled 3 mm in each direction.

Finally, the normalized functional images were smoothed isotropically with a Gaussian kernel of 8 mm full width at half maximum.

Resting-state images were analyzed using spatial independent component analysis (ICA) with the infomax algorithm, which was implemented in the Group ICA of the fMRI Toolbox (GIFT- https://fsl.fmrib.ox.ac.uk/fsl) [27].

Two data reduction steps were performed using the principal component analysis (PCA): participant-specific and group-level steps.

First, the participant-specific data were reduced to 50 components and the participant-reduced data were concatenated across time. Secondly, at the group level, data were reduced to 20 group-independent components (ICs) using the expectation-maximization algorithm included in GIFT [28].

Two separate group spatial ICAs were also performed in the HCs and patients to ensure that the resulting components had similar resting-state fluctuations in the two groups, that is the resulting components obtained from all 46 participants combined.

The number of ICs was estimated using the minimum description length (MDL) criterion [29]. Participant-specific spatial maps and time courses were obtained using the back-reconstruction approach (GICA) [30].

An expert neuroradiologist (F.C.) analyzed all group ICs identifying the RSNs [31, 32], omitting those located in the CSF, white matter, or with low correlation to gray matter because they can be artifacts, such as eye movements, head motion, or ballistic artifacts.

Indeed, we obtained eight functional networks: visuospatial (IC1), default mode network (DMN, IC3), executive control (ECN, IC5), salience (SN, IC7), ECN right and left (IC10 & IC12), DMN (IC16, ventral part), and medial visual (IC19) to be processed in the following step.

The Functional Network Toolbox (FNC; http://trendscenter.org/software/gift/) [27] was used to evaluate whether there were different correlations between the groups’ networks (expressed as CorrPosΔ, i.e. the difference in correlation between groups of each networks’ combination). It also shows the constrained maximal time-lagged (lag) correlation for every pair of component combinations.

Bandpass filter values were set between 0.033 Hz and 0.13 Hz.

DTI

Before pre-processing, all DTI volumes were visually inspected to screen for noisy artifacts due to cardiac pulsations, signal dropout, and motion artifacts.

Functional MRI of the Brain (FMRIB) Software Library (FSL version 6.0.6, https://fsl.fmrib.ox.ac.uk/fsl) was used to image data process [33,34,35].

Firstly, the b = 0 volumes AP and PA phase-encoding directions were used as references, and were processed by means of top-up tool to estimate [36] and correct [33] susceptibility-induced distortions.

The brain extraction tool (BET) creates brain masks from the topup’s output b = 0 volumes [37].

Eddy tool corrected DTI volumes for susceptibility, eddy currents and subject movements, based on topup function output files, the brain mask created in the previous step and each input diffusion volume acquisition features.

Before the final step, the MRI-processed images were assessed using a quality control framework [38] to identify and possibly remove the bad quality dataset. In brief, quality control framework checked all participants’ topup and eddy functions output files, distinguishing each dataset quality, finally identifying those need carefully visually inspection. At the time of scanning, it checked each dataset for artifacts. No artefactual DTI data were detected.

Lastly, the DTIFIT toolbox fits the preprocessed images based on a diffusion tensor model to yield the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), distortion-corrected DTI volumes, brain mask previously created, b values and vectors files as inputs.

Hypothalamus ROI [39] were defined by an expert neuroradiologist (F.C.) in MNI standard space using FSLeyes software (https://open.win.ox.ac.uk/pages/fsl/fsleyes/fsleyes/userdoc/index.html). Left and right thalamic ROIs were defined using FSLeyes atlases and inspected by the same neuroradiologist (F.C.) (Fig. 1). All ROIs were registered as MRI diffusion images using algorithms embedded in the FDT toolbox [40,41,42,43].

Fig. 1
figure 1

Sagittal, coronal, and axial ROIs representations used to achieve DTI characteristics: hypothalamus and thalami highlighted in red

Full size image

Statistical analysis

Group differences in demographic data were estimated using SPSS version 23 (IBM Corp., USA).

An unpaired 2-sample t-test was used to detect significant differences in the correlations and lag values between the independent components for controls and patients [27].

A p-value of 0.05 false discovery rate (FDR) corrected for multiple comparisons was considered significant.

The DTI characteristics were estimated based on previously defined ROIs for each group, and their values were compared using an unpaired 2-sample t-test.

An additional Holm-Bonferroni correction was performed to compensate for the number of ROIs; thus, the p-value was set to 0.01.

To search for correlations between DTI metrics, regional RS-fMRI network changes, and clinical features, the Z-max scores (voxel-wise analysis) of each IC network were extracted for each participant.

A p-value of 0.01 (0.05 / 4) was chosen to compensate for multiple comparisons due to the number of clinical variables.

Fig. 2
figure 2

Resting state functional connectivity between the salience network (IC7) and left executive control network (IC10). (A) A depiction of the two distinct components IC7 (hot metal scale) and IC10 (azure-blue) that were identified by independent component analysis (ICA). The functional connectivity absolute value of these components was found to be reduced in patients with episodic cluster headache (eCH) as compared to healthy controls (HC). The process of co-registration has been applied to align all images with the MNI template space. The numerals underneath each image indicate the z coordinate in Talairach’s system. (B) The bar graph on the right shows the correlation between the 2 ICs in HC and eCH, at p < 0.05 FDR corrected

Full size image
Fig. 3
figure 3

Resting state functional connectivity between the right executive control network (IC12) and default-mode network (IC16). (A) A depiction of the two distinct components IC12 (hot metal scale) and IC16 (azure-blue) that were identified by independent component analysis (ICA). The functional connectivity absolute value of these components was found to be reduced in patients with episodic cluster headache (eCH) as compared to healthy controls (HC). The process of co-registration has been applied to align all images with the MNI template space. The numerals underneath each image indicate the z coordinate in Talairach’s system. (B) The bar graph on the right shows the correlation between the 2 ICs in HC and eCH, at p < 0.05 FDR corrected

Full size image

Results

All the participants completed the recording sessions. Structural brain MRI revealed no white matter lesions.

Resting-state functional connectivity

We found a difference in FC between ICs encompassing interconnected areas of the SN (IC7) and left ECN (IC10), and in FC between ICs encompassing interconnected areas of the right ECN (IC12) and DMN (IC16) in patients with CH compared to HCs (Figs. 2 and 3). The difference between IC7-IC10 (corrPosΔ = 0.1994; p = 0.0004) was because of a lower positive significant correlation between the IC pairs in patients with CH. In contrast, the difference between IC12-IC16 was because of significant negative CH connectivity and a lack of significant negative connectivity in HCs (corrPosΔ = -0.1880; p = 0.0015). No significant lag differences were detected between the contrasts listed above (See Table 1).

No additional significant differences were detected in the other ICs FC between eCHs and HCs.

Table 1 Demographic and clinical characteristics (mean ± standard deviation) of the patients with episodic cluster headache (eCH) and of heathy control (HC) groups
Full size table

Diffusion tensor imaging metrics

In patients with CH, the FA value of the hypothalamus was lower, and the MD was higher than in HCs (p < 0.001, Table 2). Additionally, the FA values of the bilateral thalami were higher in the CH group than in HC group (p = 0.002, Table 3).

Table 2 Diffusion tensor imaging (DTI) metrics of the hypothalamus of healthy controls (HC) and patients with episodic cluster headache (eCH). Data are expressed as means ± SD; * p < 0.001
Full size table
Table 3 Diffusion tensor imaging (DTI) metrics of bilateral thalami of healthy controls (HC) and in patients with episodic cluster headache (eCH). Data are expressed as means ± SD; * p < = 0.002
Full size table

Correlation analyses

There were no significant correlations between DTI metrics and the following clinical features of patients with CH: daily attack frequency, mean severity of headache attacks, and duration of attacks. The only correlation we found was that the higher the AD (R2 = 27.84%, p = 0.009) and RD (R2 = 30.50%, p = 0.005) of the hypothalamus in CH patients, the longer the history of the disease.

There were no correlations between ICs Z-score and DTI parameters.

Discussion

In the present study, we searched for structural and functional MRI abnormalities in patients with eCH who were not receiving prophylactic medication at the time of scanning. The key results of this DTI-fMRI study are summarized as follows:

  1. a)

    Compared to HCs, the functional connectivity between the salience network and the left executive control network was reduced in patients with CH.

  2. b)

    The right executive control and default mode network were positively connected in patients and negatively connected in HCs.

  3. c)

    The FA value of the hypothalamus was significantly lower and the MD value was significantly higher in patients with CH than in HCs.

  4. d)

    The FA values of the bilateral thalami were higher in patients with CH than in HCs.

  5. e)

    A longer disease history was associated with higher AD and RD metrics in the hypothalamus.

Microstructural alterations

Using 1.5T DTI and tract-based spatial statistics, significant differences in white matter diffusivity metrics (axial, radial, and mean) were found in the parahippocampal gyrus, amygdala, insula, frontal subgyral area, extranuclear area of the putamen, and medial frontal gyrus areas consistently during the in-bout and out-of-bout periods in 17 patients with CH compared with HCs [6]. The ipsilateral hypothalamus was highly connected to the ipsilateral medial frontal gyrus and the contralateral parahippocampal gyrus [6]. Analysis of whole-head 1.5T MRI DTI in tract-based spatial statistics in a variable number of patients (from 7 to 22) revealed diffuse white matter microstructure plastic changes in patients with CH [7, 44, 45]. In seven male patients with episodic CH, significant microstructural white matter tissue changes were detected in the brainstem; frontal, temporal, and occipital lobes; internal capsule; and right thalamus and cerebellum bilaterally [44]. This widespread involvement of the white matter regions in CH was confirmed by Szabo et al., who found higher mean, axial, and perpendicular diffusivity in the frontal, parietal, temporal, and occipital lobes; lower FA in the corpus callosum; and some frontal and parietal white matter tracts mainly contralateral to the pain [45]. The mean FA of the right amygdala, mean AD and MD of the right caudate nucleus, and RD of the right pallidum were higher, and the mean FA of the right pallidum was lower in a DTI study in patients with CH than in HC [7]. None of the previous studies have included the hypothalamic ROI in their analysis. Here, we found a lower FA value and a higher MD value in the hypothalamus of patients with CH than in HCs. These altered values can support the hypothesis that the hypothalamus plays a role in the pathogenesis of CH. Within white matter, diffusion is more likely to occur in a direction that aligns with the orientation of the fibers. This emphasizes that the main factors contributing to an increase in FA are a decrease in RD and/or an increase in AD [46]. This DTI technique is valuable for identifying both large brain white matter pathways and white matter tracts within gray matter nuclei, such as the hypothalamus and thalamus [47]. These brain structures consist of separate nuclei bound together by highly anisotropic myelinated fibers [48].

Nevertheless, it must be pointed out that myelin accounts for merely 20% of anisotropy, as variations in the volume of the axonal membrane and changes in the structure of glial cells appear to be additional factors in the development of MD and FA, respectively [46, 49]. Furthermore, in the gray matter, the primary factors contributing to FA are the abundance of neuronal connections through the branching and crossing of dendritic trees, number of local circuits, and abundance of axonal membranes [49]. Therefore, the present diffusivity pattern of decreased FA and increased MD compared with those of HCs may reflect the loss of preferential direction of the fibers in combination with increased cell swelling. From a neurophysiological perspective, this pattern may coincide with an increased neuronal electrical response with a consequent increase in neuronal connections and dendritic arborization, resulting in an increased number of local circuits [49, 50]. Interestingly, a longer history of the disease was associated with higher AD and RD values in the hypothalamus. However, as both metrics in the eCH group were within normal limits, we hypothesized that disease history may only marginally influence microstructural changes in the hypothalamus.

Contrary to what we found in the hypothalamus, the FA of the bilateral thalami increased in the presence of normal MD, AD, and RD in the patients compared to HCs. From a microstructural perspective, these findings may indicate an increase in the directional arrangement while maintaining the same neuronal and glial cell size and density. Based on these results, we argue that the thalamus also plays a role in CH pathophysiology, regardless of the side of pain. Given the thalamus’s established role in both descending and ascending trigeminal pain processing and autonomic system regulation, we can only speculate that the increased directionality of the thalamic fibers may result from recurrent headaches amplifying pain transmission in our patients with eCH. The recent finding in a cohort of eCH of diminished thalamic-to-SN FC irrespective of headache lateralization, may corroborate our hypothesis, as an anomalous involvement of the thalamus in pain processing could impair saliency detection mechanisms in the brain [16], specifically its ability to switch between systems engaged in processing exogenous and self-relevant information [51]. Further studies of functional connectivity are required to elucidate this point.

Between networks connectivity

Previous investigations using resting-state functional MRI have identified intrinsic changes in the connectivity of brain networks in individuals with CH. Patients have FC alterations in various brain networks, including the temporal, frontal, salience, default mode, sensorimotor, dorsal attention, and visual networks, regardless of whether they were in or out of the bouts [52]. Decreased functional coactivation between the hypothalamus ipsilateral and contralateral to the headache side and the SN indicated that dysfunction in the hypothalamus on the same side as the headache is insufficient to explain all abnormalities associated with CH [12]. A combined voxel-based morphometry and functional MRI study showed that in patients with CH, compared to migraine without aura patients and HCs, decreased regional grey matter volume in the frontal cortex and higher FC in the prefrontal cortex, brain area belonging to the ECN, and in the DMN were observed [53].

In humans, the SN detects and filters salient environmental stimuli and regulates attention and behavior in connection with the neurolimbic system. In healthy individuals, the SN switches between the DMN, which is active when the brain is at rest and not focused on the outside world, and the ECN, a task-oriented brain network, during goal-directed tasks [54, 55]. The SN, which includes the dorsal anterior cingulate cortex and bilateral anterior insula/frontal operculum, may be essential for emotions, pain, and interoception. The ACC of the SN has a vital role in affective and attentional modulation of pain perception, as well as in antinociception. Analysis of extensive brain networks led to the hypothesis that these three principal networks (SN, ECN, and DMN) constitute the ultimate common channel through which various internal or environmental disturbances may affect the brain [56]. Deviant connections within and among these brain networks have been shown to promote the onset of neuropsychiatric disorders [57] and have been further applied to elucidate the chronicity of pain [58]. By exploring between independent networks connectivity, we found reduced FC between the SN and left ECN and the presence of an unphysiological co-activation and increased FC between the DMN and right ECN in patients compared with HCs. Based on prior results acquired from healthy individuals, our findings in patients with CH may be a functional correlate of the patients’ SN being unable to switch between the DMN and ECN during demanding cognitive tasks, such as integration of attentional, sensory and affective problems related to recurring headaches. These problems may contribute significantly to morbidity, resulting in heightened functional disability and diminished quality of life. Additional research is required to confirm whether this connectivity pattern is a physiological mechanism by which the brain attempts to cognitively modify the perceptions and neural responses triggered by the sensation of pain [59]. Typically, this neurological process includes increased natural pain-relieving activity in the descending pain-modulatory system (such as the prefrontal cortex belonging to the ECN) and reduced activity in regions that contribute to pain [60].

Limitations

Our study has several limitations. First, cross-sectional fMRI studies with a relatively small cohort of subjects restrict their ability to draw conclusions regarding causality. Furthermore, as all patients were in the bout at the time of scanning, the data did not offer any insight into the brain processes during the period of remission. However, disturbances in the connectivity of large-scale brain networks have consistently been detected both in and out of bouts in individuals with eCH. Second, a limitation of the current analysis is its failure to account for headache laterality, given that CH is characterized by strictly unilateral pain. Third, this a cross-sectional study on a relatively small cohort of subjects and with retrospective collection of clinical data. Further research employing the same techniques in a larger cohort of subjects is required to control for the laterality of pain, track patients over time, and investigate individuals with chronic CH, where a more significant impact on the midbrain has been suggested [3].

Conclusions

In our study, we emphasized how the hypothalamic microstructure is altered during the in-bout period outside of attacks. We also highlighted the presence of altered bilateral thalamic metric values and demonstrated the role of the thalamus in the pathogenesis of CH attacks. In addition, we demonstrated that altered connectivity in networks that differentiate between patients with CH and HCs may be related to the SN and not the switching ability between internalizing the DMN and externalizing the ECN during pain. Further studies are needed to determine whether these functional abnormalities are related to the constant activity of the hypothalamus or to stable, genetically determined, disease-predisposing anomalies.

Data availability

The informed consent signed by all participants in this study did not include a provision stating that individual raw data can be made publicly accessible. Therefore, in agreement with the Italian data protection law, individual de-identified participant raw data cannot be shared publicly. Researchers meeting the criteria for access to confidential data may access the data upon request, involving the documentation of data access.

Abbreviations

AD:

axial diffusion

CH:

cluster headache

DMN:

default-mode network

DTI:

diffusion tensor imaging

eCH:

episodic cluster headache

ECN:

executive control network

FA:

fractional anisotropy

FC:

functional connectivity

FDR:

false discovery rate

fMRI:

functional magnetic resonance imaging

HC:

healthy control

IC:

independent component

MD:

mean diffusion

RD:

radial diffusion

SN:

salience network

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Acknowledgements

The contribution of the IRCCS - Fondazione Bietti in this paper was supported by the Italian Ministry of Health and Fondazione Roma.

Funding

The authors did not receive funding for the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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  1. Chiara Abagnale and Antonio Di Renzo contributed equally to this work.

Authors and Affiliations

  1. Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino, Latina, Italy

    Chiara Abagnale, Gabriele Sebastianelli, Francesco Casillo, Cherubino Di Lorenzo, Mariano Serrao & Gianluca Coppola

  2. IRCCS – Fondazione Bietti, Rome, Italy

    Antonio Di Renzo, Lucia Ziccardi & Vincenzo Parisi

  3. Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy

    Giada Giuliani, Francesca Caramia & Vittorio Di Piero

  4. Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pontino - ICOT, Via Franco Faggiana 1668, Latina, 04100, Italy

    Chiara Abagnale

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Contributions

CA, ADR, and GC made substantial contributions to protocol development, interpretation of data as well as in drafting the manuscript. VP, LZ, MS, FCar, and VDP were implied in the interpretation of data as well as in drafting the manuscript; GG, GS, and FCas contributed to participant enrolment and recording. ADR and FCar were implied in data processing, analysis, and statistics.

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Correspondence to Chiara Abagnale.

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Abagnale, C., Di Renzo, A., Giuliani, G. et al. MRI-based analysis of the microstructure of the thalamus and hypothalamus and functional connectivity between cortical networks in episodic cluster headache. J Headache Pain 26, 12 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-024-01920-1

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The Journal of Headache and Pain

ISSN: 1129-2377

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