Background
Traumatic brain injury (TBI) is a significant worldwide health problem with major effects on both morbidity and mortality [
1]. Among all traumatic brain injuries, mild traumatic brain injury (mTBI) is highly prevalent [
2]. Following mTBI, patients frequently suffer lifelong disabilities, including post-traumatic headache (PTH), depression, insomnia, dizziness and hypomnesia. PTH is the most common and persistent symptom, and almost 70% of individuals with mTBI report pain-related problems and complaints. According to the International Classification of Headache Disorders Third Edition (ICHD-3), PTH is considered as an “acute” headache disorder if it develops within 3 months after the injury and as a “persistent” condition if it continues for longer than 3 months [
3]. Persistent post traumatic injury (PPTH) may sometimes be underestimated because many patients never go to the hospital to obtain headache medication, which ultimately leads to long-lasting disability and imposes major burdens on society. However, it is still challenging for us to identify patients with mTBI with PTH, since the conventional computed tomography (CT) and magnetic resonance imaging (MRI)) cannot identify brain abnormalities [
4]. Therefore, the underlying pathophysiologic mechanisms of PTH following mTBI are poorly understood.
The main phenotype of PTH in patients with mTBI is consistent with that of migraine [
5,
6], and PTH commonly has characteristics similar to migraine. Thus, there are shared underlying neurochemical mechanisms between migraine and PTH [
7]. Several studies have shown that various brain structures, such as the brainstem, central dopaminergic system and hypothalamus, are involved in the pathophysiology of migraine [
8‐
10]. In particular, recently, the hypothalamus has been suggested to play an important role in the generation of migraine attacks and the sustainment of migraine pain [
8]. Furthermore, in migraine, the hypothalamus has been reported to be involved not only in different stages of the migraine cycle (interictal, preictal and ictal) and the pathophysiology of migraine chronification, but also in clinical features of migraine, including yawning, tiredness and mood changes [
8]. How hypothalamic changes might result in migraine is more intriguing. Neuroimaging studies revealed structural and functional alterations of the hypothalamus within migraine. One recent study showed that the volume of the hypothalamus was significantly decreased in migraine patients, compared with controls and that the volume of the hypothalamus was negatively correlated with headache frequency [
10]. Additionally, several studies using functional MRI (fMRI) have indicated that migraine patients had both increased hypothalamic functional connectivity (FC) with a number of brain regions, including the frontal, parietal, temporal, subcortical, brainstem and cerebellum regions, and decreased hypothalamic FC with frontal and occipital regions [
9,
11]. Given some overlapping pathophysiological features underlying migraine and PTH, the hypothalamus is presumed to be an important biomarker for the diagnosis and treatment of PTH. Morphological differences (including multifocal lower gray matter, cortical thinning and volume loss and functional alterations regarding pain processing) have been shown in patients with PTH after mTBI. Dumkrieger et al. reported that headache frequency was significantly correlated with static FC of the right posterior insula with the left hypothalamus in PTH [
12]. However, to date, no study directly focusing on the hypothalamic FC alterations has been conducted in PTH following mTBI.
Thus, the present study aimed to investigate the FC between the hypothalamus and other brain regions in mTBI patients with PTH and further explore the association between any functional brain abnormality and various clinical features of PTH. By doing so, we utimately aimed to detect the possible pathophysiologic mechanisms of the hypothalamus in PTH following acute mTBI.
Discussion
mTBI can cause injury to the hypothalamus through damage to hypothalamic cell bodies. One study demonstrated both microstructural and functional connectivity abnormalities of the hypothalamus in mTBI patients by using diffusional kurtosis imaging (DKI) and resting state fMRI (rs-fMRI) [
17]. The main finding in the present study was the significantly decreased FC between the hypothalamus and frontal gyrus in patients with mTBI with PTH compared with patients with mTBI without PTH. These decreased FC alterations were significantly correlated with the headache frequency and headache intensity. Frontal regions as part of the brain network are involved in pain processing including the affective and cognitive evaluation of pain. Notably, areas within the frontal lobe have previously been found to have abnormal structure, function, and FC in individuals with various pain disorders including PTH, migraine, cluster headache, and medication overuse headache [
5,
18‐
20]. Several other studies have identified relationships between headaches and structural and functional brain alterations in the frontal gyrus [
2].
Of interest, we found that the FC between the left hypothalamus and right MFG and that between the right hypothalamus and right MFG were significantly decreased in patients with mTBI with PTH compared with patients with mTBI without PTH. This reduced FC between the left and right hypothalamus and right MFG was significantly positively correlated with headache frequency and headache intensity, respectively. The MFG, as part of the prefrontal cortex that regulates pain perception [
21], has been reportedly involved in both dorsal and ventral attentional networks, responses to fearful expressions, emotional management and the detection of salient behaviorally relevant but task-irrelevant stimuli in patients with migraine compared with controls [
22]. In particular, the MFG is considered to play an important role in the cognitive evaluation and modulation of pain. Both abnormal neurostructural and functional alterations in the MFG have been reported in patients with PTH relative to healthy controls in previous studies [
2,
23]. Structurally, patients with PTH showed decreased structural integrity (smaller surface area, volume or thickness, or higher curvature) in the MFG. In addition, one recent voxel-based morphometric (VBM) study showed that the decreased volume in the left MFG is significantly correlated with disease duration [
24‐
26]. Functionally, a study by Dumkrieger and colleagues examined static and dynamic FC of 59 regions of interest involved in pain processing and found dynamic FC alterations in the left and right MFG in patients with PTH [
12]. From this perspective, our results were consistent with those of researchers [
27,
28]. The reason might be explained by the fact that impaired FC related to the MFG might diminish the capacity for pain evaluation and modulation.
We also demonstrated the significantly reduced FC between the left hypothalamus and right mSFG, and this decreased FC was significantly positively correlated with the headache frequency and headache intensity. The SFG region belongs to Brodmann area 10 (BA 10), which is the largest frontal brain region and is known as the anterior prefrontal cortex, frontopolar prefrontal cortex, or rostral prefrontal cortex. The cytoarchitecture of BA10 is characterized by more dendritic spines, a higher spine density, and a lower cell body density compared with other areas of the cortex, suggesting that BA 10 is more likely to accomplish these tasks of information integration [
29]. In fact, BA 10 has been implicated in multiple integrative roles, including working memory, abstract reasoning, decision making, behavior control, nociceptive processing, and perceptual metacognition. Thus, the SFG, as one of the rich-club regions of BA 10, may have been involved in a great number of connections may lead to the modulation of cortical and subcortical nociceptive pathways. Compared with healthy controls, patients with PTH had less cortical thickness in the left and right SFG and demonstrated a negative correlation between left and right SFG thickness and headache frequency [
2]. In addition, patients with pain disorders showed significant functional alterations, such as lower regional homogeneity (ReHo) and FC abnormalities in the superior frontal gyrus [
24,
30]. More specifically, the medial frontal gyrus is known as the pain anticipation and modulation area through the anterior cingulate cortex (ACC), a key region of the pain matrix [
30]. Sarmento et al. reported reduced N-acetylaspartate (NAA)/creatinine and increased choline/creatinine in the medial frontal lobe in patients with PTH compared with controls [
31]. Our data of decreased FC between the left hypothalamus and right mSFG in mTBI patients with PTH are consistent with previous findings [
32]. In the literature, this reduced FC may result in a permissive brain condition and the initiation of headache attacks, ultimately reflecting an insufficient pain modulating capacity.
Interestingly, our study demonstrated significant FC reduction between the left hypothalamus and contralateral MFG and mSFG. This asymmetry in connectivity during the resting state is small but consistent [
33]. In the present study, hemispheric dominance may potentially play a role in defining the areas injured.
In the current study, we further showed that decreased FC between the left hypothalamus and left fusiform gyrus, left Rolandic operculum, right MFG and right mSFG as well as decreased FC between the right hypothalamus and right MFG, right postcentral gyrus and left supplementary motor area in mTBI patients compared with healthy controls. Among these brain regions, the fusiform is involved in nociception/antinociception and neurocognitive aspects of pain processing [
34,
35]. In PTH, functional connectivity altered in the fusiform gyrus [
12]. Evidence suggests that increased Rolandic operculum activation is correlated with some anticipatory processes. However, the exact role of the Rolandic operculum in pain disorders is unclear. fMRI studies have revealed activation of postcentral regions in response to painful stimulation [
36]. Although no structural or functional alterations in the postcentral gyrus were found in PTH studies, cortical thinning, decreased amplitude of low-frequency fluctuation, hypoperfusion and FC abnormalities were shown in the postcentral gyrus in migraineurs [
28]. The supplementary motor area, a region involved in motor planning and preparation, is activated in response to painful stimuli. Decreased supplementary motor area activation in patients with mTBI with PTH might indicate patients’ response to avoid movement during pain because physical movement worsens the pain [
37,
38]. Nevertheless, these four brain regions were not significantly related to the hypothalamus in patients with mTBI with PTH. This may be attributed to the small samples of participants and requires further work to investigate why these brain areas are not involved in PTH.
Our study has several limitations. First, our research has a cross-sectional design with a small sample size. Second, the different parts of the hypothalamus have distinct roles; the anterior part seems to play an important role in headache attack generation and headache chronification, while the posterior part of the hypothalamus seems to be important for the acute headache stage. However, the entire hypothalamus, rather than hypothalamus subregions, was examined in this study. The current study could be extended to the hypothalamic subdivisions to investigate the FC patterns of mTBI patients with PTH. Third, scales to measure neuropsychological state, including depression and anxiety during a headache, were not measured; hence, the influence of these neuropsychological factors on hypothalamic FC was not assessed. Finally, the phenotype of PTH was not classified in detail, and different phenotypes may influence hypothalamic FC.
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