Altered hypothalamic functional connectivity in post-traumatic headache after mild traumatic brain injury

DOI: https://doi.org/10.1186/s10194- 020- 01164- 9

Abstract-Summary Post-traumatic headache (PTH) is one of the most frequent symptoms following mild traumatic brain injury (mTBI).

It is unknown whether there are alterations in the hypothalamus-based resting state FC within PTH following mTBI at the acute stage and its relationship with headache symptom measurement.

The correlations between hypothalamic resting state networks and headache fre- quency, headache intensity and MoCA scores was investigated in mTBI patients with PTH using Pearson rank correlation.

Compared with mTBI patients without PTH, mTBI patients with PTH at the acute stage presented significantly decreased left hypothalamus-based FC with the right middle frontal gyrus (MFG) and right medial superior frontal gyrus (mSFG), and significantly decreased right hypothalamus-based FC with the right MFG.

Decreased FC of the right MFG was significantly positively associated with headache frequency and headache intensity (r  =  0.339, p  =  0.024; r  =  0.408, p = 0.006, respectively).

Decreased FC of the right mSFG was significantly positively associated with headache frequency and headache intensity (r  =  0.740, p  <  0.0001; r  =  0.655, p < 0.0001, respectively).

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Our data provided evidence of disrupted hypothalamic FC in patients with acute mTBI with PTH, while abnormal FC significantly correlated with headache symp- tom measurement.

Extended: It is still challenging for us to identify patients with mTBI with PTH, since the conventional computed tomography (CT) and magnetic resonance imag- ing (MRI)) cannot identify brain abnormalities [196].

Background Following mTBI, patients frequently suffer lifelong disabilities, including post- traumatic headache (PTH), depression, insomnia, dizziness and hypomnesia.

The main phenotype of PTH in patients with mTBI is consistent with that of

migraine [197, 198], and PTH commonly has characteristics similar to 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 [199].

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.

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 mecha-

nisms of the hypothalamus in PTH following acute mTBI.

Methods The fMRI sequence took 8 min and 8 s. The three-dimensional turbo fast-echo (3D- TFE) T1WI sequence had high resolution: TR = 8.1 ms; TE = 3.7 ms; slices = 170; thickness  =  1  mm; gap  =  0  mm; FA  =  8°; acquisition matrix  =  256  ×  256; and FOV = 256 mm × 256 mm; For fluid-attenuated inversion recovery (FLAIR), the specifications were as follows: TR = 7000 ms; TE = 120 ms; slices = 18; slice thick- ness = 6 mm; gap = 1.3 mm; FA = 110°; and voxel size = 0.65 × 0.95 × 6 mm3.

Differences in FC of the bilateral hypothalamus were compared between groups (mTBI vs. healthy controls; mTBI + PTH vs. mTBI-PTH; mTBI + PTH vs. healthy controls; mTBI-PTH vs. healthy controls) using one-way analysis of variance (ANOVA) and subsequent t-tests at a threshold of p < 0.001 with multiple compari- sons correction using the AlphaSim program (http://afni.nih.gov/afni/docpdf/ AlphaSim.pdf) determined by Monte Carlo simulation (single voxel p value = 0.001, a minimum cluster size of 13, within a GM mask corresponding to the AAL atlas) and controlling for age and gender.

Results After follow-up evaluation, 71 patients with mTBI and 43 healthy controls were enrolled in this study.

All the participants were divided into three groups: mTBI + PTH (patients with PTH after mTBI, n = 44); mTBI – PTH (patients without PTH after mTBI, n = 27); and healthy controls (healthy volunteers without any headache, n = 43).

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Compared with healthy controls, mTBI patients without PTH and mTBI patients

without PTH showed no significant difference, respectively.

Discussion 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.

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. 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 [200].

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.

Conclusion This study revealed hypothalamic functional disconnections in mTBI patients with PTH compared to mTBI patients without PTH and healthy controls.

These results together could provide a new perspective to understanding the neu- ropathological mechanism underlying the PTH following acute mTBI to determine more appropriate management.

Acknowledgement A machine generated summary based on the work of Lu, Liyan; Li, Fengfang; Wang, Peng; Chen, Huiyou; Chen, Yu-Chen; Yin, Xindao 2020 in The Journal of Headache and Pain.

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