Enhanced functional connectivity between habenula and salience network in medication-overuse headache complicating chronic migraine positions it within the addiction disorders: an ICA-based resting-state fMRI study

DOI: https://doi.org/10.1186/s10194- 021- 01318- 3

Abstract-Summary It is believed that MOH is associated with dependence behaviors and substance addiction, in which the salience network (SN) and the habenula may play an impor- tant role.

This study aims to investigate the resting-state (RS) functional connectivity between the habenula and the SN in patients with MOH complicating chronic migraine (CM) compared with those with episodic migraine (EM) and healthy con- trols (HC).

The RS-fMRI data were analyzed using the independent component analysis (ICA) method to investigate the group differences of functional connectivity between the habenula and the SN in three groups.

Increased functional connectivity between bilateral habenula and SN was detected in patients with MOH + CM compared with patients with EM and HC respectively.

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Correlation analysis showed significant correlation between medication overuse

duration and habenula-SN connectivity in MOH + CM patients.

The enhanced functional connectivity of the habenula with SN may correlate to

the development or chronification of MOH.

Background Neuroimaging, genetic and biological studies indicated that MOH shares similar imaging features, associated gene polymorphisms, and neurobiological changes with substance addiction [513–517].

MOH patients can develop behaviors including ritualized drugs intake, psycho- logical drug attachment and withdraw symptoms which are believed to be associ- ated with addiction [518–520].

Previous resting-state functional magnetic resonance imaging (RS-fMRI) method has indicated dysregulation of the reward circuit in MOH patients in line with substance abusers [476, 488].

The habenula functions in addiction, cognition, reward, pain and analgesia while the SN is to modulate information via integrating sensory, affective and cognitive inputs, and assigning relevance of the stimuli for continuous processing [521–524]. This study aims to investigate the resting-state function connectivity of the habenula and the SN in patients with MOH complicating chronic migraine (CM) compared with those with episodic migraine (EM) and healthy controls (HC).

Materials and Methods Clinical data as well as the Patient Health Questionnaire 9 Depression Scale (PHQ-9) and Generalized Anxiety Disorder Assessment 7-item Scale (GAD-7) were collected before MRI scan.

They were: (1) removing the first 5 volumes, (2) correcting the head motion by MCFLIRT, (3) removing the nonbrain tissues by BET (Brain Extraction Tool), (4) spatial smoothing using a 4-mm FWHM (full width at half maximum) Gaussian kernel, (5) removing slow drift with a high-pass temporal filter of 0.01 Hz, and (6) registering the RS-fMRI data to the 3-dimensional T1-weighted images and then to Montreal Neurological Institute-152 standard space.

We built individual-subject-level spatial maps by applying dual regression to the

preprocessed RS-fMRI data of each participant by using the same approach.

For each subject, firstly we used the previously obtained GICA spatial maps to regress against the individual’s preprocessed RS-fMRI data to estimate the matrices of network time series of each component.

The 50 network time series which we obtained were regressed against each sub- ject’s preprocessed 4-dimensional RS-fMRI data to estimate the subject’s network spatial component maps.

Results Disease duration of MOH + CM group (22.8 ± 8.9, range: 3–40 years) was signifi- cantly higher (p < 0.001) than EM group (10.8 ± 6.9, range: 0.83–20 years).

The medication-overuse duration of MOH + CM subjects was 7.3  ±  6.4 with

range of 0.25–17 years.

3.5 Medication Overuse and Addiction

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The visual analog scale of MOH + CM and EM group resulted no significant

difference.

The PHQ-9 depression scale of MOH + CM patients (8.7 ± 6.7, range: 0–23) was significantly higher than EM (2.4 ± 4.8 range: 0–11) and HC (2.5 ± 2.2, range: 0–6), with p value of 0.018 and 0.002 separately.

We identified an increased functional connectivity of habenula-SN in both the right and left habenula masks of the MOH + CM subjects compared with EM and HC.

Discussion It is the first time that functional connectivity between the habenula and the SN in patients with MOH + CM and EM were investigated.

Based on the independent component analysis (ICA) method, bilateral habenula showed increased resting-state functional connectivity with the SN in MOH + CM patients compared with EM and HC.

The increased functional connectivity of habenula-SN was shown in patients with MOH and CM but not in EM or HC, or between subgroup of MOH + CM patients with or without depression, which indicated that this alteration may corre- late with either repetitive headache attacks or overuse of medication.

The increased synchronous neuronal activity of habenula-SN is likely to corre- late with the MOH processing and might contribute to the MOH development or chronification through aberrant overactivation to unspecific sensory stimuli.

Limitations Although PHQ-9 and GAD-7 scale were used as covariates to minimize these effects, and further subgroup comparisons within MOH patients were performed based on two scales, we cannot definitely exclude the possibility that part of the functional connectivity changes may be due to depression or anxiety.

We were not able to draw a causative relationship of the increased functional

connectivity of habenula-SN and the MOH development.

We were not able to compare the habenula-SN functional connectivity amongst patients overusing different medications in MOH, since all our participants had overused combination analgesics.

Previous studies based in China showed patients who overused combination analgesics and more than two kinds of analgesics accounted for almost 90 % of MOH [525, 526].

Conclusions The current study demonstrated an increased functional connectivity of habenula- SN in patients with MOH + CM compared with EM and HC by ICA-based analyses of RS-fMRI data.

The enhanced functional connectivity of the habenula with SN may correlate to

the development or chronification of MOH.

The habenula may be an indicator or treatment target for MOH for its integrative

role involved in multiple aspects of MOH.

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Acknowledgement A machine generated summary based on the work of Dai, Wei; Qiu, Enchao; Chen, Yun; Xing, Xinbo; Xi, Wei; Zhang, Meichen; Li, Ke; Tian, Lixia; Dong, Zhao; Yu, Shengyuan. 2021 in The Journal of Headache and Pain.

Volumetric abnormalities of thalamic subnuclei in medication-overuse headache