Headaches are universal experiences and among the most common disorders. While headache may be physiological in the acute setting, it can become a pathological and persistent condition. The mechanisms underlying the transition from episodic to chronic pain have been the subject of intense study. Using physiological and imaging methods, researchers have identified a number of different forms of neural plasticity associated with migraine and other headaches, including peripheral and central sensitization, and alterations in the endogenous mechanisms of pain modulation. While these changes have been proposed to contribute to headache and pain chronification, some findings are likely the results of repetitive noxious stimulation, such as atrophy of brain areas involved in pain perception and modulation. In this review, we provide a narrative overview of recent advances on the neuroimaging, electrophysiological and genetic aspects of neural plasticity associated with the most common forms of chronic headaches, including migraine, cluster headache, tension-type headache, and medication overuse headache.
In its 2010 Global Burden of Disease Survey, the World Health Organization reported tension-type headache (TTH) and migraine as the second (20.1%) and third (14.7%) most prevalent disorders in the world, exceeded only by dental caries [
While such a commonplace condition may be easily dismissed, the impact of headache is not to be taken lightly. Using “years living with disability” as a measure of disease impact, the WHO rated migraine as the 7th most disabling of all 289 diseases surveyed (excluding the nonspecific “other musculoskeletal disorders”) [
Unfortunately, the mechanisms responsible for the development of chronic headaches remain unknown. Barring rare exceptions such as “new daily persistent headache,” most patients with chronic headaches initially experience only episodic attacks [
Thanks to recent advances in electrophysiology and neuroimaging, now we are able to test these hypotheses directly on the human brain. In this review, we first provide a narrative overview of the most common forms of chronic headaches and then discuss the neural plasticity underlying specific headache disorders by comparing available electrophysiological and neuroimaging studies in their episodic and chronic forms, according to the tools used and the hypotheses proposed. Emphasis will be laid on migraine as it is the most well studied type of these headaches.
Although it is not the most common of the headache disorders we will discuss, migraine headache is by far the most disabling and most researched condition [
CH is a primary headache disorder characterized by severe, strictly unilateral pain, lasting from 15 to 180 minutes [
TTH is the most common type of headache [
MOH results from regular overuse of abortive medication, exceeding 10 or 15 days per month (depending on the analgesic), for more than 3 months [
Sensitization of the trigeminal pain network (i.e., even beyond the first-order neuron) has been proposed to underlie migraine pathophysiology. As shown by the animal studies conducted by Burstein and colleagues, applying brief chemical stimulation with inflammatory agents to the dura in rats led to peripheral sensitization of the first-order neurons in the dorsal root ganglia of C2/C3 and trigeminal ganglion and central sensitization of the second order neurons in the trigeminal nucleus caudalis (also known as trigeminocervical complex). As a result, the rats treated with inflammatory agents had increased excitability in response to brush or nonnoxious heat stimulation [
Electrophysiological studies of trigeminal processing also characterize neural plasticity in association with CH [
In TTH, evidence is mounting in support of a neural plasticity characterized by central sensitization. An intriguing study in patients with chronic TTH showed increased suprathreshold pain sensitivity both in skin and in muscle, and in both cephalic and extracephalic regions [
Neural plasticity in the pathogenesis of MOH has also been linked to sensitization. Using SSEP, studies have shown an increase in the amplitude of painful and nonpainful cortical responses, with the latter normalizing following recovery from MOH [
Habituation refers to “a response decrement as a result of repeated stimulation” [
Research also suggests that changes in habituation may be associated with the transition from EM to CM. Habituation studies using nonpainful somatosensory evoked potentials (SSEP) have reported similarities between the electrophysiological patterns of ictal EM and CM, including initial excessive cortical activation followed by normal habituation during stimulus repetition [
Neural plasticity in episodic and chronic migraine, without medication overuse.
Episodic migraine (EM) | Chronic migraine (CM) | |
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Electrophysiology | ||
VEP | Lack of habituation and peri-ictal normalization [ |
No specific study |
MEG | Peri-ictal normalization of visual cortical excitability, reflecting a dynamic modulation of cortical activities [ |
Persistent ictal-like visual cortex excitability [ |
TMS | Hyperexcitability measured by TMS indices of phosphene thresholds and magnetic suppression of perceptual accuracy [ |
Reduced visual suppression correlating with high cortical excitability [ |
SSEP | Abnormal habituation during interictal period and central sensitization (increase of N20-P25 amplitude) during ictal period [ |
Increase of N20-P25 amplitudes recorded interictally in patients with CM compared with in patients with EM, indicating excessive cortical activation of the somatosensory pathway [ |
BAEP | Lack of habituation of wave IV-V, especially with symptomatic vertigo [ |
No specific study |
LEP | Lack of habituation of N1 (generated by secondary somatosensory cortex) and N2-P2 (generated by ACC and insula) during interictal and ictal periods |
Increase of amplitudes and rostral shift within ACC in patients with CM, similar to EM patients in the ictal period [ |
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Neuroimaging | ||
Functional | ||
PET | Activation of certain brain areas during ictal period indicating the involvement of specific brain areas associated with various symptoms in migraine including photophobia, nausea, and vertigo [ |
Increased cerebral metabolism at brainstem compared to the global flow and also decreased cerebral metabolism in the medial frontal, parietal, and somatosensory cortex, indicating a potential dysfunction in the inhibitory pathways [ |
fMRI | Greater activation of pain-matrix areas and less activation of pain inhibition areas [ |
No specific study |
rs-fMRI | Aberrant functional connectivity mostly in pain-matrix and also involving different networks including salience, default mode, central-executive, somatomotor, and frontoparietal attention networks [ |
Aberrant functional connectivity in affective pain regions including anterior insula, amygdala, pulvinar, mediodorsal thalamus, middle temporal cortex, and periaqueductal gray [ |
Structural | ||
VBM | Decrease of gay matter volume of multiple brain areas within pain-matrix [ |
No specific study; only two studies recruited small numbers of CM patients (11 and 3 patients each) without definite conclusions [ |
SBM | Increase thickness of the somatosensory cortex and visual motion areas [ |
No specific study |
DTI | Changes of white matter microstructures in areas such as corpus callosum and cingulate gyrus [ |
No changes in one study recruiting both CM and EM patients [ |
Biochemical | ||
MRS | Higher NAA/Cr ratio at dorsal pons, indicating possible neuronal hypertrophy; inverse correlation with headache frequency and intensity [ |
Lower NAA/Cr as compared with EM with inverse correlation with headache frequency and intensity, indicating possible progression of neuronal loss during evolution [ |
VEP: visual evoked potential, MEG: magnetoencephalography, TMS: transcranial magnetic stimulation, SSEP: somatosensory evoked potential, BAEP: brainstem auditory evoked potential, LEP: laser evoked potential, ACC: anterior cingulate cortex, PET: positron emission topography, fMRI: functional magnetic resonance imaging, rs-fMRI: resting state functional magnetic resonance imaging; VBM: voxel-based morphometry, SBM: surface-based morphometry, DTI: diffusion tensor imaging, MRS: magnetic resonance spectroscopy, and NAA/Cr: N-acetylaspartate/creatine.
A lack of habituation in the blink reflex on the affected side has been observed in episodic CH patients [
Moreover, MOH patients have also shown deficient habituation mechanisms during contingent negative variation [
The role of the central nervous system in pain is not limited to the processing of nociception from the periphery to the higher order regions of the brain; rather, the central nervous system is capable of actively modulating pain perception through descending pain modulatory mechanisms. Among the oldest theories of central inhibition, spinal gate control theory posits a top-down mechanism operating from the cortex to modulate the responses of dorsal horn neurons in the spinal cord [
To date, a number of studies have shown vastly altered endogenous pain modulation in migraine patients. In the first exploration of DNIC dysfunction associated with migraine, researchers used the cold pressor test as a conditioning stimulus and assessed the nociceptive flexion reflex [
As we saw with habituation, changes in DNIC may also be associated with the transformation from EM to CM. Using capsaicin as a conditioning stimulus, research has shown increased R2 area of the blink reflex in CM sufferers, as compared to their EM (with aura) counterparts [
Functional neuroimaging has played a remarkable role in elucidating the pathophysiology of migraine, from demonstrating that hypoperfusion and cortical spreading depression are the underlying mechanisms of visual aura [
Significant efforts have also been made to link migraine to abnormalities in functional connectivity measured by resting-state fMRI (rs-fMRI). Unlike experiments examining brain responses to stimuli (including both experimentally applied stimulation and clinical pain), functional connectivity experiments instead look for concurrent fluctuations of the fMRI signals during a task-free rest period [
While some of the abovementioned experiments have been conducted exclusively with CM patients, many of the studies in the literature have been limited by their inclusion of both chronic and episodic migraine patients. Among those that have focused on CM, a combined electrophysiology and PET study noted increased cerebral metabolism in the brainstem [
Just like migraine, recent years have seen many neuroimaging studies probing the etiology of episodic and chronic CH. Early PET studies provided evidence of activation in the ipsilateral hypothalamus, contralateral thalamus, anterior cingulate cortex, and bilateral insulae in CH [
Neuroimaging studies have provided valuable information on neural plasticity underlying MOH as well. An early PET study provided evidence of hypometabolism in the orbitofrontal cortex that persisted after detoxification, implying that the dysfunction observed is the cause, rather than a consequence, of MOH [
Studies from a wide variety of chronic pain conditions, including chronic back pain [
The mechanisms underlying structural changes in the brain associated with migraine remain to be determined. Based simply on the similarity of findings between migraine studies and those of other headache subtypes and other pain disorders, it has been proposed that these changes are consequences rather than causes of repeated attacks [
Another technique used to evaluate structural alteration in patients with migraine and other pain disorders is surface-based morphometry, a technique that allows the measurement of cortical thickness instead of volume [
In line with these observations, two early studies by Hadjikhani and colleagues reported increased, rather than decreased, cortical thickness in the somatosensory and visual motion areas in patients with EM [
Structural imaging studies of CH also have had mixed results, disagreeing not only on the brain regions affected, but even on the direction of grey matter volume changes. Using VBM, a pioneering structural imaging study revealed gray matter volume increases in the bilateral posterior hypothalamus, a region colocalized with the functional changes observed in PET imaging of CH [
Reversibility of morphological changes has been reported in other chronic pain conditions, including a recent surface-based morphometry study [
Decreases in gray matter volume of pain-related brain structures were also reported in patients with chronic TTH, including anterior cingulate cortex, insula, orbitofrontal cortex, parahippocampal gyrus, and dorsal rostral pons [
In MOH patients with migraine history, significant gray matter volume decreases were reported in the orbitofrontal cortex, anterior cingulate cortex, insula and precuneus, as well as volume increases in the periaqueductal gray, thalamus and ventral striatum [
While the clinical significance is unclear, migraine patients have well-documented white matter hyperintensities [
Another promising line of research in the study of the neural mechanisms underlying chronic headache or pain disorders is represented by the use of magnetic resonance spectroscopy (MRS). MRS allows noninvasive and in vivo exploration of the molecular composition of tissue, by identifying certain metabolites involved in physiological or pathological processes. By using techniques such as single voxel spectroscopy or chemical shift imaging, researchers were able to reveal the presence of biochemical alterations in the brain of patients with various chronic pain disorders. For instance, studies have demonstrated a reduced concentration of N-Acetylaspartate (NAA), a marker of neuronal integrity in chronic low back pain [
Despite the great potential, not many MRS studies have been conducted in migraine patients. Of those that have been conducted, the majority focus on disturbed energy metabolism, indicating a possible role of mitochondrial dysfunction in migraine pathophysiology [
Genes may influence the cerebral processes that lead to the progression from episodic to chronic headache and determine distinctive morphofunctional properties [
Though few in number, studies have been conducted to examine whether select gene polymorphisms might influence neural plasticity (habituation/sensitization) in MOH. The angiotensin-converting enzyme D/D genotype appears to serve as an influencing factor in migraine attack frequency [
Considering that MOH bears resemblance to an abuse disorder and that previously identified susceptibility genes, such as the angiotensin-converting enzyme polymorphism, have also been linked to substance abuse behavior, researchers have sought to examine whether there are psychiatric differences between MOH sufferers with various polymorphisms. Researchers have examined whether the brain-derived neurotrophic factor (BDNF) Val66Met and wolframin His611Arg (WFSI) polymorphisms, both being linked to psychiatric illness and dependence behavior, might be related also to MOH. They observed that individuals carrying the RR WFSI [
Others have taken an epigenetic approach with the hopes of assessing whether gene expression patterns may change along with patients’ migraine state. Hershey et al. [
Genetic linkage studies have reported a significant association between CM and the long allele of monoamine oxidase A 30 bp VNTR and
In summary, inheritance appears to play an important role in determining predisposition to specific clinical manifestations of migraine and the progression to CM, especially when related to MOH. Furthermore, the association between gene polymorphisms and characteristic neurophysiologic patterns in CM suggests that genetics can influence the way the brain responds plastically to chronic head pain and excessive drug consumption.
To date electrophysiological and neuroimaging studies have revealed different aspects of neural plasticity associated with chronic headaches, especially migraine. Table
Other common forms of chronic headaches, such as chronic CH and chronic TTH and MOH, also share some features of neural plasticity with CM, notably changes in brain excitability (Table
Neural responses to episodic headache are initially adaptive and physiologic but later become maladaptive and pathologic, eventually creating a vicious cycle resulting in chronic headache. This process of headache evolution is associated with neural plasticity in brain excitability, biochemistry, function, and even structures. Genetic factors are likely to contribute to this process. Further studies are needed to elucidate if there are common features of neural plasticity among various chronic headaches that may serve as neurologic signatures for chronic headaches, or conversely, headache-specific neural plasticity that may help in the diagnosis and treatment of different chronic headaches.
The authors declare that there is no conflict of interests regarding the publication of this paper.
This project was supported by the Italian Ministry of Health and Fondazione Roma (Gianluca Coppola), W81XWH-14-1-0543 (Marco L. Loggia), R21 NS087472 (Marco L. Loggia), Ministry of Science and Technology, Taiwan (MOST 103-2628-B-075-001-MY3 to Wei-Ta Chen and MOST 103-2314-B-418-009 to Tzu-Hsien Lai), Taipei Veterans General Hospital (VGHUST104-G7-1-3 and V104C-115 to Wei-Ta Chen), and Far Eastern Memorial Hospital (FEMH-2015-C-017 to Tzu-Hsien Lai).