Pre-clinical Research of Post-Traumatic Headache with Migrainous Features


On an annual basis, approximately 3.17 million people with traumatic brain injury (TBI) experience long-term disability (TBI) [1, 2]. P(PTH) is the most common chronic pain syndrome within the TBI population [3, 4]. PTH can be a new headache resulting from head trauma or worsening of a pre-existing headache disorder. PTH may result from direct injury to the skull, brain, meninges, vasculature, or neck. The degree, severity, and manifestations within the brain that lead to PTH are diverse. PTH may have a phenotype similar to primary headache disorders, including migraine, tension-type headache, or cluster headache [5, 6].

The time-course of PTH is important. In many patients, it resolves in three months; in others, it persists for much longer. Persistence beyond the expected tissue-healing time suggests that peripheral and central sensitization may have developed [7-9]. According to the International Classification of Headache Disorders (ICDH-2), PTH develops within seven days after injury or regaining consciousness, but PTH may be delayed in a subset of people with head trauma. In a prospective study, the onset of PTH occurred between seven and 30 days after injury or later in nearly half of patients [10]. Ofek et al. report the mean onset of chronic pain, including head pain, was just over six months after TBI [9]. TBI is also a risk factor for the conversion of episodic headache (headache occurring less than 15 days/month) into chronic headache (>15 days/month) [11, 12]. In a study by Hoffman and colleagues, 41% of patients with TBI reported a headache at three, six, and 12 months after injury. Studies using quantitative sensory testing (eg. von Frey mechanical stimuli for allodynia [cutaneous sensitivity to mechanical stimuli that are innocuous under normal conditions]) show that 40% of patients with TBI experience chronic head and face pain after head injury [9, 13]. Significant reductions in pressure-pain thresholds were found at least one year after mild to moderate TBI [13]. Developing new PTH treatments and understanding the underlying mechanisms of the disorder have been hindered by a lack of pre-clinical models. In this letter, we discuss potential mechanisms of PTH and related pre-clinical research initiatives using a reproducible model of TBI.

Enhanced sensory input to the trigeminovascular pathway

Migraine-type headache is mediated by the trigeminovascular system; abnormal and/or persistent activation of this system leads to the development of chronic headaches [14, 15]. The trigeminovascular system is made up of sensory nerve fibers that extend peripherally from the trigeminal ganglion to innervate the extracranial skin, cranial meninges, periosteum, and cerebral vasculature. Central afferent fibers of the trigeminal ganglion relay nociceptive signals to the brainstem trigeminal nuclei. Peripheral nociceptor sensitization results in enhanced responsiveness to stimuli [14, 16]. Synaptic function may be enhanced characterized by increases in neurotransmitter release, neuronal activation, or new synapse formation. Sensitization of cranial nociceptors after TBI depends on the location and type of head injury.

Pain generated by peripheral nociceptor sensitization is the result of a lowered activation threshold or increased responsiveness to activation (temporal-spatial summation) [17]. Injury and/or neuroinflammation modifies the excitability, transduction, and neurotransmitter properties of nociceptors contributing to sensitization, increased nociceptive synaptic transmission, and/or enhanced synaptic efficacy. The release of nociceptive excitatory neurotransmitters (glutamate, calcitonin gene-related peptide (CGRP), substance P (SP), and nitric oxide) increases. Neurons undergo a phenotypic change after neural injury: SP (which is normally expressed only by C-fiber neurons) becomes expressed by A-fibers, contributing to the sensitization process[18-22]. SP increased around cerebral blood vessels in the forebrain and in the caudal trigeminal nucleus for up to two days after TBI [23, 24]. CGRP increased in both serum and cerebrospinal fluid in humans and animals following injury [25, 26]. Acute, transient increases in CGRP have been shown to have a protective function for cerebrovascular autoregulation, though it is unclear what role continued CGRP increases might have in the development and maintenance of post-traumatic headache [27-29]. The role of CGRP in migraine was determined in the 1990’s by Goadsby and Edvinsson; clinical and pre-clinical migraine studies showed that CGRP increases in the intracranial and extracerebral circulation [30]. CGRP antagonists are effective in the treatment of migraine.

Central activators of the pain pathway

Peripheral nociceptor sensitization can result in central sensitization, which may occur in chronic pain states. Central sensitization refers to the heightened sensitivity (i.e., modified activation threshold and responsiveness to synaptic input) of second order neurons in the brainstem and spinal cord or higher order thalamic and cortical neurons [8]. Following induction by peripheral nociceptor activation and sensitization, central sensitization may be centrally mediated [31]. Central sensitization can be input-independent, outlasting peripheral input; it may be a transcription-dependent phenomenon. Transcription-dependent central sensitization is seen in the neurokinin peptide-receptor system, which consists of SP and its receptor, neurokinin-1, in response to peripheral inflammatory stimuli [17]. Migraine involves central sensitization, resulting in extratrigeminal allodynia, this may also be the case in TBI. This can be studied in models of TBI [32-34]. In rats, midline fluid percussion injury results in whisker hypersensitivity and increased neuronal activation in the thalamus, due to a combination of inflammation, hyper-excitation, and disrupted circuitry in the thalamus and cortex [35]. Loss of inhibitory interneurons and cortical spreading depression can contribute to sensory disorders after TBI.

Nitric oxide (NO) is an important signaling molecule with a well-known role in the pathophysiology of migraine; its role in PTH is poorly understood. Constitutive nitric oxide synthase (NOS), endothelial NOS (eNOS) and neuronal NOS (nNOS), are known to contribute to the pathology of migraine [36]. The constituitive NOS isoforms, eNOS and nNOS, are increased early after TBI, while inducible NOS (iNOS) may be substantially increased for days to weeks [37, 38]. NO stimulates the release of CGRP and CGRP stimulates the release of NO [36, 39]. A NO donor, glyceryl trinitrate (GTN), has been used to study migraine in both humans and rodents. GTN administered to rats undergoing repeated extradural inflammatory soup infusions results in decreased periorbital sensory threshold and increased extracellular glutamate levels in the trigeminal nucleus caudalis (TNC) [16, 40]. In mice, GTN induced hindpaw thermal and mechanical allodynia that was associated with increases in neuronal activation in the TNC and upper cervical spinal cord [41]. The exact contribution of increases in NOS and NO expression to post-traumatic morbidity remains unclear.

TBI may result in neuroinflammation, which can produce chronic pain, including headache. Most animal models of migraine involve administration of pro-inflammatory mediators to induce migraine-type responses [14, 40, 42]. An important source in endogenous inflammatory mediators is activated glial cells in the central nervous system. These are important  in the initiation and maintenance of chronic pain states [43]. Glia, macrophages, microglia, and astrocytes are the major source of mediators (eg. cytokines, chemokines, NO, prostaglandins, excitatory amino acids) that contribute to neuronal sensitization. Pro-inflammatory cytokines directly sensitize nociceptors and promote pro-nociceptive pathways, such as cyclooxygenase-2-mediated prostanoid release. Reactive astrocytes in the traumatized brain have reduced ability to clear glutamate, resulting in increased excitation. Astrogliosis in the injured brain may contribute to altered neuronal function, driving pathological sensory changes.

In summary, TBI may result in extracranial and/or intracranial nociceptor sensitization or independent of central sensitization within the traumatized brain. Well-designed studies using animal models with the necessary controls will help to tease out these postulated mechanisms.

Pre-clinical research to study post-traumatic headache

We propose that ongoing neuroinflammatory-excitatory cascades induced by TBI stimulate, sensitize, and initiate neuronal plasticity in the trigreminovascular pain pathway, producing an altered sensory phenotype. To date, our data in a model of cortical contusion impact (CCI) injury suggest meningeal nociceptor sensitization, along with mechanisms of central sensitization may be involved. We demonstrated that, two days after cortical impact injury, substance P immunoreactivity occurs within the TNC accompanied by microglial activation and neurogenic inflammation in the injured cortex [23]. Our preliminary studies show that cortical injury induces increases in CGRP levels in the brainstem associated with bilateral periorbital allodynia, which persists up to four weeks after injury. Pro-inflammatory mediators and excitatory neurotransmitters released in the traumatized brain may activate and sensitize meningeal nociceptor sensory afferents, in turn resulting in activation of the trigeminal nociceptive pathway and eliciting allodynia.  Findings by our laboratory show increases in CGRP and mechanical allodynia  of outlasted glial activation in the injured cortex, indicating that additional mechanisms, such as transcriptional-dependent sensitization, are involved. Following diffuse TBI, in a model of midline fluid percussion injury, hypersensitivity of the rodent whiskers is associated with increased neuronal activation and neuroplasticity in the somatosensory cortex, thalamus, and hippocampus [35]. The periorbital skin is innervated by the same peripheral axons of the trigeminal ganglion that innervate the meninges, cerebral vasculature, and anterior scalp, as well as the whiskers in rodents. Periorbital and facial allodynia exist in humans with TBI, migraine models, and humans with migraine. Our laboratory is the first to report persistent periorbital allodynia in a model of TBI. The cortical injury in our model includes the lateral primary motor cortex and primary sensory hindlimb and forelimb regions, but not the primary sensory barrel field. There is no gross morphological damage in the contralateral hemisphere, thalamus, or brainstem in our TBI model. Therefore, investigations into altered synaptic function and specific inflammatory-excitatory molecular mediators in areas along the pain pathway such as the trigeminal ganglia, sensory cortices, and thalamus are warranted. In summary, persistent changes in central neuropeptides and allodynia in a TBI model are indicative of abnormal, sustained activation of the trigeminovascular complex. These changes indicate that our model simulates secondary post-traumatic headache disorder with migrainous features. Whether changes persist or worsen beyond the acute neuroinflammatory phase has yet to be fully studied.


Despite the magnitude of PTH, understanding its pathophysiology and advances in treatment have remained limited, due in part to a significant gap in pre-clinical research and lack of a means to study this disorder. Pre-clinical research utilizing graded injury models and comparisons among TBI models of different injury mechanisms that are designed to account for the chronicity of headache are needed. Pre-clinical research is needed to enhance our understanding of the complex molecular substrates that contribute to the chronification of post-traumatic headache. To begin addressing post-traumatic headache from the bench, research identifying factors that are important for pro-nociceptive rewiring of the pain circuitry along with strategies to prevent and reverse this maladaptive post-traumatic plasticity is necessary.


We would like to thank Dr. Jack Jallo and the Department of Neuroscience at Thomas Jefferson University for their support and resources to conduct research involving PTH.


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Corresponding Author

Melanie B. Elliott, PhD
Assistant Professor
Department of Neurosurgery, Thomas Jefferson University
1025 Walnut Street, Suite 516 College
Philadelphia, PA 19107 
Phone: 215-955-3776 Fax: 215-503-9871


 Stephen D. Silberstein, M.D. 
Department of Neurology
111 South 11th Street, Suite 8130 
Philadelphia, Pennsylvania 19107 
Phone: 215-955-2072 Fax: 215-955-6682

Michael L. Oshinsky, PhD
Assistant Professor
Department of Neurology, Thomas Jefferson University
1020 Locust St., Suite 398 JAH 
Philadelphia, Pennsylvania 19107
Phone: 215-955-0433 Fax: 215-955-4878

There are no conflicts of interest to report for any of the authors.