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17. Migraine and Cluster Headache: Differences and Similarities
Keywords
Cluster headacheMigrainePainPathophysiologyAutonomic symptomsNeuroimagingAbbreviations
- CH
Cluster headache
- ICHD-III
International Classification of Headache Disorders 3rd edition
- TAC
Trigeminal autonomic cephalalgia
- CAS
Cranial autonomic symptoms
- CSD
Cortical spreading depression
- DBS
Deep brain stimulation
- IHS
International Headache Society
- GON
Greater occipital nerve
- TCC
Trigeminocervical complex
- CGRP
Calcitonin gene-related peptide
- NO
Nitric oxide
- NKA
Neurokinin A
- MRS
Magnetic resonance spectroscopy
- fMRI
Functional magnetic resonance imaging
- FC
Functional connectivity
- VBM
Voxel-based morphometry
- GMV
Gray matter volume
- DTI
Diffusion tensor imaging
- WM
White matter
17.1 Introduction
Migraine and cluster headache (CH) are widely regarded as two of the most disabling primary headache disorders. According to the International Classification of Headache Disorders (ICHD-III) criteria, there is a clear diagnostic distinction between migraine and CH [1]. Migraine—which affects approximately 10% of the global adult population with female predominance [2]—is characterized by recurrent attacks of 4–72 h moderate-to-severe headache of pulsating quality, aggravation during routine activities, and the presence of nausea, vomiting, photophobia, and phonophobia [2]. Patients with migraine can also experience autonomic, affective, and cognitive symptoms before (premonitory phase), during, or after (postdrome) each headache episode [3]. Furthermore, approximately one-third of patients with migraine experience transient focal neurological deficits or “auras” (e.g., visual, speech and/or language, sensory, motor, brainstem, or retinal deficits) [4]. CH is much less prevalent than migraine (0.1% of the population) and occurs more frequently in men than in women [5]. CH is the most common form of trigeminal autonomic cephalalgias (TACs) and has been regarded as one of the most painful conditions people can experience, with a pain intensity estimated to be 100–1000 times worse than migraine [6, 7]. CH attacks are characterized primarily by severe, unilateral, and relatively short-lasting (15–180 min) headache episodes. These episodes occur in association with ipsilateral cranial autonomic symptoms (CAS) such as conjunctival injection and/or lacrimation, nasal congestion and/or rhinorrhea, eyelid edema, forehead and facial sweating, and miosis and/or ptosis [7] (ICHD-3 criteria). CH is also characterized by circadian and circannual rhythmicity: CH attacks may occur at the same time(s) each day during episodes that last for weeks or months (in-bout period), separated by pain-free remission periods (out-of-bout period) [7]. Although the characteristic features of migraine and CH are very different, in practice there can be substantial overlap in the clinical presentations of the two disorders [8].
Furthermore, research indicates that migraine and CH share some pathophysiologic mechanisms, such as head pain being mediated by activation of neuronal pathways within the trigeminovascular system [9, 10]. Previous research suggests that the pathophysiology of migraine may involve the diencephalon and brainstem, regions that might also be involved in cluster headache [11]. Additional studies have indicated that cortical spreading depression (CSD)—a wave of neuronal hyperactivity followed by cortical depression—is the most likely pathophysiological mechanism underlying the generation of migraine auras [12]. Neuroimaging studies and the reported efficacy of deep brain stimulation (DBS) have suggested that CH attacks involve the ipsilateral hypothalamus, particularly during the active headache period [13].
In this chapter, we review the similarities and differences in the clinical and pathophysiological characteristics of these two headache disorders.
17.2 Differences and Similarities in the Clinical Features of CH and Migraine
17.2.1 Pain Location and Duration
In both migraine and CH, the location of the pain is primarily in the first division of the trigeminal nerve, with more than three-quarters of patients with CH reporting periorbital pain localization [7, 14]. Although approximately two-thirds of patients with migraine report unilateral pain, pain can be bilateral or begin unilaterally before developing into generalized pain. The headache side may also change within the same attack [15].
The pain of a CH attack is almost exclusively side-locked, and the patient usually experiences attacks consistently on the same side of the head. However, studies have reported that approximately 17% of patients with migraine also experience side-locked headaches [16]. Moreover, some patients with CH experience pain that shifts sides during attacks, and very rarely pain can occur on both sides during a single attack [14, 15]. This shift may occur following invasive treatment such as unilateral occipital nerve stimulation [17]. Most CH attacks last between 30 and 120 minutes, seldom persisting for more than 3 h (when untreated) [15]; however, most migraine attacks last for at least 4 h and may last for 2–3 days if untreated [18].
17.2.2 Circannual and Circadian Periodicity
Many patients with CH experience extended periods of time in which headache attacks recur from one every other day to up to eight per day. These in-bout periods last for weeks or months, during which time most patients experience one to two attacks per day. These periods are followed by headache-free periods of weeks to years (out-of-bout periods) [7]. Furthermore, patients with CH tend to experience attacks at the same time(s) each day. This pattern may persist for days or weeks, and a nocturnal preponderance is commonly observed [15]. CH may also exhibit seasonal periodicity, with the onset of in-bout periods occurring once or twice yearly, especially in the spring and autumn (following solstices) [7, 19].
This consistent circannual and circadian periodicity is rarely observed in patients with migraine. The median migraine attack frequency is 1.5 attacks per month, although approximately 10% of patients experience migraine attacks at least weekly [18]. However, some reports have indicated that migraine attacks with aura peak once per year in May [20], and some patients with migraine may similarly experience frequent headaches during a limited period (several weeks to months), which may even recur during the same season. This condition has often been described as cyclical migraine [21]. Studies have also demonstrated that patients with cyclical migraine respond well to lithium carbonate, which is generally accepted as a standard prophylactic therapy for CH [19, 21].
17.2.3 Cranial Autonomic Symptoms (CAS)
CH attacks are usually accompanied by ipsilateral CAS, including conjunctival injection, lacrimation, nasal congestion, eyelid edema, forehead/facial sweating, miosis, and ptosis [7]. These distinct CAS are suggestive of a parasympathetic discharge with a sympathetic deficit, although the precise reason for unilateral CAS in patients with CH remains unknown. Researchers have hypothesized that ipsilateral activation of the hypothalamus during headache attacks may stimulate ipsilateral while simultaneously suppressing contralateral, trigeminal autonomic reflexes [22]. However, patients with CH may also experience bilateral CAS such as conjunctival injection or facial/forehead sweating [23, 24]. This may be because the trigeminal autonomic reflex includes an often minor contralateral component, likely due to crossover within the brainstem [25].
These CAS are also observed in 67–95% of patients with migraine. Therefore, migraines accompanied by autonomic symptoms may clinically mimic CH [23, 26]. However, patients with migraine mainly experience a single CAS, which tends to be less consistent, bilateral, less severe, and unrelated to the headache side [27]. In contrast, patients with CH are more likely to report multiple and more severe CAS [14, 23]. Collectively, these differences in the clinical characteristics of CAS may aid physicians in differentiating CH from migraine with CAS.
17.2.4 Aura Symptoms
Although aura symptoms usually involve visual sensations (flashing lights, scintillating scotomas), they may occasionally include facial and limb paresthesias, speech disturbances, weakness, vertigo, and mild ataxia. Previously, such symptoms were regarded as being solely characteristic of migraine with aura [4]; however, aura symptoms have been reported in up to 20% of patients with CH [28, 29]. Furthermore, Asian patients with CH tend to present less frequent aura symptoms (approximately 1%) than Western patients [30]. Studies have also indicated that only 1.8% of patients with CH have comorbid migraine with aura [31].
17.2.5 Restlessness
While headaches during migraine attacks are usually aggravated by movement or routine physical activity [18], between 51% and 99.2% of patients with CH experience restlessness and/or agitation during attacks [7, 14]. Thus, individuals with migraine typically remain quite still during attacks (e.g., lying in bed), while those with CH often pace or rock during CH attacks. Despite the agitated behavior that is common during CH attacks, physical activity can worsen headache intensity in a minority of patients with CH. Although it was previously believed that the pain of CH attacks is not exacerbated by activity or movement, more recent studies have reported that approximately 7–45.8% of patients with CH also experience aggravation of headache pain during physical activity or movement [30, 32]. While restlessness and avoidance of movement are hallmarks of CH and migraine, respectively, Asian patients with CH tend to exhibit less frequent pacing/restlessness than Western patients [30].
17.2.6 Other Features
Nausea and vomiting are commonly observed during acute migraine attacks [18, 33]. Sensory hypersensitivity is also observed in most patients with migraine, with photophobia and phonophobia occurring in up to 90% of patients [18, 33]. Interestingly, a high proportion of patients with CH also report at least one accompanying symptom (photophobia, phonophobia, nausea, or vomiting) typically associated with migraine [7, 14]. Studies have reported that 27–53% of patients with CH experience nausea, 12–32% experience vomiting, 54–78% experience photophobia, and 15–49% experience phonophobia [7, 14]. Individuals with CH more commonly report unilateral photophobia and phonophobia, while those with migraine nearly always report that these symptoms are bilateral [34]. Some patients with CH have also reported a variety of triggers for their attacks (e.g., certain foods, odors, or chocolate), many of which are supposed triggers of migraine attacks as well [19].
Although premonitory symptoms such as fatigue, apathy, irritability, yawning, and neck pain/stiffness are not included in the International Headache Society (IHS) classification criteria for migraine, such symptoms are known to precede migraine attacks in the majority of patients with migraine [15, 35]. However, these symptoms are also observed in approximately 8–11% of patients with CH [15, 36].
Comparisons of the clinical features between CH and migraine
CH | Migraine | |
|---|---|---|
Prevalence | Approximately 0.1% | Approximately 10% |
Sex predominance | Majority male | Majority female |
Location of pain | Primarily in the first division of the trigeminal nerve, one-sided, around the eyes | Primarily in the first division of the trigeminal nerve, one-sided or both sides |
Duration of each headache attack (when untreated) | 15–180 min | 4–72 h |
Intensity of pain | Severe or very severe | Moderate or severe |
Occurrence of attacks | Multiple attacks daily for weeks during the in-bout period (0.5–8/day) | Usually 1–7 per month |
Circannual and circadian periodicity | Common | Rare |
Cranial autonomic symptoms | Most accompanied by ipsilateral cranial autonomic symptoms Consistent, severe, ipsilateral to headache side | Approximately 67–95% of patients Inconsistent, less severe, bilateral |
Aura | Rare | Approximately 1/3 of patients |
Restlessness and/or agitation during attacks | Approximately 51% and 99.2% of patients | Rare |
Headache exacerbated by activity or movement | Approximately 7–45.8% of patients | Approximately up to 90% of patients |
Nausea and vomiting during attacks | Nausea, approximately 27–53% of patients; vomiting, 12–32% of patients | Approximately 50–90% of patients |
Photophobia and/or phonophobia | Photophobia, approximately 54–78% of patients; phonophobia, 15–49% of patients | Approximately up to 90% of patients |
Premonitory symptoms | Approximately 8–11% of patients | Approximately up to 88% of patients |
Allodynia | Approximately 40–49% of patients | Approximately up to 62% of patients |
Prophylactic treatment is important for both CH and migraine. Some prophylactic treatments are similarly effective for patients with CH and for those with migraine, such as calcium channel blockers (i.e., verapamil) and anticonvulsants (i.e., sodium valproate, topiramate). However, others such as beta-blockers and tricyclic antidepressants are more effective in patients with migraine than in those with CH [39, 40]. In contrast, oxygen and lithium are more often used in patients with CH.
While many women with migraine notice that their headaches greatly improve during the second and third trimesters of pregnancy, few large-scale prospective studies have investigated the effect of pregnancy on patients with CH, as the condition is observed in less than 0.3% of pregnancies [41]. In one previous study, approximately 25% of pregnant women with CH reported that an expected cluster period did not develop during gestation, although many reported that clusters began soon after delivery. Additionally, the majority of these women reported that CH attacks did not change in frequency or intensity during pregnancy [42]. Menstruation, the use of oral contraceptives, and menopause also exert a much smaller influence on CH attacks than on migraine attacks. However, CH may have an impact on women with the condition, who may refrain from having children due to their symptoms [42].
17.3 Pathophysiological Similarities and Differences Between CH and Migraine
17.3.1 The Trigeminovascular System
In CH and migraine, headache pain originates from activation of the trigeminovascular system. The trigeminovascular system consists of the neurons innervating the cerebral vessels whose cell bodies are located in the trigeminal ganglion [43]. This ganglion contains bipolar cells: the peripheral fiber making a synaptic connection with the vessels in the meninges, the extracranial arteries, and those in the circle of Willis; and the centrally projecting fiber synapsing in the caudal brainstem or high cervical cord [43]. Furthermore, the peripheral fibers—which are mainly found in the ophthalmic division of the trigeminal nerve—exhibit synaptic connections with the dura mater, vessels, and other widespread brain structures involved in pain processing [44, 45]. In CH, activation of the trigeminovascular system may trigger CAS through the trigeminal autonomic reflex [46]. The trigeminal nucleus caudalis exhibits a connection with the superior salivatory nucleus, from which the parasympathetic efferent fibers of the facial nerve arise. Activation of these parasympathetic fibers may result in symptoms such as rhinorrhea, lacrimation, nasal congestion, ptosis, and miosis [47]. Furthermore, fibers originating from the superior salivatory nucleus synapse in the pterygopalatine ganglia, with postganglionic fibers innervating the cerebral vessels as well as the lacrimal and nasal glands [47]. This explains why blockade of the sphenopalatine ganglion may relieve the symptoms of CH attacks in some patients [48]. It is widely accepted that high-flow oxygen is an efficient abortive therapy for acute CH attacks [49]. Indeed, previous animal studies have suggested that oxygen may produce these effects by acting on parasympathetic outflow to the cranial vasculature and trigeminovascular system [50].
Although most migraine pain is localized to the ophthalmic division of the trigeminal nerve, some patients report headache sites outside this region, such as in the occipital area, the area of innervation for the greater occipital nerve (GON) [51]. This may be due to the convergence of trigeminal and cervical afferent neurons in the trigeminocervical complex (TCC)—the region of the brainstem in contact with the caudal portion of the trigeminal nucleus caudalis and the dorsal horn of the C1–C2 segments of the spinal cord [51]. Additionally, the pathophysiology of migraine attacks involves both central and peripheral sensitization. Peripheral sensitization is associated with the activation of primary afferent nociceptive neurons [52]: A first-order neuron in the trigeminal ganglion receives input from dura-level blood vessels. This signal is then transmitted to a second-order neuron in the trigeminal brainstem nuclear complex, followed by a third-order neuron in the thalamus to the sensory cortex [53]. The major clinical symptom associated with first-order-neuron sensitization is throbbing pain that is aggravated by physical activity or certain postures that increase intracranial pressure (e.g., coughing) [53]. Moreover, sensitization of the nociceptors innervating the meninges may also result in intracranial hypersensitivity [54].
The central sensitization hypothesis suggests that, when peripheral sensitization later spreads to second-order neurons in the trigeminovascular system, cutaneous allodynia (pain evoked by applying non-noxious stimuli to normal skin) will occur [55]. Furthermore, the sensitization of third-order neurons in the thalamus is clinically expressed as extracranial hypersensitivity [54]. Thus, altered sensory processing in the brainstem may lead to hyperexcitability of TCC neurons [56]. Central sensitization may contribute to reducing the pain threshold, aggravating the pain response, and resulting in typically non-painful stimuli being perceived as painful (i.e., allodynia) [57]. Interestingly, central sensitization is also believed to be a risk factor for increasing headache frequency, such as transforming from episodic migraine to chronic migraine [55, 58].
17.3.2 Neuropeptide Release
Release of vasoactive neuropeptides from trigeminovascular sensory afferents results in vasodilatation, leakage of plasma protein from blood vessels, and mast cell degranulation [59, 60]. Following activation of the trigeminal fibers or trigeminal ganglion, neuropeptides such as calcitonin gene-related peptide (CGRP), substance P, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) [61] are released. These neuropeptides have been associated with the pathophysiology of both CH and migraine [60].
CGRP is also a powerful vasodilator that may contribute to dilation of the dura vessels [62]. Previous studies have also reported that substance P-immunoreactive fibers are more highly concentrated around the cerebral arteries, while CGRP-immunoreactive fibers are more highly concentrated around the middle meningeal artery [62]. Animal studies have demonstrated that small nerve fibers containing CGRP and substance P arise from the trigeminal ganglion and innervate the dura mater [62], thereby allowing for the transmission of nociceptive information from nerves innervating meningeal blood vessels to the trigeminal nucleus caudalis [63]. Accumulating evidence also suggests that migraine can be successfully treated using antibodies against CGRP, CGRP receptor antagonists, and CGRP-regulating triptans [64, 65]. Such findings support an important role for CGRP in migraine and other primary headache disorders [66–69].
Previous studies have demonstrated that elevated plasma concentrations of CGRP, substance P, and VIP occur during migraine attacks and during CH attacks (for a review see [70]). Furthermore, since VIP is derived from parasympathetic afferents, elevated plasma VIP may be associated with parasympathetic activation, which has been linked to CH pathophysiology [71]. Nitric oxide (NO), which may interact with CGRP, is also a potent vasodilator in the meningeal circulation [71]. The interaction between NO and CGRP may contribute to vasodilation and peripheral sensitization of perivascular afferent fibers [72]. Furthermore, infusion of nitro-vasodilators can trigger CH attacks, supporting a key role for NO in CH pathophysiology and nociceptive processing, as well as migraine [73].
Research has further revealed that substance P and neurokinin A (NKA) may increase vascular permeability in response to trigeminal nerve activation [74]. Moreover, it has been hypothesized that activation of substance P neurons in the ophthalmic and maxillary divisions can cause all the symptoms of an acute CH attack, and this could explain the observed improvement in symptoms following blockade of the Gasserian or sphenopalatine ganglia [75]. Although there is a potentially prominent link between the release of several important neuropeptides in migraine and CH pathophysiology, further research is required to fully elucidate this relationship and its role in triggering and maintaining individual attacks.
17.3.3 Structural and Functional Brain Changes
17.3.3.1 Cluster Headache
Clinically, the circadian rhythmicity and ipsilateral cranial autonomic features of CH underlie the hypothesis that the disorder may involve the hypothalamus [76, 77]. Indeed, functional imaging studies have documented increased ipsilateral posterior hypothalamic activation in patients with CH during acute attacks [78–80]. Proton magnetic resonance spectroscopy (MRS) studies have provided additional evidence in support of the hypothesis that CH is caused by hypothalamic neuronal dysfunction [81, 82]. In addition to the hypothalamus, several regions of the pain matrix have been strongly implicated in CH, including the anterior cingulate cortex, posterior thalamus, basal ganglia, insula, and the cerebellar hemispheres [79, 80, 83]. Furthermore, dynamic functional differences in the central descending pain-modulatory system have been observed between in-bout (without acute attacks) and out-of-bout periods [84].
Several functional magnetic resonance imaging (fMRI) studies have reported abnormal functional connectivity (FC) between the hypothalamus and other brain areas (i.e., areas of the pain network) in patients with CH experiencing acute attacks [85, 86]. Additionally, FC disruptions in nontraditional pain-processing areas (e.g., occipital and salience networks) may also be involved in CH pathophysiology [87, 88]. These FC differences in nontraditional pain-processing areas have also been associated with the patient’s in- or out-of-bout status [88, 89], advancing our understanding of network functionality in episodic CH.
Using T1 voxel-based morphometry (VBM), structural imaging studies have demonstrated changes in the gray matter volume (GMV) of the hypothalamus and several pain-processing regions in patients with CH [83, 90–93]. GMV differences have also been observed between in-bout and out-of-bout periods. These changes in GMV may reflect an insufficient capacity to modulate pain in frontal areas, which may contribute to the pathophysiology of shifts in bout status among patients with CH [92].
Several diffusion tensor imaging (DTI) studies have documented controversial microstructural white matter (WM) changes in patients with CH, while others have reported no differences between patients with CH and healthy controls [91]. Still other studies have reported changes primarily in regions related to the pain matrix [94, 95]. Such discrepancies may be attributable to differences in bout status among the study populations. An additional study documented dynamic microstructural differences in the frontal and limbic WM between patients with CH and healthy controls (with the exception of the cerebellum), noting that these changes persisted during the out-of-bout period [96]. Consistent anatomical connections have also been observed between these altered areas and the hypothalamus [96]. These findings may also partially explain the shifts between in-bout and out-of-bout periods in patients with CH.
17.3.3.2 Migraine
Functional neuroimaging studies have demonstrated differences in brain activation patterns during migraine attacks compared to the interictal phase, highlighting the potential importance of brainstem regions such as the dorsal midbrain, dorsolateral pons, and trigeminal nucleus caudalis and of the hypothalamus for generating acute migraine attacks [97, 98]. Increased activation has also been observed in the red nucleus, substantia nigra, posterior thalamus, cerebellum, insula, cingulate, prefrontal cortices, hippocampus, and anterior temporal pole during migraine attacks [10, 97–99]. However, these areas do not appear to be specific to migraine and are collectively referred to as the “pain matrix,” which exhibits increased activation in other pain disorders that are thought to occur secondary to central hypersensitivity (e.g., low back pain, irritable bowel syndrome, fibromyalgia, and cardiac pain) [100].
Evidence obtained from fMRI studies indicates that activation of the thalamic pulvinar occurs during migraine attacks accompanied by extracephalic allodynia, suggesting that sensitization of posterior thalamic neurons may mediate the spread of multimodal allodynia and hyperalgesia beyond the locus of the migraine headache [101]. Patients with episodic migraine also experience greater pain-induced activation in regions primarily associated with the cognitive aspects of pain perception, including attending to pain and pain memory [102]. Therefore, enhanced cognitive pain processing by migraineurs may reflect cerebral hypersensitivity, which may in turn be associated with high expectations and hypervigilance for pain [102]. Migraine may also be associated with altered FC in the insular region during the interictal state, especially with the dorsal pons [103]. Moreover, the FC of various brain regions and networks may be altered during the pain stage of migraine attacks [104]. More recently, Schulte and May investigated the different stages of the native migraine cycle in a single patient with episodic migraine. The authors observed heightened hypothalamic, pontine, trigeminal nucleus caudalis and visual cortex activity shortly before the onset of migraine pain. Furthermore, the FC between the hypothalamus and trigeminal nucleus caudalis/dorsal rostral pons differed between the pre-ictal and ictal phases, providing evidence that changes in hypothalamic FC occur during different stages of the migraine cycle [105].
In addition to functional alterations, VBM and DTI studies have also demonstrated GMV reductions in the insula, motor/premotor cortex, prefrontal cortex, cingulate cortex, posterior parietal cortex, and orbitofrontal cortex in patients with migraine, along with thickening of the somatosensory cortex and increased gray matter density in the caudate [106–108]. Furthermore, several reports have indicated that such changes in areas mostly related to pain processing may be associated with the frequency and duration of migraine attacks [106–108]. Similarly, these structural changes have also been observed in patients with other chronic pain disorders, including osteoarthritis, chronic low back pain, and pelvic pain [109].
The accumulated evidence from structural and functional neuroimaging studies draws a complex picture of the central mechanisms underlying CH and migraine, with some key similarities and differences. First, the hypothalamus and the dorsal rostral pons likely play key roles during the acute stages of migraine, similar to the key role of the hypothalamus in acute CH attacks. Furthermore, the trigeminal nuclei are essential for headache generation in both migraine and CH [110]. Recent evidence suggests that the hypothalamus is not only a potential generator of CH attacks but also a generator of migraine-like accompanying symptoms [105]. Furthermore, the descending projections of the hypothalamus may activate or disinhibit the trigeminal nucleus caudalis and the dorsal rostral pons, both of which are thought to be specifically associated with the activation of migraine attacks [105]. Additionally, the activation of the trigeminal system via trigeminal autonomic reflexes may explain the variation in CAS observed in patients with CH who exhibit migraine-like accompanying features [111]. Finally, although these structural and functional changes in pain-related areas can be observed in patients with CH and in those with migraine, some overlap is also observed with other chronic pain disorders, suggesting that CH and migraine may also be related to these pain disorders. However, unique to CH are the dynamic changes in the structure and functional linkage of pain-modulatory networks—as well as regions outside of the traditional pain-processing networks—that occur between in-bout and out-of-bout periods. Such changes may indeed be more specific to the pathophysiology of CH.
17.4 Conclusions
Both migraine and CH are disorders of the trigeminovascular system with complex pathophysiological origins. Although the two conditions can be differentiated based on differences in clinical symptoms, neurochemical mechanisms, and neuroimaging patterns, some overlap (e.g., some clinical features and similar responses to triptans) can be observed between the two. Identifying the similarities and differences between CH and migraine may advance the current understanding of the shared pathophysiology of these two conditions and aid in the development of novel therapeutic strategies.
