Research proposal on neurostimulation for Cluster Headache Ana Ruela 1263919 CecĂlia Nunes 1263897 Joana Rodrigues 1263935 Master in Biomedical Engineering, Technology for the support of human functions
Abstract: Cluster headache (CH) is a type of neurovascular headache, characterized by extremely severe unilateral pain attacks, localized at the temple and periorbital region. There are several available treatments that minimize the symptoms. However, a small percentage of patients is refractory to any treatment. Therefore, neurostimulation techniques, such as deep brain stimulation (DBS), have become an important therapeutic option. About 80 patients worldwide have had DBS for cluster headaches, with 60% of them having experienced significant improvement. After many years of investigation and different hypotheses, the pathophysiology of CH is not yet understood. The genesis of CH must account for its distinguishing features: the trigeminal distribution of the pain, the autonomic features, the consistent circadian and circannual periodicity and the male prevalence. Only a dysfunction in a central component of the nervous system could account for them, such that, hypotheses of peripheral attack triggers have long been abandoned. Most available data indicate the involvement of the body’s biological clock, the suprachiasmatic nucleus (SCN), and the inferior posterior hypothalamus (PH). The role of these structures in the disease is unclear. The aim of presented research proposal is to suggest a microrecording experiment that may hinder insights regarding the involvement of the inferior PH and the SCN is the pathological mechanisms of CH. For this, an experimental setting with the implantation of microarrays in those locations is suggested, in association with the implantation of a DBS device in the PH. The specific goal is to investigate the neuronal firing patters of these brain areas, comparing the results obtained during an ongoing attack with the results for a basal state, within and outside a cluster period. Keywords: pain, cluster headache, deep brain stimulation, hypothalamus, suprachiasmatic nucleus.
1. Anatomical and physiological Background of Pain
emotional and behavioral factors associated with actual or potential tissue injury. Pain presents a challenge to medical staff because it is highly subjective [1] and impossible to quantify. Therefore, the information given by the patients is crucial. [2] In order to provide the best possible care for patients experiencing pain, medical
Pain can be defined as an unpleasant sensation often caused by intense or damaging stimuli. This feeling is a personal, subjective experience that involves sensory,
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professionals must understand the mechanisms underlying the physiology of pain, the different types of pain and their main manifestations but also the diversity of patients’ response.
fibers and C fibers. The large A delta fibers produce sharp well-defined pain, also known as “fast pain” or “first pain”. Typically these fibers are stimulated by a cut, an electrical shock, or a physical blow and transmission through them is very fast. After this pain, the smaller C fibers transmit dull, burning or aching sensations, known as “second pain”. Compared to the A fibers, C fibers are slower in pain transmission, because they are smaller and unmyelinated. These fibers are the ones that are responsible for the constant pain. Finally, there are the A beta fibers, which are sensory receptors, that, when stimulated, dominate and block the transmission through the other fibers. This ability to block pain impulses is the reason a person is prone to immediately grab and massage the foot, when he or she stubs a toe. The touch will block the transmission and duration of pain impulses [1]. The basic sensation of pain occurs at the thalamus. It continues to the limbic system, which corresponds to the emotional center, and the cerebral cortex, where the pain is perceived and interpreted (Figure 2).
Figure 1. Nociceptive Processing - Three neuron chain [3].
1.1 Pathways of pain The physiological component of pain is termed nociception, which corresponds to the process of transduction, transmission and modulation of neural signals generated as a response to an external noxious stimulus [3]. The first step of nociception (transduction) involves the encoding of mechanical, chemical or thermal energy into electric impulses by a type of specialized nerve endings named nociceptors. Nociceptors, also known as pain receptors, correspond to free nerve endings of primary afferent neurons that respond to painful stimuli. Their function is to preserve tissue homeostasis by signaling actual or potential tissue injury [3]. Nociceptors are found in all tissues, except in the brain. Pain perception occurs when stimuli are transmitted through the spinal cord to central areas of the brain.
There are three types of fibers involved in pain transmission: A delta fibers, A beta
Figure 2. Pathways of pain [1]
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and "chemical" (iodine in a cut, chili powder in the eyes). Nociceptive pain usually has a limited healing time, which means that when the damaged tissue heals, the pain typically ceases. Neuropathic pain - consequence of damage to the nervous system. Like inflammatory pain states, neuropathic pain is characterized by altered sensory processing of stimuli and results in several distinct and unique manifestations of hypersensitivity. Patients who suffer from this kind of pain typically experience persistent burning sensations, partial or focal loss of sensitivity, allodynia and hyperresponsiveness to multiple stimuli (hyperpathia) [3].
1.2 Types of pain In 1994, the International Association for the Study of Pain (IASP), due to the need of a more useful system to describe chronic pain, started classifying pain according to specific characteristics, such as: 1. region of the body; 2. system whose dysfunction may be causing the pain; 3. duration and pattern of occurrence of the pain; 4. intensity and time since onset; and 5.etiology (causes). Concerning the duration of the pain, it can be divided into acute pain and chronic pain. The first is usually confined to the affected area and limited over time. It can last for a few minutes up to six months. Chronic pain, on the other hand, persists even after the trauma has healed, or in neuropathic pain. Chronic pain lasts longer than six months. Taking into consideration the characteristics 1 and 3 mentioned above, it is possible to classify pain into:
Phantom Pain - painful sensation that a patient may experience in a missing limb, following its amputation. The painful sensations, which are typically intermittent, are described as shooting, stabbing, picking, squeezing, throbbing, and burning. Almost 70% of patients who suffer amputation of a limb, report this kind pain within the first week after amputation.
Nociceptive pain - type of pain that
is caused by stimulation of the peripheral nerve fibers (nociceptors) that respond only to stimuli approaching or exceeding harmful intensity and may be classified according to the mode of noxious stimulation (Figure 3).
Central Pain is a form of chronic
pain that is usually caused by a lesion or a dysfunction in the Central Nervous System (CNS). Patient with central pain often report burning, aching, lancing, pricking, lacerating and pressing sensations. It is a type of neuropathic pain.
1.3 Gate control theory In 1965, Melzack and Wall published a theory that explains why thoughts and emotions influence pain perception, known as Gate Control Theory of pain [4]. According to this theory, there is a mechanism in the brain that acts as a gate to increase or decrease the flow of nerve impulses from the
Figure 3. Different Responses to Low- and Highintensity peripheral stimuli [3].
The most common categories of noxious stimulus are "thermal" (heat or cold), "mechanical" (crushing, tearing, etc.)
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peripheral fibers to the Central Nervous System. An “open” gate allows the flow of nerves impulses, and the brain can perceive pain. A “closed” gate does not allow flow of nerves impulses, decreasing the perception pain [1]. The underlying mechanism of the Gate Control Theory, involves Small nerve fibers (A delta Fibers), C Fibers (or pain receptors) and large nerve fibers (A beta Fibers). They synapse on projection cells (P), which go up the spinothalamic tract to the brain, and inhibitory interneurons (I) within the dorsal horn (Figure 4). Based on Figure 5, it is possible to observe that: 1.when no input comes in, the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed). This means that there is reduced; 2. If a normal somatosensory input happens, there is more large-fiber stimulation (or only large-fiber stimulation). Both the inhibitory neuron and the projection neuron are stimulated, but the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed). There is an innocuous sensation; 3. In contrast, if there is more small-fiber stimulation or only smallfiber stimulation, nociception (pain reception) happens. This inactivates the inhibitory
neuron, and the projection neuron sends signals to the brain informing it of pain (gate is open). This theory, however, doesn't explain everything about pain perception, just some facts, such as, if you rub or shake your hand after you bang your finger, you stimulate normal somatosensory input to the projector neurons. This closes the gate and reduces the perception of pain. [a]
2. Cluster Headache “Imagine, your eye is pushed out of its socket and your right eyelid is beginning to swell shut. You start squinting and your eye is tearing, you are convinced there was blood pouring out. A red-hot knife is crushed into your head, excruciating, horrible, horrible pain. Your only saving grace is to pace from room to room, crying, flinging yourself to the floor, until eventually the pain drains from you. Waiting for the next attack to happen is a terrible, scary feeling. I sometimes think that I will go mad. I’m exhausted but then the next one hits.” [5]
2.1 Characteristics Cluster headache (CH) is a neurovascular disease that causes excruciating retro-ocular pain attacks, reason why it is often nicknamed “suicide headache”. This disease strikes 0.1%-0.2% of the population, with higher male prevalence. Male patients often present peculiar overmasculinized features. People who suffer from CH can have one attack every other day, up to eight attacks per day. An attack begins rapidly and most often without preliminary signs; it can last from 15 to 180 minutes. Most of the times, the attacks are accompanied by a feeling of restlessness and autonomic symptoms: ptosis, miosis, lacrimation, conjunctival injection, rhinorrhea and nasal congestion.
Figure 4. Gate Control Theory
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These symptoms occur only during the pain attack and are ipsilateral to the pain. Although the headache is said to be strictly unilateral, cases have been reported of “sideshifting� between cluster periods. The time during which patients experience recurrent attacks, usually weeks but at times months or years, is referred to as a cluster period. CH can appear in the episodic form or in the chronic form. The first type is characterized by daily attacks for some weeks, usually lasting 7 days to 1 year, followed by a period of remission, lasting 14 days or more. This form of CH affects 85% of the people who suffer from this disease. The chronic type is characterized by daily attacks that occur for more than a year without remission, or with remissions that last less than a month. A signature feature of CH is its unmistakable circadian and circannual periodicity. The attacks often occur with daily clock-work regularity and cluster periods occur cyclically within a year, often at the same time of the year. The beginning of cluster periods is related to photoperiod duration, increased in July and January, after the longest and shortest days of the year, respectively. Conversely, it decreases following daylight-saving time changes in April and October. Attacks often develop during the REM phase of sleep, waking the patient.
differentiate idiopathic headache syndromes. The diagnosis is made accordingly to the diagnostic criteria of the Headache Classification Committee, of the International Headache Society (IHS), which is shown in Table 1. However, in the case of an abnormal neurological examination, a cranial CT scan and cranial MRI should be considered, to exclude abnormalities of the brain. In fact, mass lesions or malformations in the midline have been described in patients with symptomatic cluster headache, especially older patients [5]. Table 1. Diagnostic criteria of cluster headache
A. At least five attacks fulfilling B-D. B. Severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 min untreated. C. Headache is associated with at least one of the following signs that have to be present on the pain side: 1. Conjunctival injection. 2. Lacrimation. 3. Nasal congestion. 4. Rhinorrhea. 5. Forehead and facial sweating. 6. Miosis. 7. Ptosis. 8. Eye lid oedema. D. Frequency of attacks: from one every other day to eight a day. E. History or physical and neurological examination do not suggest any other disorder and/or they are ruled out by appropriate investigations.
3.2 Diagnosis CH is often undiagnosed for many years, and confused with migraines or other types of headaches. Short lived and unilateral pain attacks that are accompanied by autonomic features constitute evidences of CH. Other distinctive features include the circadian and circannual periodicity and the fact that they are frequently nocturnal. There is no single instrumental examination that can define, ensure and
3.3 Management Nowadays several kinds of treatments are used in CH. There are drug treatments (abortive, preventive or transitional), destructive surgery and neurostimulation. Drug treatments
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The abortive drug treatment is used during a CH attack and aims to provide rapid pain relief. In order to be considered effective it should take no more than 15 minutes to work. As examples of abortive drug treatments, there is oxygen therapy and subcutaneous sumatriptan therapy that will be further explained. The oxygen therapy consists in the inhalation of 100% oxygen, usually 12-15 liters per minute in a non-breathing mask. However, further studies obtained better results with 25 liters per minute. A study that started in the beginning of this year uses an "on-demand" valve that can deliver up to 160 liters per minute. If the oxygen is inhaled in the beginning of the attack, it can induce its abortion. If the oxygen is inhaled at the peak of the attack the therapeutic effect is smaller [6]. Subcutaneous sumatriptan is the most effective self-administered medication for the symptomatic relief of CH. Experiments have been made to compare the effect of sumariptan (subcutaneous administration of 6 mg) with the placebo effect; it was concluded that the first (76% having complete relief for 15 minutes) is considerably more effective than the second one (24%). The relief of subcutaneous sumatripan was felt within 15 minutes. This treatment is more effective in patients with episodic CH. The preventive drug treatment aims at long-term reduction or elimination of the attacks. The transitional drug therapy temporarily relieves pain while the preventive treatments haven’t become fully active. This type of treatment not only is dependent of preventive and abortive medication but it also relies on the patient behavior. People with CH should avoid afternoon naps, alcoholic drinks, prolonged exposure to volatile substances, high
altitudes, among others, since attacks may be induced. Destructive surgery: Destructive surgery is a very invasive treatment that is only applied when drug treatments fail. A patient can only be submitted to surgery if: the headaches are exclusively unilateral, because after surgery a “side-shift� of the pain could occur, the patient has a stable personality and psychological profile and presents low addiction proneness. Among all the destructive surgeries, the ones involving the sensory trigeminal nerve have been the most successful. Radiofrequency rhizotomies have shown encouraging results: 75% of the patients presented good-to-excellent results with a long-term recurrence rate of only 20%. Some patients even managed to stay pain free after 20 years [7]. These procedures use highly localized heat, generated with radiofrequency, in order to destroy the nerves that innervate the facet joints as a way to cut the communication link that signals pain from the spinal cord to the brain [8]. However, there are dangerous risks involved in these procedures. Patients may suffer from transient complications, such as diplopia, hyperacusis, ice-pick pain, and jaw deviation. Long-term complications may include corneal anaesthesia and anaesthesia dolorosa. Another type of surgery is the gamma knife radiosurgery, an experiment showed good results in 6 medically recalcitrant patients. The relief was immediate or felt within a week. After 8 months, 4 patients still remained pain-free. However no further experiments were made and long-term effects are not known yet. Lovely at al. reported that microvascular decompression of the trigeminal nerve is effective in chronic CH (CCH). In their 6
experiment 28 patients, including two with bilateral cluster headaches underwent 39 operations for microvascular decompression of the trigeminal nerve, alone or in combination with section and/or microvascular decompression of the nervus intermedius. Initially a 50% relief (or greater) was verified in 22 of the 30 first-time procedures and relief greater than 90% was achieved in 15. Long-term follow-up showed a fall in good-to-excellent relief to 46% [9].
ONS is a minimal invasive procedure, the least invasive of these neurostimulation techniques. A stimulator is implanted at the level of the occipitocervical junction, uni or bilaterally, such that stimulation causes slight paresthesia in the distribution of the occipital nerves, after adjusting stimulation parameters such as pulse width, frequency and amplitude. Although the mechanisms of action of ONS are not yet completely understood, it is believed that it is related with the pain gate theory and with the interaction of this nerve with the trigeminal system [11].
Neurostimulation Although, successful in many cases, the aforementioned treatments do not always work. For example, 10-15% of the CCH patients are refractory to medication. They may also have undesired side-effects. Therefore, and together with other evidence, attention was turned to neurostimulation treatments.
- Hypothalamic deep brain stimulation (HDBS) Neuroimaging findings have provided evidence for involvement of the hypothalamic area in CH attacks. These observations have provided the rationale for hypothalamic DBS in CH. As this is the technique suggested in the research proposal it will be described with further detail.
- Spinal Cord Stimulation (SCS) So far, only one case spinal cord stimulation for CH has been reported [10]. The patient had already been subject to several types of cluster headache treatments, all unsuccessful: drug treatments, local anesthetic block of the occipital nerve, C1 and C2 root’s block, neurolysis of the nerve root C2 and of the greater occipital nerve, among others. After the implantation of the stimulation electrode (2004) the patient felt immediate pain relief. In the follow-up, three years after, the spinal cord stimulator was still providing pain relief but the patient had to stimulate several times per day, for 30-60 minutes. The pain relief lasted a few hours, outlasting the stimulation. The stimulation could not abort an ongoing attack but reduces pain intensity.
General information DBS involves the implantation of a device that transmits electrical impulses in a deep location within the brain. It directly interferes with the brain activity in a controlled manner, and is nowadays preferred over destructive surgery. The underlying mechanisms of action of DBS remain unclear, namely in the case of CH. DBS has adjustable parameters, such as amplitude, frequency and pulse width. Patient Selection Hypothalamic DBS for the treatment of CH is an extremely invasive procedure that can only be performed in patients that fulfill
- Occipital Nerve Stimulation (ONS) 7
all the established inclusion criteria. Table 2 shows the guidelines for hypothalamic DBS
patient selection in CCH proposed by Lione et al. [12].
Table 2 - Criteria for hypothalamic DBS patient selection in CCH [12]
Inclusion Criteria A. CCH diagnosed according to IHS criteria; in addition both of the following: a. CCH for at least 24 months b. attacks should normally occur on daily basis B. Attacks must have always been strictly unilateral C. Patients must be hospitalized to witness attacks and document their characteristics D. All state of the art drugs for CH prophylaxis must have been tried in sufficient dosages (unless contraindicated or have unacceptable side-effects, etc.) alone and in combination, where applicable. These comprise verapamil, lithium carbonate, methysergide, valproate, topiramate, gabapentin, melatonin (where available), pizotifen, indomethacin and steroids. E. Normal psychological profile F. No medical/neurological conditions contraindicating DBS including: a. Recent myocardial infarction b. Cardiac arrhythmia c. Cardiac malformation d. Epilepsy e. Stroke f. Deep brain stimulation for other reason g. Degenerative disorder of central nervous system h. Arterial hypertension or hypotension, not controlled by drugs i. Autonomic nervous system disorder j. Endocrinological illnesses k. Major disturbance in electrolyte balance (e.g. due to renal insufficiency or hyperaldosteronism) G. Normal neurological examination except for symptoms characteristic of CH (e.g. persistent Horner’s syndrome) H. Normal CT scan (base of the skull window). Normal cerebral MRI including craniocervical transition and MRI arterial and venous angiography I. Neurosurgical team experienced at performing stereotactic implant of electrodes J. Patient not pregnant K. Ethics Committee/Institutional Review Board approval. L. Patient gives up smoking and drinking alcohol M. Patient informed and gives written consent. coordinates, surgery can be performed. Surgery is performed with the patient under Surgical Technique First of all, it is necessary to define the local anesthesia. A parasagittal frontal burr brain target for the placement of the hole is created through a small incision and the electrodes are temporarily placed. electrode. This procedure requires the Intraoperative physiological stimulation and placement of a stereotactic frame in the recording are required to define the exact patient’s head, followed by a high resolution target for stimulation, since the stereotactic stereotactic MRI. After obtaining the MRI can only provide approximate 8
coordinates. This can be performed through microelectrode recording. When the exact target is located, the permanent electrodes are placed. Typically, a postoperative CT scan or MRI is obtained to confirm electrode placement and to assess possible intracerebral hemorrhage. [13]
Hypothalamic DBS have shown promising results in many, but not all, patients. Table 3 shows a summary of results of hypothalamic stimulation for drug-resistant CCH patients from various centers [15]. In all studies but one, half or more than half of the patients improved after the DBS for periods of, at least, 1-4 years.
Efficacy
Table 3 - Summary of results of hypothalamic stimulation for drug-resistant chronic cluster headache patients from various centers [14].
Study
No. of implanted patients 16 11
Mean follow up (years) 4 ˃1
Nº. of patients improved*
Leone et al. (2006b) 10 Fontaine et al. (2010) 6 Starr et al. (2007), Sillay 8 1 5 et al. (2009) Bartsch et al. (2008) 6 1.4 3 Schoenen et al. (2005) 4 4 2 Owen et al. (2007) and 3 1 3 Brittain et al. (2009) D’Andrea et al. (2006) 3 2.5 2 (abstr) Black et al. (2007) 2 2.6 2 (abstr) Mateos et al. (2007) 2 1 2 (abstr) Benabid et al. (2006) 1 1 1 (abstr) Nikka et al. (2006)** 2 2 0 Totals 58 36 * Improvement: pain free or almost pain free. ** Personal communication, with authors’ permission. This table was first published in Neurotherapeutics 2010, April, Vol. 7, no. 2
Percentage Improved 62 55 62 50 50 100 66 100 100 100 0 62
regarding its cause must account for the three major aspects of the disease: • trigeminal distribution of the pain, which suggests the involvement of the trigeminal nociceptive pathways;
3.4 Evolution of the knowledge about
CH The pathological mechanism underlying CH is not yet known. The hypotheses 9
• autonomic features, that imply activation of the cranial parasympathetic system; • circadian and circannual consistency, which strongly indicates the involvement of the suprachiasmatic nucleus in the genesis of the attacks; • higher male prevalence.
during CH attacks, are an epiphenomenon of trigeminal activation and do not play a role in the genesis of cluster headache. Cavernous sinus inflammation as a cause for CH has been refuted through MRI studies, since 1994. Evidence from experimented medication In the late 1970’s, lithium was experimented as a therapy for CH, with good prophylactic results despites the side-effects. It’s mechanism of action is not clear. Lithium accumulates in the hypothalamus, namely in the area concerned with temperature regulation. There is evidence that it modulates the metabolism of cortical, hippocampal and hypothalamic serotonin and the structure of sleep and sleep–wake rhythms. Also, long-term administration of lithium modified the pattern of serotonin release in the rat brain, with spontaneous serotonin release being reduced in several places, including the hypothalamus. Hence, its prophylactic effectiveness was one of the ideas that first directed researchers towards a central origin of CH. Nowadays, one of the most effective prophylactic drugs is verapamil. Studies show that verapamil modulates the activity of central neurons via interactions with muscarinic, serotoninergic and dopaminergic receptors. For example, verapamil increases norepinephrine levels in the hypothalamus and inhibits the release of cerebral dopamine. The opioid system is particularly sensitive to verapamil, since this drug modulates the effect of morphine. Lithium acts mainly to restore serotoninergic tone, while verapamil acts mainly on the opioid system. Both serotonin and opioids are concerned with the modulation of pain pathways and act by inhibiting pain perception. This evidence points to a different
Peripheral origin Since the 1950's, theories about the pathophysiology of CH supported a peripheral origin of the attacks. These included a trigeminovascular origin, an allergic origin, and an inflammatory process in the cavernous sinus (end of the 1980’s). Indeed, there is an activation of the trigeminovascular system, marked by an increase in the level of calcitonin gene related peptide (a potent vasodilator) in cranial circulation, with vasodilation of the ophthalmic artery during an attack; histamine levels are increased in blood but not in urine, during attacks; furthermore parasympathetic activation also occurs in the attacks. Although it provides the anatomical basis for the trigeminovascular and autonomic features, the activation of these pathways is not specific to CH. Any painful stimulation of the ophthalmic branch of the trigeminal nerve causes alteration in the blood flow of the sinus cavernosus, due to the trigeminoparasympathetic reflex. This refutes both vascular and sinus cavernosus inflammation hypothesis. The circadian and circannual regularity of CH attacks shifted focus from a peripheral hypothesis to a central origin, most likely related to the regulation of homeostasis and biological rhythms. Together with this reasoning, throughout the years evidence has been obtained that refuted peripheral hypotheses. Since the yearly 1990's, it is accepted that the blood flow changes, seen 10
hypothesis regarding the genesis of CH: dysfunction of the locus coeruleus and dorsal raphe nucleus of the brainstem. These nuclei modulate pain input from the trigeminal nucleus and vascular activity. An anatomical connection between these nuclei and the hypothalamus, via noradrenergic fibers, exists in rats. Lesions in the dorsal raphe nucleus can dramatically decrease serotonin concentration in the hypothalamus. (To be noted is that the SCN is the hypothalamic area with higher levels of serotonin.) Therefore, a dysfunction in these areas could give rise to an altered regulation of the hypothalamus and explain the onset of CH.
cluster period, others in the remission period as well. Some of the hormones (LH, cortisol, and prolactin) had altered secretory circadian rhythms. The most relevant changes were found for melatonin and testosterone. One possible explanation for the lowered levels of these hormones in CH patients is the frequent interruption of sleep, at the time of REM sleep onset, due to headache attacks. The secretion is hence interrupted and overall concentration low. Functional and morphometric imaging evidence In 1998, PET studies revealed increased blood flow in the areas of the anterior cingulate cortex, insular cortex and contralateral thalamus, during CH attacks. They also showed activation of the hypothalamic grey matter ipsilateral to the side of the pain, in the region of the circadian pacemaker neurons (the SCN)[17]. The first areas are known to be involved in normal pain processing. The hypothalamic grey areas are not, so they are thought to interfere in a permissive or triggering manner in CH attacks. This area of the brain was proposed as a possible generator of the attacks. Later imaging studies showed that it is also activated during other similar types of headache, also with unilateral pain and craniofacial autonomic phenomena. In 1999, voxel-based morphometry studies of the anatomy of structural MRI scans of CH patients found an increased neuronal density in the inferior posterior hypothalamus, on the same side of the pain, the same area identified by PET imaging during attacks. CH patients has an increased hypothalamic volume, compared to normal subjects. This finding was important since it supported imaging evidence. The hemodynamic evidence pointed towards inferior hypothalamic neuronal
Hormonal evidence The hypothalamus is involved in many functions concerning homeostasis. These include hormone synthesis, autonomic nervous system regulation, temperature regulation, and the control of biologic rhythms, behavior and arousal. Hypothalamic regulation of the endocrine system is central in the maintenance of homeostasis and involves rhythmic modulation of pituitary hormones and melatonin. Lowered concentrations of testosterone during the cluster period in men, observed in 1976, together with the effective prophylactic effect of lithium, and other scientific observations, provided the first evidence of hypothalamic involvement in cluster headache[16]. To evaluate hypothalamic involvement, a number of hormone studies have been carried out on CH patients, in the yearly 1990's. These studies documented altered responses in the production of melatonin, cortisol, luteinizing hormone (LH), testosterone, follicle stimulating hormone (FSH), prolactin, growth hormone (GH), thyrotropin and thyroid stimulating hormone (TSH), supporting the hypothesis of hypothalamic dysfunction[16]. Some were altered in the 11
hyperactivity during the attacks, in addition to anatomical changes. This location might explain the circadian rhythmicity of the syndrome. On that account, the idea of inhibitory high frequency inhibitory deep brain stimulation as a potential treatment emerged, around 2001. Particularly, when facing the need for new therapeutic approaches, since drugs and destructive surgery were the most common treatments but they were not (and still are not) effective for all patients.
pressure, sleep-waking cycle, appetite, thirst or EEG patterns. Patients tend to lose weight in the months following implantation, for which the explanation is not known but may be related to the withdrawal of steroid drugs. The levels of several hormones, including cortisol, prolactin, thyroid hormones, thyroidstimulating hormone and testosterone, also remained unchanged with long-term stimulation. Character changes have not been observed either. Sleep was also investigated during hypothalamic stimulation. This group observed that nocturnal CH frequency was lowered. The stimulation provided a more continuous sleep, with increased total sleep time and higher prominence of slow-wave sleep stages, which are important in homeostatic control.
Hypothalamic stimulation evidence Acute hypothalamic stimulation The research on acute hypothalamic deep brain stimulation, in an attempt to block ongoing attacks, proved to be ineffective [Leone et al. 2006]. On the other hand, positive hypothalamic stimulation did not trigger CH attacks. These results challenged the hypothesis of the generator role of the posterior hypothalamus, at least as a sole generator.
Evidence from the trigeminohypothalamic pathway Information from the meninges, cranial skin and intracranial blood vessels is conveyed to the hypothalamus through the trigeminohypothalamic tract (THT). The exact nature of this pathway is not clear. Animal experiments have shown that the hypothalamus is a physiological modulator of the activity of trigeminal nucleus caudalis (TNC) neurons. In humans, the functional connection between the trigeminal system and the hypothalamus has been demonstrated by PET imaging: the stimulation of the hypothalamus elicited an increased blood flow in the trigeminal system without headache generation. The interaction between the hypothalamus and the trigeminal system is yet to be clear, but evidence points to a modulating role of the hypothalamus upon input from the pain through the THT.
Long-term hypothalamic stimulation From 2001 up until now, many long-term hypothalamic deep brain stimulation experiments were carried for the treatment of CH, by different groups. This modality aims at prevention, rather than acute arrest of the attacks. Coherent with the ineffective results of acute stimulation, long-term stimulation requires several weeks of continuous stimulation to reduce or eliminate the attacks. Overall, it is effective with a small incidence of side effects, the main one being diplopia when the stimulation amplitude is raised rapidly. This side-effect was consistent among different experiments. Nowadays, it is considered an established treatment for CH. Prolonged stimulation did not provoke changes on various central aspects, such as body temperature, electrolyte balance, blood
CH time consistency As referred, a peripheral generator of the 12
attacks would not account for its striking periodicity. It strongly implies the involvement of the body's biological clock, which is located in the hypothalamic grey: the suprachiasmatic nucleus. As possible evidence of its involvement, altered levels of melatonin have been observed, in CH patients. Melatonin's rhythmic secretion is under the control of the suprachiasmatic nucleus, influenced mainly by light and closely synchronized with the hours of sleep. Melatonin production is low during the day and increases during the hours of darkness and sleep, until it peaks. In CH patients, inside cluster periods, the levels of 24-hour plasma melatonin are reduced, the timing of the nocturnal peak is blunt and there's a phase advance in the nocturnal secretion. There is no consensus regarding the reason why this happens.
identify a 1-Hz oscillatory pattern, possibly due to pulse artifact. A study in 6 patients identified a slow, regular spontaneous firing with wide low-amplitude action potentials. The mean discharge rate was about 13 Hz [18] and other studies. The only recordings obtained during an ongoing CH attack showed increased power in local field potentials of hypothalamic neurons, supporting neuroimaging data regarding hypothalamic activation in CH attacks (2009).
3. Research Proposal The different sources of information mentioned before point to the involvement of the PH and the SCN in the genesis of CH, namely, results from hormonal evidence, from functional and morphometric imaging and from short-term microrecording. The periodic pattern of the attacks and clusters, together with altered levels of serum melatonin, and alterations in the circadian secretion rhythms of important hormones, strongly imply the involvement of the SCN, the body’s biological clock.
Microrecordings Microrecordings of the electrical activity of neurons are considered to be a helpful technique in getting insight about the characteristics of the hypothalamic function in CH. Not much information is available about the firing patters of the PH or the SCN. So far, only unit microrecordings have been done and in a short-term preimplantation surgical context, also as guide to correct placement of the stimulator. The first microrecording study was performed by Franzini and colleagues in 2003, with no quantitative results. In another study, recordings near the target area of two patients found bursts of action potentials synchronous to the heart beats (2005). In 2004, PH recordings with an average firing rate of 17 Hz (range 13-35 Hz) were obtained. A quantitative study recorded enough data from CH patients to allow the identification of a firing rate of 24 spikes per second, in a random tonic fashion[18]. They were able to
The exact role of both these structures is not understood. Concerning the PH, the inefficacy of acute stimulation and the positive results for prolonged stimulation made clear that this structure is not the sole CH generator. In addition, positive stimulation did not provoke CH attacks. The fact that CH prevention is achieved by prolonged stimulation suggests that this part of the brain may be involved in the modulation of antinociceptive systems. (One finding that supports this is the increased threshold for cold pain, upon the application of stimulation.) This is also indicated by the hemodynamic activation of brain areas related to the normal pain pathways upon prolonged hypothalamic stimulation. Some authors believe that the PH may actually be 13
involved in the termination of CH attacks [12]. The interaction of the hypothalamus with the trigeminal system, through the THT, also suggests a pain modulatory function of the hypothalamus over the trigeminal system.
any therapeutic effect is not plausible. Therefore, one proposes to implant the recording electrodes in patients that are already going to be submitted to a DBS procedure. A microarray of recording electrodes will be placed in the SCN and another in the PH, if surgically possible. A stimulating lead will be placed in the PH, the established target for DBS. The recording electrodes will be on for a period of three days, whereas the stimulation electrodes will be off. After that period, the stimulation electrodes will be turned on and the recording electrodes will be kept on for another three days. Following surgery, there should be a recovery period, during which the patient may take pain medication. The decision of when to stop the CH medication and start the recordings has to ponder the neurologist opinion, according to the patient’s best interest. Thereafter, signal processing of the firing patterns will be made. Following the model used in [18], single unit events will be discriminated in the 100x2 neuronal signals obtained, and the signals obtained from only one neuron will be selected, using templatematching spike sorting software. The firing rate is calculated by dividing the total number of isolated spikes by the length of the recording. The properties of the firing patterns will be inspected by plotting interspike interval histograms. In order to evaluate the rhythmicity of the spike trains, autocorrelograms will be plotted.
Little information exists about the SCN, in the context of CH. Together with these factors, little is known about the electrical activity of both the SCN and PH, especially in CH patients. To date, only short-term surgical microrecordings have been obtained, and only one recording during an attack was obtained. In this context, the following research question is posed: What are the differences in the firing patterns between an ongoing CH attack and a basal state, of the inferior posterior hypothalamus (PH) neurons and the suprachiasmatic nucleus (SCN) neurons, in CCH patients?
3.1 Description of the Methods This research proposal aims at obtaining long-term microelectrode recordings of PH and SCN neuronal electrical activity, during ongoing attacks and during a basal state, within a cluster period. The time of the recording is to be followed by hypothalamic DBS for the treatment of CH. From the recordings, one expects to investigate the firing patterns of the neurons during an attack, and compare them with those obtained when an attack is not occurring. After stimulation has been started, recordings can be obtained in the same manner, to compare ongoing attacks with periods of peace. This way, one will be able to compare the firing patterns before and after turning on the stimulation electrode. The stimulation is performed alongside with the recordings, because submitting a patient to such an invasive surgery without
Patient selection and behavior In order to have more feasible results, the higher the number of patients the better. However, as this experience is extremely invasive and entails several ethical issues, a small group of 3 to 5 patients will be used. In the first place, a neurologist and a neurosurgeon have to check if the patients 14
fulfill the patient selection criteria. Patient selection is done according to the same guidelines used for DBS, listed above. Additionally, the patient must be inside a cluster period. The patients will have to make headache diaries daily for a period of four weeks right before de surgery, for 3 months right after the surgery, and during the 6th and the 12th months after the surgery. The diary shall include the time, the duration and the intensity of the CH attack. The intensity will be measured in a visual-analog scale from 1 to 10, where 1 means slight pain and 10 means worst imaginable pain [15]. Furthermore, patients will have to be monitored and follow a regular awake-sleep cycle, which means go to sleep and wake up at the same time.
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One portable recording device One lead with four platinum electrodes. One implanted pulse generator (IPG) and extension. Software for signal processing.
Anatomical positioning will be performed through stereotactic framing.
3.2 Expected microrecording results Given the previous microrecording experiments, the following characteristics of the recorded signals are expected. First of all, the neurons in any part of the brain present constant activity. Therefore, electrical activity of some kind is expected to occur. The absence of any activity is an artifact. A common artifact that might be present is the 1-Hz circulatory artifact. A random tonic firing pattern, with a firing rate within a range of 13-35 Hz is expected, due to the reported previous results. The possible results for the suggested modalities are open, and therefore difficult to predict. It would make sense to encounter differences in the amplitude, power or firing rate between different states: during an attack or in a basal state. Augmented power has already been reported in a PH microrecording during a CH attack. It would also make sense, if differences were to be found in patterns obtained before and after the stimulation onset. Due to the regulation of the SCN by light, electrical activity with patterns differentiated according to the time of the day would be a reasonable result. Also, it may be possible to establish a relation between the CH onset and the period of the day when it occurs. Overall, one expects to learn about the electrical activity of the target areas.
Different modalities Other approaches could be used in this research proposal. One could also obtain the firing pattern of the neurons in a patient outside the cluster period in order to compare with those obtained within the cluster period, with the purpose of analyze different behaviors. Another option would be to compare firing patterns obtained from patients with different CH severities. An alternative would be to compare the firing patterns of attacks with different reported severities from the same person. At last, it could also be possible to compare the firing patterns, from the same person, obtained using different stimulation settings in order to optimize those settings. Equipment For this research proposal, the list of needed material is as follows: - Two microarrays of 100 recording electrodes each 15
relief for the attacks. The question that rises is whether it is legitimate to subject patients to suffering for 3 more days without starting stimulation or providing medication. However, patients submitted to this study would have to be completely refractory CH patients, who wouldn't obtain relief from medication anyway. Also, we suggest that the post-surgical recovery period should be overcome with the patient usual CH medication, in order to avoid the overlap of headache attacks with unpleasant postoperative pain and side effects. To deal with the aforementioned considerations that may stop ethical committees, patients have to go through a thorough selection following the referred guidelines. This prevents many of the side effects and risks of the procedure and promotes the success of the stimulation, and possibly the recording. Patient must be fully informed about all the consequences and be in agreement with every step of it. And despite the potential risks and complications, DBS is an established successful treatment for CH. Therefore, at least this part of the experimental setting should be safe. In spite of the ethical issues, microrecording of the PH and the SCN emerge as the next step in the investigation of CH, due to all the strong evidence concerning its involvement. Overall, one hopes that the suggested microrecording experiments will represent a step further in the long challenging path of understanding the pathophysiology of CH, and hence provide improvements in the treatments and quality of life of the sufferers of this devastating condition.
4. Discussion and Conclusion Although the proposed research may allow insights about the pathophysiology of CH, it raises numerous ethical issues. Experiments related to CH have to be performed in humans, due to the absence of suitable animal models. This fact has constituted a major impediment in the progress of CH knowledge, leaving many unanswered questions. Together with the need for human CH-suffering volunteers, any DBS is accompanied by a highly invasive electrode implantation procedure, since it involves cutting a burr hole in a deep central location of the brain. This involves many risks for the patient, such as brain hemorrhage and lesions of the central nervous system. Although DBS is already an established procedure, with demonstrated reduction of attack frequency and severity, our proposal presents other delicate aspects. For recording and stimulation, several electrodes need to be included in a very small and delicate location of the brain. It is not known if this electrode setting is actually feasible. Also, the physiological and behavioral consequences are unpredictable. One solution for this is suggested in the further ideas below, and consists of using biodegradable recording electrodes, which would be absorbed by the patient's system and not longer affect the brain. A second characteristic of our proposal is that it aims at two close, yet distinct, anatomical areas: the SCN and PH. Therefore, it might not be possible to reach both locations using the same stereotactic coordinates. Hence, patients would be subject to either two brain surgeries, or one surgery with two stereotactic framing sequences, which would clearly be very challenging. Another aspect of this research is that the patients would be subject to 3 full days of recording, without any kind of treatment
5. Further ideas If this experiment was to succeed, a few improvements can be suggested regarding the technique. Concerning the long-term 16
implantation of recording electrodes, these become superfluous after all the recording studies have been done. Therefore, we suggest the use of biodegradable microelectrodes, which are yet to be developed. Another suggestion would be to try using the same electrode for recording and stimulating. However, this is highly demanding in terms of the instrumentation due to the different impedance requirements for both functions. In addition, this would impede the simultaneous stimulation and collection of data. In the case of elucidating findings regarding the SCN involvement in the genesis of CH, one could propose the stimulation of this part of the brain as a potential therapy. This new modality would hinder, not only information regarding the efficacy of the treatment, but would also provide further insights about the mechanism of the disease. One modality than can be further tried is measuring the secretion of hormones directly related to the SCN and the hypothalamus, such as melatonin. Then, mapping between its pattern of production and the pattern of neuronal discharge could attempt to establish a relation between these variables.
[5] May, A. (2005). Cluster headache: pathogenesis, diagnosis, and management. Available from www.thelancet.com [6] http://en.wikipedia.org/wiki/Cluster_headach e, visited in November 4. [7] Dodick, D.W., et all. (2000). Cluster headache. Cephalagia, 20, pp. 787-803. London. ISSN 0333-1024 [8] http://www.cdirad.com/Default.aspx?tabid=2 57 [9]. Ford, R.G., Ford, K.T., Swaid, S., Young, P, Jennelle, R. (1998). Gamma knife treatment of refractory cluster headache. Headache, 38, pp.1-9. [10]. Wolter, T., Kaube, H., Mohadjer, M. (2008). High cervical epidural neurostimulation for cluster headache: case report and review of the literature. Cephalagia, 28, pp. 1091-1094 [11]. Paemeleire, K., Bartsch T. (2010). Occipital nerve stimulation for headache disorders, Neurotherapeutics, 7(2), pp. 213219. [12]. Leone, M., et all. (2004). Deep brain stimulation for intractable chronic cluster headache: proposals for patient selection. Cephalalgia, 24 (11), pp. 934–937. [13]. Levy, R., Deer, T.R., Henderson, J. (2010). Intracranial Neurostimulation for Pain Control: A Review. Pain Physician, 13, pp. 157-165. [14]. Leone, M., et al. (2010). Hypothalamic deep brain stimulation in the treatment of chronic cluster headache. Therapeutic Advances in Neurological Disorders, 3, 187 [15]. Sillay, K.A., Sani, S., Starr, P.A. (2010). Deep brain stimulation for medically intractable cluster headache. Neurobiology of Disease, 38, pp. 361–368 [16] Leone, M., Bussone, G. (1993). A review of hormonal findings in cluster headache. Evidence for hypothalamic involvement. Cephalalgia, 13(5), pp. 309-317.
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[17] Arne, M. et al., (1998) Hypothalamic activation in cluster headache attacks The Lancet, 352, pp. 275–78. [18]Cordella, R. et al. (2007). Spontaneous neuronal activity. Activity of posterior hypothalamus in TACs, 28, pp. 93-95. [19] Bussone, G. (2008). Cluster headache: from treatment to pathophysiology. Neurol Sci, (29), pp. S1–S6.
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