DBS for Psychiatric and Headache Disorders
As use of DBS evolved for psychiatric conditions, the recognition that the pain matrix overlapped with many psychiatric disorders led to exploration of DBS for headache and pain conditions. Primary headache disorders include a variety of conditions that differ in both pathophysiology and anatomical structures. The production of pain among these disorders is not limited to the central nervous system, but also involves cranial and cervical neck structures that have also been neuromodulation targets. This review will begin by describing some of the pathophysiology and anatomy that led to trials of neuromodulation in headache and pain.
It is crucial to understand the functional relationship of various brain structures to conceptualize neurostimulation interventions. The overall basis of this relationship manifests in the association between peripheral afferent nerve fibers of the head and neck, brain stem, subcortical structures, and higher order processing centers in the brain. The fifth (trigeminal) cranial nerve supplies the anterior head and face, while the upper cervical nerves supply the posterior head. This is described as the trigeminocervical system and has been demonstrated using animal models.
The stimulation of the feline superior sagittal sinus in rats has been shown to increase metabolism in the trigeminal nucleus caudalis, cervical dorsal horn, and dorsolateral cervical spine to the C2 level. The same result also occurred when stimulating the greater occipital nerves. Increased metabolism in the trigeminocervical complex was also shown when stimulating the middle meningeal arteries in monkeys and cats. Taking these findings all together suggests a common anatomical relationship functionally sharing a potential target, with the brainstem is seemingly involved in this process. Brainstem involvement was shown when stimulating the peri-aqueductal gray area of cats, causing an alteration in trigeminal neuronal activity.
The activation of the trigeminovascular pathways has also been shown to activate the superior salivatory nucleus at the pontine level. This nucleus is the origin of parasympathetic fibers synapsing in the sphenopalatine ganglion (SPG). Post-synaptic parasympathetic fibers then exit from the SPG on their way to peripheral targets. The SPG is therefore a major target for neuromodulation.
Moreover, stimulating both the dura and grater occipital nerve in rats elicited a response in the C2 spinal dorsal horn neurons, thus suggesting signal processing at the level of second-order neurons within the spinal cord.
Second-order neurons of afferent signals present the final common pathways for peripheral and centrally induced head pain. These pathways project to the thalamus and further to areas of the cortex. They have been mapped through utilization of functional imaging among migraine patients where activation was found in the dorsal pons, right anterior cingulate, posterior cingulate, cerebellum, prefrontal cortex, and thalamus.
The 3 TACs in which DBS has been utilized are cluster headache (CH), paroxysmal hemicrania (PH), and short short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). CH, PH, and SUNCT constitute primary headache disorders that are part of the TACs. These headache disorders are characterized by short-lasting hemicranial pain attacks accompanied by autonomic features. The posterior hypothalamus is activated during attacks, thus playing an important role in the pathophysiology of TACs.
DBS involves the placement of electrodes within the subcortical structures. These electrodes are inserted through the skull and cortex. The structures involved in the treatment of TACs include the posterior hypothalamus, yet the ideal target remains in dispute. Other structures include the mesencephalic grey substance, the red nucleus, the fascicle retroflexus, the fascicle longitudinal dorsal, the nucleus of ansa lenticularis, the medial longitudinal fasciculus, and the medial thalamus superficialis.
Even neurosurgeons who perform DBS suggest the potential use of less invasive neuromodulation techniques for treatment of TACs before the more invasive techniques. DBS is reserved for those patients in whom medications, non-invasive neuromodulation, or peripheral or minimally invasive neuromodulation techniques have failed.
CH. Numerous cases of DBS for CH have been reported. Franzini and his group published the first cases in 2003 in Milan, Italy. This Milan group identified 5 patients with drug-resistant CH and applied electrical stimulation to the ipsilateral hypothalamus. All 5 patients went into in remission following the procedure. Periods of remission varied from 2 to 22 months postprocedure. By 2006, the same group in Milan had utilized DBS in 16 patients. Thirteen patients had marked improvement in their pain, of which 10 were pain free. The remaining 3 only experienced sporadic headaches. The average time to reach stable benefit was 42 days. Adverse events reported included one patient who suffered a small, subclinical hemorrhage in the third ventricle.
A second European group in Belgium reported variable results for several patients with chronic CH receiving DBS. Six patients received stimulation targeting the ipsilateral hypothalamus and were followed over a mean period of 14.5 consecutive months. Two patients became completely pain free, one patient had less than 3 attacks per month, while a fourth patient continued having attacks for 7 months before becoming pain free. One patient had to drop out because of a panic attack during the procedure, while another suffered an intracerebral hemorrhage and was found to have a saccular aneurysm. This patient died 3 days later.
A case series of 4 patients was reported in a 2007 study conducted at the University of California San Francisco. Two patients had more than 50% reduction in both headache frequency and intensity when followed over a 1-year period. A fifth patient was also found to be responsive to the procedure. One patient, who had become headache free, sustained transient ipsilateral hemiplegia. Emergent computerized tomography was negative, and the incident was attributed to a possible misplacement of the electrode. The patient's headaches resumed 3 months after the devices were shut off.
In a 2007 Mayo Clinic study, 2 patients with chronic CH showed response to DBS. One patient's attack frequency dropped from 60 attacks to 8 attacks per month and to 6 attacks per month down from 3.5 per day for the second patient.
A German team reported another case series of 6 chronic cluster patients in 2008. Mean attack frequency at baseline was 30 to 100 attacks per month. Patients were treated with DBS with a 17 months follow up. Three of the 6 patients were close to free from cluster attacks with a significant reduction in pain severity. A fourth patient remained in remission for 6 months following the procedure before relapsing again to baseline attacks. Two patients had minimal benefit. No significant adverse events were reported.
A randomized controlled study published in France in 2009 compared active to sham stimulation. Eleven patients with chronic CH received DBS and underwent treatment randomization in the first 2 months. No difference between sham and active stimulation was detected. During the open phase over the next 10 months, 3 patients became headache free, and 6 patients sustained more than a 50% decrease in headache frequency. One patient had a hemiparesis following the test stimulation but had a negative computed tomography (CT) scan.
PH. A 2009 case report found an initial response for a patient with PH that received DBS. Leads were implanted within the ipsilateral posterior hypothalamus.
SUNCT. There have been 2 patients with SUNCT that have undergone treatment with DBS. The first patient was implanted by the Milan group and received treatment in 2005. The patient had failed drug treatment and was averaging 70 attacks per day. Following stimulation, the patient would have pain-free periods, but would again develop attacks when stimulation was stopped. Stimulation was continued over several intervals. Finally, the patient had to be placed on daily therapy with lamotrigine for sporadic attacks.
The second patient with SUNCT was treated at the Mayo Clinic in Phoenix, Arizona in 2009. The patient was averaging 120 attacks per day prior to DBS. His attacks gradually decreased to 25 per day without any adjunctive medication therapy.
DBS and Headache Disorders
As use of DBS evolved for psychiatric conditions, the recognition that the pain matrix overlapped with many psychiatric disorders led to exploration of DBS for headache and pain conditions. Primary headache disorders include a variety of conditions that differ in both pathophysiology and anatomical structures. The production of pain among these disorders is not limited to the central nervous system, but also involves cranial and cervical neck structures that have also been neuromodulation targets. This review will begin by describing some of the pathophysiology and anatomy that led to trials of neuromodulation in headache and pain.
Understanding Pathophysiology of Intrinsic Head Pain
It is crucial to understand the functional relationship of various brain structures to conceptualize neurostimulation interventions. The overall basis of this relationship manifests in the association between peripheral afferent nerve fibers of the head and neck, brain stem, subcortical structures, and higher order processing centers in the brain. The fifth (trigeminal) cranial nerve supplies the anterior head and face, while the upper cervical nerves supply the posterior head. This is described as the trigeminocervical system and has been demonstrated using animal models.
The stimulation of the feline superior sagittal sinus in rats has been shown to increase metabolism in the trigeminal nucleus caudalis, cervical dorsal horn, and dorsolateral cervical spine to the C2 level. The same result also occurred when stimulating the greater occipital nerves. Increased metabolism in the trigeminocervical complex was also shown when stimulating the middle meningeal arteries in monkeys and cats. Taking these findings all together suggests a common anatomical relationship functionally sharing a potential target, with the brainstem is seemingly involved in this process. Brainstem involvement was shown when stimulating the peri-aqueductal gray area of cats, causing an alteration in trigeminal neuronal activity.
The activation of the trigeminovascular pathways has also been shown to activate the superior salivatory nucleus at the pontine level. This nucleus is the origin of parasympathetic fibers synapsing in the sphenopalatine ganglion (SPG). Post-synaptic parasympathetic fibers then exit from the SPG on their way to peripheral targets. The SPG is therefore a major target for neuromodulation.
Moreover, stimulating both the dura and grater occipital nerve in rats elicited a response in the C2 spinal dorsal horn neurons, thus suggesting signal processing at the level of second-order neurons within the spinal cord.
Second-order neurons of afferent signals present the final common pathways for peripheral and centrally induced head pain. These pathways project to the thalamus and further to areas of the cortex. They have been mapped through utilization of functional imaging among migraine patients where activation was found in the dorsal pons, right anterior cingulate, posterior cingulate, cerebellum, prefrontal cortex, and thalamus.
Trigeminal Autonomic Cephalgias (TAC)
The 3 TACs in which DBS has been utilized are cluster headache (CH), paroxysmal hemicrania (PH), and short short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). CH, PH, and SUNCT constitute primary headache disorders that are part of the TACs. These headache disorders are characterized by short-lasting hemicranial pain attacks accompanied by autonomic features. The posterior hypothalamus is activated during attacks, thus playing an important role in the pathophysiology of TACs.
DBS involves the placement of electrodes within the subcortical structures. These electrodes are inserted through the skull and cortex. The structures involved in the treatment of TACs include the posterior hypothalamus, yet the ideal target remains in dispute. Other structures include the mesencephalic grey substance, the red nucleus, the fascicle retroflexus, the fascicle longitudinal dorsal, the nucleus of ansa lenticularis, the medial longitudinal fasciculus, and the medial thalamus superficialis.
Even neurosurgeons who perform DBS suggest the potential use of less invasive neuromodulation techniques for treatment of TACs before the more invasive techniques. DBS is reserved for those patients in whom medications, non-invasive neuromodulation, or peripheral or minimally invasive neuromodulation techniques have failed.
CH. Numerous cases of DBS for CH have been reported. Franzini and his group published the first cases in 2003 in Milan, Italy. This Milan group identified 5 patients with drug-resistant CH and applied electrical stimulation to the ipsilateral hypothalamus. All 5 patients went into in remission following the procedure. Periods of remission varied from 2 to 22 months postprocedure. By 2006, the same group in Milan had utilized DBS in 16 patients. Thirteen patients had marked improvement in their pain, of which 10 were pain free. The remaining 3 only experienced sporadic headaches. The average time to reach stable benefit was 42 days. Adverse events reported included one patient who suffered a small, subclinical hemorrhage in the third ventricle.
A second European group in Belgium reported variable results for several patients with chronic CH receiving DBS. Six patients received stimulation targeting the ipsilateral hypothalamus and were followed over a mean period of 14.5 consecutive months. Two patients became completely pain free, one patient had less than 3 attacks per month, while a fourth patient continued having attacks for 7 months before becoming pain free. One patient had to drop out because of a panic attack during the procedure, while another suffered an intracerebral hemorrhage and was found to have a saccular aneurysm. This patient died 3 days later.
A case series of 4 patients was reported in a 2007 study conducted at the University of California San Francisco. Two patients had more than 50% reduction in both headache frequency and intensity when followed over a 1-year period. A fifth patient was also found to be responsive to the procedure. One patient, who had become headache free, sustained transient ipsilateral hemiplegia. Emergent computerized tomography was negative, and the incident was attributed to a possible misplacement of the electrode. The patient's headaches resumed 3 months after the devices were shut off.
In a 2007 Mayo Clinic study, 2 patients with chronic CH showed response to DBS. One patient's attack frequency dropped from 60 attacks to 8 attacks per month and to 6 attacks per month down from 3.5 per day for the second patient.
A German team reported another case series of 6 chronic cluster patients in 2008. Mean attack frequency at baseline was 30 to 100 attacks per month. Patients were treated with DBS with a 17 months follow up. Three of the 6 patients were close to free from cluster attacks with a significant reduction in pain severity. A fourth patient remained in remission for 6 months following the procedure before relapsing again to baseline attacks. Two patients had minimal benefit. No significant adverse events were reported.
A randomized controlled study published in France in 2009 compared active to sham stimulation. Eleven patients with chronic CH received DBS and underwent treatment randomization in the first 2 months. No difference between sham and active stimulation was detected. During the open phase over the next 10 months, 3 patients became headache free, and 6 patients sustained more than a 50% decrease in headache frequency. One patient had a hemiparesis following the test stimulation but had a negative computed tomography (CT) scan.
PH. A 2009 case report found an initial response for a patient with PH that received DBS. Leads were implanted within the ipsilateral posterior hypothalamus.
SUNCT. There have been 2 patients with SUNCT that have undergone treatment with DBS. The first patient was implanted by the Milan group and received treatment in 2005. The patient had failed drug treatment and was averaging 70 attacks per day. Following stimulation, the patient would have pain-free periods, but would again develop attacks when stimulation was stopped. Stimulation was continued over several intervals. Finally, the patient had to be placed on daily therapy with lamotrigine for sporadic attacks.
The second patient with SUNCT was treated at the Mayo Clinic in Phoenix, Arizona in 2009. The patient was averaging 120 attacks per day prior to DBS. His attacks gradually decreased to 25 per day without any adjunctive medication therapy.
SHARE
