Unlocking Pain
Deep brain stimulation might be the key to easing depression and chronic pain. by Nathalie Gosset and Nicholas Dietz
D
epression and chronic pain know no geographical boundaries. About 350 million people around the world experience long-lasting sadness and an unshakeable sense of hopelessness, and one person out of ten tries to live each day to its fullest despite continuous physical pain. These two difficult conditions frequently coexist, becoming more common with age. Looking ahead, we can
expect the incidence of depression and chronic illness to grow, since more people over age 65 will populate the world by 2020 than children younger than five. Amid an array of pain-management therapies and moodaltering therapeutics, researchers are looking at technologies focused on patients who are immune to drug and psychotherapy interventions. Among them, deep brain stimulation (DBS) has been found to provide much-needed relief for those experiencing treatment-resistant depression and refractory chronic pain. This article investigates new frontiers of DBS in depression and pain management in the context of a historical review and current market analysis of this platform technology.
Brain scan courtesy of AMI USC. Brain image: ©istockphoto/7activestudio
DBS for Depression and Chronic Pain
16 ieee pulse ▼ march/april 2015
2154-2287/15©2015IEEE
To date, DBS represents an advanced surgical procedure to treat motor deficiencies in a growing scope of neurological illnesses that includes Parkinson’s disease, essential tremor, and dystonia. Using variable electric impulses sent to specific brain regions, DBS amplifies or suppresses neural circuits to reverse pathology. While DBS intervention is considered to be young—having been clinically incorporated for only 16 years—its encouraging results in patient health outcomes have garnered much attention and raised hopes for the treatment of traditionally untreatable conditions. Interestingly, advancements in DBS have ignited curiosity about its efficacy in treating behavioral maladies and psychopathologies that might not otherwise be treated by drug therapy. Specifically, Digital Object Identifier 10.1109/MPUL.2014.2386511 Date of publication: 13 March 2015
the World Health Organization reports that 22% of it has been shown to effectively minimize symptoms Advancements in DBS primary care patients struggle with persistent pain of intractable obsessive-compulsive disorder (OCD) conditions, where pain is the most common cause and major depressive disorder (MDD). have ignited curiosity of medical attention. Despite their prevalence, a Americans are more depressed than Europeans about its efficacy in wide range of neuropathic and nociceptive pain and four times more than Australians. With a lifetime treating behavioral conditions are not sufficiently relieved through prevalence of depression of 15% in the United States maladies and surgical or pharmaceutical intervention. Moreover, and 9% in Europe, MDD or depression is a complex psychopathologies pain due to injury, stroke, back, or spine pathology mental illness marked by depressed mood or severely that might not and other persistent aches can result from complex diminished interest in all activities along with a host pathways that are not presently treatable. A signifiof other factors, which result in functional impairotherwise be treated cant market for DBS may also be found in alleviment, including insomnia, significant weight change, by drug therapy. ating chronic pain in individuals who suffer from psychomotor agitation or retardation, fatigue, and refractory pain states. recurrent suicidal ideation. Further, depressive mood As a growing market for this technology develdisorders are becoming increasingly related to comorops, new indications for treatment have been proposed to furbid medical conditions and lowered immune function, which contribther expand the scope of use while also providing unprecedented ute to the World Health Organization’s recognition of depression as alternatives of improved health for certain patient populations. the leading cause of disability worldwide (Figure 1). Although antiAmong those who suffer from MDD, a leading cause of disability depressant drug therapy is often effective, up to 30% of those with worldwide, treatment-resistant depression is a particularly debilidepression are resistant to traditional forms of rehabilitation, includtating illness immune to drug and psychotherapy interventions. ing electroconvulsive therapy and psychotherapy. For patients with Similarly, intractable chronic pain conditions cause significant refractory or treatment-resistant depression, DBS may provide a viaimpairment of daily function with limited treatment options. ble solution to an otherwise impervious illness. Another potential use of DBS—unapproved by the U.S. Food and Drug Administration (FDA)—is for the treatment of chronic pain Biological Mechanisms conditions. According to a recent poll conducted by the American Clinical application of DBS targets specific subcortical brain Pain Society, 30.7% of adults in the United States experience some regions that are believed to be the site of dysfunctional neuform of chronic pain for at least a six-month period. Additionally, ral activity. Procedural execution for Parkinson’s disease, for
Depression Knows No Geographical Boundaries But Affects Continents Differently
Depression and Chronic Pain Frequently Coexist Australia Europe >50%
North America South America Africa Underreported Due to Cultural Pressure
Asia
Depression
Chronic Pain
1.5 Billion People Suffer from Chronic Pain Back Pain
Migraine Neck Pain
Women Are Twice as Likely to Suffer from Depression Than Men
X2
X1
27%
15%
15%
FIGURE 1 The epidemiology of depression and chronic pain, global statistics. [Graphics courtesy of the Alfred E. Mann Institute for Biomedical Engineering at the University of Southern California (AMI USC), 2014.] march/april 2015 ▼ ieee pulse 17
DBS Electrode
pain states, including paraplegia and anesthesia dolorosa. However, DBS meets many chronic pain states with success, including stroke, amputation rehabilitation, multiple sclerosis, and spine injury, with improved emotional well-being and quality of life.
History and Regulatory Conditions DBS technology was first experimentally used for the treatment of chronic pain in the 1960s. Much of its initial appeal during that time has been attributed to the success of cardiac pacemakers, which helped to legitimize the use of electrical stimulation for clinical interventions. In fact, the DBS device blueprint closely matches and evolved from traditional cardiac pacemaker units—the first prototyped models of neurostimulators were, FIGURE 2 The subthalmic stimulation principle illustrated with a indeed, fashioned from the circuit boards of pacemakers. While functional magnetic resonance imaging (fMRI) diffusion tensor Medtronic pioneered the effort of neurostimulatory devices in tractography imaging model. (Image courtesy of AMI USC, 2014.) chronic pain, the first FDA approval of DBS was for treatment of essential tremor in 1997. Subsequent additions to approval of DBS for treatable conditions under FDA regulation were Parkinson’s disease in 2002 and dystonia in 2003. example, directs electrode implantation into the subthalamic Due to the inherent risk associated with the DBS procenucleus or globus pallidus due to abnormal neuronal synchrony dure, regulatory approval has been limited to conditions in related to the motor circuit (Figure 2). Electrical stimulation which the intervention is seen as a last resort when all other in one of these regions has been shown to correct tremor and traditional forms of treatment have failed. Perhaps the more dyskinesia for patients with Parkinson’s disease. For depresapparent reductions in quality of life for movement disorders sion, several regions have been identified that may contriblike Parkinson’s disease and dystonia have been a contributing ute to its pathology. The most commonly targeted brain region factor for their approval in recent years. While no FDA clearfor DBS in clinical trials has been the subgenual cingulate ance has since been granted for the use of DBS for psychiatgyrus (SCN), also known as Brodmann area 25, as it has been ric conditions or chronic pain, allowance has been made for shown to yield heightened metabolic activity during depression intractable OCD. In 2009, the FDA approved the (Figure 3). The SCN is also a key facet of the Medtronic Reclaim DBS device to treat refraclimbic-cortical system, which contributes to an tory and drug-resistant forms of OCD under integrated neural network responsible for mood Market analysts the humanitarian device use exemption (HDE). state that may result from multiple interacting predict that the The HDE FDA regulation recognizes medical brain regions. Several studies corroborate the DBS market will technologies that treat a small and underserved effectiveness of DBS targeting the white matter reach US$1 billion in population of patients and is similar in form associated with the SCN to confer sustained longto a premarket approval with fewer regulatory term relief of depressive symptoms. Another area revenues by 2018. hurdles prior to acceptance. targeted for refractory depression has been the nucleus accumbens (NAcc) that is closely related to reward systems of the brain that drive behavior. DBS targetMarket Analysis and Reimbursement ing the NAcc—and its accompanying system of the medial foreOne of the attractive and unique qualities of DBS technology is its brain bundle—has also been demonstrated to reduce depressive potential universality to treat a broad range of conditions. Because symptoms as soon as days after intervention and result in full of its interventional modality in the brain, it represents a platform remission of MDD months after the procedure. While the precise technology, wherein minor modifications to the device or lead mechanisms of DBS are still not fully understood, it appears that placement can be adapted to affect a wide range of behavioral electrical stimulation may realign pathological molecular and and neurological changes. Considering the prevalence of depreschemical imbalances to restore normal functioning. sion (15%) in the United States and the many chronic pain states DBS has also been proven to have long-lasting effects to treat that arise from injury and disease, the market for DBS could see certain cases of refractory chronic pain. Most research to date has a significant expansion. It should be noted that high variability focused on two areas, depending on the nature of the pain conis present on a case-by-case basis in the decision and efficacy of dition: the periaqueductal gray (PAG) and the sensory thalamus treating refractory pain states and depressive illness. Thus, it would (ST). In a meta-analysis conducted by Bittar et al., the long-term be difficult to predict what percentage would be eligible for the efficacy of pain alleviation of a variety of pain conditions was highintervention from current regulatory standards. What is clear, est in stimulation of the PAG (79%) when compared to stimulation however, is the predicted rise in need for DBS within its current of the ST (58%). The greatest improvement was seen in simultaneframework of treatable conditions. The prevalence of Parkinson’s ous stimulation of the PAG and ST at 87%. Additionally, DBS was disease, for example, is expected to rise for those over 50 years old, found to be more effective in sustained relief of nociceptive pain as to the extent that the approximately 4.5 million afflicted in 2005 opposed to neuropathic pain states and nonresponsive to certain will double by 2030 to 9 million. Connective Wires
18 ieee pulse ▼ march/april 2015
The procedure for DBS is often defined by two separate surgeries to 1) implant the elecThe SCN is also a key trodes and 2) insert the generator (Figure 4). facet of the limbicFirst, the electrodes are inserted through the cortical system, which skull either unilaterally or bilaterally, where contributes to an two incisions would be made—both options integrated neural have separate billing codes for reimbursement. The average cost for unilateral insertion of DBS network responsible is between US$35,000 and US$50,000 and can for mood state that be doubled for concurrent bilateral electrode may result from implantation. Most insurance companies, howmultiple interacting ever, do cover the costs for FDA-cleared DBS brain regions. devices. The insertion of the generator or battery pack is usually placed under the clavicle and requires a second inpatient procedure for which there are supplementary current procedural terminology codes. Subsequent procedures may include battery replacement and electrode lead removal.
In recent years, the DBS market has seen promising growth. Between 2012 and 2013, the DBS market grew 6.7%, with sales revenues for 2013 reaching a record US$677 million. The procedure has proven its efficacy for the treatment of neurological disorders as the adoption rate will steadily increase, with 7–9% annual growth forecasted. Kalorama Information reports an estimated US$4–5 billion annual market for electrical stimulation devices in treating pharmacoresistant depression alone. Some calculations even predict that DBS will reach US$1 billion in revenues by 2018.
Current Business Models Opening the use of DBS to a new set of psychiatric applications will benefit from the clinical validations Medtronic and Boston Scientific carved for the treatment of Parkinson’s disease. The first device that received FDA clearance—and perhaps the most widely used clinically—is the Medtronic model 3389. Medtronic was even credited with coining the term “deep brain stimulation” after opening up a neurosciences division in 1975 to investigate the technology. Currently, Medtronic has four neurostimulators available, all of which treat Parkinson’s disease and essential tremor, and three of the four are also used for dystonia (Table 1). Boston Scientific produces a single DBS device called the Vercise, which is advertised as having the smallest stimulator footprint and boasts a multiple independent current control for precise treatment.
FIGURE 3 The NAcc and subgenual cingulate cortex targets highlighted through an fMRI diffusion tensor imaging model. (Image courtesy of AMI USC, 2014.)
TABLE 1. A CURRENT PRODUCT LIST OF DBS TECHNOLOGIES, REPORTING TREATMENT OPTIONS, BATTERY LIFE, CHANNEL CAPACITY, AND FDA AND CE MARK APPROVALS FOR PROMINENT COMPANY MODELS. PD: PARKINSON’S DISEASE; ET: ESSENTIAL TREMOR; AND D: DYSTONIA. Distributor
Model
Channels
Treatments
FDA Approval
Battery Life (Years)
Medtronic
37601
Two
PD, ET, D
Yes
Nine
Medtronic
37612
Two
PD, ET
Yes
Nine
Medtronic
37602
One
PD, ET, D
Yes
Nine
Medtronic
37603
One
PD, ET, D
Yes
Nine
Boston Scientific
Vercise
Two
PD, D
Yes
25
St. Jude Medical
Libra
One
PD, D
No
Ten
St. Jude Medical
Brio
Two
PD, D
No
Ten
St. Jude Medical
Libra XP
Two
PD, D
No
Ten
march/april 2015 ▼ ieee pulse 19
European sales that funded clinical trials in the United States for FDA approval.
Final Thoughts 3
Successfully ameliorating chronic and debilitating disease states, DBS has emerged as a platform technology with unparalleled 2 potential across a number of medical fields to reverse intractable pathology. Regulatory clearance of DBS for certain motor-related diseases has shown promising results in patient health outcomes, and yet further investigation may lead to an approved expansion of treatable conditions to include psychiatric illnesses such as MDD and relief from refractory chronic pain. Progression of DBS may also benefit from a recent push in fed1 eral funding in the neurosciences. In 2013, the Human BRAIN Project (Brain Research Advancement through Innovative Neurotechnologies), funded by the U.S. National Institutes of Health, was announced to represent a large-scale effort to better underFIGURE 4 DBS device illustrating function of 1) pulse generator, 2) lead extension, and 3) electrode implants. (Image courtesy of stand the pathways of brain function and autonomic regulation. AMI USC, 2014.) For the fiscal year 2014, the Human BRAIN Project received presidential support with a pledge of US$100 million in funding— and determination of “high priority”—for progressing innovative technologies for brain imaging and neuromodulation. AdditionConsidering the portfolio of similar medical stimulation sysally, the U.S. Defense Advanced Research Projects Agency has tems, DBS has outperformed its competition. Medtronic’s Restorlaunched a US$70 million plan over the next four ative Therapies Group includes the manufacture of years specifically to develop and enhance DBS surgical technologies, neuromodulation and spine technology. A hopeful future awaits the investigastimulation systems. In 2013, this suite of therapy DBS represents an tion of neuroscience as an imminent convergence technologies performed well due to the outstanding advanced surgical of knowledge, technology, and clinical application success of the DBS product revenue, which balanced procedure to treat may maximize the potential of DBS. the decline in sales of spine stimulation systems that motor deficiencies now compete with morphogenetic protein and balNathalie Gosset ([email protected]) is the senior direcin a growing scope loon kyphoplasty. Medtronic was estimated to own tor of market and technology innovation evaluation at of neurological roughly 40% of the global DBS market in 2012. the Alfred E. Mann Institute for Biomedical Engineering Every unique clinical indication for the use of illnesses that includes at the University of Southern California. She is responsiDBS requires separate FDA approval. Despite prior Parkinson’s disease, ble for estimating the commercial value of more than 100 FDA clearance for the use of DBS to treat Parkinson’s essential tremor, medical innovations each year developed by elite research disease, for example, new standards of approval are centers. Nicholas Dietz ([email protected]) and dystonia. necessary before psychiatric applications are purgraduated from the University of California Los Angeles sued. Several business strategies can accelerate the (UCLA) in 2012 with a B.S. degree in psychobiology and approval process for DBS technology for the treatis currently a medical student at Georgetown University School of Medicine. ment of psychiatric conditions if the disease selected affects a small Prior to attending medical school, he worked for two years as a clinical population in the United States. The FDA approved the use of the research coordinator at the UCLA Department of PsychoneuroimmunolMedtronic Reclaim DBS device for the treatment of OCD in 2009 ogy, investigating spectral analysis of mindfulness meditation as well as the under the provision of HDE—targeting a condition affecting fewer effects of sleep deprivation in older adult populations. than 4,000 Americans per year. An HDE application includes similar requirements to a premarket approval application but does not have the rigorous standards for device clearance that large clinical trials For More Information require. An applicant seeking the HDE consideration must provide T. E. Schlaepfer, B. H. Bewernick, S. Kayser, B. Madler, and V. A. Coenen, evidence of the rarity of the clinical condition and the absence of “Rapid effects of deep brain stimulation for treatment-resistant major an appropriate treatment for the condition. This approach has been depression,” Biol. Psychiatry, vol. 73, no. 12, pp. 1204–1212, 2013. effective for Medtronic and pursued again for receiving approval for A. M. Gray, E. Pounds-Cornish, F. J. Eccles, T. Z. Aziz, A. L. Green, the treatment of chronic, intractable primary dystonia. and R. B. Scott, “Deep brain stimulation as a treatment for neuropathic St. Jude Medical pursued another effective business approach pain: a longitudinal study addressing neuropsychological outcomes,” to speeding up the market availability of the Libra and Brio J. Pain, vol. 15, no. 3, pp. 283–292, 2014. neurostimulator DBS systems for the treatment of Parkinson’s E. A. Pereira, A. L. Green, and T. Z. Aziz, “Deep brain stimulation for disease. Both products were first launched in Europe, followed by pain,” in Brain Stimulation (Handbook of Clinical Neurology, vol. 116). later approval to sell in the United States. Libra and Brio obtained Amsterdam, The Netherlands: Elsevier, 2013, pp. 277–294. the CE Mark in 2009, which created a channel of revenues from 20 ieee pulse ▼ march/april 2015
Deep brain stimulation might be the key to easing depression and chronic pain. by Nathalie Gosset and Nicholas Dietz
D
epression and chronic pain know no geographical boundaries. About 350 million people around the world experience long-lasting sadness and an unshakeable sense of hopelessness, and one person out of ten tries to live each day to its fullest despite continuous physical pain. These two difficult conditions frequently coexist, becoming more common with age. Looking ahead, we can
expect the incidence of depression and chronic illness to grow, since more people over age 65 will populate the world by 2020 than children younger than five. Amid an array of pain-management therapies and moodaltering therapeutics, researchers are looking at technologies focused on patients who are immune to drug and psychotherapy interventions. Among them, deep brain stimulation (DBS) has been found to provide much-needed relief for those experiencing treatment-resistant depression and refractory chronic pain. This article investigates new frontiers of DBS in depression and pain management in the context of a historical review and current market analysis of this platform technology.
Brain scan courtesy of AMI USC. Brain image: ©istockphoto/7activestudio
DBS for Depression and Chronic Pain
16 ieee pulse ▼ march/april 2015
2154-2287/15©2015IEEE
To date, DBS represents an advanced surgical procedure to treat motor deficiencies in a growing scope of neurological illnesses that includes Parkinson’s disease, essential tremor, and dystonia. Using variable electric impulses sent to specific brain regions, DBS amplifies or suppresses neural circuits to reverse pathology. While DBS intervention is considered to be young—having been clinically incorporated for only 16 years—its encouraging results in patient health outcomes have garnered much attention and raised hopes for the treatment of traditionally untreatable conditions. Interestingly, advancements in DBS have ignited curiosity about its efficacy in treating behavioral maladies and psychopathologies that might not otherwise be treated by drug therapy. Specifically, Digital Object Identifier 10.1109/MPUL.2014.2386511 Date of publication: 13 March 2015
the World Health Organization reports that 22% of it has been shown to effectively minimize symptoms Advancements in DBS primary care patients struggle with persistent pain of intractable obsessive-compulsive disorder (OCD) conditions, where pain is the most common cause and major depressive disorder (MDD). have ignited curiosity of medical attention. Despite their prevalence, a Americans are more depressed than Europeans about its efficacy in wide range of neuropathic and nociceptive pain and four times more than Australians. With a lifetime treating behavioral conditions are not sufficiently relieved through prevalence of depression of 15% in the United States maladies and surgical or pharmaceutical intervention. Moreover, and 9% in Europe, MDD or depression is a complex psychopathologies pain due to injury, stroke, back, or spine pathology mental illness marked by depressed mood or severely that might not and other persistent aches can result from complex diminished interest in all activities along with a host pathways that are not presently treatable. A signifiof other factors, which result in functional impairotherwise be treated cant market for DBS may also be found in alleviment, including insomnia, significant weight change, by drug therapy. ating chronic pain in individuals who suffer from psychomotor agitation or retardation, fatigue, and refractory pain states. recurrent suicidal ideation. Further, depressive mood As a growing market for this technology develdisorders are becoming increasingly related to comorops, new indications for treatment have been proposed to furbid medical conditions and lowered immune function, which contribther expand the scope of use while also providing unprecedented ute to the World Health Organization’s recognition of depression as alternatives of improved health for certain patient populations. the leading cause of disability worldwide (Figure 1). Although antiAmong those who suffer from MDD, a leading cause of disability depressant drug therapy is often effective, up to 30% of those with worldwide, treatment-resistant depression is a particularly debilidepression are resistant to traditional forms of rehabilitation, includtating illness immune to drug and psychotherapy interventions. ing electroconvulsive therapy and psychotherapy. For patients with Similarly, intractable chronic pain conditions cause significant refractory or treatment-resistant depression, DBS may provide a viaimpairment of daily function with limited treatment options. ble solution to an otherwise impervious illness. Another potential use of DBS—unapproved by the U.S. Food and Drug Administration (FDA)—is for the treatment of chronic pain Biological Mechanisms conditions. According to a recent poll conducted by the American Clinical application of DBS targets specific subcortical brain Pain Society, 30.7% of adults in the United States experience some regions that are believed to be the site of dysfunctional neuform of chronic pain for at least a six-month period. Additionally, ral activity. Procedural execution for Parkinson’s disease, for
Depression Knows No Geographical Boundaries But Affects Continents Differently
Depression and Chronic Pain Frequently Coexist Australia Europe >50%
North America South America Africa Underreported Due to Cultural Pressure
Asia
Depression
Chronic Pain
1.5 Billion People Suffer from Chronic Pain Back Pain
Migraine Neck Pain
Women Are Twice as Likely to Suffer from Depression Than Men
X2
X1
27%
15%
15%
FIGURE 1 The epidemiology of depression and chronic pain, global statistics. [Graphics courtesy of the Alfred E. Mann Institute for Biomedical Engineering at the University of Southern California (AMI USC), 2014.] march/april 2015 ▼ ieee pulse 17
DBS Electrode
pain states, including paraplegia and anesthesia dolorosa. However, DBS meets many chronic pain states with success, including stroke, amputation rehabilitation, multiple sclerosis, and spine injury, with improved emotional well-being and quality of life.
History and Regulatory Conditions DBS technology was first experimentally used for the treatment of chronic pain in the 1960s. Much of its initial appeal during that time has been attributed to the success of cardiac pacemakers, which helped to legitimize the use of electrical stimulation for clinical interventions. In fact, the DBS device blueprint closely matches and evolved from traditional cardiac pacemaker units—the first prototyped models of neurostimulators were, FIGURE 2 The subthalmic stimulation principle illustrated with a indeed, fashioned from the circuit boards of pacemakers. While functional magnetic resonance imaging (fMRI) diffusion tensor Medtronic pioneered the effort of neurostimulatory devices in tractography imaging model. (Image courtesy of AMI USC, 2014.) chronic pain, the first FDA approval of DBS was for treatment of essential tremor in 1997. Subsequent additions to approval of DBS for treatable conditions under FDA regulation were Parkinson’s disease in 2002 and dystonia in 2003. example, directs electrode implantation into the subthalamic Due to the inherent risk associated with the DBS procenucleus or globus pallidus due to abnormal neuronal synchrony dure, regulatory approval has been limited to conditions in related to the motor circuit (Figure 2). Electrical stimulation which the intervention is seen as a last resort when all other in one of these regions has been shown to correct tremor and traditional forms of treatment have failed. Perhaps the more dyskinesia for patients with Parkinson’s disease. For depresapparent reductions in quality of life for movement disorders sion, several regions have been identified that may contriblike Parkinson’s disease and dystonia have been a contributing ute to its pathology. The most commonly targeted brain region factor for their approval in recent years. While no FDA clearfor DBS in clinical trials has been the subgenual cingulate ance has since been granted for the use of DBS for psychiatgyrus (SCN), also known as Brodmann area 25, as it has been ric conditions or chronic pain, allowance has been made for shown to yield heightened metabolic activity during depression intractable OCD. In 2009, the FDA approved the (Figure 3). The SCN is also a key facet of the Medtronic Reclaim DBS device to treat refraclimbic-cortical system, which contributes to an tory and drug-resistant forms of OCD under integrated neural network responsible for mood Market analysts the humanitarian device use exemption (HDE). state that may result from multiple interacting predict that the The HDE FDA regulation recognizes medical brain regions. Several studies corroborate the DBS market will technologies that treat a small and underserved effectiveness of DBS targeting the white matter reach US$1 billion in population of patients and is similar in form associated with the SCN to confer sustained longto a premarket approval with fewer regulatory term relief of depressive symptoms. Another area revenues by 2018. hurdles prior to acceptance. targeted for refractory depression has been the nucleus accumbens (NAcc) that is closely related to reward systems of the brain that drive behavior. DBS targetMarket Analysis and Reimbursement ing the NAcc—and its accompanying system of the medial foreOne of the attractive and unique qualities of DBS technology is its brain bundle—has also been demonstrated to reduce depressive potential universality to treat a broad range of conditions. Because symptoms as soon as days after intervention and result in full of its interventional modality in the brain, it represents a platform remission of MDD months after the procedure. While the precise technology, wherein minor modifications to the device or lead mechanisms of DBS are still not fully understood, it appears that placement can be adapted to affect a wide range of behavioral electrical stimulation may realign pathological molecular and and neurological changes. Considering the prevalence of depreschemical imbalances to restore normal functioning. sion (15%) in the United States and the many chronic pain states DBS has also been proven to have long-lasting effects to treat that arise from injury and disease, the market for DBS could see certain cases of refractory chronic pain. Most research to date has a significant expansion. It should be noted that high variability focused on two areas, depending on the nature of the pain conis present on a case-by-case basis in the decision and efficacy of dition: the periaqueductal gray (PAG) and the sensory thalamus treating refractory pain states and depressive illness. Thus, it would (ST). In a meta-analysis conducted by Bittar et al., the long-term be difficult to predict what percentage would be eligible for the efficacy of pain alleviation of a variety of pain conditions was highintervention from current regulatory standards. What is clear, est in stimulation of the PAG (79%) when compared to stimulation however, is the predicted rise in need for DBS within its current of the ST (58%). The greatest improvement was seen in simultaneframework of treatable conditions. The prevalence of Parkinson’s ous stimulation of the PAG and ST at 87%. Additionally, DBS was disease, for example, is expected to rise for those over 50 years old, found to be more effective in sustained relief of nociceptive pain as to the extent that the approximately 4.5 million afflicted in 2005 opposed to neuropathic pain states and nonresponsive to certain will double by 2030 to 9 million. Connective Wires
18 ieee pulse ▼ march/april 2015
The procedure for DBS is often defined by two separate surgeries to 1) implant the elecThe SCN is also a key trodes and 2) insert the generator (Figure 4). facet of the limbicFirst, the electrodes are inserted through the cortical system, which skull either unilaterally or bilaterally, where contributes to an two incisions would be made—both options integrated neural have separate billing codes for reimbursement. The average cost for unilateral insertion of DBS network responsible is between US$35,000 and US$50,000 and can for mood state that be doubled for concurrent bilateral electrode may result from implantation. Most insurance companies, howmultiple interacting ever, do cover the costs for FDA-cleared DBS brain regions. devices. The insertion of the generator or battery pack is usually placed under the clavicle and requires a second inpatient procedure for which there are supplementary current procedural terminology codes. Subsequent procedures may include battery replacement and electrode lead removal.
In recent years, the DBS market has seen promising growth. Between 2012 and 2013, the DBS market grew 6.7%, with sales revenues for 2013 reaching a record US$677 million. The procedure has proven its efficacy for the treatment of neurological disorders as the adoption rate will steadily increase, with 7–9% annual growth forecasted. Kalorama Information reports an estimated US$4–5 billion annual market for electrical stimulation devices in treating pharmacoresistant depression alone. Some calculations even predict that DBS will reach US$1 billion in revenues by 2018.
Current Business Models Opening the use of DBS to a new set of psychiatric applications will benefit from the clinical validations Medtronic and Boston Scientific carved for the treatment of Parkinson’s disease. The first device that received FDA clearance—and perhaps the most widely used clinically—is the Medtronic model 3389. Medtronic was even credited with coining the term “deep brain stimulation” after opening up a neurosciences division in 1975 to investigate the technology. Currently, Medtronic has four neurostimulators available, all of which treat Parkinson’s disease and essential tremor, and three of the four are also used for dystonia (Table 1). Boston Scientific produces a single DBS device called the Vercise, which is advertised as having the smallest stimulator footprint and boasts a multiple independent current control for precise treatment.
FIGURE 3 The NAcc and subgenual cingulate cortex targets highlighted through an fMRI diffusion tensor imaging model. (Image courtesy of AMI USC, 2014.)
TABLE 1. A CURRENT PRODUCT LIST OF DBS TECHNOLOGIES, REPORTING TREATMENT OPTIONS, BATTERY LIFE, CHANNEL CAPACITY, AND FDA AND CE MARK APPROVALS FOR PROMINENT COMPANY MODELS. PD: PARKINSON’S DISEASE; ET: ESSENTIAL TREMOR; AND D: DYSTONIA. Distributor
Model
Channels
Treatments
FDA Approval
Battery Life (Years)
Medtronic
37601
Two
PD, ET, D
Yes
Nine
Medtronic
37612
Two
PD, ET
Yes
Nine
Medtronic
37602
One
PD, ET, D
Yes
Nine
Medtronic
37603
One
PD, ET, D
Yes
Nine
Boston Scientific
Vercise
Two
PD, D
Yes
25
St. Jude Medical
Libra
One
PD, D
No
Ten
St. Jude Medical
Brio
Two
PD, D
No
Ten
St. Jude Medical
Libra XP
Two
PD, D
No
Ten
march/april 2015 ▼ ieee pulse 19
European sales that funded clinical trials in the United States for FDA approval.
Final Thoughts 3
Successfully ameliorating chronic and debilitating disease states, DBS has emerged as a platform technology with unparalleled 2 potential across a number of medical fields to reverse intractable pathology. Regulatory clearance of DBS for certain motor-related diseases has shown promising results in patient health outcomes, and yet further investigation may lead to an approved expansion of treatable conditions to include psychiatric illnesses such as MDD and relief from refractory chronic pain. Progression of DBS may also benefit from a recent push in fed1 eral funding in the neurosciences. In 2013, the Human BRAIN Project (Brain Research Advancement through Innovative Neurotechnologies), funded by the U.S. National Institutes of Health, was announced to represent a large-scale effort to better underFIGURE 4 DBS device illustrating function of 1) pulse generator, 2) lead extension, and 3) electrode implants. (Image courtesy of stand the pathways of brain function and autonomic regulation. AMI USC, 2014.) For the fiscal year 2014, the Human BRAIN Project received presidential support with a pledge of US$100 million in funding— and determination of “high priority”—for progressing innovative technologies for brain imaging and neuromodulation. AdditionConsidering the portfolio of similar medical stimulation sysally, the U.S. Defense Advanced Research Projects Agency has tems, DBS has outperformed its competition. Medtronic’s Restorlaunched a US$70 million plan over the next four ative Therapies Group includes the manufacture of years specifically to develop and enhance DBS surgical technologies, neuromodulation and spine technology. A hopeful future awaits the investigastimulation systems. In 2013, this suite of therapy DBS represents an tion of neuroscience as an imminent convergence technologies performed well due to the outstanding advanced surgical of knowledge, technology, and clinical application success of the DBS product revenue, which balanced procedure to treat may maximize the potential of DBS. the decline in sales of spine stimulation systems that motor deficiencies now compete with morphogenetic protein and balNathalie Gosset ([email protected]) is the senior direcin a growing scope loon kyphoplasty. Medtronic was estimated to own tor of market and technology innovation evaluation at of neurological roughly 40% of the global DBS market in 2012. the Alfred E. Mann Institute for Biomedical Engineering Every unique clinical indication for the use of illnesses that includes at the University of Southern California. She is responsiDBS requires separate FDA approval. Despite prior Parkinson’s disease, ble for estimating the commercial value of more than 100 FDA clearance for the use of DBS to treat Parkinson’s essential tremor, medical innovations each year developed by elite research disease, for example, new standards of approval are centers. Nicholas Dietz ([email protected]) and dystonia. necessary before psychiatric applications are purgraduated from the University of California Los Angeles sued. Several business strategies can accelerate the (UCLA) in 2012 with a B.S. degree in psychobiology and approval process for DBS technology for the treatis currently a medical student at Georgetown University School of Medicine. ment of psychiatric conditions if the disease selected affects a small Prior to attending medical school, he worked for two years as a clinical population in the United States. The FDA approved the use of the research coordinator at the UCLA Department of PsychoneuroimmunolMedtronic Reclaim DBS device for the treatment of OCD in 2009 ogy, investigating spectral analysis of mindfulness meditation as well as the under the provision of HDE—targeting a condition affecting fewer effects of sleep deprivation in older adult populations. than 4,000 Americans per year. An HDE application includes similar requirements to a premarket approval application but does not have the rigorous standards for device clearance that large clinical trials For More Information require. An applicant seeking the HDE consideration must provide T. E. Schlaepfer, B. H. Bewernick, S. Kayser, B. Madler, and V. A. Coenen, evidence of the rarity of the clinical condition and the absence of “Rapid effects of deep brain stimulation for treatment-resistant major an appropriate treatment for the condition. This approach has been depression,” Biol. Psychiatry, vol. 73, no. 12, pp. 1204–1212, 2013. effective for Medtronic and pursued again for receiving approval for A. M. Gray, E. Pounds-Cornish, F. J. Eccles, T. Z. Aziz, A. L. Green, the treatment of chronic, intractable primary dystonia. and R. B. Scott, “Deep brain stimulation as a treatment for neuropathic St. Jude Medical pursued another effective business approach pain: a longitudinal study addressing neuropsychological outcomes,” to speeding up the market availability of the Libra and Brio J. Pain, vol. 15, no. 3, pp. 283–292, 2014. neurostimulator DBS systems for the treatment of Parkinson’s E. A. Pereira, A. L. Green, and T. Z. Aziz, “Deep brain stimulation for disease. Both products were first launched in Europe, followed by pain,” in Brain Stimulation (Handbook of Clinical Neurology, vol. 116). later approval to sell in the United States. Libra and Brio obtained Amsterdam, The Netherlands: Elsevier, 2013, pp. 277–294. the CE Mark in 2009, which created a channel of revenues from 20 ieee pulse ▼ march/april 2015
