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Clinical trials for deep brain stimulation: Current state of affairs
Brain Stimulation xxx (xxxx) xxx
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Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation
Clinical trials for deep brain stimulation: Current state of affairs Irene E. Harmsen a, 1, Gavin J.B. Elias a, 1, Michelle E. Beyn a, Alexandre Boutet a, b, Aditya Pancholi a, Jürgen Germann a, Alireza Mansouri c, Christopher S. Lozano a, Andres M. Lozano a, * a
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada Joint Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada c Department of Neurosurgery, Pennsylvania State University, Hershey, PA, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2019 Received in revised form 7 November 2019 Accepted 17 November 2019 Available online xxx
Background: Deep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes. Objective: To update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide. Methods: A search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic. Results: In total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS. Conclusions: This overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS. © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Deep brain stimulation Clinical trial Current trends Movement disorders Psychiatric disorders Cognitive disorders
Introduction Deep brain stimulation (DBS) is a neurosurgical intervention that involves the placement of electrodes within the brain in order to electrically stimulate specific targets and thereby modulate dysregulated neural circuitry [1]. Given its relative safety, therapeutic efficacy, and reversible and adjustable nature, DBS has become a mainstream surgical procedure over the last three
* Corresponding author. Toronto Western Hospital, University of Toronto, 399 Bathurst St., WW 4-431, M5P 2S5, Toronto, ON, Canada. E-mail address: [email protected] (A.M. Lozano). 1 These authors contributed equally.
decades. To date, it is estimated that over 150,000 patients have been implanted at over 700 centers worldwide [2]. While DBS is most often employed as a treatment for movement disorders such as Parkinson’s disease and essential tremor, it is increasingly being examined for its therapeutic potential across a range of neuropsychiatric and cognitive disorders, as well as for conditions such as neuropathic pain and epilepsy [3]. The growing demand for minimally-invasive approaches to neurological disorders and refractory neuropsychiatric conditions has boosted interest in neuromodulatory approaches such as DBS. As the field continues to expand, well-designed and executed clinical trials are needed as they are the pinnacle of evidence that will shape the practice of DBS. Progress in the field may be impeded
https://doi.org/10.1016/j.brs.2019.11.008 1935-861X/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
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by our limited understanding of the mechanism(s) of action of DBS, underutilization of adjuncts such as imaging, and by the constraints of regulatory considerations. The analysis of trends of past and current clinical trial landscapes can elucidate some of these challenges and provide insights into better/novel target selection, multi-modal planning, and improved stimulation parameter choices and ultimately, the optimization of therapeutic outcomes.
whether trials were described as involving ‘imaging’ (e.g., CT, MRI, PET) or ‘electrophysiology’ (e.g., single-unit recordings, local field potentials, EEG, MEG) in any capacity beyond standard clinical practice. Where applicable, ‘rate of change’ metrics were calculated in order to examine how rapidly new clinical trials of different classes, purposes, or origins were being generated.
Methods and materials A comprehensive search for past and ongoing clinical trials pertaining to DBS was conducted using the publicly available trial registry, ClinicalTrials.gov (https://clinicaltrials.gov/). This search was conducted in January of 2019 and included the search terms, ‘deep brain stimulation’ OR ‘DBS’. Identified clinical trial entries were screened to ensure they pertained to DBS, with relevant trials retained for further analysis. Trial start date, study completion status, clinical phase, projected subject enrollment, and funding source were recorded as posted in trial entries. Treatment condition was captured according to the specific disorder(s) described in each trial’s entry and subsequently, broadly categorized as either ‘movement disorder’, ‘psychiatric disorder’, ‘cognitive disorder’, ‘epilepsy’, ‘pain’, or ‘other’. Brain target for electrode insertion was also recorded as posted in trial entries and grouped into more general categories where appropriate. To account for studies that specified multiple targets, each individual target was enumerated; accordingly, these multiple-target studies were double-counted for the analysis of targets. The country of origin was determined according to the country of the responsible party (i.e., the lead center in multi-center studies). Device manufacturer was captured by noting any mention of specific manufacturer’s DBS hardware or relationship with a specific manufacturer in the trial entry. Depending on whether or not an intervention/treatment was being evaluated, study design was classified as ‘interventional’ (e.g., study determining the efficacy of novel brain targets) or ‘non-interventional’ (e.g., study examining imaging or neurophysiological changes). Finally, study topic was examined with reference to
Fig. 2. Number of trials by phase categorized by projected enrollment of subjects. 106 trials (27.6% of all trials) listed since 1997 provided information on study phase and projected subject enrollment. Phase I studies were most common (46.2% of trials), followed sequentially by Phase II (27.4%), Phase III (16.0%), and Phase IV (10.4%). Projected enrollment ranged from 1 to 10 subjects (37.7% of trials) to >500 subjects (0.9%), with an enrollment of 11e50 subjects being most common (41.5%).
Table 1 Trials by clinical disorder.
Fig. 1. Trials by status of completion. 327 trials (85.2% of all trials) listed since 1997 reported a known status of completion. (A) The number of studies by start date (ranging from 1997 to 2019) categorized by the status of completion. 138 trials are completed (42.2%), 116 trials are recruiting (35.5%), 37 trials are not yet recruiting (11.3%), 19 trials are withdrawn (5.8%), 15 trials are terminated (4.6%), and 2 trials are suspended (0.6%).
Clinical disorder
Number of Percent of total studies studies (%)
Parkinson’s disease Tremor Dystonia Huntington’s disease Other movement disorder (dyskinesia, multiple sclerosis, multiple system atrophy, cerebellar ataxia) Mixed movement disorder Major depressive disorder Bipolar disorder Obsessive-compulsive disorder Post-traumatic stress disorder Anorexia nervosa Schizophrenia Alcohol/Drug addiction Mixed psychiatric disorder Obesity Pain (including neuropathic pain and headache) Epilepsy Alzheimer’s disease Non-Alzheimer’s dementia Tourette’s syndrome Coma/Decreased level of consciousness Traumatic brain injury/Spinal injury/Stroke Mixed movement disorder/psychiatric/memory Other (tinnitus, lower urinary tract symptoms) Not specified Total
151 16 28 3 8
39.3 4.2 7.3 0.8 2.1
26 26 2 27 3 5 3 11 6 6 5 13 9 2 7 3 6 6 4 8 384
6.8 6.8 0.5 7.0 0.8 1.3 0.8 2.9 1.6 1.6 1.3 3.4 2.3 0.5 1.8 0.8 1.6 1.6 1.0 2.1 100
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
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Results Our search of the ClinicalTrials.gov database generated an initial list of 426 registered clinical trials. Following screening for pertinence to DBS, a total of 384 entries were identified, a count that included active trials as well as those that have already been completed or suspended, terminated, or withdrawn. The registration date for these trials ranged from 2019 back to the creation of the ClinicalTrials.gov database following the Food and Drug Administration Modernization Act of 1997. Studies by start date and status of completion Approximately half of all studies commenced within the last five years (Fig. 1A). All studies that began in the late 1990s and early 2000s have at this point either been completed or terminated. The
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oldest clinical trial that was still listed as actively recruiting started in 2006 and is an interventional study evaluating the efficacy of DBS of the subgenual cingulate white matter for treatmentresistant depression. Of the 327 trials (85.2% of all trials) with a known status of completion, most were either already completed (42.2%) or actively recruiting (35.5%). A considerable portion of trials e over 10% in total e were listed as either withdrawn (5.8%), terminated (4.6%), or suspended (0.6%). With regards to the projected trial duration, the mean length of a DBS-related clinical trial was found to be 48.4 ± 1.9 months (SEM). The maximum and minimum projected trial length were 194 months (for a study recruiting for N ¼ 300 subjects) and 2 months (for four studies with between N ¼ 2 and N ¼ 26 subjects, two of which were completed, one of which was withdrawn, and one of which was terminated), respectively.
Fig. 3. Trials by clinical disorder. 384 trials (100% of all trials) listed since 1997 provided information on the clinical disorder being studied. (A) Pie chart representing the percentage of clinical trials categorized by major clinical disorder. 238 trials study movement disorders (62.0%), 91 trials study psychiatric disorders (23.7%), 18 trials study cognitive disorders (4.7%), 13 trials study epilepsy (3.4%), 7 trials study pain (1.8%), and 17 trials study mixed or other disorders (4.4%). (B) Line plots of the three major disorder categories (movement, psychiatric, cognitive) show cumulative growth in the number of studies from 1997 to 2018.
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Studies by phase and projected enrollment For the 384 clinical trials identified, projected enrollment ranged from 1 to 10 subjects (33.3% of trials) to >500 subjects (1.6%), with an enrollment of 11e50 subjects being most common (43.8%). Studies enrolling 51e100 subjects and 101e500 subjects accounted for 7.8% and 8.1% of trials, respectively, while 5.5% of trials did not provide enrollment information. Information regarding the study phase was found to be lacking, with 72.1% of trial entries omitting this information. Of the 107 studies (27.9% of all trials) that specified phase, Phase I studies were most common (45.8% of trials), followed sequentially by Phase II (27.1%), Phase III (16.8%), and Phase IV (10.3%). Fig. 2 shows the relationship between phase and projected enrollment numbers for the 106 trials (27.6% of all trials) that provided information on both these aspects. Studies by clinical disorder Registered clinical trials studied a total of 28 different conditions (Table 1). Over half of registered DBS-related clinical trials pertained to movement disorders (62.0%) (Fig. 3A). Clinical trials for psychiatric disorders accounted for 23.7% of studies, followed by cognitive disorders (4.7%), epilepsy (3.4%), and pain (1.8%). The number of new trials registered per year for movement, psychiatric, and cognitive disorders has increased from 3.0, 1.3, and 0.1 (1997e2007) to 17.9, 6.9, and 1.6 (2008e2018), respectively (Fig. 3B, Supplementary Table 1). Some of the more novel indications described, each with a total of three studies, include Huntington’s disease, post-traumatic stress disorder, schizophrenia, and decreased level of consciousness/coma. Studies by brain target From the 384 studies listed since 1997, 26 distinct brain targets were identified (Table 2). 57% of brain areas targeted in registered clinical trials were subcortical components of the cortico-basal ganglia-thalamo-cortical motor circuit. The most frequent target overall was the subthalamic nucleus (STN) or neighboring posterior subthalamic area (33% of all trials collectively), followed by the globus pallidus pars internus (GPi) (12%). Affective limbic structures such as ventral striatum/ventral capsule (VS/VC), anterior limb of the internal capsule (ALIC), and subgenual cingulate were the next most frequently engaged group of targets, while memoryimplicated structures like the fornix and nucleus basalis occupied the third-largest group, collectively (Table 2). Single studies that examined more novel targets include the putamen for the treatment of Parkinson’s disease, hippocampus for refractory epilepsy, periventricular/periaqueductal grey for pain and autonomic dysreflexia, and the dentatorubrothalamic tract for essential tremor. A considerable number of trials used multiple electrodes to target different structures or used a single electrode to stimulate more than one structure. Of these multi-target trials, 46 trials listed two different targets and 9 trials listed three or more targets. Notably, only 15 multi-target trials were registered between 1997 and 2010, while 40 were registered between 2011 and 2019. Interesting multi-target studies that used a single electrode to stimulate multiple structures include the targeting of the STN and nucleus basalis of Meynert (NBM) for the treatment of Parkinson’s disease with dementia, and the STN and substantia nigra (SN) for resistant freezing of gait and dysphagia in Parkinson’s disease.
Table 2 Number of clinical trials by brain target. Target
Number of studies
Percent of total studies (%)
Subthalamic nucleus Posterior subthalamic area Globus pallidus pars internus Substantia nigra Caudate Putamen Unspecified basal ganglia Ventral intermediate nucleus of thalamus Ventro-oralis nucleus of thalamus Anterior nucleus of thalamus Other thalamus Hypothalamus Nucleus basalis Habenula Subgenual anterior cingulate/Subcallosal area Ventral striatum/Anterior limb of the internal capsule Bed nucleus of stria terminalis Amygdala Medial forebrain bundle Prefrontal cortex Fornix Hippocampus Pedunculopontine nucleus Periventricular/periaqueductal grey Dentatorubrothalamic tract Other brainstem targets Cerebellum Not specified/ambiguous Totala
145 3 52 6 2 1 9 19 2 7 10 6 8 5 14
32.6 0.7 11.7 1.4 0.5 0.2 2.0 4.3 0.5 1.6 2.3 1.4 1.8 1.1 3.2
44
9.9
3 2 4 2 7 2 7 2 1 2 2 78 445
0.7 0.5 0.9 0.5 1.6 0.5 1.6 0.5 0.2 0.5 0.5 17.5 100
a Studies that specified more than one target were counted for each separate target. As such, the number of studies listed in this column sums to 445 rather than 384.
(14.8%), China (8.9%), Germany (6.8%), and Canada (6.5%) (Fig. 4A, Table 3). Rates of trial registration signifying the number of new trials started per year are represented in Fig. 4B and reported in Supplementary Table 2. Although the USA led with the highest number of new trials started per year, China showed rapid growth in the number of new trials started per year, especially given its relatively recent arrival to the field of DBS in 2010. Notably, 61.8% of China’s clinical trials involve non-motor indications, of which 47.1% focus specifically on psychiatric indications (e.g., major depression, addiction, anorexia, OCD). Studies by manufacturer and funding source Out of the 384 studies identified, 157 (40.9% of all trials) listed a manufacturer. Two-thirds of these studies used Medtronic DBS systems (68.8%); by comparison, the second (Boston Scientific Corp.) and third (Abbott Laboratories, formerly St. Jude Medical, Inc.) largest manufacturers by clinical trial support accounted for 10.2% and 7.6% of trials, respectively (Fig. 5A, Table 4). A breakdown by the year of the study’s start date shows the cumulative growth in the number of studies using a certain manufacturer, from 1997 to 2018 (Fig. 5B). The number of new trials started per year are listed in Supplementary Table 3. Close to a quarter (24.2%) of clinical trials were noted to be funded by industry. The remaining trials (75.8%) were funded by non-industry sources such as the government (e.g., NIH).
Studies by country of origin
Studies by design and primary topic
By country of study origin, the top five countries that accounted for the highest percentage of trials include the USA (41.9%), France
In order to survey the principal content and design of identified clinical trials, all 384 studies were first classified as either
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Fig. 4. Trials by country of origin. 384 trials (100% of all trials) listed since 1997 provided information on the study’s country of origin. (A) World map illustrating the percentage distribution of clinical trials as organized by the country of the responsible party. The USA has the highest number of registered trials at 161 (41.9%), followed by 57 trials registered in France (14.8%), and 34 trials registered in China (8.9%). (B) Line plots of the top 5 contributing countries show the cumulative total of clinical trials conducted from 1997 to 2018.
interventional (78.4%) or non-interventional (21.6%). Of the 301 interventional studies that provided information about randomization design, approximately half were found to be randomized (48.2%) and the other half non-randomized (50.8%). 15.4% of all trials involved DBS-related neuroimaging, while 19.3% addressed electrophysiological recordings. While only four studies begun between 1997 and 2007 included a neuroimaging component, 53 studies initiated between 2008 and 2018 involved neuroimaging.
Discussion We identified and categorized 384 past and present publicly registered clinical trials pertaining to DBS. The number of registered clinical trials has grown rapidly since the ClinicalTrials.gov database was first introduced, indicating that human DBS-related research is a rapidly growing field.
Current trends and future directions Our analyses on DBS-related clinical trials revealed many interesting trends. With regard to country of origin, the United States has conducted the greatest number of DBS trials of any country to date by a notable margin. France has the second-highest number of registered clinical trials, followed by China, Germany, and Canada. While China has historically lagged behind Western countries in the development of DBS, this appears to be changing. It has been suggested that factors contributing to the lower volume of DBS in China in the past include lack of health insurance, high out-ofpocket costs, and limited resources [4,5]. Despite the absence of DBS trials up until 2010, China’s rate of trials per year has rapidly increased to place it amongst the top three DBS trials contributors, above Germany and Canada. DBS has quickly evolved in China, perhaps in part due to the establishment of local manufacturing
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Table 3 Clinical trials by country of origin. Country
Number of studies
Percent of total studies (%)
United States France China Germany Canada United Kingdom Belgium Spain Israel Netherlands Italy Switzerland Austria Denmark Brazil Turkey Australia Finland Norway Taiwan Hungary Mexico Egypt South Korea Total
161 57 34 26 25 11 8 7 7 6 5 6 5 5 5 3 3 2 2 2 1 1 1 1 384
41.9 14.8 8.9 6.8 6.5 2.9 2.1 1.8 1.8 1.6 1.3 1.6 1.3 1.3 1.3 0.8 0.8 0.5 0.5 0.5 0.3 0.3 0.3 0.3 100
capacity that decreases the high costs of hardware e a major obstacle in DBS implantation [6]. It is interesting to note that although China’s first DBS surgery was only performed in 1998 on a PD patient [7], the country is now leading trials on novel indications for DBS such as drug addiction [8,9]. As expected, movement disorders DBS e which has been FDAapproved for over two decades (i.e., essential tremor in 1997, PD in 2002, dystonia in 2003 [10e12]) e constitutes the largest clinical research focus in the field. Befitting the more established nature of this indication, movement disorder trials tend to investigate quality of life outcomes, economic benefit, and novel DBS parameters to optimize therapy as opposed to assessing the safety and efficacy of novel brain targets [13e15]. It is notable that, although movement disorders accounted for over 60% of registered trials, they represent a considerably larger share (we estimate at >90% of DBS surgeries), suggesting that current clinical research is in fact disproportionately focused on experimental indications and not on established treatments. Psychiatric and cognitive indications account for the second and third largest area of active trials, respectively, reflecting their progressively later entry onto the DBS stage. The distribution of brain targets reflects the same pattern as that of the disorders given their close association. Key subcortical hubs of the cortico-basal ganglia-thalamo-cortical motor circuits, such as the STN, GPi, and motor thalamus, are collectively targeted by half of all studies. Structures implicated in affective (e.g., VS/VC, ALIC, subgenual cingulate) and cognitive (e.g., fornix, nucleus basalis) limbic circuitry account for smaller but still sizeable proportions of the total body of clinical trials. It is important to note that, in many cases, multiple targets have been explored for single indications. Major depressive disorder, for instance, has been addressed using at least five different brain targets, including the subgenual cingulate, VS/VC, inferior thalamic peduncle, medial forebrain bundle (MFB), and bed nucleus of stria terminalis (BNST) [16]. Some of these targets were identified via unanticipated results observed during other DBS studies. The VS/VC became a target for depression as a result of improved mood in OCD patients who underwent VC/VS DBS [17]. In another example, hypothalamic DBS intended to treat obesity resulted in memory enhancement, which led to the emergence of forniceal DBS for Alzheimer’s disease [18].
Our results also highlight the growing popularity of multi-target studies, a trend that may be driven in part by advances in imagingguided targeting [19] and electrode technology, such as the development of longer, dual-frequency electrodes [20] and the recent advent of directional leads [21,22]. A multi-target strategy may be promising for complex disorders that involve symptoms with different pathogenic mechanisms and may also reflect the burgeoning notion that distributed circuits e and nodes along these circuits e rather than discrete structures are the optimal substrates for stimulation [19]. Along these lines, it is important to note the critical role of imaging for preoperative planning, intraoperative guidance, and postoperative programming. The growing number of clinical trials involving a neuroimaging component reflects this shift in clinical practice. Tractography and functional networks have been used to individualize targeting, accounting for slight anatomical variations in patients. Recent studies have also shown the value of intraoperative guidance, without the need for awake surgery [23,24]. A detailed connectivity map that includes an individual’s precise electrode location will be a useful tool to direct stimulation on intended structures and avoid stimulating adjacent areas. This would improve therapeutic outcomes while reducing stimulation-induced side effects [19]. Industry partnerships and funding dynamics play an important role in shaping the field of DBS research, especially in terms of driving innovation and technological advancements. The global market value of DBS devices was estimated at USD 664.4 million in 2015 and is projected to increase by 8.2% during the forecast period from 2016 to 2024 [25]. Several different companies manufacture DBS systems; some of these (e.g., Medtronic) have existed for decades, while others have arisen following the FDA approval of DBS for movement disorders in the early 2000s. There are also some companies that are relatively new to the scene (e.g., SceneRay Corp., Ltd. and Beijing PINS Medical Co., Ltd.) [6]. Despite the emergence of several new DBS manufacturers over the past decades, Medtronic is still the most prominent manufacturer of devices used in clinical research. This has important implications, given that the availability and accessibility of hardware from different manufacturers influence the type of clinical work that is being done. For example, directional electrodes e currently produced only by Boston Scientific Corp. and Abbott Laboratories e permit programming optimization work that is otherwise not possible. Although not much detail was provided on studies’ funding sources, a quarter of studies were explicitly stated to be industry-funded. This is less than what was reported for a representative sample of 200 clinical trials that addressed pharmacological and surgical interventions, whereby the most frequent funding sources were governmental (58%) and industry/privatefor-profit (40%) [26]. To ensure transparency, standardized reporting of funding information is important at the time of publication and should include specification of the role of the funder. Methodological limitations An important limitation of this study is its reliance on the USbased clinical trials registry, ClinicalTrials.gov. Although this is the largest clinical trials database in the world, with over 230,000 trial registrations from 195 countries, it is run by the United States National Library of Medicine at the National Institutes of Health. Only trials conducted in or using materials produced in the US are mandated by the FDA to register with ClinicalTrials.gov. As such, this database is likely biased towards US-centric entries, which could account for the large difference in the total number of trials conducted between the US and the rest of the world. Nonetheless, peer-reviewed journals are increasingly moving toward adoption of the ICMJE policy that requires appropriate ClinicalTrials.gov
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
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Fig. 5. Trials by device manufacturer. 157 trials (40.9% of all trials) listed since 1997 provided information on the device manufacturer which was obtained by documenting any relationship to a specific manufacturer in the trial entry; i.e., manufacturer-sponsored trial and/or use of specified manufacturer equipment. (A) Pie chart represents the percentage of clinical trials categorized by manufacturer. Medtronic contributes to the greatest percentage of registered trials at 68.8%. (B) Line plots of top 5 contributing manufacturers show cumulative growth in the number of studies from 1997 to 2018. Table 4 Clinical trials by manufacturer. Manufacturer
Number of studies
Percent of total studies (%)
Medtronic Boston Scientific Abbott (St. Jude) PINS SceneRay Aleva Therapeutics Totala
108 16 12 12 7 2 157
68.8 10.2 7.6 7.6 4.5 1.3 100
a The total number of studies does not sum to 384 because only 157 studies (40.9% of all trials) listed a manufacturer.
registry as a prerequisite for publication, a move that appears to be driving increased registration of international studies [27].
this field, shedding light on the worldwide topography, subject matter, and pragmatic factors that characterize this important research. As the DBS research field continues to expand, this type of analysis offers insight into what we can expect in the future with regards to new brain targets, indications, programming paradigms, and advanced DBS technologies.
Funding This work is supported by the Canadian Institutes of Health Research (I.E.H.) and a Canada Research Chair in Neuroscience (A.M.L.).
Role of the funding source Conclusions This overview of past and present DBS-related clinical trials provides a dissection of the work that has been conducted so far in
The funding sources had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication.
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Authors’ roles Study design: I.E.H., G.J.B.E., A.M.L. Writing and figure preparation: I.E.H., G.J.B.E. prepared the initial draft of the manuscript and figures; all authors reviewed and/or edited the manuscript and approved of the submitted version. Analysis: I.E.H., G.J.B.E., M.E.B., A.B., A.P., J.G., A.M., and C.L. performed analyses of data. Study supervision: A.M.L. Declaration of competing interest A.M.L. has served as a consultant for Medtronic, Abbott, Boston Scientific, PINS, SceneRay, and Functional Neuromodulation. All other authors declare no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.brs.2019.11.008. References [1] Lozano AM, Eltahawy H. How does DBS work? Suppl Clin Neurophysiol 2004;57:733e6. [2] Hariz M. My 25 stimulating years with DBS in Parkinson’s disease. J Parkinson’s Dis 2017;7:S33e41. https://doi.org/10.3233/JPD-179007. [3] Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013;77:406e24. https://doi.org/10.1016/ j.neuron.2013.01.020. [4] Hu W-H, Zhang K, Meng F-G, Ma Y, Zhang J-G. Deep brain stimulation in China: present and future. Neuromodulation Technol Neural Interface 2012;15:251e9. https://doi.org/10.1111/j.1525-1403.2012.00439.x. [5] Hu S, Tang S, Liu Y, Zhao Y, Escobar M-L, de Ferranti D. Reform of how health care is paid for in China: challenges and opportunities. Lancet 2008;372: 1846e53. https://doi.org/10.1016/S0140-6736(08)61368-9. [6] Liu H, Ma Y, Zhang K, Ge M, Meng F, Feng T, et al. Subthalamic deep brain stimulation with a new device in Parkinson’s disease: an open-label trial. Neuromodulation Technol Neural Interface 2013;16:212e8. https://doi.org/ 10.1111/ner.12050. [7] Guan X, Chu J, Luan G, Zhang B. The effect of deep brain stimulation and follow-up treatment on tremor and spasm of Parkinson’s disease. Mod Rehabil J 2001;33e5. [8] Chen L, Li N, Ge S, Lozano AM, Lee DJ, Yang C, et al. Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: an open-label pilot study. Brain Stimul 2019;12:175e83. https://doi.org/10.1016/j.brs.2018.09.006. [9] Ge S, Chen Y, Li N, Qu L, Li Y, Jing J, et al. Deep brain stimulation of nucleus accumbens for methamphetamine addiction: two case reports. World Neurosurg 2019;122:512e7. https://doi.org/10.1016/j.wneu.2018.11.056. [10] Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang A, et al. Highfrequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997;42:292e9. https://doi.org/10.1002/ ana.410420304. [11] Zhang K, Bhatia S, Oh MY, Cohen D, Angle C, Whiting D. Long-term results of thalamic deep brain stimulation for essential tremor. J Neurosurg 2010;112: 1271e6. https://doi.org/10.3171/2009.10.JNS09371.
[12] Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 1998;339:1105e11. https://doi.org/10.1056/ NEJM199810153391603. [13] Schüpbach WMM, Tonder L, Schnitzler A, Krack P, Rau J, Hartmann A, et al. Quality of life predicts outcome of deep brain stimulation in early Parkinson disease. Neurology 2019;92:e1109e20. https://doi.org/10.1212/ WNL.0000000000007037. [14] McIntosh E, Gray A, Daniels J, Gill S, Ives N, Jenkinson C, et al. Cost-utility analysis of deep brain stimulation surgery plus best medical therapy versus best medical therapy in patients with Parkinson’s: economic evaluation alongside the PD SURG trial. Mov Disord 2016;31:1173e82. https://doi.org/ 10.1002/mds.26423. [15] Harmsen IE, Lee DJ, Dallapiazza RF, De Vloo P, Chen R, Fasano A, et al. Ultrahigh-frequency deep brain stimulation at 10,000 Hz improves motor function. Mov Disord 2019;34:146e8. https://doi.org/10.1002/mds.27550. [16] Drobisz D, Damborsk a A. Deep brain stimulation targets for treating depression. Behav Brain Res 2019;359:266e73. https://doi.org/10.1016/ j.bbr.2018.11.004. [17] Aouizerate B, Cuny E, Martin-Guehl C, Guehl D, Amieva H, Benazzouz A, et al. Deep brain stimulation of the ventral caudate nucleus in the treatment of obsessivedcompulsive disorder and major depression. J Neurosurg 2004;101: 682e6. https://doi.org/10.3171/jns.2004.101.4.0682. [18] Hamani C, McAndrews MP, Cohn M, Oh M, Zumsteg D, Shapiro CM, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008;63:119e23. https://doi.org/10.1002/ana.21295. [19] Boutet A, Gramer R, Steele CJ, Elias GJB, Germann J, Maciel R, et al. Neuroimaging technological advancements for targeting in functional neurosurgery. Curr Neurol Neurosci Rep 2019;19:42. https://doi.org/10.1007/s11910-0190961-8. [20] Hollingworth M, Sims-Williams HP, Pickering AE, Barua N, Patel NK. Single electrode deep brain stimulation with dual targeting at dual frequency for the treatment of chronic pain: a case series and review of the literature. Brain Sci 2017;7:9. https://doi.org/10.3390/brainsci7010009. [21] Schüpbach WMM, Chabardes S, Matthies C, Pollo C, Steigerwald F, Timmermann L, et al. Directional leads for deep brain stimulation: opportunities and challenges. Mov Disord 2017;32:1371e5. https://doi.org/10.1002/ mds.27096. [22] Steigerwald F, Müller L, Johannes S, Matthies C, Volkmann J. Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device. Mov Disord 2016;31:1240e3. https://doi.org/ 10.1002/mds.26669. [23] Foltynie T, Zrinzo L, Martinez-Torres I, Tripoliti E, Petersen E, Holl E, et al. MRIguided STN DBS in Parkinson’s disease without microelectrode recording: efficacy and safety. J Neurol Neurosurg Psychiatry 2011;82:358e63. https:// doi.org/10.1136/jnnp.2010.205542. [24] Lee PS, Richardson RM. Interventional MRIeguided deep brain stimulation lead implantation. Neurosurg Clin N Am 2017;28:535e44. https://doi.org/ 10.1016/j.nec.2017.05.007. [25] Shah S. Global deep brain stimulation devices market, by application (Parkinson’s disease, essential tremor, dystonia, others), and by geography trends, outlook, and forecast from 2016-2024 2017:1e69. accessed August 12, 2019, https://www.coherentmarketinsights.com/market-insight/deep-brainstimulation-devices-market-84. [26] Hakoum MB, Jouni N, Abou-Jaoude EA, Hasbani DJ, Abou-Jaoude EA, Lopes LC, et al. Characteristics of funding of clinical trials: cross-sectional survey and proposed guidance. BMJ Open 2017;7:e015997. https://doi.org/10.1136/ bmjopen-2017-015997. [27] Zarin DA, Tse T, Williams RJ, Rajakannan T. Update on trial registration 11 Years after the ICMJE policy was established. N Engl J Med 2017;376:383e91. https://doi.org/10.1056/NEJMsr1601330.
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Contents lists available at ScienceDirect
Brain Stimulation journal homepage: http://www.journals.elsevier.com/brain-stimulation
Clinical trials for deep brain stimulation: Current state of affairs Irene E. Harmsen a, 1, Gavin J.B. Elias a, 1, Michelle E. Beyn a, Alexandre Boutet a, b, Aditya Pancholi a, Jürgen Germann a, Alireza Mansouri c, Christopher S. Lozano a, Andres M. Lozano a, * a
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada Joint Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada c Department of Neurosurgery, Pennsylvania State University, Hershey, PA, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 August 2019 Received in revised form 7 November 2019 Accepted 17 November 2019 Available online xxx
Background: Deep brain stimulation (DBS) is a surgical neuromodulation procedure with a historically wide range of possible therapeutic indications, including movement disorders, neuropsychiatric conditions, and cognitive disorders. Ongoing research in this field is critical to gain further insights into the mechanisms of DBS, to discover novel brain targets for new and existing indications, and to refine targeting and post-operative programming techniques for the optimization of therapeutic outcomes. Objective: To update on the state of DBS-related clinical human research by cataloging and summarizing clinical trials that have been completed or are currently ongoing in this field worldwide. Methods: A search was conducted for clinical trials pertaining to DBS, currently listed on the ClinicalTrials.gov database. Trials were analyzed to generate a detailed overview of ongoing DBS-related research. Specifically, trials were categorized by trial start date, study completion status, clinical phase, projected subject enrollment, disorder, brain target, country of origin, device manufacturer, funding source, and study topic. Results: In total, 384 relevant clinical trials were identified. The trials spanned 28 different disorders across 26 distinct brain targets, with almost 40% of trials being for conditions other than movement disorders. The majority of DBS trials have been US-based (41.9% of studies) but many countries are becoming increasingly active. The ratio of investigator-sponsored to industry-sponsored trials was 3:1. Emphasizing the need to better understand the mechanism of action of DBS, one-third of the studies predominantly focus on imaging or electrophysiological changes associated with DBS. Conclusions: This overview of current DBS-related clinical trials provides insight into the status of DBS research and what we can anticipate in the future concerning new brain targets, indications, techniques, and developing a better understanding of the mechanisms of action of DBS. © 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Deep brain stimulation Clinical trial Current trends Movement disorders Psychiatric disorders Cognitive disorders
Introduction Deep brain stimulation (DBS) is a neurosurgical intervention that involves the placement of electrodes within the brain in order to electrically stimulate specific targets and thereby modulate dysregulated neural circuitry [1]. Given its relative safety, therapeutic efficacy, and reversible and adjustable nature, DBS has become a mainstream surgical procedure over the last three
* Corresponding author. Toronto Western Hospital, University of Toronto, 399 Bathurst St., WW 4-431, M5P 2S5, Toronto, ON, Canada. E-mail address: [email protected] (A.M. Lozano). 1 These authors contributed equally.
decades. To date, it is estimated that over 150,000 patients have been implanted at over 700 centers worldwide [2]. While DBS is most often employed as a treatment for movement disorders such as Parkinson’s disease and essential tremor, it is increasingly being examined for its therapeutic potential across a range of neuropsychiatric and cognitive disorders, as well as for conditions such as neuropathic pain and epilepsy [3]. The growing demand for minimally-invasive approaches to neurological disorders and refractory neuropsychiatric conditions has boosted interest in neuromodulatory approaches such as DBS. As the field continues to expand, well-designed and executed clinical trials are needed as they are the pinnacle of evidence that will shape the practice of DBS. Progress in the field may be impeded
https://doi.org/10.1016/j.brs.2019.11.008 1935-861X/© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
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by our limited understanding of the mechanism(s) of action of DBS, underutilization of adjuncts such as imaging, and by the constraints of regulatory considerations. The analysis of trends of past and current clinical trial landscapes can elucidate some of these challenges and provide insights into better/novel target selection, multi-modal planning, and improved stimulation parameter choices and ultimately, the optimization of therapeutic outcomes.
whether trials were described as involving ‘imaging’ (e.g., CT, MRI, PET) or ‘electrophysiology’ (e.g., single-unit recordings, local field potentials, EEG, MEG) in any capacity beyond standard clinical practice. Where applicable, ‘rate of change’ metrics were calculated in order to examine how rapidly new clinical trials of different classes, purposes, or origins were being generated.
Methods and materials A comprehensive search for past and ongoing clinical trials pertaining to DBS was conducted using the publicly available trial registry, ClinicalTrials.gov (https://clinicaltrials.gov/). This search was conducted in January of 2019 and included the search terms, ‘deep brain stimulation’ OR ‘DBS’. Identified clinical trial entries were screened to ensure they pertained to DBS, with relevant trials retained for further analysis. Trial start date, study completion status, clinical phase, projected subject enrollment, and funding source were recorded as posted in trial entries. Treatment condition was captured according to the specific disorder(s) described in each trial’s entry and subsequently, broadly categorized as either ‘movement disorder’, ‘psychiatric disorder’, ‘cognitive disorder’, ‘epilepsy’, ‘pain’, or ‘other’. Brain target for electrode insertion was also recorded as posted in trial entries and grouped into more general categories where appropriate. To account for studies that specified multiple targets, each individual target was enumerated; accordingly, these multiple-target studies were double-counted for the analysis of targets. The country of origin was determined according to the country of the responsible party (i.e., the lead center in multi-center studies). Device manufacturer was captured by noting any mention of specific manufacturer’s DBS hardware or relationship with a specific manufacturer in the trial entry. Depending on whether or not an intervention/treatment was being evaluated, study design was classified as ‘interventional’ (e.g., study determining the efficacy of novel brain targets) or ‘non-interventional’ (e.g., study examining imaging or neurophysiological changes). Finally, study topic was examined with reference to
Fig. 2. Number of trials by phase categorized by projected enrollment of subjects. 106 trials (27.6% of all trials) listed since 1997 provided information on study phase and projected subject enrollment. Phase I studies were most common (46.2% of trials), followed sequentially by Phase II (27.4%), Phase III (16.0%), and Phase IV (10.4%). Projected enrollment ranged from 1 to 10 subjects (37.7% of trials) to >500 subjects (0.9%), with an enrollment of 11e50 subjects being most common (41.5%).
Table 1 Trials by clinical disorder.
Fig. 1. Trials by status of completion. 327 trials (85.2% of all trials) listed since 1997 reported a known status of completion. (A) The number of studies by start date (ranging from 1997 to 2019) categorized by the status of completion. 138 trials are completed (42.2%), 116 trials are recruiting (35.5%), 37 trials are not yet recruiting (11.3%), 19 trials are withdrawn (5.8%), 15 trials are terminated (4.6%), and 2 trials are suspended (0.6%).
Clinical disorder
Number of Percent of total studies studies (%)
Parkinson’s disease Tremor Dystonia Huntington’s disease Other movement disorder (dyskinesia, multiple sclerosis, multiple system atrophy, cerebellar ataxia) Mixed movement disorder Major depressive disorder Bipolar disorder Obsessive-compulsive disorder Post-traumatic stress disorder Anorexia nervosa Schizophrenia Alcohol/Drug addiction Mixed psychiatric disorder Obesity Pain (including neuropathic pain and headache) Epilepsy Alzheimer’s disease Non-Alzheimer’s dementia Tourette’s syndrome Coma/Decreased level of consciousness Traumatic brain injury/Spinal injury/Stroke Mixed movement disorder/psychiatric/memory Other (tinnitus, lower urinary tract symptoms) Not specified Total
151 16 28 3 8
39.3 4.2 7.3 0.8 2.1
26 26 2 27 3 5 3 11 6 6 5 13 9 2 7 3 6 6 4 8 384
6.8 6.8 0.5 7.0 0.8 1.3 0.8 2.9 1.6 1.6 1.3 3.4 2.3 0.5 1.8 0.8 1.6 1.6 1.0 2.1 100
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Results Our search of the ClinicalTrials.gov database generated an initial list of 426 registered clinical trials. Following screening for pertinence to DBS, a total of 384 entries were identified, a count that included active trials as well as those that have already been completed or suspended, terminated, or withdrawn. The registration date for these trials ranged from 2019 back to the creation of the ClinicalTrials.gov database following the Food and Drug Administration Modernization Act of 1997. Studies by start date and status of completion Approximately half of all studies commenced within the last five years (Fig. 1A). All studies that began in the late 1990s and early 2000s have at this point either been completed or terminated. The
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oldest clinical trial that was still listed as actively recruiting started in 2006 and is an interventional study evaluating the efficacy of DBS of the subgenual cingulate white matter for treatmentresistant depression. Of the 327 trials (85.2% of all trials) with a known status of completion, most were either already completed (42.2%) or actively recruiting (35.5%). A considerable portion of trials e over 10% in total e were listed as either withdrawn (5.8%), terminated (4.6%), or suspended (0.6%). With regards to the projected trial duration, the mean length of a DBS-related clinical trial was found to be 48.4 ± 1.9 months (SEM). The maximum and minimum projected trial length were 194 months (for a study recruiting for N ¼ 300 subjects) and 2 months (for four studies with between N ¼ 2 and N ¼ 26 subjects, two of which were completed, one of which was withdrawn, and one of which was terminated), respectively.
Fig. 3. Trials by clinical disorder. 384 trials (100% of all trials) listed since 1997 provided information on the clinical disorder being studied. (A) Pie chart representing the percentage of clinical trials categorized by major clinical disorder. 238 trials study movement disorders (62.0%), 91 trials study psychiatric disorders (23.7%), 18 trials study cognitive disorders (4.7%), 13 trials study epilepsy (3.4%), 7 trials study pain (1.8%), and 17 trials study mixed or other disorders (4.4%). (B) Line plots of the three major disorder categories (movement, psychiatric, cognitive) show cumulative growth in the number of studies from 1997 to 2018.
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Studies by phase and projected enrollment For the 384 clinical trials identified, projected enrollment ranged from 1 to 10 subjects (33.3% of trials) to >500 subjects (1.6%), with an enrollment of 11e50 subjects being most common (43.8%). Studies enrolling 51e100 subjects and 101e500 subjects accounted for 7.8% and 8.1% of trials, respectively, while 5.5% of trials did not provide enrollment information. Information regarding the study phase was found to be lacking, with 72.1% of trial entries omitting this information. Of the 107 studies (27.9% of all trials) that specified phase, Phase I studies were most common (45.8% of trials), followed sequentially by Phase II (27.1%), Phase III (16.8%), and Phase IV (10.3%). Fig. 2 shows the relationship between phase and projected enrollment numbers for the 106 trials (27.6% of all trials) that provided information on both these aspects. Studies by clinical disorder Registered clinical trials studied a total of 28 different conditions (Table 1). Over half of registered DBS-related clinical trials pertained to movement disorders (62.0%) (Fig. 3A). Clinical trials for psychiatric disorders accounted for 23.7% of studies, followed by cognitive disorders (4.7%), epilepsy (3.4%), and pain (1.8%). The number of new trials registered per year for movement, psychiatric, and cognitive disorders has increased from 3.0, 1.3, and 0.1 (1997e2007) to 17.9, 6.9, and 1.6 (2008e2018), respectively (Fig. 3B, Supplementary Table 1). Some of the more novel indications described, each with a total of three studies, include Huntington’s disease, post-traumatic stress disorder, schizophrenia, and decreased level of consciousness/coma. Studies by brain target From the 384 studies listed since 1997, 26 distinct brain targets were identified (Table 2). 57% of brain areas targeted in registered clinical trials were subcortical components of the cortico-basal ganglia-thalamo-cortical motor circuit. The most frequent target overall was the subthalamic nucleus (STN) or neighboring posterior subthalamic area (33% of all trials collectively), followed by the globus pallidus pars internus (GPi) (12%). Affective limbic structures such as ventral striatum/ventral capsule (VS/VC), anterior limb of the internal capsule (ALIC), and subgenual cingulate were the next most frequently engaged group of targets, while memoryimplicated structures like the fornix and nucleus basalis occupied the third-largest group, collectively (Table 2). Single studies that examined more novel targets include the putamen for the treatment of Parkinson’s disease, hippocampus for refractory epilepsy, periventricular/periaqueductal grey for pain and autonomic dysreflexia, and the dentatorubrothalamic tract for essential tremor. A considerable number of trials used multiple electrodes to target different structures or used a single electrode to stimulate more than one structure. Of these multi-target trials, 46 trials listed two different targets and 9 trials listed three or more targets. Notably, only 15 multi-target trials were registered between 1997 and 2010, while 40 were registered between 2011 and 2019. Interesting multi-target studies that used a single electrode to stimulate multiple structures include the targeting of the STN and nucleus basalis of Meynert (NBM) for the treatment of Parkinson’s disease with dementia, and the STN and substantia nigra (SN) for resistant freezing of gait and dysphagia in Parkinson’s disease.
Table 2 Number of clinical trials by brain target. Target
Number of studies
Percent of total studies (%)
Subthalamic nucleus Posterior subthalamic area Globus pallidus pars internus Substantia nigra Caudate Putamen Unspecified basal ganglia Ventral intermediate nucleus of thalamus Ventro-oralis nucleus of thalamus Anterior nucleus of thalamus Other thalamus Hypothalamus Nucleus basalis Habenula Subgenual anterior cingulate/Subcallosal area Ventral striatum/Anterior limb of the internal capsule Bed nucleus of stria terminalis Amygdala Medial forebrain bundle Prefrontal cortex Fornix Hippocampus Pedunculopontine nucleus Periventricular/periaqueductal grey Dentatorubrothalamic tract Other brainstem targets Cerebellum Not specified/ambiguous Totala
145 3 52 6 2 1 9 19 2 7 10 6 8 5 14
32.6 0.7 11.7 1.4 0.5 0.2 2.0 4.3 0.5 1.6 2.3 1.4 1.8 1.1 3.2
44
9.9
3 2 4 2 7 2 7 2 1 2 2 78 445
0.7 0.5 0.9 0.5 1.6 0.5 1.6 0.5 0.2 0.5 0.5 17.5 100
a Studies that specified more than one target were counted for each separate target. As such, the number of studies listed in this column sums to 445 rather than 384.
(14.8%), China (8.9%), Germany (6.8%), and Canada (6.5%) (Fig. 4A, Table 3). Rates of trial registration signifying the number of new trials started per year are represented in Fig. 4B and reported in Supplementary Table 2. Although the USA led with the highest number of new trials started per year, China showed rapid growth in the number of new trials started per year, especially given its relatively recent arrival to the field of DBS in 2010. Notably, 61.8% of China’s clinical trials involve non-motor indications, of which 47.1% focus specifically on psychiatric indications (e.g., major depression, addiction, anorexia, OCD). Studies by manufacturer and funding source Out of the 384 studies identified, 157 (40.9% of all trials) listed a manufacturer. Two-thirds of these studies used Medtronic DBS systems (68.8%); by comparison, the second (Boston Scientific Corp.) and third (Abbott Laboratories, formerly St. Jude Medical, Inc.) largest manufacturers by clinical trial support accounted for 10.2% and 7.6% of trials, respectively (Fig. 5A, Table 4). A breakdown by the year of the study’s start date shows the cumulative growth in the number of studies using a certain manufacturer, from 1997 to 2018 (Fig. 5B). The number of new trials started per year are listed in Supplementary Table 3. Close to a quarter (24.2%) of clinical trials were noted to be funded by industry. The remaining trials (75.8%) were funded by non-industry sources such as the government (e.g., NIH).
Studies by country of origin
Studies by design and primary topic
By country of study origin, the top five countries that accounted for the highest percentage of trials include the USA (41.9%), France
In order to survey the principal content and design of identified clinical trials, all 384 studies were first classified as either
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Fig. 4. Trials by country of origin. 384 trials (100% of all trials) listed since 1997 provided information on the study’s country of origin. (A) World map illustrating the percentage distribution of clinical trials as organized by the country of the responsible party. The USA has the highest number of registered trials at 161 (41.9%), followed by 57 trials registered in France (14.8%), and 34 trials registered in China (8.9%). (B) Line plots of the top 5 contributing countries show the cumulative total of clinical trials conducted from 1997 to 2018.
interventional (78.4%) or non-interventional (21.6%). Of the 301 interventional studies that provided information about randomization design, approximately half were found to be randomized (48.2%) and the other half non-randomized (50.8%). 15.4% of all trials involved DBS-related neuroimaging, while 19.3% addressed electrophysiological recordings. While only four studies begun between 1997 and 2007 included a neuroimaging component, 53 studies initiated between 2008 and 2018 involved neuroimaging.
Discussion We identified and categorized 384 past and present publicly registered clinical trials pertaining to DBS. The number of registered clinical trials has grown rapidly since the ClinicalTrials.gov database was first introduced, indicating that human DBS-related research is a rapidly growing field.
Current trends and future directions Our analyses on DBS-related clinical trials revealed many interesting trends. With regard to country of origin, the United States has conducted the greatest number of DBS trials of any country to date by a notable margin. France has the second-highest number of registered clinical trials, followed by China, Germany, and Canada. While China has historically lagged behind Western countries in the development of DBS, this appears to be changing. It has been suggested that factors contributing to the lower volume of DBS in China in the past include lack of health insurance, high out-ofpocket costs, and limited resources [4,5]. Despite the absence of DBS trials up until 2010, China’s rate of trials per year has rapidly increased to place it amongst the top three DBS trials contributors, above Germany and Canada. DBS has quickly evolved in China, perhaps in part due to the establishment of local manufacturing
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Table 3 Clinical trials by country of origin. Country
Number of studies
Percent of total studies (%)
United States France China Germany Canada United Kingdom Belgium Spain Israel Netherlands Italy Switzerland Austria Denmark Brazil Turkey Australia Finland Norway Taiwan Hungary Mexico Egypt South Korea Total
161 57 34 26 25 11 8 7 7 6 5 6 5 5 5 3 3 2 2 2 1 1 1 1 384
41.9 14.8 8.9 6.8 6.5 2.9 2.1 1.8 1.8 1.6 1.3 1.6 1.3 1.3 1.3 0.8 0.8 0.5 0.5 0.5 0.3 0.3 0.3 0.3 100
capacity that decreases the high costs of hardware e a major obstacle in DBS implantation [6]. It is interesting to note that although China’s first DBS surgery was only performed in 1998 on a PD patient [7], the country is now leading trials on novel indications for DBS such as drug addiction [8,9]. As expected, movement disorders DBS e which has been FDAapproved for over two decades (i.e., essential tremor in 1997, PD in 2002, dystonia in 2003 [10e12]) e constitutes the largest clinical research focus in the field. Befitting the more established nature of this indication, movement disorder trials tend to investigate quality of life outcomes, economic benefit, and novel DBS parameters to optimize therapy as opposed to assessing the safety and efficacy of novel brain targets [13e15]. It is notable that, although movement disorders accounted for over 60% of registered trials, they represent a considerably larger share (we estimate at >90% of DBS surgeries), suggesting that current clinical research is in fact disproportionately focused on experimental indications and not on established treatments. Psychiatric and cognitive indications account for the second and third largest area of active trials, respectively, reflecting their progressively later entry onto the DBS stage. The distribution of brain targets reflects the same pattern as that of the disorders given their close association. Key subcortical hubs of the cortico-basal ganglia-thalamo-cortical motor circuits, such as the STN, GPi, and motor thalamus, are collectively targeted by half of all studies. Structures implicated in affective (e.g., VS/VC, ALIC, subgenual cingulate) and cognitive (e.g., fornix, nucleus basalis) limbic circuitry account for smaller but still sizeable proportions of the total body of clinical trials. It is important to note that, in many cases, multiple targets have been explored for single indications. Major depressive disorder, for instance, has been addressed using at least five different brain targets, including the subgenual cingulate, VS/VC, inferior thalamic peduncle, medial forebrain bundle (MFB), and bed nucleus of stria terminalis (BNST) [16]. Some of these targets were identified via unanticipated results observed during other DBS studies. The VS/VC became a target for depression as a result of improved mood in OCD patients who underwent VC/VS DBS [17]. In another example, hypothalamic DBS intended to treat obesity resulted in memory enhancement, which led to the emergence of forniceal DBS for Alzheimer’s disease [18].
Our results also highlight the growing popularity of multi-target studies, a trend that may be driven in part by advances in imagingguided targeting [19] and electrode technology, such as the development of longer, dual-frequency electrodes [20] and the recent advent of directional leads [21,22]. A multi-target strategy may be promising for complex disorders that involve symptoms with different pathogenic mechanisms and may also reflect the burgeoning notion that distributed circuits e and nodes along these circuits e rather than discrete structures are the optimal substrates for stimulation [19]. Along these lines, it is important to note the critical role of imaging for preoperative planning, intraoperative guidance, and postoperative programming. The growing number of clinical trials involving a neuroimaging component reflects this shift in clinical practice. Tractography and functional networks have been used to individualize targeting, accounting for slight anatomical variations in patients. Recent studies have also shown the value of intraoperative guidance, without the need for awake surgery [23,24]. A detailed connectivity map that includes an individual’s precise electrode location will be a useful tool to direct stimulation on intended structures and avoid stimulating adjacent areas. This would improve therapeutic outcomes while reducing stimulation-induced side effects [19]. Industry partnerships and funding dynamics play an important role in shaping the field of DBS research, especially in terms of driving innovation and technological advancements. The global market value of DBS devices was estimated at USD 664.4 million in 2015 and is projected to increase by 8.2% during the forecast period from 2016 to 2024 [25]. Several different companies manufacture DBS systems; some of these (e.g., Medtronic) have existed for decades, while others have arisen following the FDA approval of DBS for movement disorders in the early 2000s. There are also some companies that are relatively new to the scene (e.g., SceneRay Corp., Ltd. and Beijing PINS Medical Co., Ltd.) [6]. Despite the emergence of several new DBS manufacturers over the past decades, Medtronic is still the most prominent manufacturer of devices used in clinical research. This has important implications, given that the availability and accessibility of hardware from different manufacturers influence the type of clinical work that is being done. For example, directional electrodes e currently produced only by Boston Scientific Corp. and Abbott Laboratories e permit programming optimization work that is otherwise not possible. Although not much detail was provided on studies’ funding sources, a quarter of studies were explicitly stated to be industry-funded. This is less than what was reported for a representative sample of 200 clinical trials that addressed pharmacological and surgical interventions, whereby the most frequent funding sources were governmental (58%) and industry/privatefor-profit (40%) [26]. To ensure transparency, standardized reporting of funding information is important at the time of publication and should include specification of the role of the funder. Methodological limitations An important limitation of this study is its reliance on the USbased clinical trials registry, ClinicalTrials.gov. Although this is the largest clinical trials database in the world, with over 230,000 trial registrations from 195 countries, it is run by the United States National Library of Medicine at the National Institutes of Health. Only trials conducted in or using materials produced in the US are mandated by the FDA to register with ClinicalTrials.gov. As such, this database is likely biased towards US-centric entries, which could account for the large difference in the total number of trials conducted between the US and the rest of the world. Nonetheless, peer-reviewed journals are increasingly moving toward adoption of the ICMJE policy that requires appropriate ClinicalTrials.gov
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
I.E. Harmsen et al. / Brain Stimulation xxx (xxxx) xxx
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Fig. 5. Trials by device manufacturer. 157 trials (40.9% of all trials) listed since 1997 provided information on the device manufacturer which was obtained by documenting any relationship to a specific manufacturer in the trial entry; i.e., manufacturer-sponsored trial and/or use of specified manufacturer equipment. (A) Pie chart represents the percentage of clinical trials categorized by manufacturer. Medtronic contributes to the greatest percentage of registered trials at 68.8%. (B) Line plots of top 5 contributing manufacturers show cumulative growth in the number of studies from 1997 to 2018. Table 4 Clinical trials by manufacturer. Manufacturer
Number of studies
Percent of total studies (%)
Medtronic Boston Scientific Abbott (St. Jude) PINS SceneRay Aleva Therapeutics Totala
108 16 12 12 7 2 157
68.8 10.2 7.6 7.6 4.5 1.3 100
a The total number of studies does not sum to 384 because only 157 studies (40.9% of all trials) listed a manufacturer.
registry as a prerequisite for publication, a move that appears to be driving increased registration of international studies [27].
this field, shedding light on the worldwide topography, subject matter, and pragmatic factors that characterize this important research. As the DBS research field continues to expand, this type of analysis offers insight into what we can expect in the future with regards to new brain targets, indications, programming paradigms, and advanced DBS technologies.
Funding This work is supported by the Canadian Institutes of Health Research (I.E.H.) and a Canada Research Chair in Neuroscience (A.M.L.).
Role of the funding source Conclusions This overview of past and present DBS-related clinical trials provides a dissection of the work that has been conducted so far in
The funding sources had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or decision to submit for publication.
Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008
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I.E. Harmsen et al. / Brain Stimulation xxx (xxxx) xxx
Authors’ roles Study design: I.E.H., G.J.B.E., A.M.L. Writing and figure preparation: I.E.H., G.J.B.E. prepared the initial draft of the manuscript and figures; all authors reviewed and/or edited the manuscript and approved of the submitted version. Analysis: I.E.H., G.J.B.E., M.E.B., A.B., A.P., J.G., A.M., and C.L. performed analyses of data. Study supervision: A.M.L. Declaration of competing interest A.M.L. has served as a consultant for Medtronic, Abbott, Boston Scientific, PINS, SceneRay, and Functional Neuromodulation. All other authors declare no conflicts of interest. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.brs.2019.11.008. References [1] Lozano AM, Eltahawy H. How does DBS work? Suppl Clin Neurophysiol 2004;57:733e6. [2] Hariz M. My 25 stimulating years with DBS in Parkinson’s disease. J Parkinson’s Dis 2017;7:S33e41. https://doi.org/10.3233/JPD-179007. [3] Lozano AM, Lipsman N. Probing and regulating dysfunctional circuits using deep brain stimulation. Neuron 2013;77:406e24. https://doi.org/10.1016/ j.neuron.2013.01.020. [4] Hu W-H, Zhang K, Meng F-G, Ma Y, Zhang J-G. Deep brain stimulation in China: present and future. Neuromodulation Technol Neural Interface 2012;15:251e9. https://doi.org/10.1111/j.1525-1403.2012.00439.x. [5] Hu S, Tang S, Liu Y, Zhao Y, Escobar M-L, de Ferranti D. Reform of how health care is paid for in China: challenges and opportunities. Lancet 2008;372: 1846e53. https://doi.org/10.1016/S0140-6736(08)61368-9. [6] Liu H, Ma Y, Zhang K, Ge M, Meng F, Feng T, et al. Subthalamic deep brain stimulation with a new device in Parkinson’s disease: an open-label trial. Neuromodulation Technol Neural Interface 2013;16:212e8. https://doi.org/ 10.1111/ner.12050. [7] Guan X, Chu J, Luan G, Zhang B. The effect of deep brain stimulation and follow-up treatment on tremor and spasm of Parkinson’s disease. Mod Rehabil J 2001;33e5. [8] Chen L, Li N, Ge S, Lozano AM, Lee DJ, Yang C, et al. Long-term results after deep brain stimulation of nucleus accumbens and the anterior limb of the internal capsule for preventing heroin relapse: an open-label pilot study. Brain Stimul 2019;12:175e83. https://doi.org/10.1016/j.brs.2018.09.006. [9] Ge S, Chen Y, Li N, Qu L, Li Y, Jing J, et al. Deep brain stimulation of nucleus accumbens for methamphetamine addiction: two case reports. World Neurosurg 2019;122:512e7. https://doi.org/10.1016/j.wneu.2018.11.056. [10] Koller W, Pahwa R, Busenbark K, Hubble J, Wilkinson S, Lang A, et al. Highfrequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol 1997;42:292e9. https://doi.org/10.1002/ ana.410420304. [11] Zhang K, Bhatia S, Oh MY, Cohen D, Angle C, Whiting D. Long-term results of thalamic deep brain stimulation for essential tremor. J Neurosurg 2010;112: 1271e6. https://doi.org/10.3171/2009.10.JNS09371.
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Please cite this article as: Harmsen IE et al., Clinical trials for deep brain stimulation: Current state of affairs, Brain Stimulation, https://doi.org/ 10.1016/j.brs.2019.11.008