Deep Brain Stimulation for Alzheimer’s Disease: Tackling Circuit Dysfunction

ObjectivesTreatments for Alzheimer’s disease are urgently needed given its enormous human and economic costs and disappointing results of clinical trials targeting the primary amyloid and tau pathology. On the other hand, deep brain stimulation (DBS) has demonstrated success in other neurological and psychiatric disorders leading to great interest in DBS as a treatment for Alzheimer’s disease.Materials and MethodsWe review the literature on 1) circuit dysfunction in Alzheimer’s disease and 2) DBS for Alzheimer’s disease. Human and animal studies are reviewed individually.ResultsThere is accumulating evidence of neural circuit dysfunction at the structural, functional, electrophysiological, and neurotransmitter level. Recent evidence from humans and animals indicate that DBS has the potential to restore circuit dysfunction in Alzheimer’s disease, similarly to other movement and psychiatric disorders, and may even slow or reverse the underlying disease pathophysiology.ConclusionsDBS is an intriguing potential treatment for Alzheimer’s disease, targeting circuit dysfunction as a novel therapeutic target. However, further exploration of the basic disease pathology and underlying mechanisms of DBS is necessary to better understand how circuit dysfunction can be restored. Additionally, robust clinical data in the form of ongoing phase III clinical trials are needed to validate the efficacy of DBS as a viable treatment.     

Deep Brain Stimulation-Related Surgical Site Infections: A Systematic Review and Meta-Analysis

BackgroundOver the last decades, the increased use of deep brain stimulation (DBS) has raised concerns about the potential adverse health effects of the treatment. Surgical site infections (SSIs) following an elective surgery remain a major challenge for neurosurgeons. Few studies have examined the prevalence and risk factors of DBS-related complications, particularly focusing on SSIs.ObjectivesWe systematically searched published literature, up to June 2020, with no language restrictions.Materials and MethodsEligible were studies that examined the prevalence of DBS-related SSIs, as well as studies that examined risk and preventive factors in relation to SSIs. We extracted information on study characteristics, follow-up, exposure and outcome assessment, effect estimate and sample size. Summary odds ratios (sOR) and 95% confidence intervals (CI) were calculated from random-effects meta-analyses; heterogeneity and small-study effects were also assessed.ResultsWe identified 66 eligible studies that included 12,258 participants from 27 countries. The summary prevalence of SSIs was estimated at 5.0% (95% CI: 4.0%–6.0%) with higher rates for dystonia (6.5%), as well as for newer indications of DBS, such as epilepsy (9.5%), Tourette syndrome (5.9%) and OCD (4.5%). Similar prevalence rates were found between early-onset and late-onset hardware infections. Among risk and preventive factors, the perioperative implementation of intra-wound vancomycin was associated with statistically significantly lower risk of SSIs (sOR: 0.26, 95% CI: 0.09–0.74). Heterogeneity was nonsignificant in most meta-analyses.ConclusionThe present study confirms the still high prevalence of SSIs, especially for newer indications of DBS and provides evidence that preventive measures, such as the implementation of topical vancomycin, seem promising in reducing the risk of DBS-related SSIs. Large clinical trials are needed to confirm the efficacy and safety of such measures.     

Probing responses to deep brain stimulation with functional magnetic resonance imaging

BackgroundDeep brain stimulation (DBS) is an established treatment for certain movement disorders and has additionally shown promise for various psychiatric, cognitive, and seizure disorders. However, the mechanisms through which stimulation exerts therapeutic effects are incompletely understood. A technique that may help to address this knowledge gap is functional magnetic resonance imaging (fMRI). This is a non-invasive imaging tool which permits the observation of DBS effects in vivo.ObjectiveThe objective of this review was to provide a comprehensive overview of studies in which fMRI during active DBS was performed, including studied disorders, stimulated brain regions, experimental designs, and the insights gleaned from stimulation-evoked fMRI responses.MethodsWe conducted a systematic review of published human studies in which fMRI was performed during active stimulation in DBS patients. The search was conducted using PubMED and MEDLINE.ResultsThe rate of fMRI DBS studies is increasing over time, with 37 studies identified overall. The median number of DBS patients per study was 10 (range = 1–67, interquartile range = 11). Studies examined fMRI responses in various disease cohorts, including Parkinson's disease (24 studies), essential tremor (3 studies), epilepsy (3 studies), obsessive-compulsive disorder (2 studies), pain (2 studies), Tourette syndrome (1 study), major depressive disorder, anorexia, and bipolar disorder (1 study), and dementia with Lewy bodies (1 study). The most commonly stimulated brain region was the subthalamic nucleus (24 studies). Studies showed that DBS modulates large-scale brain networks, and that stimulation-evoked fMRI responses are related to the site of stimulation, stimulation parameters, patient characteristics, and therapeutic outcomes. Finally, a number of studies proposed fMRI-based biomarkers for DBS treatment, highlighting ways in which fMRI could be used to confirm circuit engagement and refine DBS therapy.ConclusionA review of the literature reflects an exciting and expanding field, showing that the combination of DBS and fMRI represents a uniquely powerful tool for simultaneously manipulating and observing neural circuitry. Future work should focus on relatively understudied disease cohorts and stimulated regions, while focusing on the prospective validation of putative fMRI-based biomarkers.     

Deep Brain Stimulation in Movement Disorders: From Experimental Surgery to Evidence‐Based Therapy

Deep brain stimulation (DBS) of 3 different targets is the most important therapeutic innovation of the past 30 years for patients with fluctuating Parkinson's disease (PD), disabling dystonia, tremors, and refractory Gilles de la Tourette syndrome. When compared with medical treatment alone, controlled studies have shown better motor, nonmotor, and particularly quality‐of‐life outcomes with large effect sizes for advanced complicated PD that cannot be improved with medication, and also for PD patients with only early fluctuations. Class 1 studies have also shown superiority over medical treatment for generalized, segmental, and botulinum‐toxin refractory focal cervical dystonia. Long‐term efficacy is established for all indications with open studies. For tremors, open studies have shown that DBS is remarkably effective on PD and essential tremor, but efficacy on severe essential tremor and cerebellar tremors is limited by a tendency for tolerance/habituation, including concerns about long‐term efficacy. Open studies of disabling Gilles de la Tourette syndrome show an improvement in tics. New developments hold a promise for further improvement. New hardware with directional stimulation and new stimulation paradigms are further areas of research. The targets of DBS are refined with new imaging processing that will help to diversify the surgical targets. New indications are being explored. Closed‐loop DBS using brain or peripheral sensor signals have shown favorable clinical short‐term results. Long‐term data are lacking, and it is hoped that similar approaches for other movement or behavioral disorders may be developed. Exciting new developments carry the hope for a more pathophysiology‐based approach for DBS for various brain circuit disorders. © 2019 International Parkinson and Movement Disorder Society     

DBSproc: An open source process for DBS electrode localization and tractographic analysis

Deep brain stimulation (DBS) is an effective surgical treatment for movement disorders. Although stimulation sites for movement disorders such as Parkinson's disease are established, the therapeutic mechanisms of DBS remain controversial. Recent research suggests that specific white‐matter tract and circuit activation mediates symptom relief. To investigate these questions, we have developed a patient‐specific open‐source software pipeline called ‘DBSproc’ for (1) localizing DBS electrodes and contacts from postoperative CT images, (2) processing structural and diffusion MRI data, (3) registering all images to a common space, (4) estimating DBS activation volume from patient‐specific voltage and impedance, and (5) understanding the DBS contact‐brain connectivity through probabilistic tractography. In this paper, we explain our methodology and provide validation with anatomical and tractographic data. This method can be used to help investigate mechanisms of action of DBS, inform surgical and clinical assessments, and define new therapeutic targets. Hum Brain Mapp 37:422–433, 2016. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.     

Potential indications for deep brain stimulation in neurological disorders: an evolving field

Deep brain stimulation (DBS) is an established therapy for appropriately selected patients with movement disorders and neuropsychiatric conditions. Although the exact mechanisms and biology of DBS are not fully understood, it is a safe and well‐tolerated therapy for many refractory cases of neuropsychiatric disease. Increasingly, DBS has been explored in other conditions with encouraging results. In this paper, available data is reviewed and new DBS targets, challenges and future directions in neurological disorders are explored. A detailed search of the medical literature discussing the potential use of DBS for neurological disorders excluding accepted indications was conducted. All reports were analyzed individually for content and redundant articles were excluded by examining individual abstracts. The level of evidence for each indication was summarized. Multiple studies report promising preliminary data regarding the safety and efficacy of DBS for a variety of neurological indications including chronic pain, tinnitus, epilepsy, Tourette syndrome, Huntington's disease, tardive dyskinesia and Alzheimer's disease. The initial results of DBS studies for diverse neurological disorders are encouraging but larger, controlled, prospective, homogeneous clinical trials are necessary to establish long‐term safety and effectiveness. The field of neuromodulation continues to evolve and advances in DBS technology, stereotactic techniques, neuroimaging and DBS programming capabilities are shaping the present and future of DBS research and use in practice.     

Pediatric indications for deep brain stimulation

Purpose

Based on the success of deep brain stimulation (DBS) in the treatment of adult disorders, it is reasonable to assume that the application of DBS in the pediatric population is an emerging area worthy of study. The purpose of this paper is to outline the current movement disorder indications for DBS in the pediatric population, and to describe areas of investigation, including possible medically refractory psychiatric indications.

Methods

We performed a structured review of the English language literature from 1990 to 2011 related to studies of DBS in pediatrics using Medline and PubMed search results.

Results

Twenty-four reports of DBS in the pediatric population were found. Based on published data on the use of DBS for pediatric indications, there is a spectrum of clinical evidence for the use of DBS to treat different disorders. Dystonia, a disease associated with a low rate of remission and significant disability, is routinely treated with DBS and is currently the most promising pediatric application of DBS. We caution the application of DBS to conditions associated with a high remission rate later in adulthood, like obsessive-compulsive disorder and Tourette’s syndrome. Moreover, epilepsy and obesity are currently being investigated as indications for DBS in the adult population; however, both are associated with significant morbidity in pediatrics.

Conclusion

While currently dystonia is the most promising application of DBS in the pediatric population, multiple conditions currently being investigated in adults also afflict children and adolescents, and thus warrant further research.     

Advanced Imaging in Psychiatric Neurosurgery: Toward Personalized Treatment

ObjectivesOur aim is to review several recent landmark studies discussing the application of advanced neuroimaging to guide target selection in deep brain stimulation (DBS) for psychiatric disorders.Materials and MethodsWe performed a PubMed literature search of articles related to psychiatric neurosurgery, DBS, diffusion tensor imaging, probabilistic tractography, functional magnetic resonance imaging (MRI), and blood oxygen level-dependent activation. Relevant articles were included in the review.ResultsRecent advances in neuroimaging, namely the use of diffusion tensor imaging, probabilistic tractography, functional MRI, and positron emission tomography have provided higher resolution depictions of structural and functional connectivity between regions of interest. Applying these imaging modalities to DBS has increased understanding of the mechanism of action of DBS from the single structure to network level, allowed for new DBS targets to be discovered, and allowed for individualized DBS targeting for psychiatric indications.ConclusionsAdvanced neuroimaging techniques may be especially important to guide personalized DBS targeting in psychiatric disorders such as treatment-resistant depression and obsessive–compulsive disorder where symptom profiles and underlying disordered circuitry are more heterogeneous. These articles suggest that advanced imaging can help to further individualize and optimize DBS, a promising next step in improving its efficacy.     

Clinical perspectives of adaptive deep brain stimulation

BackgroundThe application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients’ changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models.ObjectiveTo review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors.Findingswhile aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging.ConclusionsWhile aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising.     

Deep brain stimulation for treatment-resistant depression: Efficacy, safety and mechanisms of action

Deep brain stimulation (DBS), a neuromodulation therapy that has been used successfully in the treatment of symptoms associated with movement disorders, has recently undergone clinical trials for individuals suffering from treatment-resistant depression (TRD). Although the small patient numbers and open label study design limit our ability to identify optimum targets and make definitive conclusions about treatment efficacy, a review of the published research demonstrates significant reductions in depressive symptomatology and high rates of remission in a severely treatment-resistant patient group. Despite these encouraging results, an incomplete understanding of the mechanisms of action underlying the therapeutic effects of DBS for TRD is highlighted, paralleling the incomplete understanding of the neuroanatomy of mood regulation and treatment resistance. Proposed mechanisms of action include short and long-term local effects of stimulation at the neuronal level, to modulation of neural network activity.     

Deep brain stimulation for movement disorders. Considerations on 276 consecutive patients

The links between Stn DBS and advanced Parkinson disease, and between GPi DBS and dystonia are nearly universally accepted by the neurologists and neurosurgeons. Nevertheless, in some conditions, targets such as the ventral thalamus and the Zona Incerta may be considered to optimize the results and avoid the side effects. Positive and negative aspects of current DBS treatments justify the research of new targets, new stimulation programs and new hardware. Since 1993, at the Istituto Nazionale Neurologico "Carlo Besta" in Milan, 580 deep brain electrodes were implanted in 332 patients. 276 patients were affected by movement disorders. The DBS targets included Stn, GPi, Voa, Vop, Vim, CM-pf, cZi, IC. The long-term follow-up is reported and related to the chosen target. DBS gave a new therapeutic option to patients affected by severe movement disorders, and in some cases resolved life-threatening pathological conditions that would otherwise result in the death of the patient, such as in status dystonicus, and post-stroke hemiballismus. Nevertheless, the potential occurrence of severe complications still limit a wider use of DBS. At today, the use of DBS in severe movement disorders is strongly positive even if further investigations and studies are needed to unveil potential new applications, and to refine the selection criteria for the actual indications and targets. The experience of different targets may be useful to guide and tailor the target choice to the individual clinical condition.     

Neuromodulatory treatments for psychiatric disease: A comprehensive survey of the clinical trial landscape

BackgroundNumerous neuromodulatory therapies are currently under investigation or in clinical use for the treatment of psychiatric conditions.Objective/hypothesisWe sought to catalogue past and present human research studies on psychiatric neuromodulation and identify relevant trends in this field.MethodsClinicalTrials.gov (https://www.clinicaltrials.gov/) and the International Clinical Trials Registry Platform (https://www.who.int/ictrp/en/) were queried in March 2020 for trials assessing the outcome of neuromodulation for psychiatric disorders. Relevant trials were categorized by variables such as neuromodulation modality, country, brain target, publication status, design, and funding source.ResultsFrom 72,086 initial search results, 1252 unique trials were identified. The number of trials registered annually has consistently increased. Half of all trials were active and a quarter have translated to publications. The largest proportion of trials involved depression (45%), schizophrenia (18%), and substance use disorders (14%). Trials spanned 37 countries; China, the second largest contributor (13%) after the United States (28%), has increased its output substantially in recent years. Over 75% of trials involved non-convulsive non-invasive modalities (e.g., transcranial magnetic stimulation), while convulsive (e.g., electroconvulsive therapy) and invasive modalities (e.g., deep brain stimulation) were less represented. 72% of trials featured approved or cleared interventions. Characteristic inter-modality differences were observed with respect to enrollment size, trial design/phase, and funding. Dorsolateral prefrontal cortex accounted for over half of focal neuromodulation trial targets. The proportion of trials examining biological correlates of neuromodulation has increased.Conclusion(s)These results provide a comprehensive overview of the state of psychiatric neuromodulation research, revealing the growing scope and internationalism of this field.     

A systematic review of psychiatric indications for deep brain stimulation,with focus on major depressive and obsessive-compulsive disorder

Background: Deep brain stimulation is a treatment under investigation for a range of psychiatric disorders. It has shown promising results for therapy-refractory obsessive–compulsive disorder (OCD) and major depressive disorder (MDD). Other indications under investigation include Tourette’s syndrome, anorexia nervosa and substance use disorders.

Aims: To review current studies on psychiatric indications for deep brain stimulation (DBS), with focus on OCD and MDD.

Method: A systematic search was carried out in MEDLINE, and the literature was searched to identify studies with DBS for psychiatric disorders. The identified studies were analysed based on patient characteristics, treatment results and adverse effects of DBS.

Results: A total of 52 papers met the inclusion criteria and described a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in six different anatomical targets, while nine studies presented 100 patients with DBS for MDD in five different targets.

Conclusion: DBS may show promise for treatment-resistant OCD and MDD but the results are limited by small sample size and insufficient randomized controlled data. Deep brain stimulation for OCD has received United States Food and Drug Administration approval. Other psychiatric indications are currently of a purely experimental nature.     

Twenty‐five years of deep brain stimulation: Celebrations and apprehensions

The year 2012 marks the 25th anniversary of the birth of modern deep brain stimulation (DBS), which was introduced by Benabid et al in 1987, initially to treat tremor with DBS of the ventral intermediate nucleus of the thalamus. The subsequent extension of DBS to the subthalamic nucleus (STN), demonstrating its efficacy on virtually all symptoms of advanced Parkinson's disease (PD), sparked an era of intense clinical and research activities, eventually transcending PD and movement disorders to encompass mood and mind. Investigations of the role of DBS in a variety of neurological, psychiatric, cognitive, and behavioral conditions is ongoing. Serendipitous discoveries and advances in functional imaging are providing “new” brain targets for an increasing number of pathologies. Toward the end of this quarter of a century of DBS, there have been some indications that the field may be at risk of gliding down a slippery slope, reminiscent of the excesses of the old‐era DBS. Although there are many reasons this year to celebrate the achievements of 25 years of modern DBS, there are also reasons to fear the opening of a new Pandora's box. © 2012 Movement Disorder Society     

Surgical and Hardware-Related Adverse Events of Deep Brain Stimulation: A Ten-Year Single-Center Experience

IntroductionAlthough deep brain stimulation (DBS) is effective for treating a number of neurological and psychiatric indications, surgical and hardware-related adverse events (AEs) can occur that affect quality of life. This study aimed to give an overview of the nature and frequency of those AEs in our center and to describe the way they were managed. Furthermore, an attempt was made at identifying possible risk factors for AEs to inform possible future preventive measures.Materials and MethodsPatients undergoing DBS-related procedures between January 2011 and July 2020 were retrospectively analyzed to inventory AEs. The mean follow-up time was 43 ± 31 months. Univariate logistic regression analysis was used to assess the predictive value of selected demographic and clinical variables.ResultsFrom January 2011 to July 2020, 508 DBS-related procedures were performed including 201 implantations of brain electrodes in 200 patients and 307 implantable pulse generator (IPG) replacements in 142 patients. Surgical or hardware-related AEs following initial implantation affected 40 of 200 patients (20%) and resolved without permanent sequelae in all instances. The most frequent AEs were surgical site infections (SSIs) (9.95%, 20/201) and wire tethering (2.49%, 5/201), followed by hardware failure (1.99%, 4/201), skin erosion (1.0%, 2/201), pain (0.5%, 1/201), lead migration (0.52%, 2/386 electrode sites), and hematoma (0.52%, 2/386 electrode sites). The overall rate of AEs for IPG replacement was 5.6% (17/305). No surgical, ie, staged or nonstaged, electrode fixation, or patient-related risk factors were identified for SSI or wire tethering.ConclusionsMajor AEs including intracranial surgery–related AEs or AEs requiring surgical removal or revision of hardware are rare. In particular, aggressive treatment is required in SSIs involving multiple sites or when Staphylococcus aureus is identified. For future benchmarking, the development of a uniform reporting system for surgical and hardware-related AEs in DBS surgery would be useful.     

Twenty-five years of deep brain stimulation: celebrations and apprehensions

The year 2012 marks the 25th anniversary of the birth of modern deep brain stimulation (DBS), which was introduced by Benabid et al in 1987, initially to treat tremor with DBS of the ventral intermediate nucleus of the thalamus. The subsequent extension of DBS to the subthalamic nucleus (STN), demonstrating its efficacy on virtually all symptoms of advanced Parkinson's disease (PD), sparked an era of intense clinical and research activities, eventually transcending PD and movement disorders to encompass mood and mind. Investigations of the role of DBS in a variety of neurological, psychiatric, cognitive, and behavioral conditions is ongoing. Serendipitous discoveries and advances in functional imaging are providing "new" brain targets for an increasing number of pathologies. Toward the end of this quarter of a century of DBS, there have been some indications that the field may be at risk of gliding down a slippery slope, reminiscent of the excesses of the old-era DBS. Although there are many reasons this year to celebrate the achievements of 25 years of modern DBS, there are also reasons to fear the opening of a new Pandora's box.     

Deep brain stimulation in the treatment of depression

Major depressive disorder is a worldwide disease with debilitating effects on a patient''s life. Common treatments include pharmacotherapy, psychotherapy, and electroconvulsive therapy. Many patients do not respond to these treatments; this has led to the investigation of alternative therapeutic modalities. Deep brain stimulation (DBS) is one of these modalities. It was first used with success for treating movement disorders and has since been extended to the treatment of psychiatric disorders. Although DBS is still an emerging treatment, promising efficacy and safety have been demonstrated in preliminary trials in patients with treatment-resistant depression (TRD). Further, neuroimaging has played a pivotal role in identifying some DBS targets and remains an important tool for evaluating the mechanism of action of this novel intervention. Preclinical animal studies have broadened knowledge about the possible mechanisms of action of DBS for TRD, Given that DBS involves neurosurgery in patients with severe psychiatric impairment, ethical questions concerning capacity to consent arise; these issues must continue to be carefully considered.     

Tiefe Hirnstimulation bei Bewegungsst?rungen

In the last 25 years deep brain stimulation (DBS) has increased the therapeutic options as well as the pathophysiological understanding of movement disorders (MDS) to an unforeseen extent. This paper covers the state of the art of DBS treatment of Parkinson's disease, tremors, dystonia and other rare forms of MDS and gives an short overview of the mechanisms of action of DBS.     

Deep brain stimulation in the treatment of movement disorders]

The introduction of deep brain stimulation (DBS) was a historical step forward for the treatment of advanced and medically intractable movement disorders that include Parkinson's disease, dystonias, essential tremor, and Holmes' tremor. DBS is able to modulate the target region electrically in a reversible and adjustable fashion in contrast to an irreversible and destructive lesioning procedure. In the treatment of movement disorders, the potential targets are the thalamic ventral intermediate nucleus (Vim), globus pallidus internus (GPi), subthalamic nucleus (STN), pedunculopontine nucleus (PPN), and thalamic Vo-complex nucleus. With the development of DBS technology and stereotactic neurosurgical techniques, its therapeutic efficacy has been increased while reducing surgical complications. DBS has become an established therapy for disabling movement disorders and is currently being used to treat neuropsychiatric disorders.     

An unexpectedly high rate of revisions and removals in deep brain stimulation surgery: Analysis of multiple databases

IntroductionDeep brain stimulation (DBS) is an established therapy for movement disorders, and is under active investigation for other neurologic and psychiatric indications. While many studies describe outcomes and complications related to stimulation therapies, the majority of these are from large academic centers, and results may differ from those in general neurosurgical practice.MethodsUsing data from both the Centers for Medicare and Medicaid Services (CMS) and the National Surgical Quality Improvement Program (NSQIP), we identified all DBS procedures related to primary placement, revision, or removal of intracranial electrodes. Cases of cortical stimulation and stimulation for epilepsy were excluded.ResultsOver 28,000 cases of DBS electrode placement, revision, and removal were identified during the years 2004–2013. In the Medicare dataset, 15.2% and of these procedures were for intracranial electrode revision or removal, compared to 34.0% in the NSQIP dataset. In NSQIP, significant predictors of revision and removal were decreased age (odds ratio (OR) of 0.96; 95% CI: 0.94, 0.98) and higher ASA classification (OR 2.41; 95% CI: 1.22, 4.75). Up to 48.5% of revisions may have been due to improper targeting or lack of therapeutic effect.ConclusionData from multiple North American databases suggest that intracranial neurostimulation therapies have a rate of revision and removal higher than previously reported, between 15.2 and 34.0%. While there are many limitations to registry-based studies, there is a clear need to better track and understand the true prevalence and nature of such failures as they occur in the wider surgical community.