Exploring the efficacy of deep brain stimulation in pediatric neurological disorders: a comprehensive review.

Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. In the last decades, interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes). To assess the efficacy, safety and tolerability of deep brain and cortical stimulation for refractory epilepsy based on randomized controlled trials. We searched PubMed (6 August 2013), the Cochrane Epilepsy Group Specialized Register (31 August 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7 of 12) and reference lists of retrieved articles. We also contacted device manufacturers and other researchers in the field. No language restrictions were imposed. Randomized controlled trials (RCTs) comparing deep brain or cortical stimulation to sham stimulation, resective surgery or further treatment with antiepileptic drugs. Four review authors independently selected trials for inclusion. Two review authors independently extracted the relevant data and assessed trial quality and overall quality of evidence. The outcomes investigated were seizure freedom, responder rate, percentage seizure frequency reduction, adverse events, neuropsychological outcome and quality of life. If additional data were needed, the study investigators were contacted. Results were analysed and reported separately for different intracranial targets for reasons of clinical heterogeneity. Ten RCTs comparing one to three months of intracranial neurostimulation to sham stimulation were identified. One trial was on anterior thalamic DBS (n = 109; 109 treatment periods); two trials on centromedian thalamic DBS (n = 20; 40 treatment periods), but only one of the trials (n = 7; 14 treatment periods) reported sufficient information for inclusion in the quantitative meta-analysis; three trials on cerebellar stimulation (n = 22; 39 treatment periods); three trials on hippocampal DBS (n = 15; 21 treatment periods); and one trial on responsive ictal onset zone stimulation (n = 191; 191 treatment periods). Evidence of selective reporting was present in four trials and the possibility of a carryover effect complicating interpretation of the results could not be excluded in 4 cross-over trials without any washout period. Moderate-quality evidence could not demonstrate statistically or clinically significant changes in the proportion of patients who were seizure-free or experienced a 50% or greater reduction in seizure frequency (primary outcome measures) after 1 to 3 months of anterior thalamic DBS in (multi)focal epilepsy, responsive ictal onset zone stimulation in (multi)focal epilepsy patients and hippocampal DBS in (medial) temporal lobe epilepsy. However, a statistically significant reduction in seizure frequency was found for anterior thalamic DBS (-17.4% compared to sham stimulation; 95% confidence interval (CI) -32.1 to -1.0; high-quality evidence), responsive ictal onset zone stimulation (-24.9%; 95% CI -40.1 to 6.0; high-quality evidence) ) and hippocampal DBS (-28.1%; 95% CI -34.1 to -22.2; moderate-quality evidence). Both anterior thalamic DBS and responsive ictal onset zone stimulation do not have a clinically meaningful impact on quality life after three months of stimulation (high-quality evidence). Electrode implantation resulted in asymptomatic intracranial haemorrhage in 3% to 4% of the patients included in the two largest trials and 5% to 13% had soft tissue infections; no patient reported permanent symptomatic sequelae. Anterior thalamic DBS was associated with fewer epilepsy-associated injuries (7.4 versus 25.5%; P = 0.01) but higher rates of self-reported depression (14.8 versus 1.8%; P = 0.02) and subjective memory impairment (13.8 versus 1.8%; P = 0.03); there were no significant differences in formal neuropsychological testing results between the groups. Responsive ictal-onset zone stimulation was well tolerated with few side effects but SUDEP rate should be closely monitored in the future (4 per 340 [= 11.8 per 1000] patient-years; literature: 2.2-10 per 1000 patient-years). The limited number of patients preclude firm statements on safety and tolerability of hippocampal DBS. With regards to centromedian thalamic DBS and cerebellar stimulation, no statistically significant effects could be demonstrated but evidence is of only low to very low quality. Only short term RCTs on intracranial neurostimulation for epilepsy are available. Compared to sham stimulation, one to three months of anterior thalamic DBS ((multi)focal epilepsy), responsive ictal onset zone stimulation ((multi)focal epilepsy) and hippocampal DBS (temporal lobe epilepsy) moderately reduce seizure frequency in refractory epilepsy patients. Anterior thalamic DBS is associated with higher rates of self-reported depression and subjective memory impairment. SUDEP rates require careful monitoring in patients undergoing responsive ictal onset zone stimulation. There is insufficient evidence to make firm conclusive statements on the efficacy and safety of hippocampal DBS, centromedian thalamic DBS and cerebellar stimulation. There is a need for more, large and well-designed RCTs to validate and optimize the efficacy and safety of invasive intracranial neurostimulation treatments.

Following the established application of deep brain stimulation (DBS) in the treatment of movement disorders, new non-neurological indications have emerged, such as for obsessive-compulsive disorders, major depressive disorder, dementia, Gilles de la Tourette Syndrome, anorexia nervosa, and addictions. As DBS is a network modulation surgical treatment, the development of DBS for both neurological and psychiatric disorders has been partly driven by advances in neuroimaging, which has helped explain the brain networks implicated. Advances in magnetic resonance imaging connectivity and electrophysiology have led to the development of the concept of modulating widely distributed, complex brain networks. Moreover, the increasing number of targets for treating psychiatric disorders have indicated that there may be a convergence of the effect of stimulating different targets for the same disorder, and the effect of stimulating the same target for different disorders. The aim of this paper is to review the imaging studies of DBS for psychiatric disorders. Imaging, and particularly connectivity analysis, offers exceptional opportunities to better understand and even predict the clinical outcomes of DBS, especially where there is a lack of objective biomarkers that are essential to properly guide DBS pre- and post-operatively. In future, imaging might also prove useful to individualize DBS treatment. Finally, one of the most important aspects of imaging in DBS is that it allows us to better understand the brain through observing the changes of the functional connectome under neuromodulation, which may in turn help explain the mechanisms of action of DBS that remain elusive.

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience

The efficacy of deep brain stimulation(DBS)for Tourette's syndrome is being well established. Herein, we performed DBS in 38 patients and confirmed that its efficacy was comparable with that reported internationally. Although many patients experience severe symptoms, the indications for surgery remain controversial. One reason for this is that Tourette syndrome has the potential for spontaneous remission, while DBS treatment results in the need for long-term management, which can be difficult for some patients. Furthermore, while several targets for DBS have been reported, no treatment guidelines have yet been established. The efficacy of DBS for neuropsychiatric disorders, such as obsessive-compulsive disorder, depression, and dementia, is gradually being reported. However, this use has many limitations in terms of expectations similar to those seen with Tourette's syndrome, leading to problems with expanding indications for these disorders. Indications for these disorders should be addressed in conjunction with ethical issues. It is expected that more data on this topic will be collected in the future.

Event Abstract Back to Event Objective measures of efficacy of Deep Brain Stimulation for treatment of tremor Colette M. Mckay1, 2, 3*, Thushara Perera1, Richard Peppard1, 4, Hugh J. McDermott1, 2 and Adam P. Vogel1, 5 1 The Bionics Institute of Australia, Australia 2 The University of Melbourne, Department of Medical Bionics, Australia 3 The University of Manchester, School of Psychological Sciences, United Kingdom 4 St. Vincent's Hospital, Australia 5 The University of Melbourne, Department of Audiology and Speech Pathology, Australia Patients with intractable tremor not alleviated by pharmaceutical therapies can be successfully treated using Deep Brain Stimulation of subcortical areas such as the Subthalamic Nucleus (STN). Current DBS devices produce constant-current or constant-voltage biphasic pulse trains and offer a range of pulse rate and pulse duration options as well as different current or voltage levels. The clinical method of setting the parameters by observation is non-ideal, firstly because of the number of possible parameter combinations, and a current lack of knowledge of how the parameters interact with each other, and secondly because subjective clinical observation is prone to observer error and bias. In this study, we aimed to develop an objective method of recording the severity of tremor and to use it to explore the effect on tremor of stimulus parameters. Six patients with Essential Tremor who had been fitted with a DBS device in the Posterior Subthalamic Area (PSA) participated in the study. Tremor was measured by position sensors attached to the arms and wrists while the patient was holding both arms stretched out in front of them and when performing a finger-nose pointing task. Clinical rating of tremor was also performed. Results of the experiments showed that the optimal stimulus parameters were subject specific and the effects of each parameter were non-monotonic, often with a very specific range providing therapeutic benefit (for example, Fig. 1). The objective measures were more sensitive than clinical judgement and show that an objective fitting method could improve benefits in individual patients. Figure 1 Acknowledgements Supported by the Helen McPherson Smith Trust and the Colonial Foundation. The Bionics Institute acknowledges the support it receives from the Victorian Government through its Operational Infrastructure Support Program References Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor. Movement Disorders 2010;25(10):1350-1356. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up. Brain 2005;128(10):2240-2249. Keywords: deep brain stimulation (DBS), Tremor management, Essential Tremor, Parkinson Disease, stimulus-specific adaptation Conference: ACNS-2012 Australasian Cognitive Neuroscience Conference, Brisbane, Australia, 29 Nov - 2 Dec, 2012. Presentation Type: Poster Presentation Topic: Motor Citation: Mckay CM, Perera T, Peppard R, McDermott HJ and Vogel AP (2012). Objective measures of efficacy of Deep Brain Stimulation for treatment of tremor. Conference Abstract: ACNS-2012 Australasian Cognitive Neuroscience Conference. doi: 10.3389/conf.fnhum.2012.208.00067 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 Oct 2012; Published Online: 07 Nov 2012. * Correspondence: Prof. Colette M Mckay, The Bionics Institute of Australia, East Melbourne, VIC, 3002, Australia, cmckay@bionicsinstitute.org Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Colette M Mckay Thushara Perera Richard Peppard Hugh J McDermott Adam P Vogel Google Colette M Mckay Thushara Perera Richard Peppard Hugh J McDermott Adam P Vogel Google Scholar Colette M Mckay Thushara Perera Richard Peppard Hugh J McDermott Adam P Vogel PubMed Colette M Mckay Thushara Perera Richard Peppard Hugh J McDermott Adam P Vogel Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Stimulate or Degenerate: Deep Brain Stimulation of the Nucleus Basalis Meynert in Alzheimer Dementia

The purpose of this review is to evaluate the current state and potential future directions of deep brain stimulation (DBS) therapy for treatment-resistant depression (TRD), a condition that significantly impacts patients' quality of life and for which conventional treatments are often ineffective. This review synthesizes evidence from clinical trials and preclinical studies published in five years, identified through PubMed searches using keywords ("Deep Brain Stimulation" OR DBS) AND ("Treatment-Resistant Depression" OR TRD). Included studies encompassed clinical research (randomized/non-randomized trials, cohort studies) and mechanistic preclinical studies, excluding non-English publications and nonhuman experiments. Screening prioritized neuroanatomical targets (e.g., SCG, NAcc) and stimulation parameter optimization data. Examining the therapeutic mechanisms of DBS, the neuroanatomical targets utilized, and the clinical outcomes observed. It also discusses the challenges faced in DBS application and proposes potential technological advancements, such as closed-loop therapy and fiber tracking technology. Preliminary evidence exists regarding the efficacy and safety of DBS in the treatment of TRD in the subcortical cingulate gyrus (SCG), nucleus accumbens (NAcc), ventral capsule/ventral striatum (VC/VS), anterior limb of the internal capsule (ALIC), and so forth. Nevertheless, the optimal stimulation target remains undetermined. The review highlights the complexity of TRD and the need for personalized treatment strategies, noting that genetic, epigenetic, and neurophysiological changes are implicated in DBS's therapeutic effects. In conclusion, while DBS for TRD remains an experimental therapy, it offers a unique and potentially effective treatment option for patients unresponsive to traditional treatments. The review emphasizes the need for further research to refine DBS targets and parameters, improve patient selection, and develop personalized treatment plans to enhance efficacy and safety in TRD management.

Objective To evaluate outcome of High-frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) for severe Gilles de la Tourette syndrome (GTS). Methods 10 cases of GTS who were resistant to at least 6 months of standard and innovative treatments, as well as to psychobehavioural techniques, underwent DBS. DBS was placed bilaterally globus pallidus internus (GPi).Patients were evaluated after surgery, using Yale Global Tic Severity Scale (YRTSS) from 2 months to 24 months. Results All patients responded well to DBS, although to differing degrees (28.2% ～ 80.0%).The duration of follow-up assessments ranged from 2 to 24 months. Except for two erosions and/or infections cases, there were no serious permanent adverse effects. Conclusion DBS is a useful and safe treatment for severe GTS. The results of ours and previous DBS reports suggest that the GPi may be a good DBS target for GTS. Key words: Gilles de la Tourette syndrome; Deep brain stimulation; Globus pallidus internus

IntroductionDepression continues to be a leading cause of disability worldwide. Despite the availability of several classes of antidepressants, a third of patients do not recover from their depression. Deep brain stimulation (DBS) is an invasive treatment approach that was found to be effective in the treatment of Parkinson’s Disease and presents as an alternative to standard antidepressant therapy for people with treatment-resistent depression (TRD).ObjectivesWe aimed to compare the use of DBS to standard antidepressant therapy and decipher whether DBS can be used for TRD. In addition, electroconvulsive therapy (ECT), a current brain stimulation method administered for TRD, was contrasted with DBS.MethodsA narrative review of the current literature concerning DBS application and TRD was conducted to evaluate whether standard antidepressant therapy was as effective as psychosurgical intervention. Emphasis on TRD-associated DBS was noted.ResultsThe studies discussed found that DBS was an effective treatment option for TRD, however, the results were limited due to the studies being conducted in small sample sizes and using DBS in combination with antidepressant therapy. Nonetheless, the concomitant use of DBS and antidepressants demonstrated to be an effective treatment for TRD, highlighting the potential benefit of DBS in inducing remission in TRD. DBS has a wider range of complications compared to ECT as it involves a more invasive neurosurgical approach to implant the device. On comparing the cost of the devices between the 2 studies, DBS costs approximately three times more than ECT.ConclusionsThe spectrum of depressive disorders is known to affect multiple regions of the brain. A more cohesive approach would be a comprehensive study using DBS in multiple brain regions while incorporating blinded controls. In summary, DBS could be a viable treatment addition for TRD, but more thorough studies are needed to deduce its true efficacy. Future collaborative studies investigating the efficacy of DBS over ECT in TRD may assess further therapeutic potential.Disclosure of InterestNone Declared

The use of deep brain stimulation in psychiatric disorders has received great interest owing to the small risk of the operation, the reversible nature of the technique, and the possibility of optimizing treatment postoperatively. Currently, deep brain stimulation in psychiatry is investigated for obsessive–compulsive disorder, Gilles de la Tourette's syndrome, and major depression. This chapter reviews the application of deep brain stimulation in obsessive–compulsive disorder. Preliminary results suggest that deep brain stimulation in obsessive–compulsive disorder can effectuate a decrease of 40–60% in at least half of the patients. Although various side effects occur, most of these are transitory and linked to specific stimulation parameters which can be changed. Because only a few studies have been performed with a limited number of patients in accordance with varying research protocols, appliance of deep brain stimulation to obsessive–compulsive disorder is still at an experimental stage. The speed of the effect of deep brain stimulation causes fundamental assumptions on the pathophysiology of obsessive–compulsive disorder.

Objective To assess the long-term outcome of globus pallidus intema (Gpi) deep brain stimulation (DBS) in adult patients with Tourette syndrome (TS). Methods Five adult drug-resistant TS patients, performed bilateral Gpi DBS in our hospital from May 2007 to May 2008,were chosen in our study; their symptoms before DBS and 3 and 6 months and 1 year after DBS,and over a year of DBS were evaluated by Yale global tic severity scale. Results The duration of follow-up ranged from 21 to 33 months.Scores of motor tic,phonic tic and social impairment in the last follow-up were significantly decreased as compared with those before DBS (P＜0.05); Scores of motor tic,phonic tic and social impairment 3 and 6 months and 1 year after DBS,and over a year of DBS were significantly decreased as compared with those before DBS (P＜0.05).The symptoms were gradually improved; in the first 6 months,the symptoms were obviously improved; 6 months after DBS,the symptoms were solid and can be mildly improved.3 and 6 months,1 year after DBS and till to the last follow-up (mean 26.4 months),the severity of symptom meanly improved 28.50％,52.35％,57.62％ and 62.88％,respectively;and till the last follow-up,the motor tic,phonic tic and social impairment was improved 51.38％,46.16％ and 71.00％,respectively; no serious adverse effects were noted. Conclusion Gpi DBS,improving the symptoms as motor tic,phonic tic and social impairment,is a useful and safe treatment method for adult patients with medically refractory TS; the long-term efficiency is solid. Key words: Tourette syndrome; Globus pallidus intema; Deep brain stimulation

Deep Brain Stimulation for Tourette Syndrome: A Prospective Pilot Study in Japan

Deep brain stimulation is a well-established treatment for generalized dystonia, but outcomes remain variable. Establishment of an imaging marker to guide device targeting and programming could possibly impact the efficacy of deep brain stimulation in dystonia, particularly in the absence of acute clinical markers to indicate benefit. We hypothesize that the stimulation-based functional and structural connectivity using resting-state fMRI and DTI can predict therapeutic outcomes in patients with generalized dystonia and deep brain stimulation. We performed a retrospective analysis of 39 patients with inherited or idiopathic-isolated generalized dystonia who underwent bilateral globus pallidus internus deep brain stimulation. After electrode localization, the volumes of tissue activated were modeled and used as seed regions for functional and structural connectivity measures using a normative data base. Resulting connectivity maps were correlated with postoperative improvement in the Unified Dystonia Rating Scale score. Structural connectivity between the volumes of tissue activated and the primary sensorimotor cortex was correlated with Unified Dystonia Rating Scale improvement, while more anterior prefrontal connectivity was inversely correlated with Unified Dystonia Rating Scale improvement. Functional connectivity between the volumes of tissue activated and primary sensorimotor regions, motor thalamus, and cerebellum was most correlated with Unified Dystonia Rating Scale improvement; however, an inverse correlation with Unified Dystonia Rating Scale improvement was seen in the supplemental motor area and premotor cortex. Functional and structural connectivity with multiple nodes of the motor network is associated with motor improvement in patients with generalized dystonia undergoing deep brain stimulation. Results from this study may serve as a basis for future development of clinical markers to guide deep brain stimulation targeting and programming in dystonia.

A case of treatment-resistant bipolar depression and comorbid OCD treated with deep brain stimulation of the medial forebrain bundle: 5 years follow-up results

BackgroundSeveral pioneering studies investigated deep brain stimulation (DBS) in treatment-refractory anorexia nervosa (AN) patients, but overall effects remain yet unclear. Aim of this study was to obtain estimates of efficacy of DBS in AN-patients using meta-analysis.MethodsWe searched three electronic databases until 1st of November 2021, using terms related to DBS and AN. We included trials that investigated the clinical effects of DBS in AN-patients. We obtained data including psychiatric comorbidities, medication use, DBS target, and study duration. Primary outcome was Body Mass Index (BMI), secondary outcome was quality of life, and the severity of psychiatric symptoms, including eating disorder, obsessive-compulsive, depressive, and anxiety symptoms. We assessed the risk of bias using the ROBINS-I tool.ResultsFour studies were included for meta-analysis, with a total of 56 patients with treatment-refractory AN. Follow-up ranged from 6–24 months. Random effects meta-analysis showed a significant increase in BMI following DBS, with a large effect size (Hedges’s g = 1 ∙ 13; 95% CI = 0 ∙ 80 to 1 ∙ 46; Z-value = 6 ∙ 75; P < 0 ∙ 001), without heterogeneity (I2 = 0 ∙ 00, P = 0 ∙ 901). Random effects meta-analysis also showed a significant increase in quality of life (Hedges’s g = 0 ∙ 86; 95% CI = 0 ∙ 44 to 1 ∙ 28; Z-value = 4 ∙ 01, P < 0 ∙ 001). Furthermore, DBS decreased the severity of psychiatric symptoms (Hedges’s g = 0 ∙ 89; 95% CI = 0 ∙ 57 to 1 ∙ 21; Z-value = 5 ∙ 47; P < 0 ∙ 001, I2 = 4 ∙ 29, P = 0 ∙ 371).DiscussionIn this first meta-analysis, DBS showed statistically large beneficial effects on weight restoration, quality of life, and reduction of psychiatric symptoms in patients with treatment-refractory AN. These outcomes call for more extensive naturalistic studies to determine the clinical relevance for functional recovery.This study is preregistered in PROSPERO,CRD42022295712.