Trial Of Deep Brain Stimulation Research Articles

Benefits and risks of unilateral and bilateral ventral intermediate nucleus deep brain stimulation for axial essential tremor symptoms

IntroductionMany experts assume bilateral deep brain stimulation (DBS) is necessary to improve axial tremor in essential tremor (ET). In the largest clinical trial of DBS for ET to date evaluating a non-directional, constant current device, we studied the effects of unilateral and staged bilateral DBS on axial tremor. MethodsWe included all participants from the original trial with unilateral ventral intermediate nucleus (VIM) DBS and 90-day follow up at minimum. Primary outcomes were changes in pooled axial subscores in the Clinical Rating Scale for Tremor (CRST) at 90 and 180 days after activation of unilateral VIM DBS compared to pre-operative baseline (n=119). Additionally, we performed within-subject analyses for unilateral versus bilateral DBS at 180 days in the cohort who underwent staged surgery to bilateral DBS (n=39). ResultsUnilateral VIM DBS improved midline tremor by 58% at 90 days (median[IQR]) (3[3] to 1[2], p<0.001) and 65% at 180 days (3[3] to 1[2], p<0.001) versus pre-op baseline. In the staged to bilateral DBS cohort, midline tremor scores further improved after bilateral DBS at 180 days by 63% versus unilateral DBS (3[3] to 1[3], p=0.007). There were, however, 35 additional DBS and surgery-related adverse events, 14 related to incoordination, gait impairment, or speech impairment, versus 6 after unilateral DBS. ConclusionUnilateral VIM DBS for ET significantly improved associated axial tremor. Staged bilateral DBS was associated with additional axial tremor improvement but also additional adverse events. Unilateral VIM DBS may be sufficient to achieve a goal of contralateral limb and axial tremor attenuation.

Recruitment and Retention in Clinical Trials of Deep Brain Stimulation in Early-Stage Parkinson's Disease: Past Experiences and Future Considerations.

Clinical trials are often hindered by inadequate patient recruitment. Overly optimistic investigator predictions of participation can lead to unmet recruitment goals and costly trial extensions. A patient-focused approach estimating recruitment in clinical trials may provide higher accuracy. To assess the feasibility of recruitment in a future deep brain stimulation (DBS) in early-stage Parkinson's disease (PD) multicenter trial by understanding motivations and concerns to participation of past and potential future DBS in early-stage PD clinical trial subjects. To identify motivating factors and barriers influencing trial participation, an end-of-trial survey was administered to subjects enrolled in a DBS in early-stage PD pilot trial with subjects randomized to receive DBS plus optimal drug therapy (DBS+ODT) or ODT alone (NCT#00282152, IDE#G050016). Pilot trial survey results were analyzed in conjunction with results of a previously-reported survey querying PD patients about potential participation in a trial for DBS in early-stage PD with similar inclusion/exclusion criteria. Pilot trial subjects reported high levels of satisfaction with their participation in the study. Similar motivations and barriers to participation were expressed in comparable proportions by subjects who successfully completed the pilot trial and patients with early-stage PD considering enrollment in a comparable DBS study. The FDA has approved a prospective, randomized, double-blind, phase III, multicenter, pivotal clinical trial evaluating DBS in early-stage PD (IDE#G050016). These results suggest that the successful recruitment and retention of early-stage PD subjects, as observed in the pilot trial, is attainable in a future pivotal trial.

Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation.

Given recent challenges in developing new treatments for Alzheimer dementia (AD), it is vital to explore alternate treatment targets, such as neuromodulation for circuit dysfunction. We previously reported an exploratory Phase IIb double-blind trial of deep brain stimulation targeting the fornix (DBS-f) in mild AD (the ADvance trial). We reported safety but no clinical benefits of DBS-f versus the delayed-on (sham) treatment in 42 participants after one year. However, secondary post hoc analyses of the one-year data suggested a possible DBS-f benefit for participants≥65 years. To examine the long-term safety and clinical effects of sustained and delayed-on DBS-f treatment of mild AD after two years. 42 participants underwent implantation of DBS-f electrodes, with half randomized to active DBS-f stimulation (early on) for two years and half to delayed-on (sham) stimulation after 1 year to provide 1 year of active DBS-f stimulation (delayed on). We evaluated safety and clinical outcomes over the two years of the trial. DBS-f had a favorable safety profile with similar rates of adverse events across both trial phases (years 1 and 2) and between treatment arms. There were no differences between treatment arms on any primary clinical outcomes. However, post-hoc age group analyses suggested a possible benefit among older (>65) participants. DBS-f was safe. Additional study of mechanisms of action and methods for titrating stimulation parameters will be needed to determine if DBS has potential as an AD treatment. Future efficacy studies should focus on patients over age 65.

Closed Loop Deep Brain Stimulation for PTSD, Addiction, and Disorders of Affective Facial Interpretation: Review and Discussion of Potential Biomarkers and Stimulation Paradigms.

The treatment of psychiatric diseases with Deep Brain Stimulation (DBS) is becoming more of a reality as studies proliferate the indications and targets for therapies. Opinions on the initial failures of DBS trials for some psychiatric diseases point to a certain lack of finesse in using an Open Loop DBS (OLDBS) system in these dynamic, cyclical pathologies. OLDBS delivers monomorphic input into dysfunctional brain circuits with modulation of that input via human interface at discrete time points with no interim modulation or adaptation to the changing circuit dynamics. Closed Loop DBS (CLDBS) promises dynamic, intrinsic circuit modulation based on individual physiologic biomarkers of dysfunction. Discussed here are several psychiatric diseases which may be amenable to CLDBS paradigms as the neurophysiologic dysfunction is stochastic and not static. Post-Traumatic Stress Disorder (PTSD) has several peripheral and central physiologic and neurologic changes preceding stereotyped hyper-activation behavioral responses. Biomarkers for CLDBS potentially include skin conductance changes indicating changes in the sympathetic nervous system, changes in serum and central neurotransmitter concentrations, and limbic circuit activation. Chemical dependency and addiction have been demonstrated to be improved with both ablation and DBS of the Nucleus Accumbens and as a serendipitous side effect of movement disorder treatment. Potential peripheral biomarkers are similar to those proposed for PTSD with possible use of environmental and geolocation based cues, peripheral signs of physiologic arousal, and individual changes in central circuit patterns. Non-substance addiction disorders have also been serendipitously treated in patients with OLDBS for movement disorders. As more is learned about these behavioral addictions, DBS targets and effectors will be identified. Finally, discussed is the use of facial recognition software to modulate activation of inappropriate responses for psychiatric diseases in which misinterpretation of social cues feature prominently. These include Autism Spectrum Disorder, PTSD, and Schizophrenia—all of which have a common feature of dysfunctional interpretation of facial affective clues. Technological advances and improvements in circuit-based, individual-specific, real-time adaptable modulation, forecast functional neurosurgery treatments for heretofore treatment-resistant behavioral diseases.

Closed-Loop Deep Brain Stimulation for Refractory Chronic Pain.

Pain is a subjective experience that alerts an individual to actual or potential tissue damage. Through mechanisms that are still unclear, normal physiological pain can lose its adaptive value and evolve into pathological chronic neuropathic pain. Chronic pain is a multifaceted experience that can be understood in terms of somatosensory, affective, and cognitive dimensions, each with associated symptoms and neural signals. While there have been many attempts to treat chronic pain, in this article we will argue that feedback-controlled ‘closed-loop’ deep brain stimulation (DBS) offers an urgent and promising route for treatment. Contemporary DBS trials for chronic pain use “open-loop” approaches in which tonic stimulation is delivered with fixed parameters to a single brain region. The impact of key variables such as the target brain region and the stimulation waveform is unclear, and long-term efficacy has mixed results. We hypothesize that chronic pain is due to abnormal synchronization between brain networks encoding the somatosensory, affective and cognitive dimensions of pain, and that multisite, closed-loop DBS provides an intuitive mechanism for disrupting that synchrony. By (1) identifying biomarkers of the subjective pain experience and (2) integrating these signals into a state-space representation of pain, we can create a predictive model of each patient's pain experience. Then, by establishing how stimulation in different brain regions influences individual neural signals, we can design real-time, closed-loop therapies tailored to each patient. While chronic pain is a complex disorder that has eluded modern therapies, rich historical data and state-of-the-art technology can now be used to develop a promising treatment.

Charting the road forward in psychiatric neurosurgery: proceedings of the 2016 American Society for Stereotactic and Functional Neurosurgery workshop on neuromodulation for psychiatric disorders

ObjectiveRefractory psychiatric disease is a major cause of morbidity and mortality worldwide, and there is a great need for new treatments. In the last decade, investigators piloted novel deep brain...

PD70 Cost-Effectiveness Of Deep Brain Stimulation For Epilepsy In Australia

Introduction:Deep brain stimulation (DBS), which uses an implantable device to modulate brain activity, is an adjunctive treatment for partial-onset seizures in patients with medically refractory epilepsy. Our objective was to perform an exploratory cost-utility analysis of DBS in conjunction with medical therapy, compared with medical therapy alone, using the latest clinical data and costs for the Australian healthcare system.Methods:A deterministic five-state Markov model was used to project treatment response and outcomes over the patients’ lifetimes, based on 5-year data from the recent Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTE) DBS trial and drug outcome data identified through a literature search. Costs were based on 2017 data for the Australian healthcare system, and response-specific utilities were derived from published literature. We estimated the lifetime discounted incremental cost-effectiveness ratio (ICER) in Australian dollars per quality-adjusted life-year (QALY) for patients 36 years of age, fifty-five percent of whom were men. Costs and effects were discounted at five percent per annum. The robustness of projections was evaluated through scenario and sensitivity analyses.Results:Under assumed continued treatment benefit, DBS was projected to add 3.48 QALYs over the patients’ lifetimes, at an increased cost of AUD 142,304 (USD 105,960), resulting in an ICER of AUD 40,951 (USD 30,492) per QALY gained. Reducing the analysis horizon to 20 years increased the ICER to AUD 49,803 (USD 37,083). Increasing the DBS generator life from 3 to 6 years decreased the ICER to AUD 23,956 (USD 17,838) per QALY. Longer follow-up periods and younger age at treatment were associated with greater cost effectiveness. Results were sensitive to assumptions about health state-specific utility estimates and long-term treatment effects.Conclusions:Our exploratory findings suggest that DBS is a cost-effective treatment strategy in the Australian healthcare system for patients with medically refractory epilepsy. DBS therapy might meaningfully improve patient outcome at a health economic profile that compares favorably to other well accepted therapies. Consideration of indirect costs would further add to this value proposition.

Psychiatric neurosurgery in the 21st century: overview and the growth of deep brain stimulation.

Ambulatory deep brain stimulation (DBS) became possible in the late 1980s and was initially used to treat people with movement disorders. Trials of DBS in people with treatment-resistant psychiatric disorder began in the late 1990s, initially focusing on obsessive–compulsive disorder, major depressive disorder and Tourette syndrome. Despite methodological issues, including small participant numbers and lack of consensus over brain targets, DBS is now being trialled in a wide range of psychiatric conditions. There has also been more modest increase in ablative procedures. This paper reviews these developments in the light of contemporary brain science, considers future directions and discusses why the approach has not been adopted more widely within psychiatry.

P 137 An ethical perspective on deep brain stimulation as an investigational treatment for Alzheimer’s disease

Question Deep brain stimulation (DBS) has been investigated as intervention to slow down the progression of Alzheimer’s disease (AD). Although there is urgent need for improvement of AD treatments, any novel interventions has to fulfill high ethical requirements to protect participants’ safety. In particular, a solid base of prior empirical evidence is required. However, what exactly constitutes sufficient evidence that outweighs the risk of investigational research is a matter of discussion. Since the rationale of DBS for AD assumes that AD is a “brain circuit pathology” it is relevant for both clinical neurophysiology and functional brain imaging. While the question “what degree of empirical evidence supports the given hypothesis?” has scientific answer, the question “when is evidence sufficient to warrant trials in humans?” is a normative one and requires ethical justification in addition to state-of-the-art scientific knowledge. Methods We assessed DBS trials ( https://clinicaltrials.gov/ ) enrolling patients with AD and conducted a comprehensive literature search ( https://www.ncbi.nlm.nih.gov/pubmed/ ). Our first aim was to identify the scientific rationale for the hypothesis of DBS as intervention for AD. The second aim was to ethically evaluate this rationale on the basis of normative standards as established in pharmacological research. Results We identified three clinical trials (total n = 56) and assessed comments, letters to editors and reviews. One trial did not make failure to provide informed consent an exclusion criterion (consent by caregivers was sufficient). We also found wide-ranging epistemic uncertainties involved in the rationale that go beyond the conventional risk of clinical trials on investigational treatments. These range from the adequacy of different neuroanatomical targets, an unrefined analogy to DBS for Parkinson disease, to diverse hypothetical mechanisms of action and the question of clinically relevance of cut-offs for outcome measures like “pathological brain circuits”. In sum, we found many open questions amenable to neuroimaging or translational research, but also that the respective clinical trials started before these questions were thoroughly examined and before the scientific rationale was proven in rodents modelling the specific pathology of AD. Conclusion There is a continuum from therapeutic protectionism to experimental adventurism. Protectionism impedes scientific progress and hampers the development of new treatment options. However, uncertainties can also pose severe risks to participants. DBS as an investigational intervention for AD did not adhere to the same ethical requirements that are legally binding for pharmacological research in Germany. In particular, whether the evidence for the scientific rationale is sufficiently robust is questionable. DBS involves invasive neurosurgery and belongs to Class III of medical devices with the highest risk (European Parliament), but is less strictly regulated than pharmaceutical agents (largely voluntary agreement among industrial stakeholders and neurosurgeons is sufficient). Ethical evaluation hinges on empirical progress and technical innovation. It is therefore imperative to promote research in clinical neurophysiology and brain imaging with the clear research objective to find robust criteria for clinical relevance of pathological brain circuit aberrations in AD.

16 A randomised controlled trial of deep brain stimulation in obsessive compulsive disorder: a comparison of ventral capsule/ventral striatum and subthalamic nucleus targets

Objective Obsessive compulsive disorder (OCD) has a lifetime prevalence of 1%–2%. Standard treatments are ineffective in up to 40% of cases. Even with the best treatments, there remains a subgroup with severe symptoms and significant disability. Studies of deep brain stimulation (DBS) for OCD have shown improvement in both symptoms and quality of life in severe OCD. Two targets in particular have shown promise: the anteromedial subthalamic nucleus (STN) and the ventral capsule/ventral striatum (VC/VS).1–3 It is not clear however if one site has advantages over the other and, with regard to the VC/VS site, whether stimulation of the anterior capsule white matter or ventral striatum/nucleus accumbens grey matter is critical for improvement.2,3 We report a within subject comparison of the effect of DBS on OCD symptoms at STN and VC/VS sites both individually and together (ClinicalTrials.gov #NCT02655926). The aims of the study were to determine: a) the efficacy of DBS at each site; b) whether stimulation of both sites improves the response compared to either site alone; and c) the critical stimulation contacts at the VC/VS site. Method Six participants, with severe treatment refractory OCD, were recruited via the UK specialist OCD service and underwent implantation of bilateral electrodes at both the VC/VS and anteromedial STN sites. A Leksell frame-based MRI-guided and MRI-verified approach under general anaesthesia was used. The subthalamic nucleus was localised on axial T2-weighted stereotactic images and the VC/VS localised on coronal and axial proton density images (Siemens, 1.5T). Using a double blind cross-over design, 12 weeks stimulation at STN and VC/VS sites was compared, followed by stimulation at both sites for 12 weeks. The primary outcome measure was YBOCS: an improvement of greater than or equal to 35% was the predefined response. Results Accurate stereotactic and anatomical lead location was confirmed on immediate postoperative stereotactic MR images in all patients. For the VC/VS target, the deepest DBS lead contact was within the nucleus accumbens, the one superior to that in the “shell” of the nucleus accumbens while the superior two contacts were within the inferior aspect of the anterior limb of the internal capsule. The response rates (defined as the number of patients with >35% reduction in YBOCS) were: STN 3/6; VC/VS: 5/6; STN + VC/VS: 5/6. In the one non-responder YBOCS reduction was 32% after the combined STN+VC/VS stimulation phase. For the whole group, the mean reduction in YBOCS scores were: STN 16.3; VC/VS: 19.2; STN + VC/VS: 22.0 which represents a mean reduction of 42%, 53%, 62% from their own baseline scores and a reduction to predefined mild/subclinical symptoms of 0%, 50% 50% respectively. The top two DBS contacts of the quadripolar lead were found to be the most effective at the VC/VS target in all 6 patients. Conclusions These results suggest that: a) The VC/VS site may be superior to the STN site for the amelioration of severe OCD symptoms; b) There is only a modest advantage of stimulating both sites together; and c) The effective stimulation site for the VC/VS target is the inferior aspect of the anterior limb of the internal capsule and not the ventral striatum/nucleus accumbens grey matter. Additional Info The study was funded by the MRC (MR/J012009/1). References . Mallet, et al. N Eng J Med2008;359:2121. . Denys, et al. Arch Gen Psychiatry2010;6:1061. . Greenberg, et al. Molecular Psychiatry2010;15:64.

Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer's Disease.

Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer's disease, with several recruiting participants <65 and thus have early-onset Alzheimer's disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

Randomized clinical trial of deep brain stimulation for poststroke pain.

The experience with deep brain stimulation (DBS) for pain is largely based on uncontrolled studies targeting the somatosensory pathways, with mixed results. We hypothesized that targeting limbic neural pathways would modulate the affective sphere of pain and alleviate suffering. We conducted a prospective, double-blinded, randomized, placebo-controlled, crossover study of DBS targeting the ventral striatum/anterior limb of the internal capsule (VS/ALIC) in 10 patients with poststroke pain syndrome. One month after bilateral DBS, patients were randomized to active DBS or sham for 3 months, followed by crossover for another 3-month period. The primary endpoint was a ≥50% improvement on the Pain Disability Index in 50% of patients with active DBS compared to sham. This 6-month blinded phase was followed by an 18-month open stimulation phase. Nine participants completed randomization. Although this trial was negative for its primary and secondary endpoints, we did observe significant differences in multiple outcome measures related to the affective sphere of pain (eg, Montgomery-Åsberg Depression Rating Scale, Beck Depression Inventory, Affective Pain Rating Index of the Short-Form McGill Pain Questionnaire). Fourteen serious adverse events were recorded and resolved. VS/ALIC DBS to modulate the affective sphere of pain represents a paradigm shift in chronic pain management. Although this exploratory study was negative for its primary endpoint, VS/ALIC DBS demonstrated an acceptable safety profile and statistically significant improvements on multiple outcome measures related to the affective sphere of pain. Therefore, we believe these results justify further work on neuromodulation therapies targeting the affective sphere of pain. Ann Neurol 2017;81:653-663.

720. Open Label and Controlled Trials of Deep Brain Stimulation (DBS) at the Ventral Capsule/Ventral Striatum (VC/VS) for Treatment Resistant Depression (TRD)- Data and Technical Issues in Trial Planning

720. Open Label and Controlled Trials of Deep Brain Stimulation (DBS) at the Ventral Capsule/Ventral Striatum (VC/VS) for Treatment Resistant Depression (TRD)- Data and Technical Issues in Trial Planning

脳深部刺激法(DBS)をめぐるドイツとフランスの事情

脳深部刺激法(DBS)をめぐるドイツとフランスの事情

Deep Brain Stimulation in Anorexia Nervosa: Hope for the Hopeless or Exploitation of the Vulnerable? The Oxford Neuroethics Gold Standard Framework.

Neurosurgical interventions for psychiatric disorders have a long and troubled history (1, 2) but have become much more refined in the last few decades due to the rapid development of neuroimaging and robotic technologies (2). These advances have enabled the design of less invasive techniques, which are more focused, such as deep brain stimulation (DBS) (3). DBS involves electrode insertion into specific neural targets implicated in pathological behavior, which are then repeatedly stimulated at adjustable frequencies. DBS has been used for Parkinson’s disease and movement disorders since the 1960s (4–6) and over the last decade has been applied to treatment-refractory psychiatric disorders, with some evidence of benefit in obsessive–compulsive disorder (OCD), major depressive disorder, and addictions (7). Recent consensus guidelines on best practice in psychiatric neurosurgery (8) stress, however, that DBS for psychiatric disorders remains at an experimental and exploratory stage. The ethics of DBS—in particular for psychiatric conditions—is debated (1, 8–10). Much of this discourse surrounds the philosophical implications of competence, authenticity, personality, or identity change following neurosurgical interventions, but there is a paucity of applied guidance on neuroethical best practice in psychiatric DBS, and health-care professionals have expressed that they require more (11). This paper aims to redress this balance by providing a practical, applied neuroethical gold standard framework to guide research ethics committees, researchers, and institutional sponsors. We will describe this as applied to our protocol for a particular research trial of DBS in severe and enduring anorexia nervosa (SE-AN) (https://clinicaltrials.gov/ct2/show/NCT01924598, unique identifier NCT01924598), but believe it may have wider application to DBS in other psychiatric disorders.

Long-Term Results of a Simultaneous Trial of Deep Brain and Motor Cortex Stimulation in Refractory Neuropathic Pain

Objective Although deep brain stimulation (DBS) and motor cortex stimulation (MCS) are effective in patients with refractory neuropathic pain, their application is still empirical; there is no consensus on which technique is better. Methods To enhance the success rate of trial stimulation of invasive neuromodulation techniques and identify approapriate stimulation targets in individual patients, we performed a simultaneous trial of thalamic ventralis caudalis (Vc) DBS and MCS in 11 patients with chronic neuropathic pain and assessed the results of the trial stimulation and long-term analgesia. Results Of the 11 patients implanted with both DBS and MCS electrodes, nine (81.8%) had successful trials. Seven of these nine patients (77.8%) responded to MCS, and two (18.2%) responded to Vc DBS. With long-term follow-up (56 ± 27.5 months), the mean numerical rating scale decreased significantly (P &lt; 0.05). The degree of percentage pain relief in the chronic MCS (n = 7) and chronic DBS (n = 2) groups were 34.1% ± 18.2% and 37.5%, respectively, and there was no significant difference (P = 0.807). Five out of the seven MCS patients (71%) and both DBS patients had long-term success with the treatments, defined as &gt;30% pain relief compared with baseline. Conclusions With simultaneous trial of DBS and MCS, we could enhance the success rate of invasive trials. Considering the initial success rate and the less invasive nature of epidural MCS over DBS, we suggest that MCS may be a better, initial means of treatment in chronic intractable neuropathic pain. Further investigations including other subcortical target-associated medial pain pathways are warranted.

Deep brain stimulation for treatment of severe Alzheimer's disease: Study protocol for a prospective, self-controlled, phase I trial (case observation)

Background: With the aging of the global population, an increasing number of people are at risk of developing Alzheimer's disease. There is currently no effective treatment to hinder or postpone the progression of Alzheimer's disease. Cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist Memantine are the commonly prescribed drugs for this disease, but their therapeutic effects are still unsatisfactory. Therefore, there is an urgent need to investigate novel treatment methods. Many animal experiments have suggested that deep brain stimulation benefits Alzheimer's disease, but clinical trials investigating this are still in their infancy. This study aims to investigate the safety and effectiveness of deep brain stimulation in the treatment of severe Alzheimer's disease. Methods/Design: This study is a prospective, self-controlled, phase I trial (case observation), which will be performed in the Department of Neurosurgery, Chinese PLA General Hospital (Beijing, China). Six patients with severe Alzheimer's disease will be enrolled to receive continuous bilateral deep brain stimulation of the fornix. Evaluations will be performed at baseline (prior to surgery) and at 1, 6, and 12 months after surgery. The primary outcome measures are disability and mortality rates during the 12-month deep brain stimulation trial period. Secondary outcome measures include the incidence of complications and Clinical Dementia Rating scale, Zarit Caregiver Burden Interview, Mini-Mental State Examination, and Barthel Index of Activities of Daily Living Scale scores. Patient recruitment will begin in August 2017, the analysis of primary outcome measures will be completed in October 2018, and the study will finish in June 2019. Discussion: The results of this study will help to determine the safety of deep brain stimulation for the treatment of severe Alzheimer's disease. We will also assess whether deep brain stimulation can improve the cognition, symptoms, and activities of daily living of patients with Alzheimer's disease. If the study succeeds, a novel option for patients with Alzheimer's disease who respond poorly to current treatments may be provided. Trial registration: The study protocol is registered with ClinicalTrials.gov (identifier: NCT03115814). Ethics: The study protocol was approved by the Ethics Committee of Chinese PLA General Hospital (approval No. S2015-013-02) and will be performed in accordance with the Declaration of Helsinki formulated by the World Medical Association in 2013. Informed consent: Written informed consent will be obtained from each patient's legal representative.

Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone?

In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients’ ailments but as a stepping stone to improved holistic care made possible by tic reduction.

Teens and Research.

On seeing promising results in a small number of patients, some researchers are conducting trials to determine whether deep brain stimulation (DBS) is an effective treatment for anorexia nervosa (AN). This article asks whether we should open enrollment in trials of DBS for AN to adolescents. Despite concerns about informed consent, parental consent, and unforeseeable psychological sequelae, the article concludes that the risks to anorexic adolescents associated with participation in trials of DBS are reasonable considering the substantial risks of not enrolling teens with AN in research on DBS. The seriousness of AN, its high incidence in teens, and serious shortfalls in the AN treatment literature point to the need for improved, evidence-based treatments for teens with AN. This unmet need generates an obligation on the part of researchers and physicians to promote and conduct research on AN in adolescents.

Deep brain stimulation in Gilles de la Tourette syndrome: killing several birds with one stone?

In patients with severe, treatment-refractory Gilles de la Tourette syndrome (GTS), deep brain stimulation (DBS) of various targets has been increasingly explored over the past 15 years. The multiplicity of surgical targets is intriguing and may be partly due to the complexity of GTS, specifically the various and frequent associated psychiatric comorbidities in this disorder. Thus, the target choice may not only be aimed at reducing tics but also comorbidities. While this approach is laudable, it also carries the risk to increase confounding factors in DBS trials and patient evaluation. Moreover, I question whether DBS should really be expected to alleviate multiple symptoms at a time. Rather, I argue that tic reduction should remain our primary objective in severe GTS patients and that this intervention may subsequently allow an improved psychotherapeutic and/or pharmacological treatment of comorbidities. Thus, I consider DBS in GTS not as a single solution for all our patients' ailments but as a stepping stone to improved holistic care made possible by tic reduction.