Question 1

ANOREXIA NERVOSA

Accepted Answer

What is the focus of DBS research in anorexia nervosa right now?

DBS research in anorexia nervosa (AN) is focused on severe, enduring, treatment-refractory illness, where standard treatments have not led to sustained recovery and medical risk remains high.¹²³ The research question is not, “Can DBS replace therapy or nutrition,” it is closer to, “Can DBS help shift brain circuits that keep the illness locked in place, so recovery treatments have a better chance to work?”¹²⁴

As of now, DBS is not an established, labeled treatment for AN in the United States, it is being studied in small trials and specialized programs.³⁵ The evidence base is still developing, with limited sample sizes, mixed targets, and variable outcome measures, which is why results must be read with both hope and precision.¹²³

Is DBS approved or labeled for anorexia nervosa in the US?

No. In the US, DBS has FDA approvals for certain movement disorders such as essential tremor and Parkinson’s disease, based on specific device indications.⁶⁷ In psychiatric care, DBS has been authorized for obsessive-compulsive disorder under a Humanitarian Device Exemption, and other psychiatric uses have largely remained in research or carefully governed clinical contexts.⁵

That matters because DBS for AN is generally considered investigational, meaning it is studied under research oversight, ethics review, and specialized selection processes.³⁵ If someone is offered DBS for AN outside a clinical trial, it is reasonable to ask what regulatory pathway is being used, what oversight exists, and what evidence is guiding the recommendation.³⁵⁸

Why would DBS even be considered for anorexia nervosa?

Modern AN research increasingly describes the illness as involving persistent, self-reinforcing brain network patterns that affect reward learning, threat sensitivity, habit formation, interoception (how the body is felt from the inside), and cognitive control.¹²⁹ DBS is being explored because it can modulate specific nodes within these networks, potentially changing how the system “weights” fear, reward, and compulsion.¹²⁹¹⁰

Importantly, DBS research in AN often targets not only weight and eating behavior, but also the affective and cognitive drivers that make nourishment feel unsafe or intolerable, such as anxiety, rigidity, obsessive thinking, and mood symptoms.¹²³ This is a research framing, not a promise of outcome, and studies repeatedly show that response varies across individuals.¹²³⁴

Which DBS brain targets have been studied for anorexia nervosa?

Two of the most studied targets in AN DBS research are the subcallosal cingulate (SCC) and the nucleus accumbens (NAc).¹²³ The SCC has been studied because of its role in mood regulation, affective processing, and network connectivity patterns linked to depression and anxiety, which frequently co-occur with severe AN.¹²³ The NAc has been studied because it is a core reward and motivation hub within the ventral striatum, connected to reinforcement learning and salience, which are often disrupted in eating disorders.⁴⁹¹⁰

Other targets appear in the literature less consistently, including ventral capsule or ventral striatum (VC/VS) and related regions, sometimes chosen when comorbid symptoms or circuit hypotheses suggest a better match.¹¹² In plain language, the field is still asking a central question: “Which circuit node is the best lever for which AN phenotype?” and the answer is not settled.³⁴¹¹

What do the earliest SCC DBS studies show, and what are their limits?

Early SCC DBS work in chronic, severe, treatment-refractory AN was published as small, prospective phase 1 studies, designed primarily to assess feasibility and safety, while also tracking clinical outcomes over time.¹² In these reports, some participants showed improvements in mood and anxiety symptoms, and a subset achieved meaningful weight restoration relative to their own baselines.¹²

The limits are equally important. Small sample sizes, open-label designs, and heterogeneity in illness history make it hard to separate DBS effects from other factors like intensive follow-up, concurrent care changes, regression to the mean, or natural fluctuations.¹²³ These studies are best read as, “DBS can be delivered in this population with careful governance, and signals of benefit exist,” not as proof of efficacy for broad clinical use.¹²³⁸

What does the 12-month SCC DBS research add beyond the earliest pilot work?

A 12-month investigation of SCC DBS in treatment-refractory AN reported safety observations and tracked clinical outcomes during a full year of active stimulation, along with neuroimaging findings to explore circuit-level effects.² This matters because AN DBS research is not only tracking symptoms, it is also trying to learn whether stimulation changes network connectivity in ways that align with clinical improvement.²¹⁰

Even with longer follow-up, the central constraint remains: small cohorts and variability in response.²³ That variability is not “noise” to ignore, it is a research signal that patient selection, target selection, stimulation strategy, and concurrent care likely shape outcomes in major ways.³⁴¹⁰

What do NAc DBS studies suggest, and how consistent are the findings?

NAc DBS in refractory AN has been reported in multiple clinical contexts, including long-term follow-up studies and smaller cohorts, with outcomes often tracking body mass index (BMI) and psychiatric symptom scales.⁹¹² In one long-term follow-up study of NAc DBS for refractory AN, investigators reported improvements in BMI and psychiatric symptoms, while also emphasizing strict selection and careful management of surgical complications.⁹

However, consistency is not guaranteed. Across studies, participants differ in AN subtype, duration, comorbidities, stimulation parameters, and definitions of “response.”³⁴ A pilot study of NAc DBS in severe enduring AN reported preliminary indications of improvement for some participants and highlighted the need to clarify predictors of outcome, including the possible influence of comorbid obsessive-compulsive traits.¹⁰

Has any DBS research in anorexia nervosa used randomized or comparative designs?

Yes, but on a small scale. A randomized trial reported initial results at 6 months for DBS targeting either the SCC or NAc in chronic, severe, treatment-refractory AN, with target selection tied to comorbidity patterns.⁵ This type of design is important because it moves the field closer to separating signal from expectation effects, and it supports more disciplined comparisons across targets.⁵³

Even so, small sample sizes limit statistical certainty, and the study does not settle which target is “best” for all patients.⁵³ Research syntheses continue to conclude that higher-quality trials are needed, with harmonized outcomes and clearer phenotyping.³⁴¹¹

What do meta-analyses and systematic reviews conclude so far?

Recent syntheses generally conclude that DBS in severe, treatment-refractory AN shows promising signals for weight restoration and improvements in some psychiatric symptoms, but the evidence is limited by small samples, heterogeneous targets, and variable outcome reporting.³⁴ A meta-analysis in Translational Psychiatry estimated overall beneficial effects of DBS across weight and symptom domains, while still highlighting uncertainty due to study design limitations.³

A network meta-analysis in Neurosurgical Focus compared targets and suggested that SCC may have relatively stronger support for BMI change at certain time points, but it also emphasized the overall limitations of available data.⁴ The practical takeaway is that the research community is still building the “map,” and current evidence supports cautious, trial-based exploration rather than routine clinical adoption.³⁴

What outcomes do DBS studies measure in anorexia nervosa, and why do they matter?

Most DBS studies track BMI and weight-related outcomes because AN is a medical illness with significant physiologic risk, and weight restoration is a central marker of medical stabilization.¹²³⁴ Many also measure eating disorder symptom severity, mood, anxiety, obsessive-compulsive symptoms, quality of life, and functional outcomes.¹²³⁴

This broader set of outcomes is crucial because some participants may show mood or anxiety improvement without major weight gain, or weight gain without meaningful reduction in intrusive eating-disorder thinking.¹²³ Research is increasingly trying to understand which outcomes move together, which do not, and whether certain symptom clusters predict response to certain targets.³⁴¹⁰

What are the main safety concerns when studying DBS in anorexia nervosa?

DBS carries standard surgical and device risks, including infection, bleeding, lead migration, hardware malfunction, and the need for additional procedures.⁶⁷ In AN, additional risks may arise from severe malnutrition, electrolyte instability, bone health issues, and medical fragility, which is why most studies apply strict inclusion criteria and require intensive medical management.¹²³⁹

Psychiatric safety is also central. DBS can influence mood, anxiety, and motivation, and AN often co-occurs with depression, anxiety disorders, and obsessive-compulsive symptoms.¹²³ Ethics-focused work emphasizes the importance of careful capacity assessment, risk-benefit transparency, and long-term follow-up because this population can be uniquely vulnerable.⁸

How do researchers think DBS might work in anorexia nervosa, at the circuit level?

Mechanism research often frames DBS as a way to modulate dysfunctional connectivity within cortico-striatal-limbic circuits, which involve the prefrontal cortex, limbic structures, striatum, thalamus, and related pathways.²⁹¹⁰ In this view, SCC stimulation may influence affective regulation and negative mood loops, while NAc stimulation may influence reward prediction, motivation, and compulsive reinforcement patterns.²⁹¹⁰

Newer work is also exploring measurable brain changes pre and post DBS, including structural and functional connectivity shifts that may correlate with symptom change.¹⁰¹³¹⁴ These studies are not yet definitive, but they represent a key research direction: identifying biomarkers that can guide patient selection and target choice, rather than relying only on clinical intuition.¹³¹⁴

What does “severe and enduring” mean in this research, and why does selection matter so much?

Many DBS AN studies focus on severe enduring anorexia nervosa (SE-AN), generally meaning long illness duration with persistent symptoms despite multiple evidence-based treatments.¹⁰¹¹ Selection matters because DBS is invasive, resource-intensive, and ethically complex, so research protocols aim to study those with the highest unmet need, while also ensuring medical stability enough to undergo surgery and follow-up.¹²³⁸

Selection also matters scientifically. If a trial includes patients with very different illness mechanisms, comorbidities, and degrees of medical fragility, outcomes may appear inconsistent even if DBS is genuinely helpful for a specific subgroup.³⁴¹⁰ This is why modern protocols increasingly emphasize phenotyping, standardized outcome measures, and explicit inclusion and exclusion criteria.¹⁰¹¹

What clinical trials are currently shaping the next phase of DBS research in anorexia nervosa?

Multiple registered trials are exploring DBS for severe AN, including studies targeting the nucleus accumbens and other circuit nodes.¹¹¹² One example is a registered clinical trial titled “Deep Brain Stimulation for Severe Anorexia Nervosa,” which describes a study evaluating the safety of chronic NAc stimulation in severe and resistant AN.¹¹ Another is STIMARS, a multicenter pilot protocol evaluating safety and feasibility of NAc DBS in severe enduring AN.¹²

ClinicalTrials.gov records are useful because they describe design, eligibility, outcomes, and status, but they are not results. The field’s next major step is consistent publication of outcomes, including negative or mixed results, so evidence does not become skewed toward success stories only.³⁴¹¹

What ethical issues are unique to DBS research in anorexia nervosa?

DBS for AN sits at the intersection of life-threatening illness, impaired decision-making risks in some patients, and an invasive intervention with uncertain benefit. Ethics scholarship highlights several key issues: assessing decision-making capacity, avoiding coercion in desperate situations, clearly communicating uncertainty, and ensuring long-term support beyond surgery.⁸

Placebo-controlled and blinded designs raise additional questions, because surgery itself carries risk, and participants may be medically fragile. Discussions in the literature emphasize that ethical trial design must balance scientific rigor with participant welfare, and must be grounded in transparent consent and independent oversight.⁸¹⁵

What does “not labeled yet for DBS therapy” mean for patients and families reading this research?

It means DBS for AN should be understood as investigational. Results are promising in some reports, but they are not definitive, and DBS is not a standard-of-care treatment pathway for AN.³⁴⁵ This also means access is typically through research trials or specialized programs with strict criteria, robust governance, and multidisciplinary teams.¹²³

For many families, this can feel like standing at the edge of bright possibility with fog still over the water. Both can be true. The responsible approach is to treat DBS research as a serious scientific effort, not a miracle story, and to keep the focus on safety, careful selection, and transparent expectations.³⁴⁸

What are the most important research gaps that still need answers?

The biggest gaps include: larger controlled studies, clearer identification of which subgroups benefit most, standardized outcome sets, and better mechanistic markers that predict response.³⁴¹⁰¹³

Another major gap is understanding how DBS interacts with ongoing treatments, for example whether it increases the ability to engage in refeeding and psychotherapy, and which supports are essential for benefit.¹²³

There is also a need for transparent reporting of adverse events and long-term trajectories, including what happens years later with device maintenance, psychiatric course, and functional recovery.²³⁴

The field is moving, but it is still early, and careful science is the path that keeps hope honest.³⁴⁸

GLOSSARY
Anorexia Nervosa: An eating disorder marked by restriction of intake, intense fear of weight gain, and disturbances in how weight and shape are experienced, with significant medical and psychological risk.
Circuit: A connected set of brain regions that communicate to produce a function, such as reward learning, habit formation, or emotion regulation.
Clinical Trial: A research study in people designed to test safety, feasibility, or effectiveness of an intervention using a defined protocol.
Comorbidity: Another condition that occurs alongside the primary condition, such as depression or obsessive-compulsive symptoms alongside anorexia nervosa.
Deep Brain Stimulation: A therapy that delivers adjustable electrical stimulation through implanted brain leads connected to an implanted pulse generator.
Humanitarian Device Exemption: A US FDA pathway that allows certain devices for rare conditions based on a different evidence threshold than standard approvals.
Investigational: Not established as standard care for a condition, typically offered within research protocols with formal oversight.
Nucleus Accumbens: A ventral striatum region involved in reward, motivation, and reinforcement learning, studied as a DBS target in severe anorexia nervosa.
Off-Label Use: Use of an approved device for a condition not listed in its official labeling, often requiring careful governance and justification.
Outcome Measure: A specific metric used to judge change during a study, such as BMI, symptom scales, or quality of life.
Severe Enduring Anorexia Nervosa: A term commonly used in research to describe long-lasting, severe illness that persists despite multiple evidence-based treatments.
Subcallosal Cingulate: A brain region involved in mood and affect regulation, studied as a DBS target in chronic, treatment-refractory anorexia nervosa.
Target: The specific brain region selected for stimulation, chosen based on symptoms, circuit hypotheses, and safety considerations.

REFERENCES
1. Lipsman N, Woodside DB, Giacobbe P, et al. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa: a phase 1 pilot trial. Lancet. 2013;381(9875):1361-1370. https://doi.org/10.1016/S0140-6736(12)62188-6()
2. Lipsman N, Lam E, Volpini M, et al. Deep brain stimulation of the subcallosal cingulate for treatment-refractory anorexia nervosa: 1 year follow-up of an open-label trial. Lancet Psychiatry. 2017;4(4):285-294. https://doi.org/10.1016/S2215-0366(17)30076-7()
3. Karaszewska D, Eberle C, Kobylińska D, et al. Efficacy and safety of deep brain stimulation for treatment-refractory anorexia nervosa: a systematic review and meta-analysis. Transl Psychiatry. 2022;12:390. https://www.nature.com/articles/s41398-022-02102-w(https://www.nature.com/articles/s41398-022-02102-w?utm_source=chatgpt.com)
4. Shaffer A, Le A, Zucker B, et al. Efficacy of deep brain stimulation for the treatment of anorexia nervosa: a systematic review and network meta-analysis. Neurosurg Focus. 2023;54(2):E5. https://thejns.org/focus/view/journals/neurosurg-focus/54/2/article-pE5.pdf(https://thejns.org/focus/view/journals/neurosurg-focus/54/2/article-pE5.pdf?utm_source=chatgpt.com)
5. Villalba Martínez G, Justicia A, Salgado P, et al. A randomized trial of deep brain stimulation to the subcallosal cingulate and nucleus accumbens in patients with treatment-refractory, chronic, and severe anorexia nervosa: initial results at 6 months of follow up. J Clin Med. 2020;9(6):1946. https://doi.org/10.3390/jcm9061946()
6. US Food and Drug Administration. Summary of Safety and Effectiveness Data (SSED): P140009, Deep Brain Stimulation System indications including Parkinson’s disease and essential tremor. https://www.accessdata.fda.gov/cdrh_docs/pdf14/p140009b.pdf(https://www.accessdata.fda.gov/cdrh_docs/pdf14/p140009b.pdf?utm_source=chatgpt.com)
7. US Food and Drug Administration. Premarket Approval (PMA) P960009/S052: Medtronic DBS System indications for essential tremor or parkinsonian tremor. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=P960009S052(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?ID=P960009S052&utm_source=chatgpt.com)
8. Maslen H, Pugh J, Savulescu J. The ethics of deep brain stimulation for the treatment of anorexia nervosa. Neuroethics. 2015;8:215-230. https://pmc.ncbi.nlm.nih.gov/articles/PMC4643100/(https://pmc.ncbi.nlm.nih.gov/articles/PMC4643100/?utm_source=chatgpt.com)
9. Liu W, Zhan S, Li D, Lin Z, Zhang C, Wang T, et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory anorexia nervosa: a long-term follow-up study. Brain Stimul. 2020;13(3):643-649. https://pubmed.ncbi.nlm.nih.gov/32289691/(https://pubmed.ncbi.nlm.nih.gov/32289691/?utm_source=chatgpt.com)
10. Scaife JC, Eraifej J, Green AL, Petric B, Aziz TZ, Park RJ. Deep brain stimulation of the nucleus accumbens in severe enduring anorexia nervosa: a pilot study. Front Behav Neurosci. 2022;16:842184. https://doi.org/10.3389/fnbeh.2022.842184()
11. ClinicalTrials.gov. Deep Brain Stimulation for Severe Anorexia Nervosa (NCT05245643). https://clinicaltrials.gov/study/NCT05245643(https://clinicaltrials.gov/study/NCT05245643?utm_source=chatgpt.com)
12. Duriez P, Simboli GA, Domenech P, et al. Nucleus accumbens deep brain stimulation in adult patients suffering from severe and enduring anorexia nervosa (STIMARS): protocol for a pilot study. Front Psychiatry. 2025;16:1554346. https://doi.org/10.3389/fpsyt.2025.1554346()
13. Abellaneda-Pérez K, Medrano S, Justicia A, et al. Structural connectivity modifications following deep brain stimulation in severe anorexia nervosa. Acta Neurochir (Wien). 2024. https://doi.org/10.1007/s00701-024-06258-w()
14. Oudijn MS, van Elst LT, van den Heuvel OA, et al. Neural effects of deep brain stimulation on reward and loss processing in anorexia nervosa. J Eat Disord. 2023;11:147. https://doi.org/10.1186/s40337-023-00863-3()
15. Lipsman N, Lam E, Giacobbe P, et al. Ethical surgical placebo-controlled trials of deep brain stimulation for anorexia nervosa. Lancet Psychiatry. 2017;4(4):277-279. https://www.thelancet.com/pdfs/journals/lanpsy/PIIS2215()

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Question 2

TREATMENT-RESISTANT AGRESSION

Accepted Answer

What does “treatment-resistant aggression” mean in research settings?

In DBS research, “treatment-resistant aggression” usually describes persistent, severe aggressive or self-injurious behavior that continues despite intensive, multidisciplinary treatment. That typically includes behavioral and environmental supports, psychiatric and medical evaluation, and trials of appropriate medications when indicated.¹² The exact definition varies across studies, and that inconsistency is one reason the evidence base is hard to compare study to study.³⁴

Researchers often quantify aggression using standardized scales so change can be tracked over time, rather than relying only on impressions. The Modified Overt Aggression Scale (MOAS) and related versions are commonly used tools for measuring observable aggression and change over time.⁵⁶ Having structured measurement matters in DBS research because it reduces “wishful thinking” effects and helps teams describe what improved, by how much, and for how long.³⁵

Is DBS approved or labeled for treating aggression in the United States?
Not yet. In the United States, DBS has FDA approvals for several neurological conditions (and an HDE pathway approval for OCD), but DBS is not specifically labeled as a treatment for aggression.⁷⁸ This means DBS for aggression is generally considered investigational or off-label, depending on the context and the treating program’s governance.³⁴

That distinction affects access, oversight, and expectations. When DBS is investigational, it is typically offered within research protocols with ethics review, defined inclusion criteria, and structured follow-up.³⁹ If someone is considering DBS for aggression, it is reasonable to ask what regulatory pathway is being used, what oversight exists, and how the team is defining benefit and risk.³⁹

Why are researchers studying DBS for severe aggression at all?

Severe aggression and self-injurious behavior can be life-altering and dangerous, sometimes causing repeated injury, caregiver burnout, social isolation, school or placement disruption, and frequent emergency interventions.³¹⁰ For a small subgroup, standard treatments may not reduce risk enough, which is why researchers have explored neurosurgical approaches historically, and DBS more recently because it is adjustable and reversible compared with permanent lesion procedures.¹¹¹²

The scientific rationale is circuit-based. Aggression can involve dysregulation in networks linking the hypothalamus, amygdala, limbic systems, and frontal control regions.¹¹¹³ DBS is being studied as a way to modulate specific nodes in those networks to reduce explosive arousal and improve behavioral stability, while allowing clinicians to tune settings over time.¹¹¹³

Which DBS targets have the strongest research signal for treatment-resistant aggression?

Across published clinical reports, the best-developed DBS literature for severe, refractory aggression has focused on the posteromedial hypothalamus (PMH), sometimes described within the posterior hypothalamic region.³¹⁴ A 2024 systematic review concluded that posterior hypothalamic region DBS may be a valuable option for severe aggression disorders in people with intellectual disability, while emphasizing that the literature remains limited.¹⁴

Other targets appear in smaller numbers of reports and mixed populations, including the nucleus accumbens (NAc) and the amygdala, especially when aggression overlaps with compulsive self-injury, severe irritability, or complex neuropsychiatric profiles.¹⁰¹³ These targets are best understood as “active research hypotheses,” not settled standards of care.³⁴¹³

What does the PMH or posterior hypothalamic DBS research show so far?

Case series from specialized centers have reported long-term reductions in severe, medication-resistant aggressiveness in some patients treated with bilateral PMH DBS.¹⁵¹⁶ In these series, improvements were often described as clinically meaningful and sustained over time for responders, with relapse reported in some cases when the neurostimulator battery depleted, followed by improvement after replacement.¹⁷¹⁸

At the same time, these are small cohorts, often with complex neurodevelopmental conditions and limited ability to run blinded trials.¹⁴¹⁶ A careful way to read the evidence is: PMH DBS has repeatedly shown signals of benefit in selected, high-risk patients, but outcomes vary, and the field still lacks large controlled trials that can more cleanly separate stimulation effects from broader care changes and long-term behavioral supports.¹⁴¹⁶

What is known about nucleus accumbens DBS for aggression and self-injurious behavior?

The nucleus accumbens is a reward and salience hub in the ventral striatum, connected to motivation, reinforcement learning, and behavioral drive.¹⁰¹⁹ Researchers have reported case series where NAc DBS was associated with substantial reductions in severe self-destructive and aggressive behaviors across mixed underlying diagnoses, including Tourette syndrome and other neuropsychiatric conditions.¹⁰

This evidence is promising, but it is early-stage. The published data largely involve small samples, heterogeneous diagnoses, and individualized programming approaches, which limits how confidently we can generalize results.¹⁰²⁰ A reasonable research conclusion right now is: NAc DBS may help a subset of patients with severe aggression or self-injury, but we still need better predictors of response and clearer separation of diagnosis-specific pathways.¹⁰²⁰

What is the evidence for amygdala DBS in severe aggression?

The amygdala has a long scientific history in aggression research because it helps process threat, emotional salience, and defensive reactions.¹²¹³ In modern DBS literature, amygdala DBS for aggression is rare, and the published human experience is limited compared with hypothalamic targeting.¹³

A 2024 systematic review focused on the amygdala as a target for aggressive and disruptive behaviors concluded that, while historical and preclinical data exist and modern DBS reports include encouraging signals, the current human clinical evidence is not strong enough to recommend amygdala DBS as a standard approach for extreme aggression.¹³ That is an important guardrail, it keeps hope honest and keeps decisions anchored to evidence quality.¹³

What populations are most represented in DBS aggression research?

A significant portion of published DBS aggression reports involve individuals with intellectual disability and severe, refractory aggression, sometimes with neurodevelopmental syndromes.¹⁴¹⁶ This is partly because the severity and safety risks in these cases drive urgent clinical need, and partly because these patients may have limited alternative options when aggression remains uncontrollable.¹⁴¹⁶

Pediatric and adolescent cases appear in the literature as well, especially in autism with severe intellectual disability and refractory aggression or self-injury. A 2024 meta-analytic review focused on pediatric autism and severe intellectual disability found that DBS was associated with significant reductions in refractory aggression in the included reports, while emphasizing variability in assessment methods and the need for stronger evidence.²⁰²¹

How do researchers measure outcomes in DBS studies for aggression?

Studies often use structured aggression scales, caregiver reports, and functional outcomes such as reduced restraints, fewer injuries, fewer emergency interventions, improved participation in school or daily routines, and improved caregiver quality of life.¹⁰¹⁴ MOAS and other standardized tools help translate “better” into measurable change, which is especially important in small-sample research where bias risk is high.⁵⁶

Researchers also track durability, meaning whether improvement holds over years and whether benefits persist with real-world stressors. Long-term follow-up papers in PMH DBS include descriptions of sustained improvement in responders and symptom worsening with device depletion, which is a useful natural experiment supporting stimulation-related effects in some cases.¹⁷¹⁶

What are the main risks and safety concerns in this research area?

DBS involves brain surgery and implanted hardware. Risks can include intracranial bleeding, infection, seizures, hardware malfunction, lead migration, and the need for revision surgery.¹⁶¹⁴ These risks are not theoretical, they are central to informed decision-making, especially when DBS is being considered for patients who may already be medically or behaviorally fragile.¹⁴¹⁶

There are also neuropsychiatric considerations. Because DBS targets are connected to mood, arousal, and motivation networks, stimulation can potentially affect sleep, anxiety, mood, or agitation, depending on target, settings, and individual sensitivity.¹¹¹³ For this reason, DBS aggression programs typically stress careful selection, cautious programming, and close follow-up with caregivers and multidisciplinary teams.¹⁴²⁰

Why is the evidence base still limited, even after decades of interest?

Severe, treatment-resistant aggression that rises to a neurosurgical discussion is relatively uncommon, and the underlying diagnoses are heterogeneous. That makes it difficult to run large randomized controlled trials, and it creates a literature dominated by case series and small cohorts.¹⁴¹⁶²⁰

There are also ethical and practical barriers. Blinded or sham-controlled designs can be difficult to justify in highly vulnerable patients with serious safety risks, and long-term follow-up requires stable caregiving systems and specialized programming resources.³⁹ These are not excuses, they are realities that shape what kinds of studies are feasible, and they are part of why systematic reviews repeatedly call for better standardization of definitions, outcomes, and reporting.¹⁴²⁰

What ethical issues are most important in DBS research for aggression?

Ethical discussions often focus on informed consent and decision-making capacity, especially when patients have intellectual disability or are minors. They also focus on avoiding coercion when families are desperate, ensuring independent oversight, and defining “benefit” beyond convenience, meaning true reduction of suffering and harm.³⁹

Regulatory pathways matter here too. For example, the FDA’s HDE pathway for DBS in OCD is sometimes cited as a reference point for how psychiatric neuromodulation can be authorized under different evidentiary standards than full PMA approvals.⁸⁹ This does not make DBS for aggression equivalent to OCD DBS, but it highlights why transparency and governance are non-negotiable in emerging indications.⁸⁹

What are the biggest research gaps that still need answers?

The field still needs clearer definitions, standardized outcome reporting, and stronger methods to identify who is most likely to benefit from which target.¹⁴²⁰ It also needs better comparative data across targets, because hypothalamic DBS, nucleus accumbens DBS, and amygdala approaches reflect different circuit hypotheses and may fit different clinical phenotypes.¹¹¹³¹⁴

Long-term trajectories matter too. Researchers need more published data on durability, device maintenance burden, psychiatric effects over years, and the ways DBS interacts with ongoing behavioral and medical care.¹⁶²⁰ If DBS becomes part of the future of treating severe aggression, it will be because evidence grows in both breadth and depth, not because early signals are ignored or oversold.¹⁴²⁰

GLOSSARY
Aggression: Behavior that causes or threatens harm to self, others, or property, ranging from verbal threats to physical injury.
Amygdala: A brain region involved in processing threat, emotional salience, and defensive responses, studied as a possible target in rare DBS cases.
Deep Brain Stimulation: A therapy that uses implanted brain leads connected to an implanted stimulator to deliver adjustable electrical stimulation to a specific target.
Humanitarian Device Exemption: A US FDA pathway that allows certain devices for rare conditions under different evidentiary requirements than full approvals.
Intellectual Disability: A neurodevelopmental condition involving limitations in intellectual functioning and adaptive behavior, often represented in severe aggression DBS reports.
Modified Overt Aggression Scale: A structured tool for rating observable aggression across categories, often used to track change over time.
Nucleus Accumbens: A ventral striatum region involved in reward and motivation, studied as a DBS target for severe self-injury and aggression in some reports.
Off-Label Use: Use of an approved device for a condition not listed on its official labeling, requiring careful clinical justification and governance.
Posterior Hypothalamic Region: A hypothalamic area studied in DBS for severe refractory aggression, often described as PMH or nearby posterior hypothalamic targets.
Posteromedial Hypothalamus: A specific hypothalamic target used in several DBS aggression case series and long-term follow-up reports.
Self-Injurious Behavior: Repetitive behavior that causes physical harm to one’s own body, sometimes occurring with severe aggression in neurodevelopmental conditions.
Treatment-Resistant: Continuing symptoms despite appropriate, sustained trials of standard treatments that would usually be expected to help.

REFERENCES
1. Benedetti-Isaac JC, Camargo L, Torres Zambrano M, et al. Deep brain stimulation may be a viable option for resistant to treatment aggression in children with intellectual disability. CNS Neurosci Ther. 2023;29(7):2010-2017. https://doi.org/10.1111/cns.14156()
2. Cojazzi V, Messina G, Cordella R, Gambini O, Franzini A. Posterior hypothalamic region deep brain stimulation for aggressive disorders and intellectual disability: a systematic review. Stereotact Funct Neurosurg. 2024;102(2):74-86. https://pubmed.ncbi.nlm.nih.gov/38272011/(https://pubmed.ncbi.nlm.nih.gov/38272011/?utm_source=chatgpt.com)
3. Cojazzi V, Messina G, Cordella R, Gambini O, Franzini A. Posterior hypothalamic region deep brain stimulation for aggressive disorders and intellectual disability: a systematic review. Stereotact Funct Neurosurg. 2024;102(2):74-86. https://karger.com/sfn/article/102/2/74/894493/Posterior-Hypothalamic-Region-Deep-Brain(https://karger.com/sfn/article/102/2/74/894493/Posterior-Hypothalamic-Region-Deep-Brain?utm_source=chatgpt.com)
4. Mofatteh M, Akram H, Aziz TZ. Deep brain stimulation of the hypothalamic region: targets and outcomes for behavioral and neuropsychiatric symptoms, systematic review. Acta Neurochir (Wien). 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC11794333/(https://pmc.ncbi.nlm.nih.gov/articles/PMC11794333/?utm_source=chatgpt.com)
5. Coccaro EF, Lee R, McCloskey MS. Overt Aggression Scale Modified (OAS-M): validity, reliability, and utility for clinical trials targeting impulsive aggression. J Psychiatr Res. 2020. https://pubmed.ncbi.nlm.nih.gov/32114032/(https://pubmed.ncbi.nlm.nih.gov/32114032/?utm_source=chatgpt.com)
6. MAPI Research Trust. Modified Overt Aggression Scale. https://eprovide.mapi-trust.org/instruments/modified-overt-aggression-scale(https://eprovide.mapi-trust.org/instruments/modified-overt-aggression-scale?utm_source=chatgpt.com)
7. US Food and Drug Administration. Humanitarian Device Exemption: Reclaim DBS Therapy for Obsessive Compulsive Disorder (OCD) System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533&utm_source=chatgpt.com)
8. US Food and Drug Administration. Humanitarian Device Exemption: Reclaim DBS Therapy for Obsessive Compulsive Disorder (OCD) System (HDE listing details). https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=388846(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=388846&utm_source=chatgpt.com)
9. Fins JJ. Misuse of the FDA’s Humanitarian Device Exemption in deep brain stimulation for obsessive-compulsive disorder. Health Aff (Millwood). 2011;30(2):302-311. https://doi.org/10.1377/hlthaff.2010.0157()
10. Harat M, Kiec M, Rudaś M, Birski M, Furtak J. Treating aggression and self-destructive behaviors by stimulating the nucleus accumbens: a case series. Front Neurol. 2021;12:706166. https://doi.org/10.3389/fneur.2021.706166()
11. Gouveia FV, Germann J, Park RJ, Aziz TZ. Amygdala and hypothalamus: historical overview with contemporary review of neurosurgical approaches to aggression. Neurosurgery. 2019;85(2):E239-E250. https://journals.lww.com/neurosurgery/fulltext/2019/07000/amygdala_and_hypothalamus__historical_overview.2.aspx(https://journals.lww.com/neurosurgery/fulltext/2019/07000/amygdala_and_hypothalamus__historical_overview.2.aspx?utm_source=chatgpt.com)
12. Gouveia FV, Germann J, Park RJ, Aziz TZ. Amygdala and hypothalamus: historical overview with contemporary review of neurosurgical approaches to aggression. Neurosurgery. 2019;85(2):E239-E250. https://doi.org/10.1093/neuros/nyy473()
13. Salcedo-Moreno JC, et al. The amygdala as a therapeutic target for aggressive and disruptive behaviors: a systematic review. Braz J Psychiatry. 2024;46:e20243582. https://pubmed.ncbi.nlm.nih.gov/39298378/(https://pubmed.ncbi.nlm.nih.gov/39298378/?utm_source=chatgpt.com)
14. Herrera-Pino J, Benedetti-Isaac JC. Effectiveness of deep brain stimulation on refractory aggression in pediatric patients with autism and severe intellectual disability: meta-analytic review. BMC Pediatr. 2024. https://pmc.ncbi.nlm.nih.gov/articles/PMC11290060/(https://pmc.ncbi.nlm.nih.gov/articles/PMC11290060/?utm_source=chatgpt.com)
15. Torres CV, Sola RG, Pastor J, et al. Long-term results of posteromedial hypothalamic deep brain stimulation for patients with aggressiveness. J Neurosurg. 2013;119(2):277-287. https://thejns.org/view/journals/j-neurosurg/119/2/article-p277.xml(https://thejns.org/view/journals/j-neurosurg/119/2/article-p277.xml?utm_source=chatgpt.com)
16. Torres CV, Sola RG, Pastor J, et al. Deep brain stimulation for aggressiveness: long-term follow-up and tractography study of the stimulated brain areas. J Neurosurg. 2020;134(2):366-375. https://pubmed.ncbi.nlm.nih.gov/32032944/(https://pubmed.ncbi.nlm.nih.gov/32032944/?utm_source=chatgpt.com)
17. Nandi D, et al. Deep brain stimulation for severe and intractable aggressiveness in intellectual disability: clinical series and outcomes. Stereotact Funct Neurosurg. 2022;100(4):210-219. https://karger.com/sfn/article/100/4/210/826843/Deep-Brain-Stimulation-for-Severe-and-Intractable(https://karger.com/sfn/article/100/4/210/826843/Deep-Brain-Stimulation-for-Severe-and-Intractable?utm_source=chatgpt.com)
18. Benedetti-Isaac JC, et al. Deep brain stimulation in the posteromedial hypothalamic region for refractory aggression: long-term follow-up and clinical observations. https://europepmc.org/article/pmc/pmc8653869()
19. Gouveia FV, et al. Reduction of aggressive behaviour following hypothalamic deep brain stimulation in an animal model: mechanistic findings. Brain Res. 2023. https://www.sciencedirect.com/science/article/pii/S0969996123001948(https://www.sciencedirect.com/science/article/pii/S0969996123001948?utm_source=chatgpt.com)
20. Herrera-Pino J, Benedetti-Isaac JC. Effectiveness of deep brain stimulation on refractory aggression in pediatric patients with autism and severe intellectual disability: meta-analytic review. BMC Pediatr. 2024. https://pubmed.ncbi.nlm.nih.gov/39080575/(https://pubmed.ncbi.nlm.nih.gov/39080575/?utm_source=chatgpt.com)
21. Benedetti-Isaac JC, Herrera-Pino J. Effectiveness of deep brain stimulation on refractory aggression in pediatric autism and severe intellectual disability: evidence synthesis and limitations. BMC Pediatr. 2024. https://link.springer.com/article/10.1186/s12887-024-04920-x(https://link.springer.com/article/10.1186/s12887-024-04920-x?utm_source=chatgpt.com)

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Question 3

TREATMENT-RESISTENT SELF HARM

Accepted Answer

What does “treatment-resistant self-harm” mean in research settings?

In DBS research, “treatment-resistant self-harm” usually refers to severe, repetitive self-injury that continues despite intensive, multidisciplinary care, often including behavioral interventions, environmental supports, medical assessment, and appropriate medication trials when indicated.

This is most commonly discussed in the context of self-injurious behavior (SIB) seen in neurodevelopmental disorders, and in rare neurologic syndromes where self-injury can be extreme.¹

The term can also be used more broadly in mental health settings, where “self-harm” may include nonsuicidal self-injury (NSSI), and suicidal behavior, which are not the same thing clinically. NSSI is typically defined as deliberate tissue damage without intent to die, while suicidal behavior involves self-harm with intent to die.²³ Because DBS studies have mostly focused on severe, repetitive SIB rather than typical outpatient NSSI, it helps to ask, “Which kind of self-harm are we talking about, and in which population?”¹²³

What does “treatment-resistant self-harm” mean in research settings?

In DBS research, “treatment-resistant self-harm” usually refers to severe, repetitive self-injury that continues despite intensive, multidisciplinary care, often including behavioral interventions, environmental supports, medical assessment, and appropriate medication trials when indicated.

This is most commonly discussed in the context of self-injurious behavior (SIB) seen in neurodevelopmental disorders, and in rare neurologic syndromes where self-injury can be extreme.¹

The term can also be used more broadly in mental health settings, where “self-harm” may include nonsuicidal self-injury (NSSI), and suicidal behavior, which are not the same thing clinically. NSSI is typically defined as deliberate tissue damage without intent to die, while suicidal behavior involves self-harm with intent to die.²³ Because DBS studies have mostly focused on severe, repetitive SIB rather than typical outpatient NSSI, it helps to ask, “Which kind of self-harm are we talking about, and in which population?”¹²³

How is severe self-injurious behavior different from nonsuicidal self-injury and suicidal self-harm?

Self-injurious behavior (SIB) is a clinical term often used in neurodevelopmental care to describe repetitive self-injury such as head banging, biting, or hitting, sometimes driven by sensory reinforcement, communication challenges, distress, or neurobiological factors, and sometimes becoming life-threatening.¹ The research literature emphasizes that SIB in intellectual and related neurodevelopmental disorders can be persistent, complex, and difficult to treat.¹

Nonsuicidal self-injury (NSSI) is usually defined as intentional destruction of one’s own body tissue without suicidal intent and not socially sanctioned, and it is often studied in adolescent and psychiatric contexts.²³ Suicidal behavior is conceptually distinct, and DSM-oriented materials explicitly separate nonsuicidal self-injury from suicidal behavior.³ In practice, these categories can overlap over time in some individuals, but research and clinical decision-making treat them as different targets with different risk frameworks.²³

Is DBS approved or labeled for self-harm or self-injurious behavior in the United States?

Not yet. In the US, DBS devices have FDA-approved indications for specific neurologic conditions such as essential tremor and certain Parkinson’s disease indications, and DBS has an FDA Humanitarian Device Exemption indication for obsessive-compulsive disorder in adults.⁴⁵ There is no FDA-labeled DBS indication specifically for self-harm, NSSI, or self-injurious behavior.⁴⁵

So, DBS for severe self-harm is generally investigational in the US, meaning it is studied under research protocols, ethics oversight, and specialized selection and follow-up processes. This matters because “investigational” is not a label of hopelessness, it is a statement about evidence maturity.

The field is still learning who might benefit, which targets are most rational, and how to measure outcomes in a way that is reliable and safe.⁶⁸¹⁰

Why are researchers studying DBS for severe, treatment-resistant self-harm?

The core idea is circuit dysfunction. Severe repetitive self-injury can be driven by dysregulated networks involving reward, threat, arousal, habit formation, and impulse control, especially in certain neurodevelopmental and neurologic conditions.¹ DBS is being studied because it can modulate specific nodes in these networks in a way that is adjustable over time, rather than permanently destroying tissue.⁶¹⁵

This research is not built on the claim that DBS “cures” self-harm. The scientific question is narrower and more practical: can stimulation reduce the intensity and frequency of the self-injury enough to lower risk, reduce injury, and improve the ability to participate in supportive therapies and daily life? That’s why many reports focus on high-risk patients with severe physical injury risk, repeated hospitalizations, or constant supervision needs.⁸⁹

Which DBS brain targets have been studied most for severe self-injurious behavior?

The nucleus accumbens (NAc) is one of the most discussed targets for severe self-injurious behavior, especially in autism and neurodevelopmental presentations. The NAc sits in the ventral striatum and is closely tied to reward learning, motivation, and reinforcement, which are relevant to repetitive behaviors that become “locked in.”⁶⁷⁸

Other targets show up when self-harm overlaps with explosive arousal, aggression, or severe behavioral dysregulation, especially in intellectual disability, including the posteromedial or posterior hypothalamic region.¹¹¹²¹⁵ In specific rare neurologic syndromes where self-injury is a defining feature, such as Lesch–Nyhan disease, globus pallidus internus (GPi) DBS has also been reported with behavioral effects that may include self-injury reduction, although outcomes vary and complications are not rare.¹³¹⁴

What does the nucleus accumbens DBS literature show so far for severe self-injurious behavior?

Evidence includes case reports, case series, and early-phase trials. A published case report described a teenager with autism and severe self-injurious behavior treated with bilateral NAc DBS, reporting marked clinical improvement in the context of refractory symptoms.⁷ A separate case series described NAc DBS in patients with aggressive and self-destructive behavior across different underlying diagnoses, suggesting that NAc targeting can reduce severe self-destructive symptoms in some patients.⁶

More recently, a first-in-children phase 1 clinical trial of NAc DBS for severe, refractory self-injurious behavior reported feasibility and safety signals that support further study, which is a key milestone because it moves beyond single cases into structured clinical research.⁸ Even with these advances, the overall evidence base remains small, and the most honest summary is: benefit is possible in selected patients, but response is not guaranteed, and the field is still defining who benefits and why.⁶⁸¹⁰

Are there ongoing clinical trials for DBS in severe self-injurious behavior?

Yes. ClinicalTrials.gov lists an ongoing randomized trial evaluating NAc DBS for severe refractory, repetitive self-injurious behaviors, reflecting an effort to strengthen evidence quality beyond open-label observations.⁹ Another registered study also focuses on NAc DBS in children with autism, emphasizing safety and potential effectiveness in severe cases.⁹

Trial listings are helpful because they show inclusion criteria, outcomes, and study design, but they are not results. A practical research mindset is to look for peer-reviewed publications that report outcomes, including adverse events, alongside trial registrations so the evidence picture is not skewed toward only success stories.⁸⁹¹⁰

What do systematic reviews and cross-condition analyses suggest about DBS and self-injurious behavior?

A 2024 research analysis focused on comorbid self-injurious behavior across multiple neurologic and psychiatric DBS indications reported that SIB can improve after DBS in some settings, across different targets and primary diagnoses.¹⁰ This is important because it suggests self-injury may be a modifiable symptom dimension in certain brain circuit disorders, not only a diagnosis-specific phenomenon.¹⁰

At the same time, cross-condition reviews can blur critical differences, for example, self-injury in Tourette syndrome is not the same as self-injury in profound autism with intellectual disability, and neither is the same as psychiatric NSSI.¹²³ So these reviews are best used as directional evidence, not as a blueprint for clinical decision-making in any one person.¹⁰

What does hypothalamic region DBS research add to the self-harm conversation?

The posterior hypothalamic region has been studied most prominently for severe refractory aggression in intellectual disability, and many of those clinical pictures include self-injury as part of the overall dangerous behavioral syndrome.¹¹¹² A 2024 systematic review concluded that posterior hypothalamic region DBS may be a valuable option for severe aggression disorders in intellectual disability, while emphasizing that experiences remain limited and evidence quality is constrained by small cohorts.¹¹

A 2025 systematic review focused on hypothalamic DBS across behavioral and neuropsychiatric symptoms provides additional context on targets and outcomes in this region.¹⁵ For “treatment-resistant self-harm,” the key point is not that hypothalamic DBS is proven for self-injury specifically, it is that certain severe, high-arousal behavioral states that include self-harm have been treated with hypothalamic region DBS in specialized settings, and the literature supports cautious, expert-driven exploration rather than general use.¹¹¹⁵

What is known about DBS for self-injury in Lesch–Nyhan disease and other rare neurologic syndromes?

Lesch–Nyhan disease is a rare disorder where severe self-injurious behavior can be a defining and dangerous feature. Reviews of DBS in Lesch–Nyhan disease report that GPi DBS can improve motor symptoms to varying degrees, and multiple published cases describe partial or complete control of self-injurious behavior, while also noting variability and a meaningful complication burden.¹³¹⁴

This literature is valuable because it demonstrates a clear “behavioral symptom” response signal in a condition with profound biologic drivers. Still, it is mostly case-based evidence, not large trials, and it does not guarantee that GPi DBS will help self-injury in other conditions. The safest interpretation is: in Lesch–Nyhan disease, GPi DBS has enough reported behavioral benefit to justify ongoing research attention, but outcomes remain unpredictable, and careful risk discussion is essential.¹³¹⁴

How do researchers measure whether DBS is helping self-harm?

Research groups often measure frequency and severity of self-injury episodes, injury burden, need for restraints or protective equipment, emergency interventions, caregiver burden, and participation in daily activities. These outcomes matter because a modest numerical reduction that does not change safety or function may not be meaningful, while a partial reduction that prevents serious injury can be life-changing.⁸¹⁰

Because many candidates for DBS in this area are medically and behaviorally complex, strong studies also track medication changes, behavioral program changes, and environmental changes alongside DBS settings. Without that context, it becomes hard to know whether improvement was due to stimulation, to concurrent care changes, or to both working together.⁸⁹¹⁰

What are the main risks and safety concerns when DBS is studied for severe self-harm?

DBS is brain surgery with device implantation, so risks can include bleeding, infection, seizures, device or lead problems, and revision surgeries. These risks are central in vulnerable populations who may have difficulty communicating symptoms, may have high rates of agitation, or may be prone to wound manipulation.⁸¹³¹⁴

There are also neuropsychiatric safety considerations. DBS can influence mood, sleep, anxiety, or arousal depending on target and settings, and careful monitoring is especially important when self-harm is present. Literature reviews on DBS and suicidality in other DBS populations underline why systematic monitoring of suicidal thinking and behavior is important in any psychiatric-adjacent DBS program, even when causality is uncertain.¹⁶

What ethical issues are especially important in DBS research for treatment-resistant self-harm?

Ethics is not a side topic here, it is the spine of the work. Many candidates are children, or adults with limited decision-making capacity due to intellectual disability, severe autism, or neurologic syndromes. That raises high-stakes questions about consent, assent when possible, caregiver authority, and independent oversight to ensure the intervention is aimed at reducing suffering and harm, not simply making care easier for others.¹¹¹⁵

Ethical practice also means being plain about uncertainty. Even when early studies show promise, DBS remains investigational for self-harm, and the burden of long-term follow-up is real: programming visits, battery replacements, and ongoing behavioral and medical supports. The most responsible programs build DBS into a broader care plan rather than treating it as a standalone fix.⁸⁹¹⁵

What are the biggest research gaps that still need answers?

The biggest gaps include larger controlled studies, clearer identification of which subgroups benefit from which targets, and standardized outcome sets that capture safety and function, not only episode counts.⁸⁹¹⁰ Another gap is mechanism: researchers still need better biomarkers or circuit-level predictors to explain why some patients respond dramatically while others do not.⁶⁸¹⁵

There is also a long-term reality gap. We need more published data on durability over years, device maintenance burdens, effects on development and quality of life in pediatric populations, and how DBS interacts with ongoing behavioral interventions. That kind of long-view evidence is what eventually separates an intriguing intervention from a reliable, ethical standard.⁸⁹¹⁵

GLOSSARY
Assent: A person’s affirmative agreement to participate in care or research, used when full legal consent may not be possible, often alongside caregiver consent and ethics oversight.
Deep Brain Stimulation: A therapy that uses implanted brain leads connected to an implanted stimulator to deliver adjustable electrical stimulation to a specific target.
Globus Pallidus Internus: A deep brain structure often targeted in DBS for dystonia, and studied in Lesch–Nyhan disease where self-injury can be severe.
Humanitarian Device Exemption: A US FDA pathway that allows certain devices for rare conditions under different evidentiary requirements than full approvals.
Investigational: Not established as standard care for a condition, typically offered within research protocols with formal oversight.
Nonsuicidal Self-Injury: Deliberate self-inflicted tissue damage without intent to die and not socially sanctioned.
Nucleus Accumbens: A ventral striatum region involved in reward and reinforcement learning, studied as a DBS target for severe self-injurious behavior.
Posterior Hypothalamic Region: A hypothalamic area studied in DBS for severe refractory aggression and related high-risk behavioral syndromes that can include self-injury.
Self-Injurious Behavior: Repetitive self-directed behaviors that cause physical harm, often discussed in neurodevelopmental and neurologic contexts.
Treatment-Resistant: Continuing symptoms despite appropriate, sustained trials of standard treatments that would usually be expected to help.

REFERENCES
1. Symons FJ, Thompson A, Rodriguez MC. Self-injurious behavior in neurodevelopmental disorders. Front Biosci (Elite Ed). 2011;3:981-987. https://pmc.ncbi.nlm.nih.gov/articles/PMC3086601/(https://pmc.ncbi.nlm.nih.gov/articles/PMC3086601/?utm_source=chatgpt.com)
2. Klonsky ED. Nonsuicidal self-injury: what we know, and what we need to know. Curr Dir Psychol Sci. 2014;23(6):1-7. https://pmc.ncbi.nlm.nih.gov/articles/PMC4244874/(https://pmc.ncbi.nlm.nih.gov/articles/PMC4244874/?utm_source=chatgpt.com)
3. American Psychiatric Association. Addition of Diagnostic Codes for Suicidal Behavior and Nonsuicidal Self-Injury in DSM-5-TR. https://www.psychiatry.org/getmedia/1f70c2ab-04dd-4267-aae7-b421c17072b8/APA-DSM5TR-SuicidalBehaviorandNonsuicidalSelfInjury.pdf(https://www.psychiatry.org/getmedia/1f70c2ab-04dd-4267-aae7-b421c17072b8/APA-DSM5TR-SuicidalBehaviorandNonsuicidalSelfInjury.pdf?utm_source=chatgpt.com)
4. US Food and Drug Administration. Premarket Approval (PMA) P960009: Deep brain stimulation system indications including essential tremor and parkinsonian tremor. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P960009(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P960009&utm_source=chatgpt.com)
5. US Food and Drug Administration. Humanitarian Device Exemption (HDE) H050003: Reclaim DBS Therapy for Obsessive Compulsive Disorder (OCD) System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533&utm_source=chatgpt.com)
6. Harat M, Rudaś M, Kiec M, Birski M, Furtak J. Treating aggression and self-destructive behaviors by stimulating the nucleus accumbens: a case series. Front Neurol. 2021;12:706166. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.706166/full(https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2021.706166/full?utm_source=chatgpt.com)
7. Park HR, Kim IH, Kang H, et al. Nucleus accumbens deep brain stimulation for a patient with self-injurious behavior and autism spectrum disorder: functional and structural changes of the brain, report of a case and review of literature. J Clin Neurosci. 2017;47:115-118. https://pubmed.ncbi.nlm.nih.gov/27807672/(https://pubmed.ncbi.nlm.nih.gov/27807672/?utm_source=chatgpt.com)
8. Gorodetsky C, Mithani K, Breitbart S, et al. Deep brain stimulation of the nucleus accumbens for severe self-injurious behavior in children: a phase I pilot trial. Biol Psychiatry. 2024. https://pubmed.ncbi.nlm.nih.gov/39645140/(https://pubmed.ncbi.nlm.nih.gov/39645140/?utm_source=chatgpt.com)
9. ClinicalTrials.gov. A Randomized Trial of Deep Brain Stimulation of the Nucleus Accumbens for Severe Self-Injurious Behaviours (NCT06529380). https://clinicaltrials.gov/study/NCT06529380(https://clinicaltrials.gov/study/NCT06529380?utm_source=chatgpt.com)
10. Mithani K, Ibrahim GM, Fasano A, et al. Effect of deep brain stimulation on comorbid self-injurious behavior across neurologic disorders and targets. Neuromodulation. 2024. https://europepmc.org/article/med/39306775()
11. Cojazzi V, Messina G, Cordella R, Gambini O, Franzini A. Posterior hypothalamic region deep brain stimulation for aggressive disorders and intellectual disability: a systematic review. Stereotact Funct Neurosurg. 2024;102(2):74-86. https://karger.com/sfn/article/102/2/74/894493/Posterior-Hypothalamic-Region-Deep-Brain(https://karger.com/sfn/article/102/2/74/894493/Posterior-Hypothalamic-Region-Deep-Brain?utm_source=chatgpt.com)
12. Benedetti-Isaac JC, Torres CV, Sola RG, et al. Deep brain stimulation in the posteromedial hypothalamic nuclei in refractory aggressiveness: post-surgical results of 19 cases. Front Hum Neurosci. 2021;15:756435. https://pmc.ncbi.nlm.nih.gov/articles/PMC8653869/(https://pmc.ncbi.nlm.nih.gov/articles/PMC8653869/?utm_source=chatgpt.com)
13. Visser JE, Barba M, Stamelou M, et al. Deep brain stimulation in Lesch–Nyhan disease: outcomes and mechanisms. Dev Med Child Neurol. 2021. https://pmc.ncbi.nlm.nih.gov/articles/PMC8350791/(https://pmc.ncbi.nlm.nih.gov/articles/PMC8350791/?utm_source=chatgpt.com)
14. Deng H, Wang Y, Zhang Y, et al. Deep brain stimulation in Lesch-Nyhan syndrome: a systematic review. Neurosurg Rev. 2023. https://pubmed.ncbi.nlm.nih.gov/36694014/(https://pubmed.ncbi.nlm.nih.gov/36694014/?utm_source=chatgpt.com)
15. Mofatteh M, Akram H, Aziz TZ. Deep brain stimulation of the hypothalamic region: targets and outcomes for behavioral and neuropsychiatric symptoms, systematic review. Acta Neurochir (Wien). 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC11794333/(https://pmc.ncbi.nlm.nih.gov/articles/PMC11794333/?utm_source=chatgpt.com)
16. Costanza A, Masson M, Nemeroff CB, et al. Suicidality associated with deep brain stimulation in extrapyramidal diseases: a critical review and hypotheses on neuroanatomical and neuroimmune mechanisms. Front Integr Neurosci. 2021;15:632249. https://pmc.ncbi.nlm.nih.gov/articles/PMC8060445/(https://pmc.ncbi.nlm.nih.gov/articles/PMC8060445/?utm_source=chatgpt.com)
17. 988 Suicide & Crisis Lifeline. https://988lifeline.org/(https://988lifeline.org/?utm_source=chatgpt.com)

Question 4

ALZHEIMERS DISEASE

Accepted Answer

What is Alzheimer’s disease, and why does DBS research focus on it specifically?

Alzheimer’s disease is a progressive brain disease that gradually affects memory, thinking, and the ability to manage everyday tasks.¹ People often move from mild symptoms to more significant impairment over time, and the pattern can include problems with language, judgment, and orientation as the disease progresses.¹

DBS research focuses on Alzheimer’s because the disease disrupts identifiable brain networks involved in memory and attention, and those networks can be targeted with stimulation in a precise, circuit-based way.²³ The goal is not to claim DBS “reverses” Alzheimer’s, it is to test whether adjusting activity in specific memory-related circuits might change symptoms or slow decline for some people.²³⁴

Is DBS approved or labeled to treat Alzheimer’s disease in the United States?
Not yet. DBS is FDA-approved for certain neurological conditions, such as essential tremor and Parkinson’s disease-related symptoms, and it has an FDA Humanitarian Device Exemption indication for obsessive-compulsive disorder in adults.⁵⁶ Alzheimer’s disease is not an FDA-labeled indication for DBS.⁵⁶

So DBS for Alzheimer’s is investigational. That means it is studied under research protocols designed to evaluate safety, feasibility, and possible benefit using defined outcomes and oversight.²⁷ If you see DBS discussed for Alzheimer’s outside a trial, it is reasonable to ask what governance is in place, what evidence is being used, and how the team is tracking outcomes and risks.⁷⁸

Why would DBS even be studied for Alzheimer’s disease?

Alzheimer’s affects brain networks, not just one “memory spot.” Imaging and physiology studies suggest that as Alzheimer’s progresses, communication within the brain’s memory circuit becomes less efficient, and downstream regions show metabolic and functional changes that relate to cognition.²⁹ DBS is being studied because stimulation can modulate network activity at a specific node, potentially influencing connected areas.²⁹

There is also a practical reason DBS keeps showing up in Alzheimer’s research: it is adjustable. Stimulation settings can be tuned over time, and if side effects occur, programming can be changed.²³ That adjustability is part of why DBS is considered an experimental tool worth studying carefully, even while efficacy remains uncertain.³⁴

What is DBS, in plain language, and what can it realistically do in Alzheimer’s?

DBS is a therapy that delivers controlled electrical stimulation through thin implanted leads placed in a specific brain target, connected by extensions to an implanted pulse generator, which is like a programmable battery.²⁵ The stimulation is adjusted over time based on symptoms and tolerability.²

In Alzheimer’s research, DBS is not expected to “remove plaques” or “cure” the disease directly, and studies have not established that it reliably slows progression across broad groups.³⁴ Instead, the research question is narrower: can stimulation of a memory-related circuit change cognitive trajectories or certain symptoms for some people, and if so, under what conditions?³⁴⁹

Which DBS targets are most studied for Alzheimer’s disease, and why those targets?

Two targets dominate modern Alzheimer’s DBS research: the fornix and the nucleus basalis of Meynert (NBM).²³ The fornix is a major white-matter pathway in the brain’s memory circuit. It connects memory-related structures and helps carry signals that support learning and recall.²¹⁰ Researchers target the fornix because it is a strategic “wiring” point in a circuit affected early in Alzheimer’s.²¹⁰

The NBM is a key cholinergic hub, meaning it provides widespread acetylcholine-related input to the cortex, which is important for attention and cognition.¹¹ Some Alzheimer’s symptom medications support cholinergic signaling, and NBM DBS is being explored as another way to modulate these systems, especially in studies focused on daily attention and cognitive engagement.¹¹¹²

What did the Phase II fornix DBS trial find at 12 months?

A Phase II randomized, double-blind study evaluated fornix DBS in people with mild Alzheimer’s disease and compared active stimulation versus sham (off) conditions, tracking cognitive measures and brain metabolism.² In that study, surgery and stimulation were reported as generally safe and well tolerated, and participants receiving stimulation showed increases in cerebral glucose metabolism at earlier time points, which is one way researchers look for network engagement.²¹³

At 12 months, there were no significant differences in the primary cognitive outcomes between “on” and “off” stimulation for the cohort as a whole.² That result is one of the central reasons Alzheimer’s DBS remains investigational, it shows feasibility and biological signals, but it does not establish consistent clinical benefit across the full trial population.²³

What did the ADvance trial follow-up show over two years?

The ADvance trial’s two-year follow-up reported that fornix DBS was generally safe in the studied population and did not demonstrate a clear overall primary clinical benefit across the full group.³ This follow-up also explored delayed activation and subgroup patterns, which helped the field refine hypotheses about who might respond and how stimulation might need to be delivered.³²

One important theme from the ADvance program is variability. Some analyses suggested age-related differences, with signals that outcomes might differ between older and younger participants, but these are not the same as definitive proof.³⁴ The responsible interpretation is: the trial supports feasibility and safety signals, while efficacy remains unproven and likely depends on factors like patient selection and network engagement.³⁴¹⁰

What does “directional” fornix DBS add, and why might it matter?

Directional DBS uses lead designs that can shape stimulation more precisely, helping clinicians steer current toward a desired pathway and away from regions that could cause side effects. This matters in fornix DBS because small differences in lead placement and which fibers are stimulated can change which networks are actually engaged.¹⁰

A published directional fornix DBS case report in early-stage Alzheimer’s suggested the approach was feasible and described mild to moderate cognitive effects early on that trended back toward baseline by longer follow-up, with specific domains behaving differently.⁵ These data are not definitive, especially because they involve very small numbers, but they support a key research idea: precision targeting and network selection may be part of why results vary across studies.⁵¹⁰

What does the evidence say about “DBS changes brain networks” in Alzheimer’s?

Network mapping work suggests that optimal stimulation sites and the specific networks engaged by fornix DBS may be linked to outcomes. In other words, it may not be enough to say “the lead is in the fornix,” the question becomes “which fibers and which connected network are being modulated.”¹⁰

This helps explain why Alzheimer’s DBS research often looks beyond cognitive tests alone and includes imaging measures like glucose metabolism or connectivity.²¹⁰ The field is trying to connect stimulation, network effects, and clinical outcomes into one chain that makes sense, rather than relying on symptoms alone.²¹⁰

What do biomarker studies suggest, and what should readers be careful about?

Biomarkers are measurable biological signals, such as imaging changes or cerebrospinal fluid (CSF) measures. A 2025 study reported changes in imaging and CSF biomarkers in participants receiving fornix DBS, including signals the authors interpreted as potentially consistent with slowed neurodegeneration or Alzheimer-related biomarker shifts in some patients.¹⁴

This is an important direction, but it is still early. Biomarker studies can be affected by sample size, variability in disease course, and measurement complexity.¹⁴ For now, biomarker findings should be read as research signals that help generate better future trials, not as confirmation that DBS is disease-modifying for Alzheimer’s.³⁴¹⁴

What do NBM DBS studies show so far in Alzheimer’s disease?

NBM DBS has been studied in small human cohorts, including a 2024 report describing NBM DBS in advanced Alzheimer’s disease. That study reported no severe adverse events in the cohort described and reported improvements in certain cognitive measures and self-care ability, while also noting that it did not change the overall direction of the disease.¹²

There are also registered trials exploring NBM DBS approaches, including intermittent stimulation protocols. These trials reflect active uncertainty about optimal dosing, meaning how much stimulation, how often, and for how long may be needed to affect cognition-related circuits.¹⁵¹⁶ The evidence is promising in places, but still early-stage, and durable, broadly reliable benefit is not established.¹²¹⁷

What do systematic reviews and meta-analyses conclude about DBS for Alzheimer’s?

Systematic reviews and meta-analyses generally conclude that DBS for Alzheimer’s remains experimental, with acceptable feasibility and safety signals reported in studied cohorts, and mixed or insufficient evidence for consistent cognitive benefit across populations.³⁴¹⁷ One meta-analysis and systematic review published in 2023 concluded that fornix DBS did not show clear cognitive improvement in subgroup analysis and noted the reporting of adverse outcomes, underscoring uncertainty.¹⁷

A 2024 systematic review focused on DBS targets for Alzheimer’s similarly emphasized that while multiple targets have been explored, evidence is heterogeneous and not yet strong enough to support routine clinical use.⁴ The shared message is steady: DBS for Alzheimer’s is serious research, not established treatment, and future progress depends on better targeting, better trial designs, and clearer responder profiles.⁴¹⁷

What Alzheimer’s DBS trials are ongoing or shaping the next research phase?

ADvance II is a registered clinical trial designed to test whether fornix DBS can slow cognitive and functional progression in mild probable Alzheimer’s disease using defined endpoints.¹⁸ This kind of trial matters because it is built to answer the question with stronger methods than early feasibility work.¹⁸

Other registered trials are evaluating NBM DBS approaches for Alzheimer’s, including intermittent stimulation protocols that specify daily stimulation schedules and structured assessments.¹⁵¹⁶ Trial registrations are not outcomes, but they are the most transparent place to see study design, eligibility criteria, and primary endpoints.¹⁵¹⁶¹⁸

What are the main risks and safety concerns in Alzheimer’s DBS research?

DBS involves brain surgery and implanted hardware. Risks can include intracranial bleeding, infection, seizures, hardware malfunction, lead migration, and the need for additional procedures.²³¹⁹ These risks are part of every DBS discussion, even when studies report an overall acceptable safety profile.²³

Alzheimer’s adds practical safety layers. Cognitive impairment can affect symptom reporting and decision-making, and long-term device follow-up depends heavily on care partners and structured clinical support.²⁸ That is why many ethics discussions emphasize careful participant selection, robust caregiver involvement, and clear post-trial planning for device management.⁸²⁰

What are the key ethical issues in DBS research for Alzheimer’s disease?

Ethical work in Alzheimer’s DBS focuses on informed consent and decision-making capacity, because Alzheimer’s can affect understanding, memory for details, and the ability to weigh risks over time. A 2017 ethics analysis highlighted the need for careful enrollment standards and dementia-sensitive consent processes in DBS Alzheimer’s research.⁸

Another major ethical issue is therapeutic misconception, meaning someone may believe the study is designed primarily to help them personally, when the study’s main purpose is to generate generalizable knowledge.²⁰ Stakeholder research on DBS for cognition also shows that people weigh potential benefit against surgical risk and long-term burden differently, which makes plain-language consent and expectation-setting essential.²⁰

What are the biggest research gaps that still need answers?

The field still needs clearer identification of who might benefit, which target best fits which Alzheimer’s profile, and what stimulation parameters most reliably engage helpful networks.⁴¹⁰¹⁷ It also needs more harmonized outcome sets so results can be compared across trials without shifting definitions.⁴¹⁷

A second major gap is linking stimulation to meaningful biological change. Biomarkers and network mapping are promising, but still early, and they need replication across larger cohorts.¹⁰¹⁴ Until those gaps narrow, DBS for Alzheimer’s should be understood as carefully governed research, a light on the horizon, but not a standard path yet.⁴¹⁷

GLOSSARY
Acetylcholine: A brain chemical involved in attention, learning, and memory; cholinergic systems are affected in Alzheimer’s disease.
ADvance II: A clinical trial designed to test whether fornix DBS can slow cognitive and functional progression in mild probable Alzheimer’s disease.
Biomarker: A measurable biological signal, such as imaging or CSF measures, used to track disease processes or treatment effects.
Cerebrospinal Fluid: Fluid around the brain and spinal cord that can be tested for Alzheimer-related proteins in clinical and research settings.
Cholinergic: Related to acetylcholine signaling in the brain.
Clinical Trial: A research study in people designed to test safety, feasibility, or effectiveness of an intervention using a defined protocol.
Deep Brain Stimulation: A therapy that uses implanted brain leads connected to an implanted stimulator to deliver adjustable electrical stimulation to a specific target.
Directional DBS: DBS technology that can shape stimulation more precisely to influence specific pathways and reduce side effects.
Fornix: A major white-matter pathway within the brain’s memory circuit, studied as a DBS target in Alzheimer’s disease.
Investigational: Not established as standard care for a condition, typically offered within research protocols with formal oversight.
Memory Circuit: A connected set of brain regions and pathways involved in learning and recalling information.
Nucleus Basalis of Meynert: A cholinergic brain region that provides widespread projections to the cortex, studied as a DBS target in Alzheimer’s disease.
Therapeutic Misconception: When someone believes a research study is guaranteed to help them personally, even when the study’s purpose is to learn.

REFERENCES
1. National Institute on Aging. Alzheimer’s Disease Fact Sheet. https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet(https://www.nia.nih.gov/health/alzheimers-and-dementia/alzheimers-disease-fact-sheet?utm_source=chatgpt.com)
2. Lozano AM, Fosdick L, Chakravarty MM, et al. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer’s Disease. J Alzheimers Dis. 2016;54(2):777-787. doi:10.3233/JAD-160017. https://doi.org/10.3233/JAD-160017()
3. Leoutsakos JMS, Yan H, Anderson WS, et al. Deep Brain Stimulation Targeting the Fornix for Mild Alzheimer Dementia (the ADvance Trial): A Two Year Follow-up Including Results of Delayed Activation. J Alzheimers Dis. 2018;64(2):597-606. doi:10.3233/JAD-180121. https://pmc.ncbi.nlm.nih.gov/articles/PMC6518401/(https://pmc.ncbi.nlm.nih.gov/articles/PMC6518401/?utm_source=chatgpt.com)
4. Picton B, Xu T, Asgari N, et al. Deep Brain Stimulation as an Emerging Therapy for Alzheimer Disease: A Systematic Review of Current Targets and Outcomes. Brain Stimul. 2024. https://pubmed.ncbi.nlm.nih.gov/38141755/(https://pubmed.ncbi.nlm.nih.gov/38141755/?utm_source=chatgpt.com)
5. US Food and Drug Administration. Premarket Approval (PMA) P960009: Deep Brain Stimulation System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P960009(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P960009&utm_source=chatgpt.com)
6. US Food and Drug Administration. Humanitarian Device Exemption (HDE) H050003: Reclaim DBS Therapy for Obsessive Compulsive Disorder (OCD) System. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfhde/hde.cfm?id=375533&utm_source=chatgpt.com)
7. ClinicalTrials.gov. ADvance DBS-f in Patients With Mild Probable Alzheimer’s Disease (NCT01608061). https://www.clinicaltrials.gov/study/NCT01608061(https://www.clinicaltrials.gov/study/NCT01608061?utm_source=chatgpt.com)
8. Siegel AM, Barrett AM, Bhati MT. Deep Brain Stimulation for Alzheimer’s Disease: Ethical Challenges for Clinical Research. J Alzheimers Dis. 2017;56(2). https://pubmed.ncbi.nlm.nih.gov/27983548/(https://pubmed.ncbi.nlm.nih.gov/27983548/?utm_source=chatgpt.com)
9. Ponce FA, Asaad WF, Foote KD, et al. Bilateral Deep Brain Stimulation of the Fornix for Alzheimer’s Disease: Surgical Safety in the ADvance Trial. J Neurosurg. 2016;125(1):75-84. https://thejns.org/view/journals/j-neurosurg/125/1/article-p75.xml(https://thejns.org/view/journals/j-neurosurg/125/1/article-p75.xml?utm_source=chatgpt.com)
10. Ríos AS, Singleton DB, Schaper FLWVJ, et al. Optimal Deep Brain Stimulation Sites and Networks for Stimulation of the Fornix in Alzheimer’s Disease. Nat Commun. 2022;13:7054. https://www.nature.com/articles/s41467-022-34510-3(https://www.nature.com/articles/s41467-022-34510-3?utm_source=chatgpt.com)
11. National Institute on Aging. Alzheimer’s Medicines: Help With Symptoms. https://www.nia.nih.gov/health/alzheimers-medicines-help-symptoms()
12. Xu J, Zhang J, Wang Y, et al. Deep Brain Stimulation of the Nucleus Basalis of Meynert in Advanced Alzheimer’s Disease. J Alzheimers Dis Rep. 2024. https://doi.org/10.1177/25424823241296780()
13. Lozano AM, Fosdick L, Chakravarty MM, et al. A Phase II Study of Fornix Deep Brain Stimulation in Mild Alzheimer’s Disease. J Alzheimers Dis. 2016;54(2):777-787. https://pmc.ncbi.nlm.nih.gov/articles/PMC5026133/(https://pmc.ncbi.nlm.nih.gov/articles/PMC5026133/?utm_source=chatgpt.com)
14. Germann J, et al. Biomarker Changes Associated With Fornix Deep Brain Stimulation in Alzheimer’s Disease. Alzheimers Dement. 2025. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70394(https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70394?utm_source=chatgpt.com)
15. ClinicalTrials.gov. A Trial to Test Intermittent Deep Brain Stimulation for Alzheimer’s Disease (NCT07218081). https://clinicaltrials.gov/study/NCT07218081(https://clinicaltrials.gov/study/NCT07218081?utm_source=chatgpt.com)
16. ClinicalTrials.gov. Deep Brain Stimulation for Alzheimer’s Disease (NCT03959124). https://www.clinicaltrials.gov/study/NCT03959124(https://www.clinicaltrials.gov/study/NCT03959124?utm_source=chatgpt.com)
17. Majdi A, et al. Deep Brain Stimulation for the Treatment of Alzheimer’s Disease: A Systematic Review and Meta-analysis. Front Neurosci. 2023;17:1154180. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1154180/full(https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1154180/full?utm_source=chatgpt.com)
18. ClinicalTrials.gov. ADvance II Study: DBS-f in Patients With Mild Alzheimer’s Disease (NCT03622905). https://www.clinicaltrials.gov/study/NCT03622905(https://www.clinicaltrials.gov/study/NCT03622905?utm_source=chatgpt.com)
19. Ponce FA, Asaad WF, Foote KD, et al. Bilateral Deep Brain Stimulation of the Fornix for Alzheimer’s Disease: Surgical Safety in the ADvance Trial. J Neurosurg. 2016;125(1):75-84. https://doi.org/10.3171/2015.6.JNS15148()
20. Klein E, Montes Daza N, Dasgupta I, et al. Views of Stakeholders at Risk for Alzheimer’s Disease About Deep Brain Stimulation for Cognition. Brain Stimul. 2023;16(3):742-747. doi:10.1016/j.brs.2023.04.007. https://pmc.ncbi.nlm.nih.gov/articles/PMC10576447/(https://pmc.ncbi.nlm.nih.gov/articles/PMC10576447/?utm_source=chatgpt.com)

Question 5

FRONTOTEMPORAL DEMENTIA

Accepted Answer

What is frontotemporal dementia (FTD), in plain language?

Frontotemporal dementia is a group of brain diseases that primarily affect the frontal and temporal lobes, areas that help guide behavior, decision-making, emotional responses, and language.¹,² As these areas change over time, a person may show noticeable shifts in personality, social behavior, motivation, judgment, or communication.¹,²

FTD is not one single condition. It is an umbrella term that includes several syndromes with different symptom patterns and different underlying protein pathologies.³ For DBS research, this matters because neuromodulation usually targets a specific symptom and a specific circuit, not the entire diagnosis.⁴,⁵

What are the main types of FTD, and which type shows up most in DBS research so far?

The most commonly discussed clinical forms include behavioral variant FTD (bvFTD), which centers on behavior and personality changes, and primary progressive aphasia (PPA) variants, which center on language changes.¹,² In bvFTD, memory can look less affected early compared with some other dementias, while motivation, empathy, impulse control, and socially appropriate behavior can change early and strongly.¹,⁶

So far, the clearest DBS research effort in FTD is aimed at bvFTD, specifically the “apathetic” presentation, where loss of motivation and initiation becomes a dominant, disabling feature.⁷,⁸ In other words, the DBS question being tested is not “DBS for all FTD,” it is closer to, “Can stimulation of a motivation-related circuit reduce apathy in bvFTD?”⁷,⁸

What symptoms of FTD are most relevant to DBS research right now?

Apathy is a central focus. Apathy is not laziness, and it is not a moral failure. It is a brain-based reduction in motivation, initiative, and goal-directed behavior that can show up as “I just can’t start,” “I don’t care,” or “nothing feels worth doing,” even when the person was previously engaged and energetic.⁶,⁹,¹⁰

In bvFTD, apathy is common and can strongly drive loss of independence and caregiver burden.⁶,⁹,¹¹ It can also coexist with other bvFTD features like disinhibition, repetitive behaviors, and reduced empathy, and those symptoms can shift over time.⁶,¹²

What is apathy, scientifically, and what brain circuits are usually involved?

Apathy is often described as a reduction in goal-directed behavior due to disrupted motivation, planning, reward valuation, or the ability to translate intention into action.¹³,¹⁴ Across disorders, apathy has been linked to disruption in networks involving the anterior cingulate cortex and ventral striatum, among other connected regions.¹⁴

In FTD, research also connects apathy severity to frontal and cingulate-region changes, which supports the idea that “motivation circuits” are part of the disease’s symptom expression.⁶,⁹,¹² That circuit framing is one reason DBS researchers are testing targets connected to mood and motivation networks rather than classic memory targets used in Alzheimer’s DBS research.⁷,⁸,¹⁵

Is DBS approved or labeled for FTD in the United States?
Not yet. In the US, DBS has FDA approvals for certain movement disorder indications, and there are other limited device pathways for specific conditions, but FTD is not an FDA-labeled indication for DBS.¹⁶,¹⁷

So DBS for FTD is investigational. That means it is being studied under formal research protocols designed to answer safety and feasibility questions first, and then, if appropriate, larger efficacy questions.⁷,¹⁸

Why is the subgenual cingulate region being studied as a DBS target in apathetic bvFTD?

The subgenual cingulate region, sometimes described in DBS literature as the subcallosal cingulate or area 25, is deeply connected to networks involved in mood regulation, motivation, and emotional behavior.¹⁵,¹⁹ This region became a major DBS research target in treatment-resistant depression because it is positioned like a junction in a larger circuit, where small shifts in network activity can sometimes produce meaningful clinical changes.¹⁹–²¹

FTD researchers are testing whether stimulating this region can “nudge” motivation-related circuits in people with bvFTD who are dominated by apathy.⁷,⁸ The idea is not that stimulation stops the disease, but that it might reduce the severity of a high-impact symptom, apathy, enough to change daily function and quality of life, even if decline continues overall.⁷,⁸

What is the FRONSTIM study, and what is it trying to learn?

FRONSTIM is a study designed to evaluate the safety of DBS of the subgenual cingulate in people diagnosed with bvFTD who have apathy and a reliable study partner.⁸ The publicly described plan includes long-term follow-up with neuropsychological testing and neuroimaging, alongside stimulation adjustment visits over months to years.⁸

A key point: FRONSTIM is positioned as an early-stage study. That usually means the goal is to establish whether the intervention can be delivered safely in this population, and to collect enough physiological and clinical signal to justify larger, more definitive trials.⁷,⁸

What do we know about results from DBS in FTD so far?

The evidence base for DBS in FTD is very small compared with DBS in movement disorders or depression, and it is best described as early and actively developing.⁷,⁸ Much of what is publicly available about DBS in bvFTD apathy comes from trial registration and study descriptions, rather than widely replicated, peer-reviewed outcome datasets.⁷,⁸

That limited evidence does not mean the approach is ineffective, it means we do not yet have the kind of replicated, controlled outcome data needed to say DBS helps apathy in bvFTD in a reliable way.¹⁸ The research posture here is careful: first confirm safety and feasibility, then test benefit with stronger study designs.⁷,¹⁸

What can we borrow, cautiously, from subgenual cingulate DBS research in depression?

Subgenual cingulate DBS has been studied in treatment-resistant depression across multiple trials, including sham-controlled studies. These studies support the overall feasibility and safety of targeting this region, even as results on antidepressant efficacy have been mixed in controlled phases.¹⁵,²⁰

For FTD research, this depression DBS literature is not proof of benefit, but it does provide practical context: implanting and programming stimulation in this target can be done in a structured way, and long-term follow-up frameworks exist.¹⁹–²¹ That background helps researchers design safer, more realistic protocols for a cognitively vulnerable population like bvFTD.⁷,⁸,²²

What outcomes matter most when DBS is studied for apathetic bvFTD?

Apathy is not just a feeling, it shows up as a functional pattern: reduced initiation, reduced engagement, reduced self-care follow-through, and reduced participation in relationships and routines.⁶,¹¹,¹² In research, it is important to measure both symptom scales and real-world function, because a small change on a questionnaire may not translate into safer, easier daily life.¹¹,¹⁸

FTD trials also need strong outcome measures because behavior can fluctuate and caregiver input is crucial.⁸,¹¹,¹⁸ That is why study designs often require a reliable partner who can report what is happening day to day, across settings, not just during clinic visits.⁸

What are the main risks and special safety considerations for DBS research in bvFTD?

DBS is brain surgery with implanted hardware, so risks can include bleeding, infection, seizures, lead or device complications, and the need for revision surgeries.¹⁵,¹⁹–²¹ These risks are part of any DBS discussion, even when a study is framed as careful and monitored.¹⁵,²⁰

FTD adds layers. Behavioral symptoms like impulsivity, reduced insight, or disinhibition can make post-operative care and wound protection more challenging, and apathy can reduce follow-through with appointments unless strong caregiver support is present.⁶,⁸,¹² That is one reason trials emphasize a study partner and structured follow-up, because safety depends on the whole system around the person, not only the device.⁸,²²

What ethical issues are especially important when DBS is studied in FTD?

FTD can affect judgment, insight, and decision-making capacity, sometimes early.¹,⁶ That raises high-stakes questions about informed consent, ongoing consent over time, and how to ensure decisions reflect the person’s values, not only crisis pressure or caregiver exhaustion.²²,²³

DBS ethics literature emphasizes that consent is not a single signature, it is a process, especially when cognition and autonomy may change.²²,²³ In practice, this often means capacity assessment, clear explanation of uncertainty, avoidance of coercion, and explicit planning for what happens if participation becomes too burdensome or capacity declines.²²,²³

What are the biggest research gaps for DBS in FTD?

The biggest gap is evidence size and strength. The field needs larger, well-designed studies that can separate true stimulation effects from natural variability in symptoms and progression.¹⁸ Another gap is identifying who might respond, meaning which bvFTD profiles, disease stages, and network patterns are most likely to benefit, if benefit exists.¹⁸

There is also a measurement gap. FTD trials need robust, sensitive outcomes that capture what matters: safety, function, and caregiver reality, not only test scores.¹¹,¹⁸ Until these gaps narrow, DBS in FTD should be viewed as a carefully governed research path, a light being tested through layers of uncertainty, not a standard therapy.⁷,¹⁸

GLOSSARY
Apathy: A reduction in motivation and goal-directed behavior that can appear as diminished initiative, reduced interest, or difficulty starting and sustaining activities.
Anterior Cingulate Cortex: A brain region involved in motivation, decision-making, emotion regulation, and integrating effort with reward.
Behavioral Variant Frontotemporal Dementia: A form of FTD where early, prominent changes in personality, social behavior, motivation, and judgment are typical.
Clinical Trial: A structured research study in people designed to test safety, feasibility, or effectiveness of an intervention using a defined protocol.
Disinhibition: Reduced ability to restrain impulses or follow social rules, leading to inappropriate actions or comments.
Frontotemporal Dementia: A group of neurodegenerative disorders that primarily affect frontal and temporal brain regions, often changing behavior or language.
Investigational: Not established as standard care for a condition, typically offered within research protocols with formal oversight.
Primary Progressive Aphasia: A group of FTD-related syndromes where progressive language difficulties are the main early symptom.
Study Partner: A reliable person, often a care partner, who supports participation and provides observations about daily behavior, thinking, and function.
Subgenual Cingulate: A region beneath the front part of the corpus callosum that is strongly connected to mood and motivation networks, studied as a DBS target.
Ventral Striatum: A set of deep brain structures involved in reward learning, motivation, and goal-directed behavior.

REFERENCES
1. Mayo Clinic. Frontotemporal dementia, symptoms and causes. https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737(https://www.mayoclinic.org/diseases-conditions/frontotemporal-dementia/symptoms-causes/syc-20354737?utm_source=chatgpt.com)
2. The Association for Frontotemporal Degeneration (AFTD). What is bvFTD? (Behavioral Variant FTD). https://www.theaftd.org/what-is-ftd/behavioral-variant-ftd-bvftd/(https://www.theaftd.org/what-is-ftd/behavioral-variant-ftd-bvftd/?utm_source=chatgpt.com)
3. Schroeter ML, Neumann J. The case of behavioral variant frontotemporal dementia. Front Neurol. 2014;5:174. https://pmc.ncbi.nlm.nih.gov/articles/PMC4108513/(https://pmc.ncbi.nlm.nih.gov/articles/PMC4108513/?utm_source=chatgpt.com)
4. Lee DJ, Lozano CS, Dallapiazza RF, Lozano AM. Current and future directions of deep brain stimulation for neurological and psychiatric disorders. J Neurosurg. 2019;131(2):333-342. https://thejns.org/view/journals/j-neurosurg/131/2/article-p333.xml(https://thejns.org/view/journals/j-neurosurg/131/2/article-p333.xml?utm_source=chatgpt.com)
5. Drevets WC, Savitz J, Trimble M. The subgenual anterior cingulate cortex in mood disorders. CNS Spectr. 2008;13(8):663-681. https://pmc.ncbi.nlm.nih.gov/articles/PMC2729429/(https://pmc.ncbi.nlm.nih.gov/articles/PMC2729429/?utm_source=chatgpt.com)
6. Zamboni G, Huey ED, Krueger F, Nichelli PF, Grafman J. Apathy and disinhibition in frontotemporal dementia. Neurology. 2008;71(10):736-742. https://pmc.ncbi.nlm.nih.gov/articles/PMC2676948/(https://pmc.ncbi.nlm.nih.gov/articles/PMC2676948/?utm_source=chatgpt.com)
7. ClinicalTrials.gov. Subgenual Cingulate Deep Brain STIMulation for Apathetic Behavioral Variant FRONtotemporal Dementia (FRONSTIM) (NCT05699330). https://clinicaltrials.gov/study/NCT05699330(https://clinicaltrials.gov/study/NCT05699330?utm_source=chatgpt.com)
8. Toronto Dementia Research Alliance. FRONSTIM. https://tdra.utoronto.ca/study/fronstim(https://tdra.utoronto.ca/study/fronstim?utm_source=chatgpt.com)
9. Quaranta D, Marra C, Rossi C, Gainotti G, Masullo C. Different apathy profile in behavioral variant of frontotemporal dementia and Alzheimer’s disease. Am J Alzheimers Dis Other Demen. 2012;27(6):433-439. https://pmc.ncbi.nlm.nih.gov/articles/PMC3376472/(https://pmc.ncbi.nlm.nih.gov/articles/PMC3376472/?utm_source=chatgpt.com)
10. Malpetti M, Ballarini T, Lorenzini L, et al. Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes. Alzheimers Dement. 2021;17(10):1628-1638. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12252(https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12252?utm_source=chatgpt.com)
11. Zhu CW, Seltzer B, Lee M, et al. Apathy and functional impairment in the course of behavioral variant frontotemporal dementia. JAMA Netw Open. 2022;5(12):e2247340. https://pmc.ncbi.nlm.nih.gov/articles/PMC9856251/(https://pmc.ncbi.nlm.nih.gov/articles/PMC9856251/?utm_source=chatgpt.com)
12. The Association for Frontotemporal Degeneration (AFTD). Understanding and responding to FTD behaviors. https://www.theaftd.org/posts/aftd-partners-in-ftd-care/pic-ftd-behaviors/(https://www.theaftd.org/posts/aftd-partners-in-ftd-care/pic-ftd-behaviors/?utm_source=chatgpt.com)
13. Levy R, Dubois B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb Cortex. 2006;16(7):916-928. https://academic.oup.com/cercor/article/16/7/916/425683(https://academic.oup.com/cercor/article/16/7/916/425683?utm_source=chatgpt.com)
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