Efficacy of deep brain stimulation for treatment-resistant depression: systematic review and meta-analysis.

BACKGROUND: Treatment-resistant depression (TRD) affects about 30% of individuals with major depressive disorder. Deep brain stimulation (DBS) is an investigational intervention for TRD with varied results. We undertook this meta-analysis to synthesize outcome data across trial designs, anatomical targets, and institutions to better establish efficacy and side effect profiles. METHODS: We conducted a systematic PubMed review following PRISMA guidelines. Seven randomized-controlled trials (n=198) and eight open-label trials (n=77) were included, spanning 2009-2020. Outcome measures included Hamilton Depression Rating Scale or Montgomery-Åsberg Depression Rating Scale scores, as well as response and remission rates over time. Outcomes were tracked at last follow-up and quantified as a time course using model-based network meta-analysis. Linear mixed models were fit to individual patient data to identify covariates. RESULTS: DBS achieved 47% improvement in long-term depression scale scores, with an estimated time to reach 50% improvement around 23 months. There were no significant subgroup effects of stimulation target, time of last follow-up, sex, age of disease onset, or duration of disease, but open-label trials showed significantly greater treatment effects compared to randomized controlled trials. Long-term (12-60 month) response and remission rates were 48% and 35%, respectively. The time course of improvement with active stimulation could not be adequately distinguished from that with sham stimulation, when available. CONCLUSIONS: DBS produces significant chronic improvement in symptoms of TRD. The limited sham-controlled data, however, does not demonstrate significant improvement over placebo. Future advancements in stimulation optimization and careful blinding and placebo schemes are important next steps for this therapy.

Current perspectives on tractography-guided deep brain stimulation for the treatment of mood disorders.

INTRODUCTION: Deep brain stimulation (DBS) is an emerging therapy for mood disorders, particularly treatment-resistant depression (TRD). Different brain areas implicated in depression-related brain networks have been investigated as DBS targets and variable clinical outcomes highlight the importance of target identification. Tractography has provided insight into how DBS modulates disorder-related brain networks and is being increasingly used to guide DBS for psychiatric disorders. AREAS COVERED: In this perspective, an overview of the current state of DBS for TRD and the principles of tractography is provided. Next, a comprehensive review of DBS targets is presented with a focus on tractography. Finally, the challenges and future directions of tractography-guided DBS are discussed. EXPERT OPINION: Tractography-guided DBS is a promising tool for improving DBS outcomes for mood disorders. Tractography is particularly useful for targeting patient-specific white matter tracts that are not visible using conventional structural MRI. Developments in tractography methods will help refine DBS targeting for TRD and may facilitate symptom-specific precision neuromodulation. Ultimately, the standardization of tractography methods will be essential to transforming DBS into an established therapy for mood disorders.

Case report: Clinical efficacy of deep brain stimulation contacts corresponds to local field potential signals in a patient with obsessive-compulsive disorder.

Introduction: Deep brain stimulation (DBS) is often effective in treating severe obsessive-compulsive disorder (OCD) when traditional therapeutic approaches have failed. However, optimizing DBS programming is a time-consuming process. Recent research in movement disorders suggests that local field potentials can dramatically speed up the process of identifying the optimal contacts for stimulation, but this has not yet been tested in a patient with OCD. Methods: In a patient with severe OCD, we first determined the optimal contact for stimulation for each hemisphere using traditional monopolar and bipolar review and then tested whether the clinically optimal contact in each hemisphere corresponded to local field potential signals. Results: Overall, we found that clinical efficacy corresponded with the contacts that showed the strongest local field potential signals across multiple frequency bands. Discussion: Our findings are the first indication that local field potentials could guide contact selection in patients with OCD. If validated in a larger sample, this methodology could decrease time to clinical benefit and improve accuracy in patients that are difficult to assess using traditional methods. Further research is needed to determine whether local field potentials could be used to guide finer resolution in programming parameters.

Deep Brain Stimulation for Obsessive-Compulsive Disorder and Depression.

The field of stereotactic neurosurgery developed more than 70 years ago to address a therapy gap for patients with severe psychiatric disorders. In the decades since, it has matured tremendously, benefiting from advances in clinical and basic sciences. Deep brain stimulation (DBS) for severe, treatment-resistant psychiatric disorders is currently poised to transition from a stage of empiricism to one increasingly rooted in scientific discovery. Current drivers of this transition are advances in neuroimaging, but rapidly emerging ones are neurophysiological-as we understand more about the neural basis of these disorders, we will more successfully be able to use interventions such as invasive stimulation to restore dysfunctional circuits to health. Paralleling this transition is a steady increase in the consistency and quality of outcome data. Here, we focus on obsessive-compulsive disorder and depression, two topics that have received the most attention in terms of trial volume and scientific effort.

Stereotactic cingulotomy and capsulotomy for obsessive-compulsive disorders: Indications and comparative results.

Stereotactic cingulotomy and capsulotomy have been used to treat obsessive-compulsive disorders (OCD) and treatment-resistant depression since the 1950s-60s. To date, these surgical procedures have gained a number of advancements due to progress of neuroimaging and upgrading of stereotactic technique. The effectiveness of operations is related to the restoration of the normal level of limbic regulation in treated patients. In cases of OCD, capsulotomy is somewhat more effective, while cingulotomy has a more favorable safety profile. Moreover, clinical experience shows that these procedures may be efficient for management not only OCD itself, but for obsessive-compulsive symptoms in cases of other mental diseases, such as Tourette syndrome and schizophrenia, thus may be considered in carefully selected patients. An individualized treatment strategy, including staged stereotactic interventions, seems most promising for attainment of the best possible outcomes, and may allow to achieve socialization of 75% of the operated patients with minimal pharmacological support. Other potential stereotactic targets for management of OCD, which selection may depend on detail of clinical manifestation of disease, include thalamic nuclei, nucleus accumbens, globus pallidus, the amygdala, etc., and are currently under active evaluation, and their use is tremendously facilitated by the development of deep brain stimulation techniques. Nevertheless, cingulotomy and capsulotomy still remain highly relevant for treatment of patients with therapy-resistant mental disorders.

Psychogenic (nociplastic) pain: Current state of diagnosis, treatment options, and potentials of neurosurgical management.

Classification of pain syndromes is quite multifaceted. However, pathogenetic classification by which chronic pain syndromes are usually divided into nociceptive, neuropathic and psychogenic, is crucial in choosing treatment tactics. In modern classifications, psychogenic pain is distinguished from nociceptive pain (associated with direct tissue injury or damage) and neuropathic pain (in which lesion can only be determined morphologically). Mental disorders play a leading role in psychogenic pain. Here, somatic/neurological disorders, if any, are of no pathogenetic significance in the dynamics of pain syndrome. There are certain algorithms (though not yet fully developed) and even guidelines for diagnosing and treating nociceptive and neuropathic pain, whereas psychogenic pain has been and still is almost out of sight for a long time. Despite its considerable prevalence, attitude towards it is still uncertain. Until now, it has no single classification, nor any strategy with regards to diagnosis, treatment and prevention.

Patients selection for psychiatric neurosurgery: pitfalls and considerations.

Neurosurgical interventions (destructive or neuromodulation) are considered as a therapeutic option for patients with treatment resistant mental disorders. However, the issues of indications and contraindications for psychiatric surgery, method and patient selection remain unresolved. This article discusses possible problems and contradictions in the selection of patients, the need for an interdisciplinary team to work to solve the question of the feasibility of using neurosurgical methods. The authors have identified the main problems that increase the risks of selection and lead to a lack of results or low efficiency of neurosurgical intervention, namely: (1) diagnostic errors or inaccuracies; (2) inconclusive data on therapeutic resistance; (3) lack of a common understanding of the goals and desired results among participants in the selection of patients for neurosurgery. Possible predictors of surgical outcome and ethical issues are also discussed. Neurosurgical interventions as a treatment option for psychiatric disorders are not officially approved in most countries. So an appropriate algorithm for patient selection and clear criteria for outcome measures are needed.

Gamma knife radiosurgery versus deep brain stimulation for treatment-refractory depression and obsessive-compulsive disorder: A brief comparative summary.

Both gamma knife surgery (GKS) and deep brain stimulation (DBS) have documented success in management of treatment-refractory major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), but there are no formal randomized controlled trials to compare these treatment modalities in cases of psychiatric illnesses. In this brief review, comparison of GKS and DBS for management of MDD and OCD was done with regard to their efficacy, accompanying risks, reversibility of therapeutic effects, costs, availability, and daily life issues. Currently available evidence does not support the superiority of either evaluated treatment modality over each other in terms of clinical efficacy in cases of MDD and OCD. Nevertheless, with regard to risks, costs, device maintenance, and daily life issues, GKS definitely seems more advantageous. Reversibility of therapeutic effects of DBS is certainly highly attractive, while may be a bit overhyped. In any case, synergy between GKS and DBS for management of mental illnesses lies in the continuing pursuit of improvement and raising the bar of excellence.

Gamma Knife capsulotomy for correction of obsessive-compulsive symptoms in a patient with schizophrenia: Case report.

The treatment of mental illnesses that are resistant to conservative therapy poses a serious problem. Surgical methods with proven efficacy have been proposed for only a small group of psychiatric diseases, while in practice non-classical clinical situations are seen rather often. A 36-year-old man with a 18-year history of "schizophrenia with a predominant obsessive-compulsive syndrome" was referred to the Burdenko National Medical Research Center of Neurosurgery for consideration of neurosurgical treatment. Based on results of longitudinal independent evaluations of the patient in several specialized clinical centers the disease was considered resistant to medical therapy. Radiosurgical procedure was performed by means of Leksell Gamma Knife Perfexion™ (Elekta AB; Stockholm, Sweden). Ventral portion of the anterior limb of internal capsule was targeted with two 4-mm isocenters on each side, with prescription dose at 50% isodose line of 80 Gy and a maximal dose of 160 Gy. No obvious complications or side effects were noted during 13-month follow-up after radiosurgery. Gradual clinical improvement was observed with 25% reduction of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score at 13 months after treatment. Similarly, the Hospital Anxiety and Depression Scale (HADS) anxiety and depression scores decreased by 24% and 58%, respectively. This is the first published case of radiosurgical treatment of a psychiatric disorder in Russia. It demonstrates the potential efficacy of Gamma Knife capsulotomy for non-classical forms of obsessive-compulsive disorder comorbid with schizophrenia. Nevertheless, definitive conclusions about the reliability of this radiosurgical indication can only be made based on the results of larger studies.

Neurosurgical management of Tourette syndrome: A literature review and analysis of a case series treated with deep brain stimulation.

Tourette syndrome (TS) is a heterogeneous disorder, which clinical presentation includes both multiple motor and vocal tics and commonly associated psychiatric conditions (obsessive-compulsive disorder, attention deficit hyperactivity disorder, depression, anxiety, etc.). Treatment options primarily consist of non-pharmacological interventions (habit reversal training, relaxation techniques, cognitive behavioral therapy, and social rehabilitation) and pharmacotherapy. In case of the intractable forms, neurosurgical treatment may be considered, primarily deep brain stimulation (DBS). DBS appear to be effective in medically intractable TS patients, although, the preferential brain target is still not defined. The majority of studies describe small number of cases and the issues of appropriate patient selection and ethics remain to be clarified. In this article, we review the main points in management of TS, discuss possible indications and contraindications for neurosurgical treatment, and analyze our experience of DBS in a case series of refractory TS patients with the focus on target selection and individual outcomes.

Stereotactic surgeries for abuse syndromes: Patient selection and results.

It is known that in present time heroin addiction is the most widespread and difficult to treat. It includes two factors: physical and psychological addiction. The vast majority of patients remained mentally addicted to drugs after physical drug addiction has been eliminated and the organism has been completely detoxed. It is an indomitable desire to take drugs. Neurophysiological mechanisms are in base of psychological dependence. It is similar to those that implement obsessive states (obsessive-compulsive disorders). The central role in these neurophysiological mechanisms is played by limbic system of the brain that provides emotional and motivational behavior of humans (and animals). It was shown that the treatment of medical-resistant forms of obsessive-compulsive disorders requires stereotactic impacts on various structures of the limbic system, including cingulate gyrus. According to literature data, there was several hundred stereotactic effects on the cingulate gyrus in the world. About 1000 stereotactic operations have been performed in our country as a mental addiction of heroin dependent patients' treatment. The efficiency was of about 70%.

A population-normalized tractographic fiber atlas of the anterior limb of the internal capsule: relevance to surgical neuromodulation.

OBJECTIVE: The anterior limb of the internal capsule (ALIC) is a white matter highway that connects several subcortical structures to the prefrontal cortex. Although surgical interventions in the ALIC have been used to treat a number of psychiatric illnesses, there is significant debate regarding what fibers are targeted for intervention. This debate is partially due to an incomplete understanding of connectivity in the region. METHODS: To better understand this complex structure, the authors employed a novel tractography-based approach to examine how fibers from the thalamus and subthalamic nucleus (STN) traverse the ALIC. Furthermore, the authors analyzed connections from the medial dorsal nucleus, anterior nucleus, and ventral anterior nucleus of the thalamus. RESULTS: The results showed that there is an organizational gradient of thalamic fibers medially and STN fibers laterally in the ALIC that fades more anteriorly. These findings, in combination with the known corticotopic organization described by previous studies, allow for a more thorough understanding of the organization of the white matter fibers in the ALIC. CONCLUSIONS: These results are important for understanding and targeting of neuromodulatory therapies in the ALIC and may help explain why differences in therapeutic effect are observed for different areas of the ALIC.

A comparative history of psychosurgery.

The term "psychosurgery" reflecting neurosurgical treatment of mental disorders, was coined by a Portuguese neurologist Egas Moniz (1874-1955), who, in 1935, suggested a procedure named prefrontal leucotomy (or lobotomy) aimed to divide white matter tracts connecting prefrontal cortex and thalamus. Starting from 1936, this technique and its subsequent modification (transorbital lobotomy) was zealously promoted by a neurologist Walter Freeman (1895-1972) and a neurosurgeon James Watts (1904-1994) at George Washington University, who in 1942 summarized their experience in a monograph, which publication resulted in a tremendous worldwide interest in psychosurgical interventions. The present review describes comparative development of prefrontal leucotomy followed by stereotactic ablation and neurostimulation in three different geographical regions: USA, USSR/Russia, and Far East (China and Japan), where psychosurgery followed nearly similar courses, progressing from the initial enthusiasm and high clinical caseloads to nearly complete disregard. The opposition to neurosurgical interventions for mental disorders around the world was led by different groups and for varying reasons, but, unfortunately, always with political considerations mixed in. Today, with vast advancements in neuroimaging, stereotactic neurosurgical techniques, and physiological knowledge, psychiatric neurosurgery can be performed with much greater precision and safety.

Modern Gamma Knife radiosurgery for management of psychiatric disorders.

Psychiatric disorders result in great suffering of affected patients, who often have rather limited treatment options. In cases refractory to standard medical and behavioral therapy, interventional procedures may be the only feasible solution. The authors experience with Gamma Knife bilateral cingulotomy for treatment-resistant major depression disorder (5 cases) and anorexia nervosa (6 cases), and bilateral anterior capsulotomy for severe obsessive-compulsive disorder (10 cases) shows that such radiosurgical techniques may be applied both effectively and safely. During post-treatment follow-up, the vast majority of patients demonstrated gradual reduction of psychiatric symptoms and improvement of the quality of life, which was confirmed by results of regular neuropsychological testing and imaging examinations. No major side effect was observed in any case. More active application of radiosurgery (using standardized technique) for management of mental illnesses in various Gamma Knife centers worldwide should be encouraged.

Gamma Knife radiosurgery for obsessive compulsive disorder.

Gamma Knife radiosurgical capsulotomy has been performed for over 40 years as a rarely used surgical intervention for the treatment of obsessive-compulsive disorder. Over time, the procedure has evolved in many ways with most significant modifications being made in target location, number of isocenters and prescribed dose, subsequently producing changes in lesion size and geometry. Long-term clinical response data and adverse outcomes to the earlier empiric treatment parameters have resulted in shifting the target from its initial location within the midpoint of the anterior limb of internal capsule to a currently used point that includes its most ventral portion as well as the ventral striatum. This led to the contemporary Gamma Knife ventral capsulotomy procedure that focuses on ventral capsule/ventral striatum. Many of the early studies, despite demonstrating efficacy in some patients, were complicated by clinically relevant radiation-induced adverse effects. More recent studies have demonstrated strong efficacy with diminished adverse effects with well-placed lesions created at lower radiation doses. Advances in neuroimaging technology such as diffusion tensor imaging (DTI) based fiber tracking may provide further insight into precisely targeting of the ventral capsule/striatum based on patient-specific variations in white matter connectivity.

LINAC-based radiosurgery for functional and psychiatric disorders: Problems and their solutions.

Stereotactic radiosurgery (SRS) is practically non-invasive treatment option, and its application for ablative procedures in functional and psychiatric brain disorders seems rather promising. In such cases, gamma knife surgery (GKS) is considered a standard option due to its proved accuracy in targeting and dosimetry. However, modern linear accelerators (LINAC), which are the most commonly used radiosurgical device, provide comparable treatment preciseness. Although at present experience with LINAC-based SRS of functional brain disorders is rather limited, from the technological viewpoint it definitely seems possible and theoretically may be of the similar efficacy as established with GKS for the same indications. However, widespread introduction of such practice requires resolution of several important methodological issues, particularly related to establishment of specific treatment standards, development of dedicated training for involved medical professionals, and creation of the data accumulation and outcome analysis systems.

The future perspectives of psychiatric neurosurgery.

The future of psychiatric neurosurgery can be viewed from two separate perspectives: the immediate future and the distant future. Both show promise, but the treatment strategy for mental diseases and the technology utilized during these separate periods will likely differ dramatically. It can be expected that the initial advancements will be built upon progress of neuroimaging and stereotactic targeting while surgical technology becomes adapted to patient-specific symptomatology and structural/functional imaging parameters. This individualized approach has already begun to show significant promise when applied to deep brain stimulation for treatment-resistant depression and obsessive-compulsive disorder. If effectiveness of these strategies is confirmed by well designed, double-blind, placebo-controlled clinical studies, further technological advances will continue into the distant future, and will likely involve precise neuromodulation at the cellular level, perhaps using wireless technology with or without closed-loop design. This approach, being theoretically less invasive and carrying less risk, may ultimately propel psychiatric neurosurgery to the forefront in the treatment algorithm of mental illness. Despite prominent development of non-invasive therapeutic options, such as stereotactic radiosurgery or transcranial magnetic resonance-guided focused ultrasound, chances are there will still be a need in surgical management of patients with most intractable psychiatric conditions.

Modern neurosurgical techniques for psychiatric disorders.

Psychosurgery refers to an ensemble of more or less invasive techniques designed to reduce the burden caused by psychiatric diseases in patients who have failed to respond to conventional therapy. While most surgeries are designed to correct apparent anatomical abnormalities, no discrete cerebral anatomical lesion is evident in most psychiatric diseases amenable to invasive interventions. Finding the optimal surgical targets in mental illness is troublesome. In general, contemporary psychosurgical procedures can be classified into one of two primary modalities: lesioning and stimulation procedures. The first group is divided into (a) thermocoagulation and (b) stereotactic radiosurgery or recently introduced transcranial magnetic resonance-guided focused ultrasound, whereas stimulation techniques mainly include deep brain stimulation (DBS), cortical stimulation, and the vagus nerve stimulation. The most studied psychiatric diseases amenable to psychosurgical interventions are severe treatment-resistant major depressive disorder, obsessive-compulsive disorder, Tourette syndrome, anorexia nervosa, schizophrenia, and substance use disorder. Furthermore, modern neuroimaging techniques spurred the interest of clinicians to identify cerebral regions amenable to be manipulated to control psychiatric symptoms. On this way, the concept of a multi-nodal network need to be embraced, enticing the collaboration of psychiatrists, psychologists, neurologists and neurosurgeons participating in multidisciplinary groups, conducting well-designed clinical trials.

Role of deep brain stimulation in management of psychiatric disorders.

Nowadays, most of patients affected by psychiatric disorders are successfully treated with conservative therapies. Still, a variable percentage of them demonstrate resistance to conventional treatments, and alternative methods can then be considered. During the last 20 years, there is a progressive interest in use of deep brain stimulation (DBS) in mental illnesses. It has become clear nowadays, that this modality may be effectively applied under specific indications in some patients with major depressive disorder, obsessive-compulsive disorder, anorexia nervosa and other eating disorders, Tourette syndrome, schizophrenia, substance use disorder, and even pathologically aggressive behavior. Despite the fact that the efficacy of neuromodulation with DBS, as well as of various lesional interventions, in cases of mental illnesses is still not fully established, there are several premises for wider applications of such "unclassical" psychiatric treatments in the future. Novel technologies of DBS, developments in non-invasive lesioning using stereotactic radiosurgery and transcranial magnetic resonance-guided focused ultrasound, and advances of neurophysiological and neuroimaging modalities may bolster further clinical applications of psychiatric neurosurgery, improve its results, and allow for individually selected treatment strategies tailored to specific needs of the patient.

Vagal nerve stimulation for treatment-resistant depression: An update on mechanism of action and clinical use.

Among few available therapeutic options for patients with treatment-resistant depression, chronic stimulation of the vagus nerve using an implanted stimulator, the so-called vagal nerve stimulation (VNS), has been shown to be both effective and safe technique, based on the multitude of studies. While the exact degree of its efficacy remains a subject of discussion, the strong scientific basis and a large body of data from completed and ongoing clinical trials suggest that VNS remains a viable option for those patients, who have exhausted less invasive treatment approaches.