Development Of Deep Brain Stimulation Research Articles

Machine learning: a new direction for assisting the application of deep brain stimulation

In recent years, deep brain stimulation has been widely used in the treatment of various difficult diseases of the nervous system. The rapid development of machine learning algorithms has greatly promoted the application and development of deep brain stimulation. Machine learning can help in preoperative screening of surgical candidates, outcome prediction and surgical planning. It can assist target localization during operation. More importantly, the local field potential signals recorded by macroscopic electrodes can be analyzed in real time after surgery, which provides a basis for the development of a closed-loop stimulation system. Of course, the application of machine learning also has its limitations and challenges, such as dimensionality reduction of high-dimensional data, development and validation of new models and etc, which need to be further explored and improved.

Role of Gamma Knife Radiosurgery in the Management of Functional Disorders - A Literature Review.

Role of radiosurgical lesioning in functional disorders has been restricted because of development of deep brain stimulation (DBS) techniques. However, many elderly patients with comorbidities and coagulation abnormalities may not be eligible for DBS. Radiosurgical lesioning may be a good alternative in such cases. The objective of the study was to review the role of radiosurgical lesioning for functional targets in common functional disorders. Literature reports pertaining to common disorders were reviewed. Disorders included are tremors (essential tremors, tremor-dominant Parkinson's disease [PD], multiple sclerosis [MS] related refractory tremors), Parkinson's disease (for rigidity, bradykinesia, drug-induced dyskinesias), dystonia, and obsessive-compulsive disorder (OCD). The most commonly performed procedure was ventral intermediate nucleus (VIM) lesioning for essential tremors and tremor-dominant PD, with about 90% patients demonstrating improvement. Intractable OCD with 60% responders is a promising indication. Other disorders are less commonly treated, with dystonia being the least commonly treated entity. Subthalamic nucleus (STN) and globus pallidus interna/posteroventral pallidum (GPi) lesioning are very rarely reported, and the available literature suggests caution due to high rates of adverse effects. Outcomes for radiosurgical lesioning for essential tremors (VIM) and OCD (anterior limb of internal capsule [ALIC]) are encouraging. Radiosurgical lesioning offers a lower immediate risk profile in patient population with several comorbidities; however, long-term adverse effects due to radiation are a concern, especially for STN and GPi lesioning.

The History of Stereotactic and Functional Neurosurgery in Zurich

Zurich's stereotactic and functional neurosurgery (SFN) has a rich legacy beginning with the studies of the physiologist and Nobel prize winner Walter Rudolf Hess over the efforts of the neurosurgeons Hugo Krayenbühl and Mahmut Gazi Yaşargil up to the work of the functional surgeon Jean Siegfried and the modern era of SFN and neuromodulation. A comprehensive review and synthesis of data acquired from institutional archives and personal interviews as well as from journal articles, included references, proceedings of scientific meetings, staff biographies, and book publications were performed to gain insight into Zurich's long journey toward contemporary SFN and to highlight its stereotactic and functional history with special reference to the development of deep brain stimulation. Zurich's history of medicine includes decisive moments for the fundamentals and development of SFN. After an early period of innovation and research later followed by a long time of clinical application during the 20th century, it became quieter at the turn of the century. Since the end of the 2000s, an impressive renaissance occurred in Zurich that revived its rich SFN tradition.

Animal Models and Animal Experimentation in the Development of Deep Brain Stimulation: From a Specific Controversy to a Multidimensional Debate.

In this article, we explore a specific controversy about animal experimentation and animal models in the recent history of deep brain stimulation (DBS), and we question its ramifications. DBS development intertwines clinical practice with fundamental research and stands at the crossroads of multiple legacies. We take up the various issues and controversies embedded in this rarely addressed dispute, from a standpoint that combines socio-anthropological and legal aspects. Our starting point is a debate on the role of animal experimentation in the development of DBS between Jarrod Bailey, a researcher promoting the abolition of animal experimentation, and Alim Louis Benabid, Marwan Hariz, and Mahlon DeLong, three key figures in the area of DBS and neuroscience. By clarifying the positions of the different protagonists and retracing the issues raised in these discussions, our objective is to show how this specific debate has extended from its initial space and how it provides an object of study with heuristic scope. We first present this partially polemic discussion about the history of DBS, and its link with a more general debate on the validity and use of animal models and the need for animal experiments. Then, we raise the issue of the relations and interactions between experiments on animals and on humans in the logics of biomedical innovation. The third step is to situate the discussion within the wider framework of opposition towards animal experimentation and the promotion of animal’ rights. Finally, combining these interweaved issues, possible implications emerge regarding the future of DBS. We show that behind these several controversies lie the question of translational research and the model of medicine upheld by DBS. We describe how the technology contributes to blurring the lines between research (fundamental, preclinical and clinical research) and care, as well as between humans and animals as substrates and objects of knowledge. The dynamics of DBS future development might then become a point of convergence for neuroscientists and animal rights defenders’ interests.

Chapter 21 - Cingulate-mediated depressive symptoms in neurologic disease and therapeutics

The depressive syndrome includes a number of symptoms that are clinically diverse. Research in the past decades has consistently demonstrated that the cingulate cortex plays an essential role in these manifestations. With anatomic studies initially showing volumetric changes, followed by the insights that functional imaging and physiology contributed to neuroscience and psychiatry, the distinct areas of the cingulate subdivisions were seen to have unique contributions. The subcallosal cingulate, with its functional responsivity to mood states and to antidepressant therapies, has been identified as a central node within the mood regulation network. In this chapter, detailed descriptions of the anatomic and functional changes that are seen in depression will be discussed. Finally, a focus on the development of deep brain stimulation in the subcallosal cingulate area will be used to emphasize the conceptualization of a network model with the cingulate as a hub, where engagement of remote areas of the depression network is needed to treat depression.

History of psychosurgery at Sainte-Anne Hospital, Paris, France, through translational interactions between psychiatrists and neurosurgeons.

Sainte-Anne Hospital is the largest psychiatric hospital in Paris. Its long and fascinating history began in the 18th century. In 1952, it was at Sainte-Anne Hospital that Jean Delay and Pierre Deniker used the first neuroleptic, chlorpromazine, to cure psychiatric patients, putting an end to the expansion of psychosurgery. The Department of Neuro-psychosurgery was created in 1941. The works of successive heads of the Neurosurgery Department at Sainte-Anne Hospital summarized the history of psychosurgery in France. Pierre Puech defined psychosurgery as the necessary cooperation between neurosurgeons and psychiatrists to treat the conditions causing psychiatric symptoms, from brain tumors to mental health disorders. He reported the results of his series of 369 cases and underlined the necessity for proper follow-up and postoperative re-education, illustrating the relative caution of French neurosurgeons concerning psychosurgery. Marcel David and his assistants tried to follow their patients closely postoperatively; this resulted in numerous publications with significant follow-up and conclusions. As early as 1955, David reported intellectual degradation 2 years after prefrontal leucotomies. Jean Talairach, a psychiatrist who eventually trained as a neurosurgeon, was the first to describe anterior capsulotomy in 1949. He operated in several hospitals outside of Paris, including the Sarthe Psychiatric Hospital and the Public Institution of Mental Health in the Lille region. He developed stereotactic surgery, notably stereo-electroencephalography, for epilepsy surgery but also to treat psychiatric patients using stereotactic lesioning with radiofrequency ablation or radioactive seeds of yttrium-90. The evolution of functional neurosurgery has been marked by the development of deep brain stimulation, in particular for obsessive-compulsive disorder, replacing the former lesional stereotactic procedures. The history of Sainte-Anne Hospital's Neurosurgery Department sheds light on the initiation-yet fast reconsideration-of psychosurgery in France. This relatively more prudent attitude toward the practice of psychosurgery compared with other countries was probably due to the historically strong collaboration between psychiatrists and neurosurgeons in France.

Effects of Deep Brain Stimulation on Autonomic Function.

Over the course of the development of deep brain stimulation (DBS) into a well-established therapy for Parkinson’s disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target.

Connections of the dorsolateral prefrontal cortex with the thalamus: a probabilistic tractography study.

The dorsolateral prefrontal cortex (DLPFC) is a cortical area involved in higher cognitive functions, and at the center of the pathophysiology of mental disorders such as depression and schizophrenia. Considering these major roles and the development of deep brain stimulation, the object of this study was to assess the patterns of connectivity of the DLPFC with its main subcortical relay, the thalamus, with the help of probabilistic tractography. We used T1-weighted imaging and diffusion data from 18 subjects from the Human Connectome Project. The DLPFC and the thalamic nuclear groups were defined using the combination of atlases, sulcogyral anatomy and cytoarchitectonic data. Probabilistic tractography was performed from the DLPFC to the thalamus. The patterns of connectivity were assessed using two indexes: (1) a connectivity index (CI) which evaluate the strength of connection (2) an asymmetry index (AI) which explores the inter-hemispheric variability. The analysis of CI showed significant connections between the DLPFC and the dorsomedial nuclei (p<0.05), the anterior nuclear groups (p<0.05) and the right centromedian nucleus (p<0.05). No link was found between handedness and AI (p>0.05). Most of subjects (15/18) had a right predominance of the thalamo cortical connections of the DLPFC. Probabilistic tractography appears as a valuable non-invasive tool for the exploration of the thalamocortical connections between the dorsolateral prefrontal cortex and thalamic nuclei. It allowed to show different inter-hemispheric patterns of connectivity, and highlighted the centromedian nucleus as a key subcortical relay of executive functions.

Oscillations in pedunculopontine nucleus in Parkinson's disease and its relationship with deep brain stimulation.

The recent development of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) for the treatment of parkinsonian patients, particularly those in advanced stages with axial symptoms, has ignited interest into the study of this brain nucleus. In contrast to the extensively studied alterations of neural activity that occur in the basal ganglia in Parkinson’s disease (PD), our understanding of the activity of the PPN remains insufficient. In recent years, however, a series of studies recording oscillatory activity in the PPN of parkinsonian patients have made important findings. Here, we briefly review recent studies that explore the different kinds of oscillations observed in the PPN of parkinsonian patients, and how they underlie the pathophysiology of PD and the efficacy of PPN-DBS in these disorders.

Profile of Mahlon DeLong and Alim Benabid, 2014 Lasker-DeBakey Medical Research awardees.

Mahlon DeLong and Alim Benabid are the recipients of the 2014 Lasker Award for their work leading to the development of deep brain stimulation as a treatment for Parkinson’s disease (PD). Their work is a tribute to how experimental laboratory research can lead to the development of new therapies for neurological diseases.

2014 Lasker-DeBakey Clinical Medical Research Award.

2014 Lasker-DeBakey Clinical Medical Research Award.

A critical reflection on the technological development of deep brain stimulation (DBS)

Since the translational research findings of Benabid and colleagues which partly led to their seminal paper regarding the treatment of mainly tremor-dominant Parkinson patients through thalamic high-frequency-stimulation (HFS) in 1987, we still struggle with identifying a satisfactory mechanistic explanation of the underlying principles of deep brain stimulation (DBS). Furthermore, the technological advance of DBS devices (electrodes and implantable pulse generators, IPG’s) has shown a distinct lack of dynamic progression. In light of this we argue that it is time to leave the paleolithic age and enter hellenistic times: the device-manufacturing industry and the medical community together should put more emphasis on advancing the technology rather than resting on their laurels.

Alim-Louis Benabid and Mahlon DeLong win the 2014 Lasker~DeBakey Clinical Medical Research Award.

The 2014 Lasker~DeBakey Clinical Medical Research Award recognizes the extraordinary efforts of two physician-scientists, Alim-Louis Benabid and Mahlon DeLong, whose combined work paved the way for the clinical use of deep brain stimulation to treat Parkinson’s disease (Figure ​(Figure1).1). Alim-Louis Benabid, a neurosurgeon at the University Hospital of Grenoble, France, pioneered the concept that high-frequency electrical stimulation in the brain could effectively treat tremors in patients. Neurologist Mahlon DeLong’s research provided the first roadmap of the circuitry of the basal ganglia, a set of structures beneath the cerebral hemispheres, and showed that a portion of the subthalamic nucleus is critically involved in relaying signals that influence movement. Their groundbreaking observations led to the development of deep brain stimulation of the subthalamic nucleus to treat dyskinesia in Parkinson’s disease patients. Figure 1 The recipients of the 2014 Lasker~DeBakey Clinical Medical Research Award. Parkinson’s disease is a progressive neurodegenerative disorder characterized by movement abnormalities that are triggered by the loss of dopamine-producing cells in a region of the midbrain known as the substantial nigra. Patients experience a range of symptoms including tremor, rigidity, difficulty in initiating movement, and slowness of movement (bradykinesia). While treatment with levodopa, a precursor of dopamine, can ameliorate symptoms, the medication itself may cause involuntary movements (dyskinesias) and motor fluctuation in patients as the disease progresses. Based on the work of Mahlon Delong and others in the field, we now know that several of the symptoms of Parkinson’s disease are caused by abnormal activity of neurons in the motor pathways of the basal ganglia, including the subthalamic nucleus. This understanding, coupled with the high-frequency deep brain stimulation technique that was developed by Alim-Louis Benabid, provided a new clinical approach that can dramatically improve the quality of life for Parkinson’s disease patients.

Deep brain stimulation and autonomic control

What is the topic of this review? This article reviews data from studies on human participants and animal models showing how electrical stimulation in deep brain structures (deep brain stimulation) can influence autonomic function. What advances does it highlight? Focusing on the control of the cardiovascular system and bladder function, it highlights the potential for development of deep brain stimulation as a new treatment option for patients with autonomic dysfunction. Deep brain stimulation (DBS) in humans has come of age as a tool to treat movement disorders including Parkinson's disease tremor and dystonia as well as a panoply of other disease states including headache, epilepsy, obesity, eating disorders, depression, obsessive compulsive disorder, Tourette's syndrome, addiction and chronic pain. Increasingly, practitioners of DBS are reporting autonomic side effects, which intriguingly, sometimes result in improved autonomic function. Focussing on the effects of stimulation at periaqueductal and periventricular sites on cardiovascular function and control of micturition, this review shows that data obtained from studies in animals is now being confirmed in humans. Lowering of blood pressure and improved baroreflex function can be evoked in humans by DBS at these midbrain sites as well as increased bladder capacity. The findings highlight the tantalizing possibility that DBS could be developed for treatment of dysfunctional autonomic states in humans.

The Development of Deep Brain Stimulation for Movement Disorders

The development of deep brain stimulation has revolutionized care for patients with movement disorders like Parkinson’s disease. Many areas of science contributed to this technology but one area, the use of animal models, has been cited as vital. We review these claims as well as the history of the discoveries that eventually led to deep brain stimulation in an attempt to ascertain: 1) the contributions of animal models; 2) the contributions from humanbased research and observation; and the role of advances in the engineering, physics, and computer science. We distinguish between advances and discoveries that were, or at least appear to be, dependent on animal models and those where animals were involved but that could have occurred, and/or were occurring simultaneously, with humanbased research. We conclude that animal-based research played a role in defining gross anatomy in the 19th and early 20th centuries, but that essentially all subsequent advances were human-based or secondary to advances in the physical and applied sciences. This has historical, funding, and ethical implications as the development of deep brain stimulation is cited as an example of the importance of animal-based research and a reason for continued social and financial support of animal models in general as opposed to clinical research, other human-based research modalities, and the various disciplines of the physical and applied sciences.

Deep Brain Stimulation for Movement Disorders – A History of Success and Challenges to Conquer

Deep Brain Stimulation for Movement Disorders – A History of Success and Challenges to Conquer

Existence and robustness of phase-locking in coupled Kuramoto oscillators under mean-field feedback

Motivated by the recent development of Deep Brain Stimulation (DBS) for neurological diseases, we study a network of interconnected oscillators under the influence of mean-field feedback and analyze the robustness of its phase-locking with respect to general inputs. Under standard assumptions, this system can be reduced to a modified version of the Kuramoto model of coupled nonlinear oscillators. In the first part of the paper we present an analytical study on the existence of phase-locked solutions under generic interconnection and feedback configurations. In particular we show that, in general, no oscillating phase-locked solutions can co-exist with any non-zero proportional mean-field feedback. In the second part we prove some robustness properties of phase-locked solutions (namely total stability). This general result allows in particular to justify the persistence of practically phase-locked states if sufficiently small feedback gains are applied, and to give explicit necessary conditions on the intensity of a desynchronizing mean-field feedback. Furthermore, the Lyapunov function used in the analysis provides a new characterization of the robust phase-locked configurations in the Kuramoto system with symmetric interconnections.

Existence of phase-locking in the Kuramoto system under mean-field feedback

AbstractMotivated by the development of Deep Brain Stimulation (DBS) for neurological diseases, we study a network of interconnected oscillators under the influence of a proportional mean-field feedback. Under standard assumptions, this system can be reduced to a modified version of the Kuramoto model of coupled nonlinear oscillators. In the first part of the paper we show that, in general, no oscillating phase-locked solution can co-exist with any non-zero feedback gain. In the second part we propose a new characterization of phase-locking between Kuramoto oscillators. In particular we derive a fixed point equation for the Kuramoto system under mean-field feedback and we show how, generically, the “standard” (with zero feedback gain) Kuramoto fixed point equation is locally invertible in terms of the implicit function theorem.

Separating Hope from Hype:Some Ethical Implications of the Development of Deep Brain Stimulation in Psychiatric Research and Treatment

Major depression is the most common serious brain disorder with a lifetime prevalence of up to 17%. Despite numerous options currently available for the treatment of depression, ~2 million people in the United States may experience an inadequate response to treatment (treatment-resistant depression [TRD]) at some point in their lives. The definition of TRD is variable, ranging from a failure to respond to two or more trials of antidepressant monotherapy to a failure to respond to four or more trials of different antidepressant therapies, including augmentation, combination therapy, and electroconvulsive therapy. It has been reported that as many as one-third of patients experience only a partial response to initial therapy, while nearly one-fifth are considered nonresponders. In addition to the obvious quality of life issues for the patient with TRD, the economic cost of TRD is significant. Annual healthcare costs increase significantly for patients with TRD with each successive change in antidepressant medication. Early in treatment (two medication changes), the annual costs are &lt;$7,000/Year. By the eighth medication change, annual costs double to nearly $14,000/year.There is a well-documented need for better long-term treatments for TRD, as witnessed by multiple efforts to establish treatment algorithms and best treatment steps when first and subsequent treatment measures prove inadequate. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which analyzed outcome following several standardized antidepressive treatment steps, reported that 33% of patients did not respond even after four evidence-based treatment steps. A substantial proportion of patients are inadequately treated and some of these will go on to suffer from chronic, debilitating, and life-threatening symptoms.

Thalamic nuclei activity in idiopathic generalized epilepsy

Idiopathic generalized epilepsies (IGE) are characterized by specific EEG changes including 3- to 5-Hz generalized spike-and-wave discharges. The thalamus and its cortical interactions are considered essential in the production and propagation of spike-and-wave discharges. In animal studies, corticoreticular and limbic system property changes have been observed in absence seizures and during spike-and-wave discharges and suggest the involvement of different types of thalamic nuclei. With the development of deep brain stimulation in epilepsy, the role of the thalamic nuclei needs to be clarified in human IGE. Ten patients with IGE were recorded using 3T EEG-fMRI during spike-and-wave discharges. Hemodynamic response functions were calculated for 4 regions of interest corresponding to the anterior thalamic and centromedian and parafascicular (CM-Pf) nuclei of each thalamus. The time to peak of the hemodynamic response function was compared within thalamic structures (left compared to right) and between structures (anterior thalamic compared to CM-Pf nucleus). CM-Pf and anterior nucleus are both activated during GSWDs. However, the positive time to peak in the CM-Pf (4.4 +/- 2.5 s) occurred significantly earlier than in the anterior nucleus (7.6 +/- 3.2 s). We demonstrated in humans the involvement of the centromedian and parafascicular part of the corticoreticular system and of the anterior nucleus part of the limbic system during generalized spike-and-wave discharges. The different time courses suggest that the posterior intralaminar nuclei may be involved in epileptic discharge initiation or early propagation, while the anterior nucleus may only play a role in its maintenance. These results may help to understand the clinical effect of deep brain stimulation within thalamic nuclei in intractable idiopathic generalized epilepsy patients.