Action Of Deep Brain Stimulation Research Articles

One View of the Current State of Understanding in Basal Ganglia Pathophysiology and What is Needed for the Future.

Deep Brain Stimulation (DBS), arguably, is the most dramatic development in movement disorders since the levodopa for Parkinson’s disease. Yet, its mechanisms of action of DBS are unknown. However, DBS related research already has demonstrated that current concepts of basal ganglia pathophysiology are wrong. Specifically, the notion that over-activity of the globus pallidus interna causes parkinsonism, the basis for the most current theories, is no longer tenable. The development of any new theory will be aided by an understanding of how current theories are wrong and why have these flawed theories persist. Many of the problems of current theories are more matters of inference, assumptions, presumptions, and the accepted level of ambiguity than they are of fact. Consequently, it is imperative that these issues be addressed. Just as the inappropriate use of a tool or method is grounds for criticism, methods of reasoning are tools that can be used inappropriately and should be subject to discussion just as misuse of any other tool. Thorough criticism can provide very important lesions though the process could be mistaken as harsh or personal; neither is the case here. At the least, such analyzes can point to potential pitfalls that could be avoided in the development of new theories. As will be discussed, theories are important for the development of therapies but perhaps most important, for the acceptance of new therapies, as was the case for the recent resurgence of interest in surgical therapies.

Automatic removal of high-amplitude stimulus artefact from neuronal signal recorded in the subthalamic nucleus

Over the last few years, deep brain stimulation ( DBS) with targets such as the subthalamic nucleus or the pallidum were found to be beneficial in the treatment of Parkinson's disease and dystonia. The investigation of the mechanisms of action of DBS by recording concomitant neural activities in basal ganglia is hampered by the large stimulus artefacts ( SA). Approaches to remove the SA with conventional filters, or other conventional digital methods, are not always effective due to the significant overlap between the spectral contents of the neuronal signal and the SA. Thus, such approaches may produce a significant residual SA or alter the neuronal signal dynamics by removing its frequency contents. In this work, we propose a method based on an on-line SA template extraction and on the Ensemble empirical mode decomposition ( EEMD) to automatically detect and remove the dynamics of the SA without altering the embedded dynamics of the neuronal signal during stimulation. The results, based on real signals recorded in the subthalamic nucleus during Motor cortex stimulation ( MCS) experiments, show that this technique, which may be applied on-line, effectively identifies, separates and removes the SA, and uncovers neuronal potentials superimposed on the artefact.

Development of a Large Animal Model for Investigation of Deep Brain Stimulation for Epilepsy

Background/Objectives: To better understand the mechanism of action of deep brain stimulation (DBS) for epilepsy and to investigate implantable device features, it is desirable to have a large animal model to evaluate clinical-grade systems. This study assessed the suitability of an ovine model of epilepsy for this purpose. Methods: Animals were anesthetized for surgery and 1.5 T MRIs collected. Unilateral anterior thalamic DBS leads, hippocampal depth electrodes and catheters were implanted using a frameless stereotactic system. Evoked responses and local field potentials were collected and stored for off-line analysis. Results: Despite limited neuroanatomic information for this species, it was possible to reliably implant leads into the target structures using MR-guided techniques. Stimulation of these regions produced robust evoked potentials within this circuit that were dependent on stimulus location and parameters. High-frequency thalamic DBS produced a clear inhibition of both spontaneous and penicillin-induced ictal activity in the hippocampus which far outlasted the duration of the stimulation. Conclusions: These preliminary results suggest that the sheep model may be useful for further investigation of DBS for epilepsy. The demonstration of marked suppression of network excitability with high-frequency stimulation supports a potential therapeutic mechanism for this DBS therapy.

Deep Brain Recordings

Depth recordings from human subcortical structures have improved our knowledge of human brain circuitries and provided better understanding of the effects and mechanism of action of deep brain stimulation. Two types of signals can be recorded: single unit spikes and local field potentials (LFP). The basal ganglia (BG) are particularly well suited for deep brain recordings and here we review how the oscillatory activities recorded in these structures helped improve our understanding of the sensorimotor brain functions in particular, along with cognitive and emotional-motivational. The oscillations may be classified by frequency into bands at 60 Hz. The best characterized band is the 8–30 Hz and existing evidence suggests that it is antikinetic and inversely related to motor processing. On the other hand, accumulating evidence suggests that the > 60 Hz band may be related to normal function.

Optimizing a Rodent Model of Parkinson's Disease for Exploring the Effects and Mechanisms of Deep Brain Stimulation

Deep brain stimulation (DBS) has become a treatment for a growing number of neurological and psychiatric disorders, especially for therapy-refractory Parkinson's disease (PD). However, not all of the symptoms of PD are sufficiently improved in all patients, and side effects may occur. Further progress depends on a deeper insight into the mechanisms of action of DBS in the context of disturbed brain circuits. For this, optimized animal models have to be developed. We review not only charge transfer mechanisms at the electrode/tissue interface and strategies to increase the stimulation's energy-efficiency but also the electrochemical, electrophysiological, biochemical and functional effects of DBS. We introduce a hemi-Parkinsonian rat model for long-term experiments with chronically instrumented rats carrying a backpack stimulator and implanted platinum/iridium electrodes. This model is suitable for (1) elucidating the electrochemical processes at the electrode/tissue interface, (2) analyzing the molecular, cellular and behavioral stimulation effects, (3) testing new target regions for DBS, (4) screening for potential neuroprotective DBS effects, and (5) improving the efficacy and safety of the method. An outlook is given on further developments of experimental DBS, including the use of transgenic animals and the testing of closed-loop systems for the direct on-demand application of electric stimulation.

Effects of DBS on auditory and somatosensory processing in Parkinson's disease

Motor symptoms of Parkinson's disease (PD) can be relieved by deep brain stimulation (DBS). The mechanism of action of DBS is largely unclear. Magnetoencephalography (MEG) studies on DBS patients have been unfeasible because of strong magnetic artifacts. An artifact suppression method known as spatiotemporal signal space separation (tSSS) has mainly overcome these difficulties. We wanted to clarify whether tSSS enables noninvasive measurement of the modulation of cortical activity caused by DBS. We have studied auditory and somatosensory-evoked fields (AEFs and SEFs) of advanced PD patients with bilateral subthalamic nucleus (STN) DBS using MEG. AEFs were elicited by 1-kHz tones and SEFs by electrical pulses to the median nerve with DBS on and off. Data could be successfully acquired and analyzed from 12 out of 16 measured patients. The motor symptoms were significantly relieved by DBS, which clearly enhanced the ipsilateral auditory N100m responses in the right hemisphere. Contralateral N100m responses and somatosensory P60m responses also had a tendency to increase when bilateral DBS was on. MEG with tSSS offers a novel and powerful tool to investigate DBS modulation of the evoked cortical activity in PD with high temporal and spatial resolution. The results suggest that STN-DBS modulates auditory processing in advanced PD. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc.

Hippocampal deep brain stimulation induces decreased rCBF in the hippocampal formation of the rat

Deep brain stimulation (DBS) is a promising experimental approach to treat various neurological disorders. However, the optimal stimulation paradigm and the precise mechanism of action of DBS are unknown. Neuro-imaging by means of Single Photon Emission Computed Tomography (SPECT) is a non-invasive manner of evaluating regional cerebral blood flow (rCBF) changes, which are assumed to reflect changes in neural activity. In this study, rCBF changes induced by hippocampal DBS are evaluated by subtraction analysis of stimulation on/off using small animal µSPECT of the rat brain. Rats (n=13) were implanted with a multi-contact DBS electrode in the right hippocampus and injected with 10mCi of HMPAO-Tc99m during application of various hippocampal DBS paradigms and amplitudes and during sham stimulation. Subtraction analysis revealed that hippocampal DBS caused a significant decrease in relative rCBF, both in the ipsi- (the side of the implanted electrode) and contralateral hippocampus. Hypoperfusion spread contralaterally with increasing stimulation amplitude. A clear distinction in spatial extent and intensity of hypoperfusion was observed between stimulation paradigms: bipolar Poisson Distributed Stimulation induced significant hypoperfusion ipsi- and contralaterally (p<0.01), while during other stimulation paradigms, rCBF-changes were less prominent. In conclusion, small animal µSPECT allows us to draw conclusions on the location, spatial extent and intensity of the hypoperfusion observed in the ipsi- and contralateral hippocampus, induced by hippocampal DBS. Our study demonstrates an innovative approach to visualize the effects of DBS and can be a useful tool in evaluating the effect of various stimulation paradigms and target areas for DBS.

Local glutamate release in the rat ventral lateral thalamus evoked by high-frequency stimulation

Thalamic deep brain stimulation (DBS) is proven therapy for essential tremor, Parkinson's disease and Tourette's syndrome. We tested the hypothesis that high-frequency electrical stimulation results in local thalamic glutamate release. Enzyme-linked glutamate amperometric biosensors were implanted in anesthetized rat thalamus adjacent to the stimulating electrode. Electrical stimulation was delivered to investigate the effect of frequency, pulse width, voltage-controlled or current-controlled stimulation, and charge balancing. Monophasic electrical stimulation-induced glutamate release was linearly dependent on stimulation frequency, intensity and pulse width. Prolonged stimulation evoked glutamate release to a plateau that subsequently decayed back to baseline after stimulation. Glutamate release was less pronounced with voltage-controlled stimulation and not present with charge balanced current-controlled stimulation. Using fixed potential amperometry in combination with a glutamate bioprobe and adjacent microstimulating electrode, the present study has shown that monophasic current-controlled stimulation of the thalamus in the anesthetized rat evoked linear increases in local extracellular glutamate concentrations that were dependent on stimulation duration, frequency, intensity and pulse width. However, the efficacy of monophasic voltage-controlled stimulation, in terms of evoking glutamate release in the thalamus, was substantially lower compared to monophasic current-controlled stimulation and entirely absent with biphasic (charge balanced) current-controlled stimulation. It remains to be determined whether similar glutamate release occurs with human DBS electrodes and similar charge balanced stimulation. As such, the present results indicate the importance of evaluating local neurotransmitter dynamics in studying the mechanism of action of DBS.

S01-03 - The search for fast acting antidepressant

ObjectivesMany researches conducted in antidepressant therapeutics aimed to obtain a reduction of the delay of action of the drugs. Until now, neither antidepressant per se, nor potentialization strategies (5HT1A agonists), have obtained some significant results. Deep Brain Stimulation (DBS) techniques used in resistant and severe depressive patients have shown a rapid improvement of several patients from the first week of treatment. In that sense, mechanism of action of DBS could represent a model for improving the duration of action of antidepressant.MethodsComparison of data extracted from clinical trials using antidepressants and those obtained from brain electro stimulation techniques.ResultsThe current data do not allow to conclude to a faster action of DBS technique in depression. However, results obtained from randomized control trials will provide some more powerful data.Conclusionsa better comprehension of the mechanism of action of DBS is crucial for the improvement of the action rapidity of new antidepressants.

Acute Depression and Suicidal Attempt Following Lowering the Frequency of Deep Brain Stimulation

Back to table of contents Previous article Next article LETTERFull AccessAcute Depression and Suicidal Attempt Following Lowering the Frequency of Deep Brain StimulationNahla A. Mahgoub M.D.Nabil Kotbi M.D.,Nahla A. Mahgoub M.D.Search for more papers by this authorNabil Kotbi M.D.Search for more papers by this author,Published Online:1 Oct 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Deep brain stimulation (DBS) is a neurosurgical intervention that enables deep brain structures to be stimulated electrically by an implanted pacemaker. 1 The method was initially developed for movement disorders in several target areas such as the thalamus, pallidum, and subthalamic nucleus. 2 It has now also been extended to other neuropsychiatric conditions and has shown some promising results in patients suffering from profound depression. 3 In depression, dysfunction of the limbic-cortico-striatal-pallidal-thalamic pathways has been proposed. 4 – 6 Although the exact mechanism of action of DBS remains elusive, stimulation of selected areas implicated in mood regulation may have therapeutic potential or lead to adverse consequences due to modulation of circuits related to depression. 5Case ReportWe report a case of a 66-year-old male who was diagnosed with Parkinson’s disease 20 years ago and was implanted with a subthalamic deep brain stimulation treatment system bilaterally for the last 8 years. He continued taking oral Parkinson’s disease medication. Subsequently, his dyskinesia and movements markedly improved. There were no psychiatric adverse events experienced following DBS implantation. Four years later, he developed a major depressive episode after his retirement and responded well to an adequate trial of bupropion. He did not report prior history of suicidal thoughts or attempts and followed up regularly with a psychiatrist.Reportedly, for the last 5 years his neurologist had been changing the frequency of the brain stimulation through the implanted devices to negate the patient’s changing dyskinetic symptoms and disease progression. The frequency of the stimulation was lowered from 185 Hz to 60 Hz. Within 24 hours of lowering the frequency, the patient developed acute depression and made a serious suicide attempt by overdosing on sleeping pills. He was admitted to an intensive care unit and transferred to a psychiatric facility. His neurologist reportedly increased the frequency while the patient was in the hospital, and accordingly, his depressive feelings improved considerably over the next few days with complete remission of his suicidal thoughts.Discussion Several case reports have been published showing the potential of deep brain stimulation in the treatment of depression. 7 Our case demonstrates the risk of suicide when lowering the frequency of the stimulation. Patients undergoing an adjustment to the stimulation parameters according to their changing motor symptoms should be prescreened and assessed thoroughly for suicide risk prior to the changes. 7 Additionally, patients should be monitored closely for suicidal behavior after the changes. 7 Patients at high risk for suicide should be excluded from deep brain stimulation surgery. 8Department of Psychiatry, Weill Medical College of Cornell University, White Plains, NY

PET Functional Imaging of Deep Brain Stimulation in Movement Disorders and Psychiatry

Deep brain stimulation (DBS) represents a major advance in the treatment of various severe movement disorders or neuropsychiatric diseases. Our understanding of the mechanism of action of this surgical treatment has greatly benefited from functional imaging studies. Most of these studies have been conducted in patients with Parkinson's disease (PD) treated by bilateral subthalamic nucleus (STN) stimulation. These studies have notably underlined the fact that STN stimulation influences motor, limbic, or associative cortical-subcortical loops in various (sometimes contradictory) ways. We present an up-to-date review of the information provided by functional imaging studies in surgery for PD, dystonia, tremor, as well as in psychiatric disorders such as depression or obsessive-compulsive disorder. On the basis of this information, proposed mechanisms of action of DBS are discussed, as well as the need for additional approaches such as improved anatomical localization of the contact used for stimulation or a better understanding of the electrical distribution around the electrode.

Rapid response of parkinsonian tremor to STN‐DBS changes: Direct modulation of oscillatory basal ganglia activity?

Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) has proved to be effective for tremor and other cardinal symptoms in Parkinson's disease (PD), the precise mechanisms of action of DBS are still unclear. We analyzed the time course of resting tremor amplitude and frequency during discontinuation and subsequent reinitiation of STN-DBS in nine PD patients, using a computerized three-dimensional motion analysis combined with surface electromyography. Following discontinuation of STN-DBS, resting tremor amplitude rapidly increased, reaching maximum amplitude after 2 min (mean +/- 95%CI: 34.3 +/- 13.8 mm; P < 0.01), subsequently stabilizing at a medium level. Reinitiation of stimulation after 30 min resulted in rapid, nearly complete suppression of tremor activity within 1 min (1.4 +/- 1.3 mm; P < 0.01) and, furthermore, increased tremor frequency within a few seconds in seven of nine patients. These findings support the hypothesis that STN-DBS acts by direct interference with the neurotransmission of basal ganglia networks involved in tremor.

Analysis of the Mechanism of Action of Deep Brain Stimulation Using the Concepts of Dither Injection and the Equivalent Nonlinearity

Deep brain stimulation (DBS) is a widely applied clinical procedure for the alleviation of pathological neural activity, and is particularly effective in suppressing the symptoms of Parkinson's disease. The mechanisms of action of DBS remain to be fully elucidated. In this paper, we present an application to DBS of the concepts of dither injection and equivalent nonlinearity from the theory of nonlinear feedback control systems. We propose that this model provides a framework for understanding the mechanism by which an injected high-frequency signal can quench undesired oscillations in closed-loop systems of interacting neurons in the brain.

Electrical Stimulation for the Treatment of Epilepsy

Despite the advent of new pharmacological treatments and the high success rate of many surgical treatments for epilepsy, a substantial number of patients either do not become seizure-free or they experience major adverse events (or both). Neurostimulation-based treatments have gained considerable interest in the last decade. Vagus nerve stimulation (VNS) is an alternative treatment for patients with medically refractory epilepsy, who are unsuitable candidates for conventional epilepsy surgery, or who have had such surgery without optimal outcome. Although responder identification studies are lacking, long-term VNS studies show response rates between 40% and 50% and long-term seizure freedom in 5% to 10% of patients. Surgical complications and perioperative morbidity are low. Research into the mechanism of action of VNS has revealed a crucial role for the thalamus and cortical areas that are important in the epileptogenic process. Acute deep brain stimulation (DBS) in various thalamic nuclei and medial temporal lobe structures has recently been shown to be efficacious in small pilot studies. There is little evidence-based information on rational targets and stimulation parameters. Amygdalohippocampal DBS has yielded a significant decrease of seizure counts and interictal EEG abnormalities during long-term follow-up. Data from pilot studies suggest that chronic DBS for epilepsy may be a feasible, effective, and safe procedure. Further trials with larger patient populations and with controlled, randomized, and closed-loop designs should now be initiated. Further progress in understanding the mechanism of action of DBS for epilepsy is a necessary step to making this therapy more efficacious and established.

A Tractography Analysis of Two Deep Brain Stimulation White Matter Targets for Depression

Deep brain stimulation (DBS) of the subcallosal cingulate white matter (SCCwm) or anterior limb of the internal capsule (ALIC) may be effective in treating depression. Connectivity patterns of these regions may inform on mechanisms of action for DBS of these targets. Diffusion tensor imaging (DTI) and probabilistic tractography were performed in 13 nondepressed subjects to determine connectivity patterns of SCCwm and ALIC. Tract maps were generated for each target in each subject, and tract voxels were coded as being unique to either target or shared. Group level tract maps were generated by including only those voxels common to at least 10 of 13 (>75%) subjects. The two targets have distinct patterns of connectivity with regions of overlap. The SCCwm showed consistent ipsilateral connections to the medial frontal cortex, the full extent of the anterior and posterior cingulate, medial temporal lobe, dorsal medial thalamus, hypothalamus, nucleus accumbens, and the dorsal brainstem. The ALIC seed, in contrast, demonstrated widespread projections to frontal pole, medial temporal lobe, cerebellum, nucleus accumbens, thalamus, hypothalamus, and brainstem. Common to both targets, albeit through distinct white matter bundles, were connections to frontal pole, medial temporal lobe, nucleus accumbens, dorsal thalamus, and hypothalamus. Connectivity patterns of these two DBS white matter targets suggest distinct neural networks with areas of overlap in regions implicated in depression and antidepressant response.

Latest view on the mechanism of action of deep brain stimulation

How does deep brain stimulation (DBS) applied at high frequency (100 Hz and above, HFS) in diverse points of cortico-basal ganglia thalamo-cortical loops alleviate symptoms of neurological disorders such as Parkinson's disease, dystonia, and obsessive compulsive disorders? Do the effects of HFS stem solely or even largely from local effects on the stimulated brain structure or are they also mediated by actions of HFS on distal structures? Indeed, HFS as an extracellular stimulation is expected to activate subsets of both afferent and efferent axons, leading to antidromic spikes that collide with ongoing spontaneous ones and orthodromic spikes that evoke synaptic responses in target neurons. The present review suggests that HFS interfere with spontaneous pathological patterns by introducing a regular activity in several nodal points of the network. Therefore, the best site of implantation of the HFS electrode may be in a region where the HFS-driven activity spreads to most of the identified, dysrhythmic, neuronal populations without causing additional side effects. This should help tackling the most difficult issue namely, how does the regular HFS-driven activity that dampens the spontaneous pathological one, restore neuronal processing along cortico-basal ganglia-thalamo-cortical loops?

Effects of cobalt and bicuculline on focal microstimulation of rat pallidal neurons in vivo

Deep brain stimulation (DBS) administered in the basal ganglia is an effective therapy for movement disorders; however, the mechanism(s) of action remain poorly understood. Because high-frequency electrical stimulation (HFS) preferentially activates fibers, one hypothesis of DBS action is that local release of transmitters from axon terminals underlies the inhibitory effects on spontaneous spiking observed in human intraoperative recordings. We hypothesize that blocking presynaptic release of transmitters will reduce any stimulation-induced effect and blocking of postsynaptic GABA receptors will reduce the inhibitory effect of HFS. We recorded neuronal responses after short HFS trains (2-37 microA, 0.5 seconds, 300 Hz) delivered through the recording electrode or via an adjacent electrode in 42 single globus pallidus (GP) units of anesthetized rats before and after injection of the synaptic blockers cobalt chloride (100 mM) and bicuculline methiodide (2 microg/microL). Responses to HFS trains were mainly transient ( approximately 350 milliseconds) inhibition of firing, but a late response ( approximately 1-2 seconds) and rebound burst were also found. Excitation was observed in 4 of 43 neurons studied. Neurons with transient inhibition had the response attenuated by 47% after injection of either synaptic blocker, in part supporting the local gamma-aminobutyric acid release hypothesis. Bicuculline methiodide and cobalt attenuated the late response as well as the rebound burst response, but the late inhibitory response was increased by bicuculline methiodide in one case. HFS-induced excitatory responses were not altered by synaptic blockers suggesting direct stimulation of postsynaptic elements of GP neurons. The results indicate HFS induces the local inhibition of ongoing activity of the somal region of GP neurons as well as the stimulation of axons and active dendrites. These observations serve to shed light on the mechanism(s) of DBS.

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

Deep brain stimulation (DBS) is an established treatment for symptoms in movement disorders and is under investigation for symptom management in persons with psychiatric disorders and epilepsy. Nevertheless, there remains disagreement regarding the physiological mechanisms responsible for the actions of DBS, and this lack of understanding impedes both the design of DBS systems for treating novel diseases and the effective tuning of current DBS systems. Currently available data indicate that effective DBS overrides pathological bursts, low frequency oscillations, synchronization, and disrupted firing patterns present in movement disorders, and replaces them with more regularized firing. Although it is likely that the specific mechanism(s) by which DBS exerts its effects varies between diseases and target nuclei, the overriding of pathological activity appears to be ubiquitous. This review provides an overview of changes in motor symptoms with changes in DBS frequency and highlights parallels between the changes in motor symptoms and the changes in cellular activity that appear to underlie the motor symptoms.

The evolution of deep brain stimulation for neuropsychiatric disorders

Deep brain stimulation (DBS) is the most focal method for stimulating the human brain. In contrast to lesions, DBS is nonablative, with the advantages of reversibility and adjustability. Thus, therapeutic effectiveness can be enhanced and stimulation-related side effects minimized during long-term patient management. While DBS is an approved adjunct therapy for severe, medication-refractory movement disorders, it remains investigational in neuropsychiatry. However, experience to date, though limited, suggests that DBS may offer a degree of hope to patients with severe and treatment-resistant neuropsychiatric illness. Thus far, work in obsessive-compulsive disorder (OCD), the first psychiatric condition studied using modern DBS devices, has shown consistently positive results across multiple small-scale studies. Work in treatment-resistant Major Depressive Disorder (MDD) also suggests therapeutic potential in preliminary studies, generating cautious optimism for this indication. With the increase in potential applications, a number of clinical and preclinical research efforts have now focused on understanding the mechanisms of action of DBS. Further development of DBS for these and other illnesses with primarily behavioral symptoms will require thoughtful collaboration among multiple disciplines.

Deep-brain stimulation

Deep-brain stimulation (DBS) is a clinical intervention that has provided remarkable therapeutic benefits for otherwise treatment-resistant movement and affective disorders. The resulting direct causal manipulation of both local and distributed brain networks is not only clinically helpful but can also help to provide novel fundamental insights into brain function. In particular, DBS can be used in conjunction with methods such as local field potentials and magnetoencephalography to map the underlying mechanisms of normal and abnormal oscillatory synchronization in the brain. The precise mechanisms of action for DBS remain uncertain but here we present an overview of the clinical efficacy of DBS, its neural mechanisms and potential future applications.