Mechanisms Of Deep Brain Stimulation Research Articles

Mind over matter: an analysis of the mechanism of deep brain stimulation in the treatment of Parkinson’s Disease

Relevance: In a population of increasing longevity, neurological disorders are becoming more prevalent - placing a large strain on NHS resources and funding, as well as an emotional burden on those affected and their families. One such example is Parkinson’s Disease (PD). This neurodegenerative disorder of the basal ganglia is characterised by a progressive loss of nigrostriatal dopaminergic transmission, commonly presenting as tremor, bradykinesia, rigidity, postural instability, akinesia, and impairments in cognition. Deep brain stimulation (DBS) has proven a successful approach to treating PD despite its mechanism of action being unclear. Summary: Three main problems of counteractive outcomes present when identifying a common mechanism of DBS within targets. Firstly, contrasting actions of DBS are required to explain DBS between targets, such as the GPe and GPi. Secondly, conflicting studies have reported both excitatory and inhibitory action of DBS within the same targets. Finally, the treatment has also paradoxically proven effective in treating hyperkinetic disorders, such as Dystonia. There remains no conclusive model for the treatment’s mechanism. Take Home Messages: To deliver effective treatment and care, it is important for doctors to understand the mechanism of action of procedures they are performing. Hence further investigation into PD aetiology and DBS action is required.

Altered Primary Motor Cortex Neuronal Activity in a Rat Model of Harmaline-Induced Tremor During Thalamic Deep Brain Stimulation.

Although deep brain stimulation (DBS) is a clinically effective surgical treatment for essential tremor (ET), and its neurophysiological mechanisms are not fully understood. As the motor thalamus is the most popular DBS target for ET, and it is known that the thalamic nucleus plays a key role in relaying information about the external environment to the cerebral cortex, it is important to investigate mechanisms of thalamic DBS in the context of the cerebello-thalamo-cortical neuronal network. To examine this, we measured single-unit neuronal activities in the resting state in M1 during VL thalamic DBS in harmaline-induced tremor rats and analyzed neuronal activity patterns in the thalamo-cortical circuit. Four activity patterns – including oscillatory burst, oscillatory non-burst, irregular burst, and irregular non-burst – were identified by harmaline administration; and those firing patterns were differentially affected by VL thalamic DBS, which seems to drive pathologic cortical signals to signals in normal status. As specific neuronal firing patterns like oscillation or burst are considered important for information processing, our results suggest that VL thalamic DBS may modify pathophysiologic relay information rather than simply inhibit the information transmission.

Stimulation-induced side effects after deep brain stimulation - a systematic review.

Deep brain stimulation (DBS) was approved by Food and Drug Administration for Parkinson's disease, essential tremor, primary generalised or segmental dystonia and obsessive-compulsive disorder (OCD) treatment. The exact mechanism of DBS remains unclear which causes side effects. The aim of this review was to assess variables causing stimulation-induced chronic psychiatric/personality-changing side effects. The analysis of scientific database (PubMed, Cochrane Library, EMBASE) was conducted. The included articles had to be research study or case report and DBS to be conducted in therapeutic purposes. The researches with mental disorders in patients' medical histories were excluded. Seventeen articles were used in the review. In the group of movement disorders the characteristic of side effects was strongly related to the placement of the electrode implantation. Tiredness/fatigue was correlated with DBS in thalamus. Implantations in subthalamic nucleus were mostly followed by affective side effects such as depression or suicide. The higher voltage of electrode was connected with more severe depression after implantation. The analysis of affective disorder contained only three articles - two about OCD and one about depression. Forgetfulness and word-finding problems as activities connected with cognition may be an inevitable side effect if obsessive thoughts are to be inhibited. DBS of subthalamic nucleus should be seen as the most hazardous place of implantation. As a result there is a strong need of 'gold standards' based on the connectivity research and closer cooperation of scientists and clinicians.

Multiple stimulation parameters influence efficacy of deep brain stimulation in parkinsonian mice.

Deep brain stimulation (DBS) is used to treat multiple neuropsychiatric disorders, including Parkinson's Disease (PD). Despite widespread clinical use, its therapeutic mechanisms are unknown. Here, we developed a mouse model of subthalamic nucleus (STN) DBS for PD, to permit investigation using cell type-specific tools available in mice. We found that electrical STN DBS relieved bradykinesia, as measured by movement velocity. In addition, our model recapitulated several hallmarks of human STN DBS, including rapid onset and offset, frequency dependence, dyskinesia at higher stimulation intensity, and associations between electrode location, therapeutic benefit, and side effects. We used this model to assess whether high frequency stimulation is necessary for effective STN DBS, or if low frequency stimulation can be effective when paired with compensatory adjustments in other parameters. We found that low frequency stimulation, paired with greater pulse width and amplitude, relieved bradykinesia. Moreover, a composite metric incorporating pulse width, amplitude, and frequency predicted therapeutic efficacy better than frequency alone. We found a similar relationship between this composite metric and movement speed in a retrospective analysis of human data, suggesting correlations observed in the mouse model may extend to human patients. Together, these data establish a mouse model for elucidating mechanisms of DBS.

High frequency electrical stimulation promotes expression of extracellular matrix proteins from human astrocytes.

Therapeutic benefits of deep brain stimulation (DBS), a neurosurgical treatment for certain movement disorders and other neurologic conditions, are well documented, but DBS mechanisms remain largely unexplained. DBS is thought to modulate pathological neural activity. However, although astrocytes, the most numerous cell type in the brain, play a significant role in neurotransmission, chemical homeostasis and synaptic plasticity, their role in DBS has not been fully examined. To investigate astrocytic function in DBS, we applied DBS-like high frequency electrical stimulation for 24h to human astrocytes in vitro and analyzed single cell transcriptome mRNA profile. We found that DBS-like high frequency stimulation negatively impacts astrocyte metabolism and promotes the release of extracellular matrix (matricellular) proteins, including IGFBP3, GREM1, IGFBP5, THBS1, and PAPPA. Our results suggest that astrocytes are involved in the long-term modulation of extra cellular matrix environments and that they may influence persistent cell-to-cell interaction and help maintain neuromodulation over time.

S147. Evidence for the Involvement of the Serotonergic System in the Therapeutic Mechanism of Deep Brain Stimulation of the Subcallosal Cingulate (SCC-DBS) for Treating Depression

S147. Evidence for the Involvement of the Serotonergic System in the Therapeutic Mechanism of Deep Brain Stimulation of the Subcallosal Cingulate (SCC-DBS) for Treating Depression

A design of raster plot for illustrating dynamic neuronal activity during deep brain stimulation

Deep brain stimulation (DBS), which usually utilizes high frequency stimulation (HFS) of electrical pulses, is effective for treating many brain disorders in clinic. Studying the dynamic response of downstream neurons to HFS and its time relationship with stimulus pulses can reveal important mechanisms of DBS and advance the development of new stimulation modes (e.g., closed-loop DBS). To exhibit the dynamic neuronal firing and its relationship with stimuli, we designed a two-dimensional raster plot to visualize neuronal activity during HFS (especially in the initial stage of HFS). Additionally, the influence of plot resolution on the visualization effect was investigated. The method was then validated by investigating the neuronal responses to the axonal HFS in the hippocampal CA1 region of rats. Results show that the new design of raster plot is able to illustrate the dynamics of indexes (such as phase-locked relationship and latency) of single unit activity (i.e., spikes) during periodic pulse stimulations. Furthermore, the plots can intuitively show changes of neuronal firing from the baseline before stimulation to the onset dynamics during stimulation, as well as other information including the silent period of spikes immediately following the end of HFS. In addition, by adjusting resolution, the raster plot can be adapted to a large range of firing rates for clear illustration of neuronal activity. The new raster plot can illustrate more information with a clearer image than a regular raster plot, and thereby provides a useful tool for studying neuronal behaviors during high-frequency stimulations in brain.

Globus Pallidus Internus Electric High-Frequency Stimulation Modulates Dopaminergic Activity in the Striatum of a Rat Model of Tourette Syndrome

The purpose of this study was to investigate the role of deep brain stimulation (DBS) of the globus pallidus internus (GPi) in dopamine and dopamine transporter metabolism and to explore the regulatory role of DBS on dopaminergic neurons in Tourette syndrome by constructing an autoimmune model. Serum with high concentrations of antinuclear antibodies or phosphate-buffered saline solution was injected into the striatum of rats by a stereotactic technique and micropump. Then, electrodes were planted in the rats' globus pallidus internus. Concentrations of dopamine and dopamine transporter in the striatum were detected by enzyme-linked immunosorbent assay, immunohistochemistry, and Western blot analysis after 7 days of high-frequency stimulation (130 Hz). The tic behavior score of rats in the Tourette syndrome group was higher than that of rats in the control group (P < 0.01). After high-frequency stimulation, the scores of the Tourette syndrome model group and the control group significantly decreased. The concentration of dopamine in the Tourette syndrome model group and the control group also significantly decreased after electric stimulation (P < 0.05). In addition, immunohistochemical analysis and Western blot test results showed that dopamine transporter in the Tourette syndrome model nonstimulation group was lower than in the Tourette syndrome model stimulation group, and that dopamine transporter in the control nonstimulation group was lower than in the control stimulation group (P < 0.05). The results of this study show that the mechanism of DBS of the GPi in the treatment of Tourette syndrome involved monoamine neurotransmitters, especially the dopamine system, that affected the metabolism and transport of corresponding neurotransmitters, playing an important role in regulating the concentration of synaptic neurotransmitters and changing the biologic activity of basal ganglia nerve circuits.

Connectivity and Dynamics Underlying Synaptic Control of the Subthalamic Nucleus.

Adaptive motor control critically depends on the interconnected nuclei of the basal ganglia in the CNS. A pivotal element of the basal ganglia is the subthalamic nucleus (STN), which serves as a therapeutic target for deep brain stimulation (DBS) in movement disorders, such as Parkinson's disease. The functional connectivity of the STN at the microcircuit level, however, still requires rigorous investigation. Here we combine multiple simultaneous whole-cell recordings with extracellular stimulation and post hoc neuroanatomical analysis to investigate intrinsic and afferent connectivity and synaptic properties of the STN in acute brain slices obtained from rats of both sexes. Our data reveal an absence of intrinsic connectivity and an afferent innervation with low divergence, suggesting that STN neurons operate as independent processing elements driven by upstream structures. Hence, synchrony in the STN, a hallmark of motor processing, exclusively depends on the interactions and dynamics of GABAergic and glutamatergic afferents. Importantly, these inputs are subject to differential short-term depression when stimulated at high, DBS-like frequencies, shifting the balance of excitation and inhibition toward inhibition. Thus, we present a mechanism for fast yet transient decoupling of the STN from synchronizing afferent control. Together, our study provides new insights into the microcircuit organization of the STN by identifying its neurons as parallel processing units and thus sets new constraints for future computational models of the basal ganglia. The observed differential short-term plasticity of afferent inputs further offers a basis to better understand and optimize DBS algorithms.SIGNIFICANCE STATEMENT The subthalamic nucleus (STN) is a pivotal element of the basal ganglia and serves as target for deep brain stimulation, but information on the functional connectivity of its neurons is limited. To investigate the STN microcircuitry, we combined multiple simultaneous patch-clamp recordings and neuroanatomical analysis. Our results provide new insights into the synaptic organization of the STN identifying its neurons as parallel processing units and thus set new constraints for future computational models of the basal ganglia. We further find that synaptic dynamics of afferent inputs result in a rapid yet transient decoupling of the STN when stimulated at high frequencies. These results offer a better understanding of deep brain stimulation mechanisms, promoting the development of optimized algorithms.

Abstract #110: Ephaptic coupling, a mechanism for spontaneous neural propagation in the brain

It is well documented that synapses play a significant role in the transmission of information between neurons in the brain. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Several experimental results have shown that propagation of epileptiform activity in rodent hippocampi propagates at a speed of ∼0.1 m/s. This observed activity in the 4-AP model propagates independently of synaptic transmission and gap junctions, and is outside the range of ionic diffusion and axonal conduction speeds. Compartment modeling of pyramidal neurons indicate that ephaptic coupling, or endogenous electric fields, could be responsible for this propagation of neural activity in pathological conditions such as epilepsy. Recent studies suggest electric fields can activate neighboring neurons, thereby generating a self-propagating wave. However, there is no experimental data suggesting ephaptic coupling is necessary and sufficient for spontaneous, self-regenerating propagation of neural activity. Using in vitro and in vivo electrophysiology in combination with imaging of trans-membrane voltages using genetically encoded voltage indicators, we test the hypothesis that ephaptic coupling is a critical mechanism for non-synaptic neural propagation. We have developed a novel extracellular electric field clamp capable of measuring the endogenous field and generate an "anti" field to block non-synaptic spontaneous propagation in the rodent hippocampus (Figure 1A). By blocking propagation, we are able to show that ephaptic coupling is a necessary mechanism for propagation of spontaneous activity. Finally, since electric fields propagate as volume conductors, we test if activity can propagate through a complete physical cut of the tissue, thereby eliminating all other forms of close cell-to-cell communication and showing that electric fields alone are sufficient to mediate non-synaptic propagation. Preliminary results suggest that spontaneous epileptiform activity propagates by triggering the activity on the other side across the cut with ephaptic coupling without changing the speed (Figure 1B). Our findings suggest that ephaptic coupling is necessary and sufficient to mediate non-synaptic neural propagation. Further investigation of this mechanism could explain how focal seizures appear to start abruptly and unpredictably, and how the rare micro-seizures of human partial epilepsy (seizure-like events that are not clinically detectable and are resistant to most common antiepileptic drugs) propagate through the hippocampus and cortex. Furthermore, endogenous electric fields could play an important role in brain function and could provide an explanation for unresolved mechanisms of deep brain stimulation or transcranial direct current stimulation (tDCS).

Abstract #23: Local and Remote Signatures of Effective Deep Brain Stimulation

Introduction: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to ameliorate Parkinson’s disease (PD) symptoms such as tremor and bradykinesia. However, the DBS mechanisms of action remain largely unknown. Thus, identifying optimal parameters for electrode placement and stimulation parameters can be challenging. Here we investigate electrophysiology and gene expression profiles in the cortex, subthalamic nucleus, striatum and hippocampus in stimulated and control animals. We show that chronic (4 days or more) stimulation modulates local field potentials (LFPs) and the transcriptome both locally and remotely. We use behavioral correlation and principal component subset analysis (PCSA) to identify electrophysiology and transcriptome signatures of effective DBS.

Deep Brain Stimulation for Obsessive Compulsive Disorder: Evolution of Surgical Stimulation Target Parallels Changing Model of Dysfunctional Brain Circuits.

Obsessive compulsive disorder (OCD) is a common, disabling psychiatric disease characterized by persistent, intrusive thoughts and ritualistic, repetitive behaviors. Deep brain stimulation (DBS) is thought to alleviate OCD symptoms by modulating underlying disturbances in normal cortico-striato-thalamo-cortical (CSTC) circuitry. Stimulation of the ventral portion of the anterior limb of the internal capsule (ALIC) and underlying ventral striatum (“ventral capsule/ventral striatum” or “VC/VS” target) received U.S. FDA approval in 2009 for patients with severe, treatment-refractory OCD. Over the decades, DBS surgical outcome studies have led to an evolution in the electrical stimulation target. In parallel, advancements in neuroimaging techniques have allowed investigators to better visualize and define CSTC circuits underlying the pathophysiology of OCD. A critical analysis of these new data suggests that the therapeutic mechanism of DBS for OCD likely involves neuromodulation of a widespread cortical/subcortical network, accessible by targeting fiber bundles in the ventral ALIC that connect broad network regions. Future studies will include advances in structural and functional imaging, analysis of physiological recordings, and utilization of next-generation DBS devices. These tools will enable patient-specific optimization of DBS therapy, which will hopefully further improve outcomes.

On the (Non-)equivalency of monopolar and bipolar settings for deep brain stimulation fMRI studies of Parkinson's disease patients.

The majority of Parkinson's disease patients with deep brain stimulation (DBS) use a monopolar configuration, which presents challenges for EEG and MRI studies. The literature reports algorithms to convert monopolar to bipolar settings. To assess brain responses of Parkinson's disease patients implanted with DBS during fMRI studies using their clinical and presumed equivalent settings using a published conversion recipe. Prospective. Thirteen DBS patients. 1.5T and 3T, fMRI using gradient echo-planar imaging. Patients underwent 30/30sec ON/OFF DBS fMRI scans using monopolar and bipolar settings. To convert to a bipolar setting, the negative contact used for the monopolar configuration remained constant and the adjacent dorsal contact was rendered positive, while increasing the voltage by 30%. fMRI activation/deactivation maps and motor Unified Parkinson's Disease Rating Scale (UPDRS-III) scores were compared for patients in both configurations. T-tests were used to compare UPDRS scores and volumes of tissue activated (VTA) diameters in monopolar and bipolar configurations. The patterns of fMRI activation in the monopolar and bipolar configurations were generally different. The thalamus, pallidum, and visual cortices exhibited higher activation using the patient's clinical settings than the presumed equivalent settings. VTA diameters were lower (7 mm vs. 6.3 mm, P = 0.047) and UPDRS scores were generally higher in the bipolar (33.2 ± 16) than in the monopolar configuration (28.3 ± 17.4), without reaching statistical significance (P > 0.05). Monopolar and bipolar configurations result in different patterns of brain activation while using a previously published monopolar-bipolar conversion algorithm. Clinical benefits may be achieved with varying patterns of brain responses. Blind conversion from one to the other should be avoided for purposes of understanding the mechanisms of DBS. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Simulation Study of Intermittent Axonal Block and Desynchronization Effect Induced by High-Frequency Stimulation of Electrical Pulses.

Deep brain stimulation (DBS) has been successfully used in treating neural disorders in brain, such as Parkinson’s disease and epilepsy. However, the precise mechanisms of DBS remain unclear. Regular DBS therapy utilizes high-frequency stimulation (HFS) of electrical pulses. Among all of neuronal elements, axons are mostly inclined to be activated by electrical pulses. Therefore, the response of axons may play an important role in DBS treatment. To study the axonal responses during HFS, we developed a computational model of myelinated axon to simulate sequences of action potentials generated in single and multiple axons (an axon bundle) by stimulations. The stimulations are applied extracellularly by a point source of current pulses with a frequency of 50–200 Hz. Additionally, our model takes into account the accumulation of potassium ions in the peri-axonal spaces. Results show that the increase of extracellular potassium generates intermittent depolarization block in the axons during HFS. Under the state of alternate block and recovery, axons fire action potentials at a rate far lower than the frequency of stimulation pulses. In addition, the degree of axonal block is highly related to the distance between the axons and the stimulation point. The differences in the degree of block for individual axons in a bundle result in desynchronized firing among the axons. Stimulations with higher frequency and/or greater intensity can induce axonal block faster and increase the desynchronization effect on axonal firing. Presumably, the desynchronized axonal activity induced by HFS could generate asynchronous activity in the population of target neurons downstream thereby suppressing over-synchronized firing of neurons in pathological conditions. The desynchronization effect generated by intermittent activation of axons may be crucial for DBS therapy. The present study provides new insights into the mechanisms of DBS, which is significant for advancing the application of DBS.

Long-Lasting Electrophysiological After-Effects of High-Frequency Stimulation in the Globus Pallidus: Human and Rodent Slice Studies.

Deep-brain stimulation (DBS) of the globus pallidus pars interna (GPi) is a highly effective therapy for movement disorders, yet its mechanism of action remains controversial. Inhibition of local neurons because of release of GABA from afferents to the GPi is a proposed mechanism in patients. Yet, high-frequency stimulation (HFS) produces prolonged membrane depolarization mediated by cholinergic neurotransmission in endopeduncular nucleus (EP, GPi equivalent in rodent) neurons. We applied HFS while recording neuronal firing from an adjacent electrode during microelectrode mapping of GPi in awake patients (both male and female) with Parkinson disease (PD) and dystonia. Aside from after-suppression and no change in neuronal firing, high-frequency microstimulation induced after-facilitation in 38% (26/69) of GPi neurons. In neurons displaying after-facilitation, 10 s HFS led to an immediate decrease of bursting in PD, but not dystonia patients. Moreover, the changes of bursting patterns in neurons with after-suppression or no change after HFS, were similar in both patient groups. To explore the mechanisms responsible, we applied HFS in EP brain slices from rats of either sex. As in humans, HFS in EP induced two subtypes of after-excitation: excitation or excitation with late inhibition. Pharmacological experiments determined that the excitation subtype, induced by lower charge density, was dependent on glutamatergic transmission. HFS with higher charge density induced excitation with late inhibition, which involved cholinergic modulation. Therefore HFS with different charge density may affect the local neurons through multiple synaptic mechanisms. The cholinergic system plays a role in mediating the after-facilitatory effects in GPi neurons, and because of their modulatory nature, may provide a basis for both the immediate and delayed effects of GPi-DBS. We propose a new model to explain the mechanisms of DBS in GPi.SIGNIFICANCE STATEMENT Deep-brain stimulation (DBS) in the globus pallidus pars interna (GPi) improves Parkinson disease (PD) and dystonia, yet its mechanisms in GPi remain controversial. Inhibition has been previously described and thought to indicate activation of GABAergic synaptic terminals, which dominate in GPi. Here we report that 10 s high-frequency microstimulation induced after-facilitation of neural firing in a substantial proportion of GPi neurons in humans. The neurons with after-facilitation, also immediately reduced their bursting activities after high-frequency stimulation in PD, but not dystonia patients. Based on these data and further animal experiments, a mechanistic hypothesis involving glutamatergic, GABAergic, and cholinergic synaptic transmission is proposed to explain both short- and longer-term therapeutic effects of DBS in GPi.

Integrity Assessment of a Hybrid DBS Probe that Enables Neurotransmitter Detection Simultaneously to Electrical Stimulation and Recording.

Deep brain stimulation (DBS) is a successful medical therapy for many treatment resistant neuropsychiatric disorders such as movement disorders; e.g., Parkinson’s disease, Tremor, and dystonia. Moreover, DBS is becoming more and more appealing for a rapidly growing number of patients with other neuropsychiatric diseases such as depression and obsessive compulsive disorder. In spite of the promising outcomes, the current clinical hardware used in DBS does not match the technological standards of other medical applications and as a result could possibly lead to side effects such as high energy consumption and others. By implementing more advanced DBS devices, in fact, many of these limitations could be overcome. For example, a higher channels count and smaller electrode sites could allow more focal and tailored stimulation. In addition, new materials, like carbon for example, could be incorporated into the probes to enable adaptive stimulation protocols by biosensing neurotransmitters in the brain. Updating the current clinical DBS technology adequately requires combining the most recent technological advances in the field of neural engineering. Here, a novel hybrid multimodal DBS probe with glassy carbon microelectrodes on a polyimide thin-film device assembled on a silicon rubber tubing is introduced. The glassy carbon interface enables neurotransmitter detection using fast scan cyclic voltammetry and electrophysiological recordings while simultaneously performing electrical stimulation. Additionally, the presented DBS technology shows no imaging artefacts in magnetic resonance imaging. Thus, we present a promising new tool that might lead to a better fundamental understanding of the underlying mechanism of DBS while simultaneously paving our way towards better treatments.

Coherence: a unifying mechanism of deep brain stimulation.

Deep brain stimulation is a powerful neurostimulation technique that proved its efficacy in treating a group of neurological diseases. Several scientific works tried to understand the mechanism of action of deep brain stimulation. Wang et al. ( J Neurosci 38: 4556-4568, 2018) demonstrated new evidence on the role of interregional neuro-oscillatory coherence as a promising model to explain mechanism the of deep brain stimulation.

Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease.

L-DOPA is still the most effective pharmacological therapy for the treatment of motor symptoms in Parkinson's disease (PD) almost four decades after it was first used. Deep brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD. Even though a clear understanding of the mechanisms of both treatment methods is yet to be obtained, the combination of both treatments is the most effective standard evidenced-based therapy to date. Recent studies have demonstrated that DBS is a therapy option even in the early course of the disease, when first complications arise despite a rigorous adjustment of the pharmacological treatment. The unique feature of this therapeutic approach is the ability to preferentially modulate specific brain networks through the choice of stimulation site. The clinical effects have been unequivocally confirmed in recent studies; however, the impact of DBS and the supplementary effect of L-DOPA on the neuronal network are not yet fully understood. In this review, we present emerging data on the presumable mechanisms of DBS in patients with PD and discuss the pathophysiological similarities and differences in the effects of DBS in comparison to dopaminergic medication. Targeted, selective modulation of brain networks by DBS and pharmacodynamic effects of L-DOPA therapy on the central nervous system are presented. Moreover, we outline the perioperative algorithms for PD patients before and directly after the implantation of DBS electrodes and strategies for the reduction of side effects and optimization of motor and non-motor symptoms.

Open-loop deep brain stimulation for the treatment of epilepsy: a systematic review of clinical outcomes over the past decade (2008-present).

OBJECTIVE The field of deep brain stimulation (DBS) for epilepsy has grown tremendously since its inception in the 1970s and 1980s. The goal of this review is to identify and evaluate all studies published on the topic of open-loop DBS for epilepsy over the past decade (2008 to present). METHODS A PubMed search was conducted to identify all articles reporting clinical outcomes of open-loop DBS for the treatment of epilepsy published since January 1, 2008. The following composite search terms were used: ("epilepsy" [MeSH] OR "seizures" [MeSH] OR "kindling, neurologic" [MeSH] OR epilep* OR seizure* OR convuls*) AND ("deep brain stimulation" [MeSH] OR "deep brain stimulation" OR "DBS") OR ("electric stimulation therapy" [MeSH] OR "electric stimulation therapy" OR "implantable neurostimulators" [MeSH]). RESULTS The authors identified 41 studies that met the criteria for inclusion. The anterior nucleus of the thalamus, centromedian nucleus of the thalamus, and hippocampus were the most frequently evaluated targets. Among the 41 articles, 19 reported on stimulation of the anterior nucleus of the thalamus, 6 evaluated stimulation of the centromedian nucleus of the thalamus, and 9 evaluated stimulation of the hippocampus. The remaining 7 articles reported on the evaluation of alternative DBS targets, including the posterior hypothalamus, subthalamic nucleus, ventral intermediate nucleus of the thalamus, nucleus accumbens, caudal zone incerta, mammillothalamic tract, and fornix. The authors evaluated each study for overall epilepsy response rates as well as adverse events and other significant, nonepilepsy outcomes. CONCLUSIONS Level I evidence supports the safety and efficacy of stimulating the anterior nucleus of the thalamus and the hippocampus for the treatment of medically refractory epilepsy. Level III and IV evidence supports stimulation of other targets for epilepsy. Ongoing research into the efficacy, adverse effects, and mechanisms of open-loop DBS continues to expand the knowledge supporting the use of these treatment modalities in patients with refractory epilepsy.

P71. MicroRNA regulation in deep brain stimulation of different targets for epilepsy

Rationale Epilepsy is a common neurological disorder with an incidence of 50.4 per 100,000 per year ( Ngugi et al., 2011 ). Up to 80% of mesial temporal lobe epilepsy (mTLE) patients are resistant to pharmacological treatment ( Semah et al., 1998 ). Many of them do not qualify for resective brain surgery. For these patients, an alternative treatment is deep brain stimulation (DBS). In epilepsy, different protocols for DBS have been tested but until now the mechanisms of DBS are not fully understood and the best protocol remains to be evaluated. MicroRNAs (miRNAs) are small, single stranded RNAs, which regulate protein synthesis on mRNA level. Various miRNAs have been found to be regulated in epilepsy, and regulation of miRNAs after DBS has been shown in Parkinson’s disease patients ( Soreq et al., 2013 ). We compared different targets and frequencies of DBS in a rat model of mTLE to identify a paradigm that inhibits epileptogenesis. Furthermore, we investigated miRNA regulation after DBS with the most effective paradigm. Methods We used the rat perforant pathways stimulation (PPS) model of mTLE ( Norwood et al., 2010 ). Thereby, stimulation electrodes are implanted into the PP and recording electrodes are implanted into the dentate gyrus (DG). After one week of recovery, rats are stimulated on two days for 30 min and on the third day for 8 h. This treatment leads to spontaneous seizures 12–34 days after stimulation. We investigated DBS of four different targets: the PP, the fimbria fornix formation (FF), the DG and the ventral hippocampal commissure (VHC); for one or two weeks starting one day after the 8 h stimulation, using three different stimulation paradigms: 130 Hz and 0.1 V, 5 Hz and 2 V or 1 V and 1 Hz. We furthermore analyzed miRNA expression in the hippocampus immediately after DBS and after a 97-day recording period. Thereafter, sequencing of active miRNAs was performed and compared to control rats which were not treated with DBS. Results A two-week DBS of the VHC with 1 Hz and 1 V significantly prolonged the latency period in the PPS model from 19 to 56 days. 8 microRNAs were significantly changed directly after DBS. Several miRNAs were changed in the control group after 97 days but showed no changes in expression in the DBS-treated group. These are potential candidates for an in vivo manipulation to inhibit epileptogenesis.