Deep Brain Stimulation Paradigms Research Articles

Can a specific deep brain stimulation paradigm slow motor progression and provide long-term motor benefit in Parkinson’s disease?

Can a specific deep brain stimulation paradigm slow motor progression and provide long-term motor benefit in Parkinson’s disease?

Characterization and closed-loop control of infrared thalamocortical stimulation produces spatially constrained single-unit responses.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to midinfrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in rat thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning (RL) for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Deep brain stimulation of ventromedial prefrontal cortex reverses depressive-like behaviors via BDNF/TrkB signaling pathway in rats

AimDeep brain stimulation (DBS) is currently under investigation as a potential therapeutic approach for managing major depressive disorder (MDD) and ventromedial prefrontal cortex (vmPFC) is recognized as a promising target region. Therefore, the present study aimed to investigate a preclinical paradigm of bilateral vmPFC DBS and examine the molecular mechanisms underlying its antidepressant-like effects using chronic unpredictable stress (CUS) model in rats. Main methodsMale rats were subjected to stereotaxic surgery and deep brain stimulation paradigm in non-stressed and CUS rats respectively, and the therapeutic effect of DBS were assessed by a series of behavioral tests including sucrose preference test, open field test, elevated plus maze test, and forced swim test. The potential involvement of the BDNF/TrkB signaling pathway and its downstream effects in this process were also investigated using western blot. Key findingsWe identified that a stimulation protocol consisting of 130 Hz, 200 μA, 90 μs pulses administered for 5 h per day over a period of 7 days effectively mitigated CUS-induced depressive-like and anxiety-like behaviors in rats. These therapeutic effects were associated with the enhancement of the BDNF/TrkB signaling pathway and its downstream ERK1/2 activity. SignificanceThese findings provide valuable insights into the potential clinical utility of vmPFC DBS as an approach of improving the symptoms experienced by individuals with MDD. This evidence contributes to our understanding of the neurobiological basis of depression and offers promise for the development of more effective treatments.

Wavelet-Based Bracketing, Time–Frequency Beta Burst Detection: New Insights in Parkinson's Disease

Studies have shown that beta band activity is not tonically elevated but comprises exaggerated phasic bursts of varying durations and magnitudes, for Parkinson's disease (PD) patients. Current methods for detecting beta bursts target a single frequency peak in beta band, potentially ignoring bursts in the wider beta band. In this study, we propose a new robust framework for beta burst identification across wide frequency ranges. Chronic local field potential at-rest recordings were obtained from seven PD patients implanted with Medtronic SenSight™ deep brain stimulation (DBS) electrodes. The proposed method uses wavelet decomposition to compute the time–frequency spectrum and identifies bursts spanning multiple frequency bins by thresholding, offering an additional burst measure, ∆f, that captures the width of a burst in the frequency domain. Analysis included calculating burst duration, magnitude, and ∆f and evaluating the distribution and likelihood of bursts between the low beta (13–20 Hz) and high beta (21–35 Hz). Finally, the results of the analysis were correlated to motor impairment (MDS-UPDRS III) med off scores. We found that low beta bursts with longer durations and larger width in the frequency domain (∆f) were positively correlated, while high beta bursts with longer durations and larger ∆f were negatively correlated with motor impairment. The proposed method, finding clear differences between bursting behavior in high and low beta bands, has clearly demonstrated the importance of considering wide frequency bands for beta burst behavior with implications for closed-loop DBS paradigms.

ID: 209539 Effect of Automated Deep Brain Stimulation (DBS) on Essential Tremor (ET) Patient Experiences and Sleep

Essential tremor (ET) is a debilitating movement disorder causing tremor that can have a significant impact on daily activities. Deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus is an approved treatment for ET. Although most patients benefit from DBS, for optimal benefit it may be necessary to utilize different programming parameters throughout a 24-hour period. Manually switching between optimal programs can be cumbersome. Additionally, to extend battery longevity, patients often turn off stimulation while sleeping. In this study, we aim to determine the effects of an automated DBS paradigm on patient experiences and sleep outcomes.

Patterned Hippocampal Stimulation Facilitates Memory in Patients With a History of Head Impact and/or Brain Injury.

Rationale: Deep brain stimulation (DBS) of the hippocampus is proposed for enhancement of memory impaired by injury or disease. Many pre-clinical DBS paradigms can be addressed in epilepsy patients undergoing intracranial monitoring for seizure localization, since they already have electrodes implanted in brain areas of interest. Even though epilepsy is usually not a memory disorder targeted by DBS, the studies can nevertheless model other memory-impacting disorders, such as Traumatic Brain Injury (TBI). Methods: Human patients undergoing Phase II invasive monitoring for intractable epilepsy were implanted with depth electrodes capable of recording neurophysiological signals. Subjects performed a delayed-match-to-sample (DMS) memory task while hippocampal ensembles from CA1 and CA3 cell layers were recorded to estimate a multi-input, multi-output (MIMO) model of CA3-to-CA1 neural encoding and a memory decoding model (MDM) to decode memory information from CA3 and CA1 neuronal signals. After model estimation, subjects again performed the DMS task while either MIMO-based or MDM-based patterned stimulation was delivered to CA1 electrode sites during the encoding phase of the DMS trials. Each subject was sorted (post hoc) by prior experience of repeated and/or mild-to-moderate brain injury (RMBI), TBI, or no history (control) and scored for percentage successful delayed recognition (DR) recall on stimulated vs. non-stimulated DMS trials. The subject’s medical history was unknown to the experimenters until after individual subject memory retention results were scored. Results: When examined compared to control subjects, both TBI and RMBI subjects showed increased memory retention in response to both MIMO and MDM-based hippocampal stimulation. Furthermore, effects of stimulation were also greater in subjects who were evaluated as having pre-existing mild-to-moderate memory impairment. Conclusion: These results show that hippocampal stimulation for memory facilitation was more beneficial for subjects who had previously suffered a brain injury (other than epilepsy), compared to control (epilepsy) subjects who had not suffered a brain injury. This study demonstrates that the epilepsy/intracranial recording model can be extended to test the ability of DBS to restore memory function in subjects who previously suffered a brain injury other than epilepsy, and support further investigation into the beneficial effect of DBS in TBI patients.

Thalamic deep brain stimulation paradigm to reduce consciousness: Cortico-striatal dynamics implicated in mechanisms of consciousness

Anesthetic manipulations provide much-needed causal evidence for neural correlates of consciousness, but non-specific drug effects complicate their interpretation. Evidence suggests that thalamic deep brain stimulation (DBS) can either increase or decrease consciousness, depending on the stimulation target and parameters. The putative role of the central lateral thalamus (CL) in consciousness makes it an ideal DBS target to manipulate circuit-level mechanisms in cortico-striato-thalamic (CST) systems, thereby influencing consciousness and related processes. We used multi-microelectrode DBS targeted to CL in macaques while recording from frontal, parietal, and striatal regions. DBS induced episodes of abnormally long, vacant staring with low-frequency oscillations here termed vacant, perturbed consciousness (VPC). DBS modulated VPC likelihood in a frequency-specific manner. VPC events corresponded to decreases in measures of neural complexity (entropy) and integration (Φ*), proposed indices of consciousness, and substantial changes to communication in CST circuits. During VPC, power spectral density and coherence at low frequencies increased across CST circuits, especially in thalamo-parietal and cortico-striatal pathways. Decreased consciousness and neural integration corresponded to shifts in cortico-striatal network configurations that dissociated parietal and subcortical structures. Overall, the features of VPC and implicated networks were similar to those of absence epilepsy. As this same multi-microelectrode DBS method–but at different stimulation frequencies–can also increase consciousness in anesthetized macaques, it can be used to flexibly address questions of consciousness with limited confounds, as well as inform clinical investigations of other consciousness disorders.

Functional dissection of neural circuitry using a genetic reporter for fMRI.

The complex connectivity of the mammalian brain underlies its function, but understanding how interconnected brain regions interact in neural processing remains a formidable challenge. Here we address this problem by introducing a genetic probe that permits selective functional imaging of distributed neural populations defined by viral labeling techniques. The probe is an engineered enzyme that transduces cytosolic calcium dynamics of probe-expressing cells into localized hemodynamic responses that can be specifically visualized by functional magnetic resonance imaging. Using a viral vector that undergoes retrograde transport, we apply the probe to characterize a brain-wide network of presynaptic inputs to the striatum activated in a deep brain stimulation paradigm in rats. The results reveal engagement of surprisingly diverse projection sources and inform an integrated model of striatal function relevant to reward behavior and therapeutic neurostimulation approaches. Our work thus establishes a strategy for mechanistic analysis of multiregional neural systems in the mammalian brain.

Mimicking CA3 Temporal Dynamics Controls Limbic Ictogenesis.

Simple SummaryMesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most often refractory to medications. Electrical deep brain stimulation (DBS) has proved effective in controlling seizures in animal models and in drug-refractory MTLE patients. However, there is still no unifying framework for DBS parameters, which are obtained by trial-and-error and based on arbitrary, fixed stimulation frequencies rather than on physiologically relevant patterns. Interictal activity may present the key to devising personalized and physiologically relevant DBS strategies. Interictal activity occurs between seizures and is a hallmark of the hyperexcitability of the epileptic brain; depending on the underlying mechanisms and site of origin, it may promote seizures (pro-ictogenic) or dampen them (anti-ictogenic). In this work, we address the possibility of controlling seizure activity by means of electrical stimulation fashioned as a surrogate interictal pattern known to be anti-ictogenic. We show that this approach can effectively control seizure activity while delivering fewer electrical pulses than fixed-frequency stimulation. Thus, mimicking the temporal dynamics of an anti-ictogenic interictal pattern may represent a straightforward, personalized and more efficient DBS strategy to ameliorate drug-refractory epilepsy. Our work heralds a paradigm shift toward physiologically meaningful rather than arbitrary DBS parameters.Mesial temporal lobe epilepsy (MTLE) is the most common partial complex epilepsy in adults and the most unresponsive to medications. Electrical deep brain stimulation (DBS) of the hippocampus has proved effective in controlling seizures in epileptic rodents and in drug-refractory MTLE patients. However, current DBS paradigms implement arbitrary fixed-frequency or patterned stimuli, disregarding the temporal profile of brain electrical activity. The latter, herein included hippocampal spontaneous firing, has been shown to follow lognormal temporal dynamics. Here, we present a novel paradigm to devise DBS protocols based on stimulation patterns fashioned as a surrogate brain signal. We focus on the interictal activity originating in the hippocampal subfield CA3, which has been shown to be anti-ictogenic. Using 4-aminopyridine-treated hippocampus-cortex slices coupled to microelectrode array, we pursue three specific aims: (1) address whether lognormal temporal dynamics can describe the CA3-driven interictal pattern, (2) explore the possibility of restoring the non-seizing state by mimicking the temporal dynamics of this anti-ictogenic pattern with electrical stimulation, and (3) compare the performance of the CA3-surrogate against periodic stimulation. We show that the CA3-driven interictal activity follows lognormal temporal dynamics. Further, electrical stimulation fashioned as a surrogate interictal pattern exhibits similar efficacy but uses less pulses than periodic stimulation. Our results support the possibility of mimicking the temporal dynamics of relevant brain signals as a straightforward DBS strategy to ameliorate drug-refractory epilepsy. Further, they herald a paradigm shift in neuromodulation, wherein a compromised brain signal can be recreated by the appropriate stimuli distribution to bypass trial-and-error studies and attain physiologically meaningful DBS operating modes.

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease

BackgroundParkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5–12 Hz) are important in cognition. MethodsWe tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients’ peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation. ResultsAcute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions. ConclusionHere, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.

Phase-Dependent Deep Brain Stimulation: A Review.

Neural oscillations are repetitive patterns of neural activity in the central nervous systems. Oscillations of the neurons in different frequency bands are evident in electroencephalograms and local field potential measurements. These oscillations are understood to be one of the key mechanisms for carrying out normal functioning of the brain. Abnormality in any of these frequency bands of oscillations can lead to impairments in different cognitive and memory functions leading to different pathological conditions of the nervous system. However, the exact role of these neural oscillations in establishing various brain functions is still under investigation. Closed loop deep brain stimulation paradigms with neural oscillations as biomarkers could be used as a mechanism to understand the function of these oscillations. For making use of the neural oscillations as biomarkers to manipulate the frequency band of the oscillation, phase of the oscillation, and stimulation signal are of importance. This paper reviews recent trends in deep brain stimulation systems and their non-invasive counterparts, in the use of phase specific stimulation to manipulate individual neural oscillations. In particular, the paper reviews the methods adopted in different brain stimulation systems and devices for stimulating at a definite phase to further optimize closed loop brain stimulation strategies.

Coherence between the hippocampus and anterior thalamic nucleus as a tool to improve the effect of neurostimulation in temporal lobe epilepsy: An experimental study

BackgroundAlthough the mechanisms by which deep brain stimulation (DBS) modifies the activity of the ictal network are mostly undefined, recent studies have suggested that DBS of the anterior nucleus of the thalamus (ANT) can be an effective treatment for mesial temporal lobe epilepsy (MTLE) when resective surgery cannot be performed. In a nonhuman primate (NHP) model of MTL seizures, we showed that the ANT was actively involved during interictal and ictal periods through different patterns and that the hippocampus (HPC) and ANT synchronously oscillate in the high beta-band during seizures. ObjectiveBased on those findings, we evaluated whether the frequency of stimulation is an important parameter that interferes with seizures and how to adapt stimulation protocols to it. MethodsWe investigated the effects of low-frequency (40 Hz - determined as the ictal frequency of correlation between structures) and high-frequency (130 Hz - as commonly used in clinic) ANT stimulation in three monkeys in which MTLE seizures were initiated. ResultsLow-frequency stimulation had a strong effect on the number of seizures and the total time spent in seizure, whereas high-frequency stimulation had no effect. The coherence of oscillations between the HPC and the ANT was significantly correlated with the success of low-frequency stimulation: the greater the coherence was, the greater the antiepileptic effect of ANT-DBS. ConclusionOur results suggest that low-frequency stimulation is efficient in treating seizures in a nonhuman primate model. More importantly, the study of the coherence between the ANT and HPC during seizures can help to predict the anti-epileptic effects of ANT stimulation. Furthermore, the DBS paradigm could be customized in frequency for each patient on the basis of the coherence spectral pattern.

A Novel DBS Paradigm for Axial Features in Parkinson's Disease: A Randomized Crossover Study.

High-frequency (130-185 Hz) deep brain stimulation (DBS) of the subthalamic nucleus is more effective for appendicular than axial symptoms in Parkinson's disease (PD). Low-frequency (60-80 Hz) stimulation (LFS) may reduce gait/balance impairment but typically results in worsening appendicular symptoms. We created a "dual-frequency" programming paradigm (interleave-interlink, IL-IL) to address both axial and appendicular symptoms. In IL-IL, 2 overlapping LFS programs are applied to the DBS lead, with the overlapping area focused on the optimal cathode. The nonoverlapping area (LFS) is thought to reduce gait/balance impairment, whereas the overlapping area (high-frequency stimulation, HFS) aims to control appendicular symptoms. We performed a randomized, double-blind crossover trial comparing patients' previously optimized IL-IL and conventional HFS paradigms. Each arm was 2 weeks in duration. The primary outcome measure was the patient/caregiver Modified Clinical Global Impression Severity (CGI-S). Secondary outcome measures included blinded motor evaluations, timed tests, patient/caregiver questionnaires, and Personal KinetiGraphs (PKG). Twenty-five patients were enrolled, and 20 completed. The patient/caregiver CGI-S for gait/balance (P = 0.01) and appendicular symptom control (P = 0.001), and the blinded rater MDS-UPDRS-III (-5.22, P = 0.02), CGI-S gait/balance (P = 0.01), and CGI-S speech (P = 0.02) were better while on IL-IL. Scores on Parkinson's Disease Quality of Life (P = 0.002) and Freezing-of-Gait Questionnaires (P = 0.04) were better on IL-IL. The Timed-Up-and-Go was 9.8% faster (P = 0.01), with 11.8% reduction in steps (P = 0.001) on IL-IL. There was no difference in PKG bradykinesia (P = 0.18) or tremor (P = 0.23) between paradigms. Our results prompt consideration of this novel programming paradigm (IL-IL) for PD patients with axial symptom impairment as a new treatment option for both axial and appendicular symptoms. © 2020 International Parkinson and Movement Disorder Society.

Parkinsonian Beta Dynamics during Rest and Movement in the Dorsal Pallidum and Subthalamic Nucleus.

In Parkinson's disease (PD), pathologically high levels of beta activity (12-30 Hz) reflect specific symptomatology and normalize with pharmacological or surgical intervention. Although beta characterization in the subthalamic nucleus (STN) of PD patients undergoing deep brain stimulation (DBS) has now been translated into adaptive DBS paradigms, a limited number of studies have characterized beta power in the globus pallidus internus (GPi), an equally effective DBS target. Our objective was to compare beta power in the STN and GPi during rest and movement in people with PD undergoing DBS. Thirty-seven human female and male participants completed a simple behavioral experiment consisting of periods of rest and button presses, leading to local field potential recordings from 19 (15 participants) STN and 26 (22 participants) GPi nuclei. We examined overall beta power as well as beta time-domain dynamics (i.e., beta bursts). We found higher beta power during rest and movement in the GPi, which also had more beta desynchronization during movement. Beta power was positively associated with bradykinesia and rigidity severity; however, these clinical associations were present only in the GPi cohort. With regards to beta dynamics, bursts were similar in duration and frequency in the GPi and STN, but GPi bursts were stronger and correlated to bradykinesia-rigidity severity. Beta dynamics therefore differ across basal ganglia nuclei. Relative to the STN, beta power in the GPi may be readily detected, modulates more with movement, and relates more to clinical impairment. Together, this could point to the GPi as a potentially effective target for beta-based adaptive DBS.SIGNIFICANCE STATEMENT It is known that subthalamic nucleus (STN) beta activity is linked to symptom severity in Parkinson's disease (PD), but few studies have characterized beta activity in the globus pallidus internus (GPi), another effective target for deep brain stimulation (DBS). We compared beta power in the STN and GPi during rest and movement in 37 people with PD undergoing DBS. We found that beta dynamics differed across basal ganglia nuclei. Our results show that, relative to the STN, beta power in the GPi may be readily detected, modulates more with movement, and relates more to clinical impairment. Together, this could point to the GPi as a potentially effective target for beta-based adaptive DBS.

Electrical stimulation of the ventral hippocampal commissure delays experimental epilepsy and is associated with altered microRNA expression

BackgroundUp to 80% of mesial temporal lobe epilepsy patients with hippocampal sclerosis (mTLE-HS) are resistant to pharmacological treatment, often necessitating surgical resection. Deep brain stimulation (DBS) has emerged as an alternative treatment for patients who do not qualify for resective brain surgery. Brain stimulation may also exert disease-modifying effects, and noncoding microRNAs have recently been proposed to shape the gene expression landscape in epilepsy. ObjectiveWe compared the effect of DBS of 4 different hippocampal target regions on epileptogenesis and manifest epilepsy in a rat model of mTLE-HS. To explore mechanisms, we profiled the effect of the most effective DBS paradigm on hippocampal microRNA levels. MethodsMTLE-HS was induced by electrical stimulation of the perforant pathway (PP) in rats. This paradigm leads to spontaneous seizures within 4 weeks. We investigated DBS of 4 targets: PP, fimbria fornix (FF) formation, dentate gyrus (DG) and ventral hippocampal commissure (VHC). We applied both high- (130 Hz) and low-frequency (5 Hz or 1 Hz) stimulation. Functional microRNAs were identified in the hippocampus immediately after VHC-DBS and after a 97-day recording period by sequencing small RNAs bound to Argonaute-2, a component of the miRNA silencing complex. ResultsLow frequency DBS of the VHC significantly delayed the occurrence of the first spontaneous recurrent seizure in the PPS model by ∼300%, from 19 to 56 days. No other stimulation regime altered the latency phase. Upregulation of 5 microRNAs during epileptogenesis was suppressed by VHC-stimulation. ConclusionWe conclude that DBS of the VHC delays epilepsy in the PPS model in rats and is associated with differential regulation of several miRNAs. Additional studies are required to determine whether VHC-regulated miRNAs serve causal roles in the anti-epileptogenic effects of this DBS model.

Development of a miniature device for emerging deep brain stimulation paradigms.

Deep brain stimulation (DBS) is a neuromodulatory approach for treatment of several neurological and psychiatric disorders. A new focus on optimising the waveforms used for stimulation is emerging regarding the mechanism of DBS treatment. Many existing DBS devices offer only a limited set of predefined waveforms, mainly rectangular, and hence are inapt for exploring the emerging paradigm. Advances in clinical DBS are moving towards incorporating new stimulation parameters, yet we remain limited in our capacity to test these in animal models, arguably a critical first step. Accordingly, there is a need for the development of new miniature, low-power devices to enable investigation into the new DBS paradigms in preclinical settings. The ideal device would allow for flexibility in the stimulation waveforms, while remaining suitable for chronic, tetherless, biphasic deep brain stimulation. In this work, we elucidate several key parameters in a DBS system, identify gaps in existing solutions, and propose a new device to support preclinical DBS. The device allows for a high degree of flexibility in the output waveform with easily altered shape, frequency, pulse-width and amplitude. The device is suitable for both traditional and modern stimulation schemes, including those using non-rectangular waveforms, as well as delayed feedback schemes. The device incorporates active charge balancing to ensure safe operation, and allows for simple production of custom biphasic waveforms. This custom waveform output is unique in the field of preclinical DBS devices, and could be advantageous in performing future DBS studies investigating new treatment paradigms. This tetherless device can be easily and comfortably carried by an animal in a back-mountable configuration. The results of in-vitro tests are presented and discussed.

Toward Electrophysiology-Based Intelligent Adaptive Deep Brain Stimulation for Movement Disorders.

Deep brain stimulation (DBS) represents one of the major clinical breakthroughs in the age of translational neuroscience. In 1987, Benabid and colleagues demonstrated that high-frequency stimulation can mimic the effects of ablative neurosurgery in Parkinson's disease (PD), while offering two key advantages to previous procedures: adjustability and reversibility. Deep brain stimulation is now an established therapeutic approach that robustly alleviates symptoms in patients with movement disorders, such as Parkinson's disease, essential tremor, and dystonia, who present with inadequate or adverse responses to medication. Currently, stimulation electrodes are implanted in specific target regions of the basal ganglia-thalamic circuit and stimulation pulses are delivered chronically. To achieve optimal therapeutic effect, stimulation frequency, amplitude, and pulse width must be adjusted on a patient-specific basis by a movement disorders specialist. The finding that pathological neural activity can be sampled directly from the target region using the DBS electrode has inspired a novel DBS paradigm: closed-loop adaptive DBS (aDBS). The goal of this strategy is to identify pathological and physiologically normal patterns of neuronal activity that can be used to adapt stimulation parameters to the concurrent therapeutic demand. This review will give detailed insight into potential biomarkers and discuss next-generation strategies, implementing advances in artificial intelligence, to further elevate the therapeutic potential of DBS by capitalizing on its modifiable nature. Development of intelligent aDBS, with an ability to deliver highly personalized treatment regimens and to create symptom-specific therapeutic strategies in real-time, could allow for significant further improvements in the quality of life for movement disorders patients with DBS that ultimately could outperform traditional drug treatment.

Predicting beta bursts from local field potentials to improve closed-loop DBS paradigms in Parkinson's patients.

Motor symptoms in Parkinson's disease (PD) correlate with an excess in synchrony in the beta frequency band (13-30Hz) of local field potentials recorded from basal ganglia circuits. Recent results have suggested that this abnormal activity arises as a result of changes in specific dynamical features of the underlying neural signatures. In particular, patterns of activity in the beta band have been shown to be structured in bursts of longer durations and higher amplitudes in untreated patients with PD. Closed-loop deep brain stimulation (DBS) paradigms that specifically target these pathological bursts of activity hold promises to help trim, and thus normalize, their abnormal behavior in real-time. Here, we developed classification algorithms that predict pathological beta bursts based on ongoing changes in LFP frequency dynamics. We then compared simulations of prediction-based DBS profiles with existing 'adaptive DBS' alternatives. We show that model-driven stimulation profiles are more precise in restricting the delivery of stimulation to bursts that are considered pathological, while preserving physiological ones. The overall stimulation time required is also diminished, thus supporting longer battery life. These results represent a conceptual and algorithmic framework for the development of more precise DBS strategies that are selectively tailored to the electrophysiological profile of each patient.

Local vs. volume conductance activity of field potentials in the human subthalamic nucleus.

Subthalamic nucleus field potentials have attracted growing research and clinical interest over the last few decades. However, it is unclear whether subthalamic field potentials represent locally generated neuronal subthreshold activity or volume conductance of the organized neuronal activity generated in the cortex. This study aimed at understanding of the physiological origin of subthalamic field potentials and determining the most accurate method for recording them. We compared different methods of recordings in the human subthalamic nucleus: spikes (300-9,000 Hz) and field potentials (3-100 Hz) recorded by monopolar micro- and macroelectrodes, as well as by differential-bipolar macroelectrodes. The recordings were done outside and inside the subthalamic nucleus during electrophysiological navigation for deep brain stimulation procedures (150 electrode trajectories) in 41 Parkinson's disease patients. We modeled the signal and estimated the contribution of nearby/independent vs. remote/common activity in each recording configuration and area. Monopolar micro- and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity. However, bipolar macroelectrode recordings inside the subthalamic nucleus can detect locally generated potentials. These results are confirmed by high correspondence between the model predictions and actual correlation of neuronal activity recorded by electrode pairs. Differential bipolar macroelectrode subthalamic field potentials can overcome volume conductance effects and reflect locally generated neuronal activity. Bipolar macroelectrode local field potential recordings might be used as a biological marker of normal and pathological brain functions for future electrophysiological studies and navigation systems as well as for closed-loop deep brain stimulation paradigms.NEW & NOTEWORTHY Our results integrate a new method for human subthalamic recordings with a development of an advanced mathematical model. We found that while monopolar microelectrode and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity, bipolar macroelectrode recordings inside the subthalamic nucleus (STN) detect locally generated potentials that are significantly different than those recorded outside the STN. Differential bipolar subthalamic field potentials can be used in navigation and closed-loop deep brain stimulation paradigms.

Comparison of Globus Pallidus Interna and Subthalamic Nucleus in Deep Brain Stimulation for Parkinson Disease: An Institutional Experience and Review.

Deep Brain Stimulation (DBS) has revolutionized the lives of patients of Parkinson disease, offering therapeutic options to those not benefiting entirely from medications alone. With its proven track record of outperforming the best medical management, the goal is to unlock the full potential of this therapy. Currently, the Globus Pallidus Interna (GPi) and Subthalamic Nucleus (STN) are both viable targets for DBS, and the choice of site should focus on the constellation of symptoms, both motor and nonmotor, which are key determinants to quality of life. Our article sheds light on the specific advantages and drawbacks of the two sites, highlighting the need for matching the inherent properties of a target with specific desired effects in patients. UT Southwestern Medical Center has a robust and constantly evolving DBS program and the narrative from our center provides invaluable insight into the practical realities of DBS. The ultimate decision in selecting a DBS target is complex, ideally made by a multidisciplinary team, tailored towards each patient's profile and their expectations, by drawing upon scientific evidence coupled with experience. Ongoing research is expanding our knowledge base, which should be dynamically incorporated into an institute's DBS paradigm to ensure that patients receive the optimal therapy.