Mechanisms Of Deep Brain Stimulation Research Articles

State identification of Parkinson's disease based on transfer learning.

The local field potential (LFP) signals are a vital signal for studying the mechanisms of deep brain stimulation (DBS) and constructing adaptive DBS containing information related to the motor symptoms of Parkinson's disease (PD). A Parkinson's disease state identification algorithm based on the feature extraction strategy of transfer learning was proposed. The algorithm uses continuous wavelet transform (CWT) to convert one-dimensional LFP signals into two-dimensional gray-scalogram images and color images respectively, and designs a Bayesian optimized random forest (RF) classifier to replace the three fully connected layers for the classification task in the VGG16 model, to realize automatic identification of the pathological state of PD patients. It was found that consistently superior performance of gray-scalogram images over color images. The proposed algorithm achieved an accuracy of 97.76%, precision of 99.01%, recall of 96.47%, and F1-score of 97.73%, outperforming feature extractors such as VGG19, InceptionV3, ResNet50, and the lightweight network MobileNet. This algorithm has high accuracy and can distinguish the disease states of PD patients without manual feature extraction, effectively assisting the working of doctors.

Deep brain stimulation for Tourette's syndrome.

Tourette's syndrome is a neuropsychiatric disorder characterized by formidable motor and vocal tics. Many individuals also present with comorbid neuropsychiatric conditions. Though patients often benefit from pharmacological and behavioral therapies, a subset of individuals develop severe, treatment-resistant symptoms that might necessitate more invasive interventions, such as Deep Brain Stimulation (DBS). DBS, particularly targeting regions like the globus pallidus internus (GPi) and the centromedian-parafascicular complex (CM-Pf) of the thalamus, has demonstrated effectiveness in reducing tic severity and improving quality of life. This review outlines the mechanism, clinical efficacy, and long-term outcome of DBS in TS. Results from clinical studies reveal significant reductions in tics. However, success with DBS is variable depending on a number of factors, including target selection and electrode placement. The use of DBS has ethical considerations, which include risks to the surgical procedure, the need for full and complete informed consent, and questions about the implications of such treatment on cognitive and emotional growth. Long-term follow-up will be required to ensure appropriate patient outcomes and complication management. Additional research and ethical debate will be needed with advancing DBS technology to ensure responsible and equitable treatment. This paper narratively summarizes the surgical options available for TS, with a focus on the current status of DBS in the management of the disease.

Cross-species brain-wide mapping reveals a conserved and coordinated network engaged by NAc DBS.

Nucleus accumbens (NAc) deep brain stimulation (DBS) has been increasingly explored as a treatment modality for refractory neuropsychiatric disorders. Uncovering the accumbens network that is engaged by DBS is a critical step forward in understanding how modulating this important node impacts the broader mesocorticolimbic circuit. Using whole-brain clearing and unbiased, brain-wide neural activity mapping, we found that NAc DBS increases neural activity in a coordinated mesocorticolimbic network in mice. Simultaneous intracranial electrophysiology recordings from the human NAc and brief stimulation epochs of homologous mesocorticolimbic nodes revealed similar connectivity. Altogether, these results identify specific connectivity conserved across species within the mesocorticolimbic circuit that may underlie mechanisms of NAc DBS.

Deep Brain Stimulation Inhibits Epileptic Seizures via Increase of Adenosine Release and Inhibition of ENT1, CD39, and CD73 Expression.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus is an efficacious treatment option for patients with refractory epilepsy. Our previous study demonstrates that adenosine is a potential target of DBS for the treatment of epilepsy. Equilibrative nucleoside transporters-1 (ENT1) and ectonucleotidases (CD39, CD73) function as regulators of extracellular adenosine in the brain. It is unclear whether ENT1, CD39, and CD73 are involved in the mechanism of DBS for epilepsy. A total of 48 SD male rats were divided into four groups: control (naïve rats), Pilo (pilocarpine induced rats with epilepsy), DBS (rats with epilepsy treated with DBS for 8weeks), and sham. In the present study, video electroencephalogram monitoring, Morris water maze assays, in vivo measurements of adenosine using fiber photometry, histochemistry, and western blot were performed on the hippocampus. DBS markedly attenuated spontaneous recurrent seizures (SRSs) and enhanced spatial learning in rats with epilepsy, assessed through video-EEG and water maze assays. Fibred photometry measurements of an adenosine sensor revealed dynamic increase in extracellular adenosine during DBS. The expressions of ENT1, CD39, and CD73 in Pilo group and sham group increased compared with the control group, while the expressions of ENT1, CD39, and CD73 in DBS group decreased compared to that of Pilo group and sham group. The findings indicate that DBS reduces the number of SRSs and improves spatial memory in rats with epilepsy with concomitant decrease of ENT1, CD39, and CD73 expressions. Adenosine-modulating enzymes might be the potential targets of DBS for the treatment of epilepsy.

Optogenetic fMRI reveals therapeutic circuits of subthalamic nucleus deep brain stimulation

While deep brain stimulation (DBS) is widely employed for managing motor symptoms in Parkinson's disease (PD), its exact circuit mechanisms remain controversial. To identify the neural targets affected by therapeutic DBS in PD, we analyzed DBS-evoked whole brain activity in female hemi-parkinsonian rats using functional magnetic resonance imaging (fMRI). We delivered subthalamic nucleus (STN) DBS at various stimulation pulse repetition rates using optogenetics, allowing unbiased examination of cell-type specific STN feedforward neural activity. Unilateral optogenetic STN DBS elicited pulse repetition rate-dependent alterations of blood-oxygenation-level-dependent (BOLD) signals in SNr (substantia nigra pars reticulata), GP (globus pallidus), and CPu (caudate putamen). Notably, this modulation effectively ameliorated pathological circling behavior in animals expressing the kinetically faster Chronos opsin, but not in animals expressing ChR2. Furthermore, mediation analysis revealed that the pulse repetition rate-dependent behavioral rescue was significantly mediated by optogenetic DBS induced activity changes in GP and CPu, but not in SNr. This suggests that the activation of GP and CPu are critically involved in the therapeutic mechanisms of STN DBS.

A Computational Model of Deep Brain Stimulation for Parkinson's Disease Tremor and Bradykinesia.

Parkinson's disease (PD) is a progressive neurological disorder that is typically characterized by a range of motor dysfunctions, and its impact extends beyond physical abnormalities into emotional well-being and cognitive symptoms. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) leads to an array of dysfunctions in the functioning of the basal ganglia (BG) circuitry that manifests into PD. While active research is being carried out to find the root cause of SNc cell death, various therapeutic techniques are used to manage the symptoms of PD. The most common approach in managing the symptoms is replenishing the lost dopamine in the form of taking dopaminergic medications such as levodopa, despite its long-term complications. Another commonly used intervention for PD is deep brain stimulation (DBS). DBS is most commonly used when levodopa medication efficacy is reduced, and, in combination with levodopa medication, it helps reduce the required dosage of medication, prolonging the therapeutic effect. DBS is also a first choice option when motor complications such as dyskinesia emerge as a side effect of medication. Several studies have also reported that though DBS is found to be effective in suppressing severe motor symptoms such as tremors and rigidity, it has an adverse effect on cognitive capabilities. Henceforth, it is important to understand the exact mechanism of DBS in alleviating motor symptoms. A computational model of DBS stimulation for motor symptoms will offer great insights into understanding the mechanisms underlying DBS, and, along this line, in our current study, we modeled a cortico-basal ganglia circuitry of arm reaching, where we simulated healthy control (HC) and PD symptoms as well as the DBS effect on PD tremor and bradykinesia. Our modeling results reveal that PD tremors are more correlated with the theta band, while bradykinesia is more correlated with the beta band of the frequency spectrum of the local field potential (LFP) of the subthalamic nucleus (STN) neurons. With a DBS current of 220 pA, 130 Hz, and a 100 microsecond pulse-width, we could found the maximum therapeutic effect for the pathological dynamics simulated using our model using a set of parameter values. However, the exact DBS characteristics vary from patient to patient, and this can be further studied by exploring the model parameter space. This model can be extended to study different DBS targets and accommodate cognitive dynamics in the future to study the impact of DBS on cognitive symptoms and thereby optimize the parameters to produce optimal performance effects across modalities. Combining DBS with rehabilitation is another frontier where DBS can reduce symptoms such as tremors and rigidity, enabling patients to participate in their therapy. With DBS providing instant relief to patients, a combination of DBS and rehabilitation can enhance neural plasticity. One of the key motivations behind combining DBS with rehabilitation is to expect comparable results in motor performance even with milder DBS currents.

Deep Brain Stimulation Mechanisms in Parkinson's Disease: Immediate and Long-Term Effects

Deep Brain Stimulation Mechanisms in Parkinson's Disease: Immediate and Long-Term Effects

Septal stimulation attenuates hippocampal seizure with subregion specificity.

Deep brain stimulation (DBS) is a promising approach for the treatment of epilepsy. However, the optimal target for DBS and underlying mechanisms are still not clear. Here, we compared the therapeutic effects of DBS on distinct septal subregions, aimed to find the precise targets of septal DBS and related mechanisms for the clinical treatment. Assisted by behavioral test, electroencephalography (EEG) recording and analyzing, selectively neuronal manipulation and immunohistochemistry, we assessed the effects of DBS on the three septal subregions in kainic acid (KA)-induced mouse seizure model. DBS in the medial septum (MS) not only delayed generalized seizure (GS) development, but reduced the severity; DBS in the vertical diagonal band of Broca (VDB) only reduced the severity of GS, while DBS in the horizontal diagonal band of Broca (HDB) subregion showed no anti-seizure effect. Notably, DBS in the MS much more efficiently decreased abnormal activation of hippocampal neurons. EEG spectrum analysis indicated that DBS in the MS and VDB subregions mainly increased the basal hippocampal low-frequency (delta and theta) rhythm. Furthermore, ablation of cholinergic neurons in the MS and VDB subregions blocked the anti-seizure and EEG-modulating effects of septal DBS, suggesting the seizure-alleviating effect of DBS was dependent on local cholinergic neurons. DBS in the MS and VDB, rather than HDB, attenuates hippocampal seizure by activation of cholinergic neurons-augmented hippocampal delta/theta rhythm. This may be of great therapeutic significance for the clinical treatment of epilepsy with septal DBS. The optical target of deep brain stimulation in the septum is still not clear. This study demonstrated that stimulation in the medial septum and vertical diagonal band of Broca subregions, but not the horizontal diagonal band of Broca, could alleviate hippocampal seizure through cholinergic neurons-augmented hippocampal delta/theta rhythm. This study may shed light on the importance of precise regulation of deep brain stimulation therapy in treating epileptic seizures.

Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

Coupled Activation of the Hyperdirect and Cerebellothalamic Pathways with Zona Incerta Deep Brain Stimulation.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or ventral intermediate nucleus (VIM) are established targets for the treatment of Parkinson's disease (PD) or essential tremor (ET), respectively. However, DBS of the zona incerta (ZI) can be effective for both disorders. VIM DBS is assumed to achieve its therapeutic effect via activation of the cerebellothalamic (CBT) pathway, whereas the activation of the hyperdirect (HD) pathway likely plays a role in the mechanisms of STN DBS. Interestingly, HD pathway axons also emit collaterals to the ZI and red nucleus (RN) and the CBT pathway courses nearby to the ZI. The aim was to examine the ability of ZI DBS to mutually activate the HD and CBT pathways in a detailed computational model of human DBS. We extended a previous model of the human HD pathway to incorporate axon collaterals to the ZI and RN. The anatomical framework of the model system also included representations of the CBT pathway and internal capsule (IC) fibers of passage. We then performed detailed biophysical simulations to quantify DBS activation of the HD, CBT, and IC pathways with electrodes located in either the STN or ZI. STN DBS and ZI DBS both robustly activated the HD pathway. However, STN DBS was limited by IC activation at higher stimulus amplitudes. Alternatively, ZI DBS avoided IC activation while simultaneously activating the HD and CBT pathways. From both neuroanatomical and biophysical perspectives, ZI DBS represents an advantageous target for coupled activation of the HD and CBT pathways. © 2024 International Parkinson and Movement Disorder Society.

Insights into neuroinflammatory mechanisms of deep brain stimulation in Parkinson's disease

Parkinson's disease, a progressive neurodegenerative disorder, involves gradual degeneration of the nigrostriatal dopaminergic pathway, leading to neuronal loss within the substantia nigra pars compacta and dopamine depletion. Molecular factors, including neuroinflammation, impaired protein homeostasis, and mitochondrial dysfunction, contribute to the neuronal loss. Deep brain stimulation, a form of neuromodulation, applies electric current through stereotactically implanted electrodes, effectively managing motor symptoms in advanced Parkinson's disease patients. Deep brain stimulation exerts intricate effects on neuronal systems, encompassing alterations in neurotransmitter dynamics, microenvironment restoration, neurogenesis, synaptogenesis, and neuroprotection. Contrary to initial concerns, deep brain stimulation demonstrates antiinflammatory effects, influencing cytokine release, glial activation, and neuronal survival.This review investigates the intricacies of deep brain stimulation mechanisms, including insertional effects, histological changes, and glial responses, and sheds light on the complex interplay between electrodes, stimulation, and the brain. This exploration delves into understanding the role of neuroinflammatory pathways and the effects of deep brain stimulation in the context of Parkinson's disease, providing insights into its neuroprotective capabilities.

Deep Brain Stimulation - Efficacy and Safety for Neurological Treatments

Though Deep Brain Stimulation (DBS) has been a popular technology in medicine with constantly reported innovation for many years, there are only limited studies that summarize its efficacy and safety. To compensate, this article thoroughly analyses these topics of DBS as treatments for multiple neurological diseases. Initially, the history and mechanism of DBS are introduced. Then, studies targeting different neurological conditions review the general efficacy of DBS. For traditional DBS targets like Parkinson’s Disease (PD), substantial disability rating improvements in patients of large-scale clinical reports are evidence of efficacy. Whereas for novel DBS targets like Obsessive-compulsive Disorder (OCD) and Huntington’s Disease (HD), evidence mainly comes from improvements in small-scale patient case studies and thus require further studies. Next, studies covering various complications discuss the safety consideration of DBS. While intra-operational (including hemorrhage and infection) and post-operational complications (including device malfunction, psychiatric impact, motor disorder, and cognitive impairment) of DBS are proven, change in patient personality, identity, autonomy, authenticity, agency, and self (PIAAAS) after DBS operation requires further information. Finally, though current DBS technique carries multiple risk concerns and needs improvements, potential prospects and solutions are explored for this potent and thriving technology.

Short-term stimulations of the entopeduncular nucleus induce cerebellar changes of c-Fos expression in an animal model of paroxysmal dystonia

Deep brain stimulation (DBS) of the globus pallidus internus (entopeduncular nucleus, EPN, in rodents) is important for the treatment of drug-refractory dystonia. The pathophysiology of this movement disorder and the mechanisms of DBS are largely unknown. Insights into the mechanisms of DBS in animal models of dystonia can be helpful for optimization of DBS and add-on therapeutics. We recently found that short-term EPN-DBS with 130 Hz (50 µA, 60 µs) for 3 h improved dystonia in dtsz hamsters and reduced spontaneous excitatory cortico-striatal activity in brain slices of this model, indicating fast effects on synaptic plasticity. Therefore, in the present study, we examined if these effects are related to changes of c-Fos, a marker of neuronal activity, in brains derived from dtsz hamsters after these short-term DBS or sham stimulations. After DBS vs. sham, c-Fos intensity was increased around the electrode, but the number of c-Fos+ cells was not altered within the whole EPN and projection areas (habenula, thalamus). DBS did not induce changes in striatal and cortical c-Fos+ cells as GABAergic (GAD67+ and parvalbumin-reactive) neurons in motor cortex and striatum. Unexpectedly, c-Fos+ cells were decreased in deep cerebellar nuclei (DCN) after DBS, suggesting that cerebellar changes may be involved in antidystonic effects already during short-term DBS. However, the present results do not exclude functional changes within the basal ganglia–thalamo-cortical network, which will be further investigated by long-term EPN stimulations. The present study indicates that the cerebellum deserves attention in ongoing examinations on the mechanisms of DBS in dystonia.

Combining magnetoencephalography with telemetric streaming of intracranial recordings and deep brain stimulation—A feasibility study

Abstract The combination of subcortical Local Field Potential (LFP) recordings and stimulation with Magnetoencephalography (MEG) in Deep Brain Stimulation (DBS) patients enables the investigation of cortico-subcortical communication patterns and provides insights into DBS mechanisms. Until now, these recordings have been carried out in post-surgical patients with externalised leads. However, a new generation of telemetric stimulators makes it possible to record and stream LFP data in chronically implanted patients. Nevertheless, whether such streaming can be combined with MEG has not been tested. In the present study, we tested the most commonly implanted telemetric stimulator—Medtronic Percept PC with a phantom in three different MEG systems: two cryogenic scanners (CTF and MEGIN) and an experimental Optically Pumped Magnetometry (OPM)-based system. We found that when used in combination with the new SenSight segmented leads, Percept PC telemetric streaming only generates band-limited interference in the MEG at 123 Hz and harmonics. However, the “legacy streaming mode” used with older lead models generates multiple, dense artefact peaks in the physiological range of interest (below 50 Hz). The effect of stimulation on MEG critically depends on whether it is done in bipolar (between two contacts on the lead) or monopolar (between a lead contact and the stimulator case) mode. Monopolar DBS creates severe interference in the MEG as previously reported. However, we found that the OPM system is more resilient to this interference and could provide artefact-free measurements, at least for limited frequency ranges. A resting measurement in the MEGIN system from a Parkinson’s patient implanted with Percept PC and subthalamic SenSight leads revealed artefact patterns consistent with our phantom recordings. Moreover, analysis of LFP-MEG coherence in this patient showed oscillatory coherent networks consistent in their frequency and topography with those described in published group studies done with externalised leads. In conclusion, Percept PC telemetric streaming with SenSight leads is compatible with MEG. Furthermore, OPM sensors could provide additional new opportunities for studying DBS effects.

Unraveling the mechanisms of deep-brain stimulation of the internal capsule in a mouse model

Deep-brain stimulation (DBS) is an effective treatment for patients suffering from otherwise therapy-resistant psychiatric disorders, including obsessive-compulsive disorder. Modulation of cortico-striatal circuits has been suggested as a mechanism of action. To gain mechanistic insight, we monitored neuronal activity in cortico-striatal regions in a mouse model for compulsive behavior, while systematically varying clinically-relevant parameters of internal-capsule DBS. DBS showed dose-dependent effects on both brain and behavior: An increasing, yet balanced, number of excited and inhibited neurons was recruited, scattered throughout cortico-striatal regions, while excessive grooming decreased. Such neuronal recruitment did not alter basic brain function such as resting-state activity, and only occurred in awake animals, indicating a dependency on network activity. In addition to these widespread effects, we observed specific involvement of the medial orbitofrontal cortex in therapeutic outcomes, which was corroborated by optogenetic stimulation. Together, our findings provide mechanistic insight into how DBS exerts its therapeutic effects on compulsive behaviors.

Sub-harmonic entrainment of cortical gamma oscillations to deep brain stimulation in Parkinson's disease: Model based predictions and validation in three human subjects

ObjectivesThe exact mechanisms of deep brain stimulation (DBS) are still an active area of investigation, in spite of its clinical successes. This is due in part to the lack of understanding of the effects of stimulation on neuronal rhythms. Entrainment of brain oscillations has been hypothesised as a potential mechanism of neuromodulation. A better understanding of entrainment might further inform existing methods of continuous DBS, and help refine algorithms for adaptive methods. The purpose of this study is to develop and test a theoretical framework to predict entrainment of cortical rhythms to DBS across a wide range of stimulation parameters. Materials and MethodsWe fit a model of interacting neural populations to selected features characterising PD patients' off-stimulation finely-tuned gamma rhythm recorded through electrocorticography. Using the fitted models, we predict basal ganglia DBS parameters that would result in 1:2 entrainment, a special case of sub-harmonic entrainment observed in patients and predicted by theory. ResultsWe show that the neural circuit models fitted to patient data exhibit 1:2 entrainment when stimulation is provided across a range of stimulation parameters. Furthermore, we verify key features of the region of 1:2 entrainment in the stimulation frequency/amplitude space with follow-up recordings from the same patients, such as the loss of 1:2 entrainment above certain stimulation amplitudes. ConclusionOur results reveal that continuous, constant frequency DBS in patients may lead to nonlinear patterns of neuronal entrainment across stimulation parameters, and that these responses can be predicted by modelling. Should entrainment prove to be an important mechanism of therapeutic stimulation, our modelling framework may reduce the parameter space that clinicians must consider when programming devices for optimal benefit.

Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study

BackgroundAnorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN.MethodsWe performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only.ResultsAt baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group.ConclusionThe results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas.Trial registration Registered in the Netherlands Trial Register (https://www.trialregister.nl/trial/3322): NL3322 (NTR3469).

Electrophysiological insights into deep brain stimulation of the network disorder dystonia.

Deep brain stimulation (DBS), a treatment for modulating the abnormal central neuronal circuitry, has become the standard of care nowadays and is sometimes the only option to reduce symptoms of movement disorders such as dystonia. However, on the one hand, there are still open questions regarding the pathomechanisms of dystonia and, on the other hand, the mechanisms of DBS on neuronal circuitry. That lack of knowledge limits the therapeutic effect and makes it hard to predict the outcome of DBS for individual dystonia patients. Finding electrophysiological biomarkers seems to be a promising option to enable adapted individualised DBS treatment. However, biomarker search studies cannot be conducted on patients on a large scale and experimental approaches with animal models of dystonia are needed. In this review, physiological findings of deep brain stimulation studies in humans and animal models of dystonia are summarised and the current pathophysiological concepts of dystonia are discussed.

Neurophysiological mechanisms of deep brain stimulation across spatiotemporal resolutions.

Deep brain stimulation is a neuromodulatory treatment for managing the symptoms of Parkinson's disease and other neurological and psychiatric disorders. Electrodes are chronically implanted in disease-relevant brain regions and pulsatile electrical stimulation delivery is intended to restore neurocircuit function. However, the widespread interest in the application and expansion of this clinical therapy has preceded an overarching understanding of the neurocircuit alterations invoked by deep brain stimulation. Over the years, various forms of neurophysiological evidence have emerged which demonstrate changes to brain activity across spatiotemporal resolutions; from single-neuron, to local field potential, to brain-wide cortical network effects. Though fruitful, such studies have often led to debate about a singular putative mechanism. In this Update we aim to produce an integrative account of complementary instead of mutually exclusive neurophysiological effects to derive a generalizable concept of the mechanisms of deep brain stimulation. In particular, we offer a critical review of the most common historical competing theories, an updated discussion on recent literature from animal and human neurophysiological studies, and a synthesis of synaptic and network effects of DBS across scales of observation, including micro-, meso-, and macroscale circuit alterations.

The Therapeutic Frequency Profile of Subthalamic Nucleus Deep Brain Stimulation in Rats Is Shaped by Antidromic Spike Failure.

The therapeutic mechanisms of subthalamic nucleus (STN) deep brain stimulation (DBS) may depend on antidromic activation of cortex via the hyperdirect pathway. However, hyperdirect pathway neurons cannot reliably follow high-stimulation frequencies, and the spike failure rate appears to correlate with symptom relief as a function of stimulation frequency. We hypothesized that antidromic spike failure contributes to the cortical desynchronization caused by DBS. We measured in vivo evoked cortical activity in female Sprague Dawley rats and developed a computational model of cortical activation from STN DBS. We modeled stochastic antidromic spike failure to determine how spike failure affected the desynchronization of pathophysiological oscillatory activity in cortex. We found that high-frequency STN DBS desynchronized pathologic oscillations via the masking of intrinsic spiking through a combination of spike collision, refractoriness, and synaptic depletion. Antidromic spike failure shaped the parabolic relationship between DBS frequency and cortical desynchronization, with maximum desynchronization at ∼130 Hz. These findings reveal that antidromic spike failure plays a critical role in mediating the dependency of symptom relief on stimulation frequency.SIGNIFICANCE STATEMENT Deep brain stimulation (DBS) is a highly effective neuromodulation therapy, yet it remains uncertain why conventionally used stimulation frequencies (e.g., ∼130 Hz) are optimal. In this study, we demonstrate a potential explanation for the stimulation frequency dependency of DBS through a combination of in vivo experimental measurements and computational modeling. We show that high-frequency stimulation can desynchronize pathologic firing patterns in populations of neurons by inducing an informational lesion. However, sporadic spike failure at these high frequencies limits the efficacy of the informational lesion, yielding a parabolic profile with optimal effects at ∼130 Hz. This work provides a potential explanation for the therapeutic mechanism of DBS, and highlights the importance of considering spike failure in mechanistic models of DBS.