Pathological Neural Activity Research Articles

Clinico-physiological correlates of Parkinson’s disease from multi-resolution basal ganglia recordings

Parkinson’s disease (PD) has been associated with pathological neural activity within the basal ganglia. Herein, we analyzed resting-state single-neuron and local field potential (LFP) activities from people with PD who underwent awake deep brain stimulation surgery of the subthalamic nucleus (STN; n = 125) or globus pallidus internus (GPi; n = 44), and correlated rate-based and oscillatory features with UPDRSIII off-medication subscores. Rate-based single-neuron features did not correlate with PD symptoms. STN single-neuron and LFP low-beta (12–21 Hz) power and burst dynamics showed modest correlations with bradykinesia and rigidity severity, while STN spiketrain theta (4–8 Hz) power correlated modestly with tremor severity. GPi low- and high-beta (21–30 Hz) power and burst dynamics correlated moderately with bradykinesia and axial symptom severity. These findings suggest that elevated single-neuron and LFP oscillations may be linked to symptoms, though modest correlations imply that the pathophysiology of PD may extend beyond resting-state beta oscillations.

Deep brain stimulation and lag synchronization in a memristive two-neuron network

In the pursuit of potential treatments for neurological disorders and the alleviation of patient suffering, deep brain stimulation (DBS) has been utilized to intervene or investigate pathological neural activities. To explore the exact mechanism of how DBS works, a memristive two-neuron network considering DBS is newly proposed in this work. This network is implemented by coupling two-dimensional Morris–Lecar neuron models and using a memristor synaptic synapse to mimic synaptic plasticity. The complex bursting activities and dynamical effects are revealed numerically through dynamical analysis. By examining the synchronous behavior, the desynchronization mechanism of the memristor synapse is uncovered. The study demonstrates that synaptic connections lead to the appearance of time-lagged or asynchrony in completely synchronized firing activities. Additionally, the memristive two-neuron network is implemented in hardware based on FPGA, and experimental results confirm the abundant neuronal electrical activities and chaotic dynamical behaviors. This work offers insights into the potential mechanisms of DBS intervention in neural networks.

Chronic intracranial recordings in the globus pallidus reveal circadian rhythms in Parkinson’s disease

Circadian rhythms have been shown in the subthalamic nucleus (STN) in Parkinson’s disease (PD), but only a few studies have focused on the globus pallidus internus (GPi). This retrospective study investigates GPi circadian rhythms in a large cohort of subjects with PD (130 recordings from 93 subjects) with GPi activity chronically recorded in their home environment. We found a significant change in GPi activity between daytime and nighttime in most subjects (82.4%), with a reduction in GPi activity at nighttime in 56.2% of recordings and an increase in activity in 26.2%. GPi activity in higher frequency bands ( > 20 Hz) was more likely to decrease at night and in patients taking extended-release levodopa medication. Our results suggest that circadian fluctuations in the GPi vary across individuals and that increased power at night might be due to the reemergence of pathological neural activity. These findings should be considered to ensure successful implementation of adaptive neurostimulation paradigms in the real-world.

Multimodal acoustic-electric trigeminal nerve stimulation modulates conscious perception

Multimodal stimulation can reverse pathological neural activity and improve symptoms in neuropsychiatric diseases. Recent research shows that multimodal acoustic-electric trigeminal-nerve stimulation (TNS) (i.e., musical stimulation synchronized to electrical stimulation of the trigeminal nerve) can improve consciousness in patients with disorders of consciousness. However, the reliability and mechanism of this novel approach remain largely unknown. We explored the effects of multimodal acoustic-electric TNS in healthy human participants by assessing conscious perception before and after stimulation using behavioral and neural measures in tactile and auditory target-detection tasks. To explore the mechanisms underlying the putative effects of acoustic-electric stimulation, we fitted a biologically plausible neural network model to the neural data using dynamic causal modeling. We observed that (1) acoustic-electric stimulation improves conscious tactile perception without a concomitant change in auditory perception, (2) this improvement is caused by the interplay of the acoustic and electric stimulation rather than any of the unimodal stimulation alone, and (3) the effect of acoustic-electric stimulation on conscious perception correlates with inter-regional connection changes in a recurrent neural processing model. These results provide evidence that acoustic-electric TNS can promote conscious perception. Alterations in inter-regional cortical connections might be the mechanism by which acoustic-electric TNS achieves its consciousness benefits.

Subthalamic high-beta oscillation informs the outcome of deep brain stimulation in patients with Parkinson's disease.

BackgroundThe therapeutic effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD) is related to the modulation of pathological neural activities, particularly the synchronization in the β band (13–35 Hz). However, whether the local β activity in the STN region can directly predict the stimulation outcome remains unclear.ObjectiveWe tested the hypothesis that low-β (13–20 Hz) and/or high-β (20–35 Hz) band activities recorded from the STN region can predict DBS efficacy.MethodsLocal field potentials (LFPs) were recorded in 26 patients undergoing deep brain stimulation surgery in the subthalamic nucleus area. Recordings were made after the implantation of the DBS electrode prior to its connection to a stimulator. The maximum normalized powers in the theta (4–7 Hz), alpha (7–13 Hz), low-β (13–20 Hz), high-β (20–35 Hz), and low-γ (40–55 Hz) subbands in the postoperatively recorded LFP were correlated with the stimulation-induced improvement in contralateral tremor or bradykinesia–rigidity. The distance between the contact selected for stimulation and the contact with the maximum subband power was correlated with the stimulation efficacy. Following the identification of the potential predictors by the significant correlations, a multiple regression analysis was performed to evaluate their effect on the outcome.ResultsThe maximum high-β power was positively correlated with bradykinesia–rigidity improvement (rs = 0.549, p < 0.0001). The distance to the contact with maximum high-β power was negatively correlated with bradykinesia–rigidity improvement (rs = −0.452, p < 0.001). No significant correlation was observed with low-β power. The maximum high-β power and the distance to the contact with maximum high-β power were both significant predictors for bradykinesia–rigidity improvement in the multiple regression analysis, explaining 37.4% of the variance altogether. Tremor improvement was not significantly correlated with any frequency.ConclusionHigh-β oscillations, but not low-β oscillations, recorded from the STN region with the DBS lead can inform stimulation-induced improvement in contralateral bradykinesia–rigidity in patients with PD. High-β oscillations can help refine electrode targeting and inform contact selection for DBS therapy.

Non-ablative doses of focal ionizing radiation alters function of central neural circuits

BackgroundModulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. ObjectiveThe goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). MethodsWe treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. ResultsDoses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. ConclusionWe provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Patch Clamp Technology for Focused Ultrasonic (FUS) Neuromodulation.

Electrical stimulation of neural tissue, such as deep brain stimulation (DBS) and cortical stimulation, is widely applied therapeutic neuromodulation techniques for neurologic disorders. Penetrating electrodes (e.g., microwires and silicon probes) for DBS provide high spatial resolution, but are invasive, displacing neural tissue, producing acute insertion trauma, and potentially eliciting a foreign-body response. Surface electrodes, while less invasive, cannot generate a highly localized electrical field. Motivated by these limitations, the goal of this chapter is to provide a protocol to run patch clamp experiments on rat brain slices with a focused ultrasonic transducer that offers minimally invasive and highly localized neuronal stimulation (and that is thin enough to let light to pass through for optical observation of neuron cells for patching). Though focused acoustic beams with high energy are traditionally used for cellular ablation, the goal here is to use low acoustic energy to avoid any ablation or lesion, exploiting the unprecedented features of self-focusing acoustic transducers (SFATs) that can focus 2-20MHz sound waves at a submillimeter-sized area. The experimental procedures described here will allow intracellular and extracellular experiments to determine the value and underlying mechanisms of neuromodulation effects induced by SFAT-based ultrasonic stimulation. The aims of this protocol are (1) to fabricate SFATs for the proposed intracellular and extracellular experiments and (2) to characterize the neuromodulatory function evoked by SFAT-based ultrasound stimulation in normal brain slices. Using patch clamp methods, one can monitor ionic flux and local field potentials, while varying the acoustic stimulation frequency, intensity, pulse width, pulse shape and pulse repetition frequency as well as the focal spot(s), focal size and force direction. The patch clamp experiments will provide insights into biologic mechanisms of ultrasonic neural stimulation, and could be a critical step toward the development of a minimally invasive alternative to neuromodulation by electrical stimulation in the treatment of neurologic disorders such as epilepsy. If the underlying mechanisms of ultrasonic neural stimulation are well understood, a transcranial focused ultrasound beam can possibly modulate pathological neural activities, without surgery, running wire, or any damaging effects from penetrating probe.

Differential Effects of Pathological Beta Burst Dynamics Between Parkinson's Disease Phenotypes Across Different Movements.

Background: Resting state beta band (13–30 Hz) oscillations represent pathological neural activity in Parkinson’s disease (PD). It is unknown how the peak frequency or dynamics of beta oscillations may change among fine, limb, and axial movements and different disease phenotypes. This will be critical for the development of personalized closed loop deep brain stimulation (DBS) algorithms during different activity states.Methods: Subthalamic (STN) and local field potentials (LFPs) were recorded from a sensing neurostimulator (Activa® PC + S, Medtronic PLC.) in fourteen PD participants (six tremor-dominant and eight akinetic-rigid) off medication/off STN DBS during 30 s of repetitive alternating finger tapping, wrist-flexion extension, stepping in place, and free walking. Beta power peaks and beta burst dynamics were identified by custom algorithms and were compared among movement tasks and between tremor-dominant and akinetic-rigid groups.Results: Beta power peaks were evident during fine, limb, and axial movements in 98% of movement trials; the peak frequencies were similar during each type of movement. Burst power and duration were significantly larger in the high beta band, but not in the low beta band, in the akinetic-rigid group compared to the tremor-dominant group.Conclusion: The conservation of beta peak frequency during different activity states supports the feasibility of patient-specific closed loop DBS algorithms driven by the dynamics of the same beta band during different activities. Akinetic-rigid participants had greater power and longer burst durations in the high beta band than tremor-dominant participants during movement, which may relate to the difference in underlying pathophysiology between phenotypes.

The great reset: Transcranial pulse stimulation reduces global EEG-entropy in Alzheimer's Disease

Abstract Background: Transcranial Pulse Stimulation (TPS) is a new therapy that uses shockwaves for the treatment of Alzheimer's Disease (AD). In humans, there is first evidence for beneficial clinical effects after a series of six TPS sessions. Magnetic resonance imaging studies suggest up-regulation of memory networks as well as increased cortical thickness after stimulation. Effects on oscillatory electrical brain activity measured with resting state electroencephalography (EEG) have not been reported so far. Methods: A consecutive number of four pilot TPS-treated AD-patients was examined. TPS-naïve resting EEGs were recorded before treatment and compared with EEG-recordings directly after first stimulation. All patients received 4Hz TPS of about 6000 pulses of 0.2 mJ/mm2 (navigated bifrontally, biparietally, bitemporally and praecuneus) using the Neurolith System (Storz Medical). Frontal, parietal, central and temporal channel clusters were analyzed with regard to their alpha, theta delta and gamma power and for a measure of Tsallis entropy. Results: The immediate effect after first TPS on grand-average EEG resting state showed an increase of power in all frequency bands and for total power, although a significant difference between pre- and post-stimulation was not revealed due to power variability. However, the grand-average across patients and channels of Tsallis entropy showed a significant reduction after a single stimulation session. Discussion / Conclusion: Limited due to a high variability (and possibly due to underpower) we found power increase across frequency bands and channels which failed signifance. On the other hand Tsallis entropy was a more sensitive measure for change on EEG activity after stimulation. This might reflect a global reset of uncoordinated and thus pathological neural activity after TPS stimulation. More measurements should be added including longitudinal serial recordings over the treatment course of six sessions with correlations of clinical treatment effects. Keywords: transcranial pulse stimulation, shock wave , Alzheimer, EEG

In vivo endocannabinoid dynamics at the timescale of physiological and pathological neural activity

The brain's endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling invivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling invivo.

An Embedded Multi-Core Real-Time Simulation Platform of Basal Ganglia for Deep Brain Stimulation.

Closed-loop deep brain stimulation (DBS) paradigm is gaining tremendous favor due to its potential capability of further and more efficient improvements in neurological diseases. Preclinical validation of closed-loop controller is quite necessary in order to minimize injury risks of clinical trials to patients, which can greatly benefit from real-time computational models and thus potentially reduce research and development costs and time. Here we developed an embedded multi-core real-time simulation platform (EMC-RTP) for a biological-faithful computational network model of basal ganglia (BG). The single neuron model is implemented in a highly real-time manner using a reasonable simplification. A modular mapping architecture with hierarchical routing organization was constructed to mimic the pathological neural activities of BG observed in parkinsonian conditions. A closed-loop simulation testbed for DBS validation was then set up using a host computer as the DBS controller. The availability of EMC-RTP and the testbed system was validated by comparing the performance of open-loop and proportional-integral (PI) controllers. Our experimental results showed that the proposed EMC-RTP reproduces abnormal beta bursts of BG in parkinsonian conditions while meets requirements of both real-time and computational accuracy as well. Closed-loop DBS experiments using the EMC-RTP suggested that the platform could perform reasonable output under different kinds of DBS strategies, indicating the usability of the platform.

Postsurgical lumbar facet joint syndrome: Therapeutic results of facet infiltration

IntroductionPostsurgical Lumbar facet joint syndrome (PLFJS) is a clinical entity characterized by acute or chronic lumbar pain which can irradiate to the lower extremities but never with a dermatomal pattern in postsurgical patients of lumbar surgery. The diagnosis and treatment are with a Diagnostic Facet Block (DFB). This study describes the outcome of patients undergoing DFB after lumbar surgery and compares the results with patients without surgery. MethodsAn analytic and longitudinal study with patients over 18 years old between January 2018 and January 2020. For the comparative analysis, we performed two groups: non-surgical lumbar facet joint syndrome (NSLFJS) and PLFJS. ResultsThe general prevalence of PLFJS in our population was 12.5%. The results after DBF showed a significant decrease in the Oswestry percentage and pain according to the Visual Analog Scale(VAS) for the NSLFJS and PLFJS groups between the 3 surgical stages (pre-DFB, post-DFB at 6 weeks and post-DFB at 6 months), but no significant differences between the 2 groups. DiscussionThe VAS and Oswestry reported a significant improvement in both groups of patients. The innervation of the lumbar facet joints causes pain, this is secondary to the pathological neural activity of facet arthritis that arises because of chronic postsurgical inflammation or chronic degenerative changes. ConclusionThe origin of the LFJS is the arthrosis of the facet, originated by postsurgical or degenerative changes.DFB is effectivefor decreasing pain of facet joint origin in patients with previous lumbar surgery.

Modulation of beta bursts in subthalamic sensorimotor circuits predicts improvement in bradykinesia.

No biomarker of Parkinson's disease exists that allows clinicians to adjust chronic therapy, either medication or deep brain stimulation, with real-time feedback. Consequently, clinicians rely on time-intensive, empirical, and subjective clinical assessments of motor behaviour and adverse events to adjust therapies. Accumulating evidence suggests that hypokinetic aspects of Parkinson's disease and their improvement with therapy are related to pathological neural activity in the beta band (beta oscillopathy) in the subthalamic nucleus. Additionally, effectiveness of deep brain stimulation may depend on modulation of the dorsolateral sensorimotor region of the subthalamic nucleus, which is the primary site of this beta oscillopathy. Despite the feasibility of utilizing this information to provide integrated, biomarker-driven precise deep brain stimulation, these measures have not been brought together in awake freely moving individuals. We sought to directly test whether stimulation-related improvements in bradykinesia were contingent on reduction of beta power and burst durations, and/or the volume of the sensorimotor subthalamic nucleus that was modulated. We recorded synchronized local field potentials and kinematic data in 16 subthalamic nuclei of individuals with Parkinson's disease chronically implanted with neurostimulators during a repetitive wrist-flexion extension task, while administering randomized different intensities of high frequency stimulation. Increased intensities of deep brain stimulation improved movement velocity and were associated with an intensity-dependent reduction in beta power and mean burst duration, measured during movement. The degree of reduction in this beta oscillopathy was associated with the improvement in movement velocity. Moreover, the reduction in beta power and beta burst durations was dependent on the theoretical degree of tissue modulated in the sensorimotor region of the subthalamic nucleus. Finally, the degree of attenuation of both beta power and beta burst durations, together with the degree of overlap of stimulation with the sensorimotor subthalamic nucleus significantly explained the stimulation-related improvement in movement velocity. The above results provide direct evidence that subthalamic nucleus deep brain stimulation-related improvements in bradykinesia are related to the reduction in beta oscillopathy within the sensorimotor region. With the advent of sensing neurostimulators, this beta oscillopathy combined with lead location could be used as a marker for real-time feedback to adjust clinical settings or to drive closed-loop deep brain stimulation in freely moving individuals with Parkinson's disease.

A Population Model of Deep Brain Stimulation in Movement Disorders From Circuits to Cells.

For more than 30 years, deep brain stimulation (DBS) has been used to target the symptoms of a number of neurological disorders and in particular movement disorders such as Parkinson’s disease (PD) and essential tremor (ET). It is known that the loss of dopaminergic neurons in the substantia nigra leads to PD, while the exact impact of this on the brain dynamics is not fully understood, the presence of beta-band oscillatory activity is thought to be pathological. The cause of ET, however, remains uncertain, however pathological oscillations in the thalamocortical-cerebellar network have been linked to tremor. Both of these movement disorders are treated with DBS, which entails the surgical implantation of electrodes into a patient’s brain. While DBS leads to an improvement in symptoms for many patients, the mechanisms underlying this improvement is not clearly understood, and computational modeling has been used extensively to improve this. Many of the models used to study DBS and its effect on the human brain have mainly utilized single neuron and single axon biophysical models. We have previously shown in separate models however, that the use of population models can shed much light on the mechanisms of the underlying pathological neural activity in PD and ET in turn, and on the mechanisms underlying DBS. Together, this work suggested that the dynamics of the cerebellar-basal ganglia thalamocortical network support oscillations at frequency range relevant to movement disorders. Here, we propose a new combined model of this network and present new results that demonstrate that both Parkinsonian oscillations in the beta band and oscillations in the tremor frequency range arise from the dynamics of such a network. We find regions in the parameter space demonstrating the different dynamics and go on to examine the transition from one oscillatory regime to another as well as the impact of DBS on these different types of pathological activity. This work will allow us to better understand the changes in brain activity induced by DBS, and allow us to optimize this clinical therapy, particularly in terms of target selection and parameter setting.

Bimodal Auditory Electrical Stimulation for the Treatment of Tinnitus: Preclinical and Clinical Studies.

Tinnitus, or the phantom perception of sound, arises from pathological neural activity. Neurophysiological research has shown increased spontaneous firing rates and synchronization along the auditory pathway correlate strongly with behavioral measures of tinnitus. Auditory neurons are plastic, enabling external stimuli to be utilized to elicit long-term changes to spontaneous firing and synchrony. Pathological plasticity can thus be reversed using bimodal auditory plus nonauditory stimulation to reduce tinnitus. This chapter discusses preclinical and clinical evidence for efficacy of bimodal stimulation treatments of tinnitus, with highlights on sham-controlled, double-blinded clinical trials. The results from these studies have shown some efficacy in reducing the severity of tinnitus, based on subjective and objective outcome measures including tinnitus questionnaires and psychophysical tinnitus measurements. While results of some studies have been positive, the degree of benefit and the populations that respond to treatment vary across the studies. Directions and implications of future studies are discussed.

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.

Deep Brain Stimulation Programming 2.0: Future Perspectives for Target Identification and Adaptive Closed Loop Stimulation.

Deep brain stimulation has developed into an established treatment for movement disorders and is being actively investigated for numerous other neurological as well as psychiatric disorders. An accurate electrode placement in the target area and the effective programming of DBS devices are considered the most important factors for the individual outcome. Recent research in humans highlights the relevance of widespread networks connected to specific DBS targets. Improving the targeting of anatomical and functional networks involved in the generation of pathological neural activity will improve the clinical DBS effect and limit side-effects. Here, we offer a comprehensive overview over the latest research on target structures and targeting strategies in DBS. In addition, we provide a detailed synopsis of novel technologies that will support DBS programming and parameter selection in the future, with a particular focus on closed-loop stimulation and associated biofeedback signals.

Implantable Multi-Modality Probe for Subdural Simultaneous Measurement of Electrophysiology, Hemodynamics, and Temperature Distribution.

The purpose of this paper is to demonstrate how the integration of the multi-channel measurement capabilities of near-infrared spectroscopy (NIRS), electrocorticography (ECoG), and negative temperature coefficient thermistor sensors into a single device compact enough for subdural implantation can provide beneficial information on various aspects of brain cortical activity and prove a powerful medical modality for pre-, intra-, and post-operative diagnoses in neurosurgery. The development of a flexible multi-modal multi-channel probe for the simultaneous measurement of the NIRS, ECoG, and surficial temperature obtained from the cerebral cortex was carried out. Photoelectric bare chips for NIRS channels, miniature temperature-coefficient thermistors for measuring localized temperature variation, and 3-mm-diameter platinum plates for ECoG recording were assembled on a polyimide-based flexible printed circuit to create six channels for each modality. A conformal coating of Parylene-C was applied on all the channels except the ECoG to make the probe surface biocompatible. As a first-in-human study, the simultaneous measurement capability of the multi-modality probe, with sufficient signal-to-noise ratio and accuracy, to observe pathological neural activities in subjects during surgery and post-operative monitoring, with no complications two weeks since the implantation, was confirmed. The feasibility of using a single device to assess the dynamic pathological activity from three different aspects was determined for human patients. The simultaneous and accurate multi-channel recording of electrical, hemodynamic, and thermographic cortical activities in a single device small enough for subdural implantation is likely to have major implications in neurosurgery and neuroscience.

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.

Parkinsonism-related β oscillations in the primate basal ganglia networks – Recent advances and clinical implications

Today, the basal ganglia (BG) network can be viewed as a three-layer neural network in which the striatum and the subthalamic nucleus (STN) are the two BG input structures and together innervate BG downstream structures using GABA and glutamate, respectively. The striatum is larger than the STN and is the main site of dopamine depletion in Parkinson's disease (PD). However, STN is the prime target for deep brain stimulation (DBS) of patients with advanced PD. Traditionally, the efficacy of STN-DBS is attributed to the suppression of the pathological synchronous β oscillations along the cortico-thalamo BG network. In conventional DBS, stimulation is delivered continuously and equally influences normal and pathological neural activity. A DBS protocol would be therefore more effective if stimulation was only applied when necessary. We recently showed in the non-human primate model of PD that parkinsonism-related β oscillations resonate across the BG network through the STN, not the striatum. Moreover, we also demonstrated that BG β oscillations are episodic and albeit extended in parkinsonism also exists in the healthy condition. Thus, not all parkinsonian β oscillatory episodes are necessarily pathological. Remarkably, the duration of BG β episodes is more highly impacted than their magnitude in parkinsonism and may be more reliable metric - especially in STN - to discriminate between normal (“good”) and pathological (“bad”) β episodes. Thus, prolonged STN β episodes is suggested as one of the biomarkers of the pathological neuronal activity in parkinsonism that could be used as a trigger for adaptive DBS.