Reduction of alpha-synuclein oligomers in preclinical models of Parkinson's disease by electrical stimulation in vitro and deep brain stimulation in vivo.

BACKGROUND: Deep brain stimulation (DBS) has been widely used to manage debilitating neurological symptoms in movement disorders such as Parkinson's disease (PD). Despite its well-established symptomatic benefits, our understanding of the mechanisms underlying DBS and its possible effect on the accumulation of pathological proteins in neurodegeneration remains limited. Accumulation and oligomerization of the protein alpha-synuclein (α-Syn) are implicated in the loss of dopaminergic neurons in the substantia nigra in PD, making α-Syn a potential therapeutic target for disease modification. OBJECTIVE: We examined the effects of high frequency electrical stimulation on α-Syn levels and oligomerization in cell and rodent models. METHODS: High frequency stimulation, mimicking DBS parameters used for PD, was combined with viral-mediated overexpression of α-Syn in cultured rat primary cortical neurons or in substantia nigra of rats. Bimolecular protein complementation with split fluorescent protein reporters was used to detect and quantify α-Syn oligomers. RESULTS: High frequency electrical stimulation reduced the expression of PD-associated mutant α-Syn and mitigated α-Syn oligomerization in cultured neurons. Furthermore, DBS in the substantia nigra, but not the subthalamic nucleus, decreased overall levels of α-Syn, including oligomer levels, in the substantia nigra. CONCLUSIONS: Taken together, our results demonstrate that direct high frequency stimulation can reduce accumulation and pathological forms of α-Syn in cultured neurons in vitro and in substantia nigra in vivo. Thus, DBS therapy could have a role beyond symptomatic treatment, with potential disease-modifying properties that can be exploited to target pathological proteins in neurodegenerative diseases.

Another Step Forward for Freezing of Gait in Parkinson's Disease.

The study "A spinal cord neuroprosthesis for locomotor deficits due to Parkinson's disease" by Milekovic et al. introduces a novel neuroprosthesis for treating locomotor deficits in late-stage Parkinson's disease (PD). This approach employs an epidural spinal array targeting dorsal roots and electromyography to create a spatiotemporal map of muscle activation, aiming to restore natural gait patterns. Significant improvements in gait freezing and balance were observed in both non-human primate models and a human patient, resulting in improved mobility and quality of life. This innovative method, integrating real-time feedback and non-invasive motor intention decoding, marks a significant advancement in PD treatment.

Multi-modal investigation of transcranial ultrasound-induced neuroplasticity of the human motor cortex.

INTRODUCTION: There is currently a gap in accessibility to neuromodulation tools that can approximate the efficacy and spatial resolution of invasive methods. Low intensity transcranial focused ultrasound stimulation (TUS) is an emerging technology for non-invasive brain stimulation (NIBS) that can penetrate cortical and deep brain structures with more focal stimulation compared to existing NIBS modalities. Theta burst TUS (tbTUS, TUS delivered in a theta burst pattern) is a novel repetitive TUS protocol that can induce durable changes in motor cortex excitability, thereby holding promise as a novel neuromodulation tool with durable effects. OBJECTIVE: The aim of the present study was to elucidate the neurophysiologic effects of tbTUS motor cortical excitability, as well on local and global neural oscillations and network connectivity. METHODS: An 80-s train of active or sham tbTUS was delivered to the left motor cortex in 15 healthy subjects. Motor cortical excitability was investigated through transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) using paired-pulse TMS. Magnetoencephalography (MEG) recordings during resting state and an index finger abduction-adduction task were used to assess oscillatory brain responses and network connectivity. The correlations between the changes in neural oscillations and motor cortical excitability were also evaluated. RESULTS: tbTUS to the motor cortex results in a sustained increase in MEP amplitude and decreased SICI, but no change in ICF. MEG spectral power analysis revealed TUS-mediated desynchronization in alpha and beta spectral power. Significant changes in alpha power were detected within the supplementary motor cortex (Right > Left) and changes in beta power within bilateral supplementary motor cortices, right basal ganglia and parietal regions. Coherence analysis revealed increased local connectivity in motor areas. MEP and SICI changes correlated with both local and inter-regional coherence. CONCLUSION: The findings from this study provide novel insights into the neurophysiologic basis of TUS-mediated neuroplasticity and point to the involvement of regions within the motor network in mediating this sustained response. Future studies may further characterize the durability of TUS-mediated neuroplasticity and its clinical applications as a neuromodulation strategy for neurological and psychiatric disorders.

Identifying the neural network for neuromodulation in epilepsy through connectomics and graphs.

Deep brain stimulation is a treatment option for patients with drug-resistant epilepsy. The precise mechanism of neuromodulation in epilepsy is unknown, and biomarkers are needed for optimizing treatment. The aim of this study was to describe the neural network associated with deep brain stimulation targets for epilepsy and to explore its potential application as a novel biomarker for neuromodulation. Using seed-to-voxel functional connectivity maps, weighted by seizure outcomes, brain areas associated with stimulation were identified in normative resting state functional scans of 1000 individuals. To pinpoint specific regions in the normative epilepsy deep brain stimulation network, we examined overlapping areas of functional connectivity between the anterior thalamic nucleus, centromedian thalamic nucleus, hippocampus and less studied epilepsy deep brain stimulation targets. Graph network analysis was used to describe the relationship between regions in the identified network. Furthermore, we examined the associations of the epilepsy deep brain stimulation network with disease pathophysiology, canonical resting state networks and findings from a systematic review of resting state functional MRI studies in epilepsy deep brain stimulation patients. Cortical nodes identified in the normative epilepsy deep brain stimulation network were in the anterior and posterior cingulate, medial frontal and sensorimotor cortices, frontal operculum and bilateral insulae. Subcortical nodes of the network were in the basal ganglia, mesencephalon, basal forebrain and cerebellum. Anterior thalamic nucleus was identified as a central hub in the network with the highest betweenness and closeness values, while centromedian thalamic nucleus and hippocampus showed average centrality values. The caudate nucleus and mammillothalamic tract also displayed high centrality values. The anterior cingulate cortex was identified as an important cortical hub associated with the effect of deep brain stimulation in epilepsy. The neural network of deep brain stimulation targets shared hubs with known epileptic networks and brain regions involved in seizure propagation and generalization. Two cortical clusters identified in the epilepsy deep brain stimulation network included regions corresponding to resting state networks, mainly the default mode and salience networks. Our results were concordant with findings from a systematic review of resting state functional MRI studies in patients with deep brain stimulation for epilepsy. Our findings suggest that the various epilepsy deep brain stimulation targets share a common cortico-subcortical network, which might in part underpin the antiseizure effects of stimulation. Interindividual differences in this network functional connectivity could potentially be used as biomarkers in selection of patients, stimulation parameters and neuromodulation targets.

Human Studies of Transcranial Ultrasound neuromodulation: A systematic review of effectiveness and safety.

BACKGROUND: Transcranial ultrasound stimulation (TUS) is gaining traction as a safe and non-invasive technique in human studies. There has been a rapid increase in TUS human studies in recent years, with more than half of studies to date published after 2020. This rapid growth in the relevant body of literature necessitates comprehensive reviews to update clinicians and researchers. OBJECTIVE: The aim of this work is to review human studies with an emphasis on TUS devices, sonication parameters, outcome measures, results, and adverse effects, as well as highlight future directions of investigation. METHODS: A systematic review was conducted by searching the Web of Science and PubMed databases on January 12, 2022. Human studies of TUS were included. RESULTS: A total of 35 studies were identified using focused/unfocused ultrasound devices. A total of 677 subjects belonging to diverse cohorts (i.e., healthy, chronic pain, dementia, epilepsy, traumatic brain injury, depression) were enrolled. The stimulation effects vary in a sonication parameter-dependant fashion. Clinical, neurophysiological, radiological and histological outcome measures were assessed. No severe adverse effects were reported in any of the studies surveyed. Mild symptoms were observed in 3.4% (14/425) of the subjects, including headache, mood deterioration, scalp heating, cognitive problems, neck pain, muscle twitches, anxiety, sleepiness and pruritis. CONCLUSIONS: Although increasingly being used, TUS is still in its early phases. TUS can change short-term brain excitability and connectivity, induce long-term plasticity, and modulate behavior. New techniques should be used to further elucidate its underlying mechanisms and identify its application in novel populations.

Deep brain stimulation targets in epilepsy: Systematic review and meta-analysis of anterior and centromedian thalamic nuclei and hippocampus.

Deep brain stimulation (DBS) is a neuromodulatory treatment used in patients with drug-resistant epilepsy (DRE). The primary goal of this systematic review and meta-analysis is to describe recent advancements in the field of DBS for epilepsy, to compare the results of published trials, and to clarify the clinical utility of DBS in DRE. A systematic literature search was performed by two independent authors. Forty-four articles were included in the meta-analysis (23 for anterior thalamic nucleus [ANT], 8 for centromedian thalamic nucleus [CMT], and 13 for hippocampus) with a total of 527 patients. The mean seizure reduction after stimulation of the ANT, CMT, and hippocampus in our meta-analysis was 60.8%, 73.4%, and 67.8%, respectively. DBS is an effective and safe therapy in patients with DRE. Based on the results of randomized controlled trials and larger clinical series, the best evidence exists for DBS of the anterior thalamic nucleus. Further randomized trials are required to clarify the role of CMT and hippocampal stimulation. Our analysis suggests more efficient deep brain stimulation of ANT for focal seizures, wider use of CMT for generalized seizures, and hippocampal DBS for temporal lobe seizures. Factors associated with clinical outcome after DBS for epilepsy are electrode location, stimulation parameters, type of epilepsy, and longer time of stimulation. Recent advancements in anatomical targeting, functional neuroimaging, responsive neurostimulation, and sensing of local field potentials could potentially lead to improved outcomes after DBS for epilepsy and reduced sudden, unexpected death of patients with epilepsy. Biomarkers are needed for successful patient selection, targeting of electrodes and optimization of stimulation parameters.

Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

Time course of the effects of low-intensity transcranial ultrasound on the excitability of ipsilateral and contralateral human primary motor cortex.

Low-intensity transcranial ultrasound stimulation (TUS) is a promising non-invasive brain stimulation technique that can modulate the excitability of cortical and deep brain structures with a high degree of focality. Previous human studies showed that TUS decreases motor cortex (M1) excitability measured by transcranial magnetic stimulation (TMS), but whether the effects appear beyond sonication and whether TUS affects the excitability of other interconnected cortical areas is not known. The time course of M1 TUS on ipsilateral and contralateral M1 excitability was investigated in 22 healthy human subjects via TMS-induced motor-evoked potentials. With sonication duration of 500 ms, we found suppression of M1 excitability from 10 ms before to 20 ms after the end of sonication, and the effects were stronger with blocked design compared to interleaved design. There was no significant effect on contralateral M1 excitability. Using ex-vivo measurements, we showed that the ultrasound transducer did not affect the magnitude or time course of the TMS-induced electromagnetic field. We conclude that the online-suppressive effects of TUS on ipsilateral M1 cortical excitability slightly outlast the sonication but did not produce long-lasting effects. The absence of contralateral effects may suggest that there are little tonic interhemispheric interactions in the resting state, or the intensity of TUS was too low to induce transcallosal inhibition.

Implantable Pulse Generators for Deep Brain Stimulation: Challenges, Complications, and Strategies for Practicality and Longevity.

Deep brain stimulation (DBS) represents an important treatment modality for movement disorders and other circuitopathies. Despite their miniaturization and increasing sophistication, DBS systems share a common set of components of which the implantable pulse generator (IPG) is the core power supply and programmable element. Here we provide an overview of key hardware and software specifications of commercially available IPG systems such as rechargeability, MRI compatibility, electrode configuration, pulse delivery, IPG case architecture, and local field potential sensing. We present evidence-based approaches to mitigate hardware complications, of which infection represents the most important factor. Strategies correlating positively with decreased complications include antibiotic impregnation and co-administration and other surgical considerations during IPG implantation such as the use of tack-up sutures and smaller profile devices.Strategies aimed at maximizing battery longevity include patient-related elements such as reliability of IPG recharging or consistency of nightly device shutoff, and device-specific such as parameter delivery, choice of lead configuration, implantation location, and careful selection of electrode materials to minimize impedance mismatch. Finally, experimental DBS systems such as ultrasound, magnetoelectric nanoparticles, and near-infrared that use extracorporeal powered neuromodulation strategies are described as potential future directions for minimally invasive treatment.

Implantable photonic neural probes for light-sheet fluorescence brain imaging.

Significance: Light-sheet fluorescence microscopy (LSFM) is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, in vitro, and in vivo mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses < 16 µ m for propagation distances up to 300 µ m in free space. Imaging areas were as large as ≈ 240 µ m × 490 µ m in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals.

Deep-Brain Stimulation for Essential Tremor and Other Tremor Syndromes: A Narrative Review of Current Targets and Clinical Outcomes.

Tremor is a prevalent symptom associated with multiple conditions, including essential tremor (ET), Parkinson's disease (PD), multiple sclerosis (MS), stroke and trauma. The surgical management of tremor evolved from stereotactic lesions to deep-brain stimulation (DBS), which allowed safe and reversible interference with specific neural networks. This paper reviews the current literature on DBS for tremor, starting with a detailed discussion of current tremor targets (ventral intermediate nucleus of the thalamus (Vim), prelemniscal radiations (Raprl), caudal zona incerta (Zi), thalamus (Vo) and subthalamic nucleus (STN)) and continuing with a discussion of results obtained when performing DBS in the various aforementioned tremor syndromes. Future directions for DBS research are then briefly discussed.

Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.

Low-intensity transcranial ultrasound (TUS) can non-invasively modulate human neural activity. We investigated how different fundamental sonication parameters influence the effects of TUS on the motor cortex (M1) of 16 healthy subjects by probing cortico-cortical excitability and behavior. A low-intensity 500 kHz TUS transducer was coupled to a transcranial magnetic stimulation (TMS) coil. TMS was delivered 10 ms before the end of TUS to the left M1 hotspot of the first dorsal interosseous muscle. Varying acoustic parameters (pulse repetition frequency, duty cycle, and sonication duration) on motor-evoked potential amplitude were examined. Paired-pulse measures of cortical inhibition and facilitation, and performance on a visuomotor task was also assessed. TUS safely suppressed TMS-elicited motor cortical activity, with longer sonication durations and shorter duty cycles when delivered in a blocked paradigm. TUS increased GABAA-mediated short-interval intracortical inhibition and decreased reaction time on visuomotor task but not when controlled with TUS at near-somatosensory threshold intensity.

Deep Brain Stimulation of the Medial Septal Nucleus Induces Expression of a Virally Delivered Reporter Gene in Dentate Gyrus.

BACKGROUND: Mechanisms of deep brain stimulation (DBS) remain controversial, and spatiotemporal control of brain-wide circuits remains elusive. Adeno-associated viral (AAV) vectors have emerged as vehicles for spatiotemporal expression of exogenous transgenes in several tissues, including specific nuclei in the brain. Coupling DBS with viral vectors to modulate exogenous transgene expression remains unexplored. OBJECTIVE: This study examines whether DBS of the medial septal nucleus (MSN) can regulate gene expression of AAV-transduced neurons in a brain region anatomically remote from the stimulation target: the hippocampal dentate gyrus. METHODS: Rats underwent unilateral hippocampal injection of an AAV vector with c-Fos promoter-driven expression of TdTomato (TdT), followed by MSN electrode implantation. Rodents received no stimulation, 7.7 Hz (theta), or 130 Hz (gamma) DBS for 1 h one week after surgery. In a repeat stimulation experiment, rodents received either no stimulation, or two 1 h MSN DBS over 2 weeks. RESULTS: No significant differences in hippocampal TdT expression between controls and acute MSN DBS were found. With repeat DBS we found c-Fos protein expression was induced and we could detect increased TdT with either gamma or theta stimulation. CONCLUSION: We demonstrate that viral vector-mediated gene expression can be regulated spatially and temporally using DBS. Control of gene expression by DBS warrants further investigation into stimulation-responsive promoters for clinical applications.

Anatomy and function of the fornix in the context of its potential as a therapeutic target.

The fornix is a white matter bundle located in the mesial aspect of the cerebral hemispheres, which connects various nodes of a limbic circuitry and is believed to play a key role in cognition and episodic memory recall. As the most prevalent cause of dementia, Alzheimer's disease (AD) dramatically impairs the quality of life of patients and imposes a significant societal burden on the healthcare system. As an established treatment for movement disorders, deep brain stimulation (DBS) is currently being investigated in preclinical and clinical studies for treatment of memory impairment in AD by modulating fornix activity. Optimal target and stimulation parameters to potentially rescue memory deficits have yet to be determined. The aim of this review is to consolidate the structural and functional aspects of the fornix in the context of neuromodulation for memory deficits. We first present an anatomical and functional overview of the fibres and structures interconnected by the fornix. Recent evidence from preclinical models suggests that the fornix is subdivided into two distinct functional axes: a septohippocampal pathway and a subiculothalamic pathway. Each pathway's target and origin structures are presented, followed by a discussion of their oscillatory dynamics and functional connectivity. Overall, neuromodulation of each pathway of the fornix is discussed in the context of evidence-based forniceal DBS strategies. It is not yet known whether driving fornix activity can enhance cognition-optimal target and stimulation parameters to rescue memory deficits have yet to be determined.

Full-field swept-source optical coherence tomography and neural tissue classification for deep brain imaging.

Optical coherence tomography can differentiate brain regions with intrinsic contrast and at a micron scale resolution. Such a device can be particularly useful as a real-time neurosurgical guidance tool. We present, to our knowledge, the first full-field swept-source optical coherence tomography system operating near a wavelength of 1310 nm. The proof-of-concept system was integrated with an endoscopic probe tip, which is compatible with deep brain stimulation keyhole neurosurgery. Neuroimaging experiments were performed on ex vivo brain tissues and in vivo in rat brains. Using classification algorithms involving texture features and optical attenuation, images were successfully classified into three brain tissue types.

Cellular, molecular, and clinical mechanisms of action of deep brain stimulation-a systematic review on established indications and outlook on future developments.

Deep brain stimulation (DBS) has been successfully used to treat movement disorders, such as Parkinson's disease, for more than 25 years and heralded the advent of electrical neuromodulation to treat diseases with dysregulated neuronal circuits. DBS is now superseding ablative techniques, such as stereotactic radiofrequency lesions. While serendipity has played a role in developing DBS as a therapy, research during the past two decades has shown that electrical neuromodulation is far more than a functional lesion that can be switched on and off. This understanding broadens the field to enable new types of stimulation, clinical indications, and research. This review highlights the complex effects of DBS from the single cell to the neuronal network. Specifically, we examine the electrical, cellular, molecular, and neurochemical mechanisms of DBS as applied to Parkinson's disease and other emerging applications.