Search

Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD.Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients.Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI),The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in β-amyloid uptake in the targeted region and no change in FDOPA PET.These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

Brain oscillations have been associated with Parkinson's disease (PD) for a long time mainly due to the fundamental oscillatory nature of parkinsonian rest tremor. Over the years, this association has been extended to frequencies well above that of tremor, largely owing to the opportunities offered by deep brain stimulation (DBS) to record electrical activity directly from the patients' basal ganglia. This chapter reviews the results of research on brain oscillations in PD focusing on theta (4-7Hz), beta (13-35Hz), gamma (70-80Hz) and high-frequency oscillations (200-400Hz). For each of these oscillations, we describe localization and interaction with brain structures and between frequencies, changes due to dopamine intake, task-related modulation, and clinical relevance. The study of brain oscillations will also help to dissect the mechanisms of action of DBS. Overall, the chapter tentatively depicts PD in terms of "oscillopathy."

IntroductionAfter several years of brain-sensing technology development and proof-of-concept studies, adaptive deep brain stimulation (aDBS) is ready to better treat Parkinson’s disease (PD) using aDBS-capable implantable pulse generators (IPGs). New aDBS devices are capable of continuous sensing of neuronal activity from the subthalamic nucleus (STN) and contemporaneous stimulation automatically adapted to match the patient’s clinical state estimated from the analysis of STN activity using proprietary algorithms. Specific studies are necessary to assess superiority of aDBS vs conventional DBS (cDBS) therapy. This protocol describes an original innovative multicentre international study aimed to assess safety and efficacy of aDBS vs cDBS using a new generation of DBS IPG in PD (AlphaDBS system by Newronika SpA, Milan, Italy).MethodsThe study involves six investigational sites (in Italy, Poland and The Netherlands). The primary objective will be to evaluate the safety and tolerability of the AlphaDBS System, when used in cDBS and aDBS mode. Secondary objective will be to evaluate the potential efficacy of aDBS. After eligibility screening, 15 patients with PD already implanted with DBS systems and in need of battery replacement will be randomised to enter a two-phase protocol, including a ‘short-term follow-up’ (2 days experimental sessions during hospitalisation, 1 day per each mode) and a ‘long-term follow-up’ (1 month at home, 15 days per each mode).Ethics and disseminationThe trial was approved as premarket study by the Italian, Polish, and Dutch Competent Authorities: Bioethics Committee at National Oncology Institute of Maria Skłodowska-Curie—National Research Institute in Warsaw; Comitato Etico Milano Area 2; Comitato Etico IRCCS Istituto Neurologico C. Besta; Comitato Etico interaziendale AOUC Città della Salute e della Scienza—AO Ordine Mauriziano di Torino—ASL Città di Torino; De Medisch Ethisch Toetsingscommissie van Maastricht UMC. The study started enrolling patients in January 2021.Trial registration numberNCT04681534.

International audience; For the last two decades, pathogenic concepts in Parkinson disease (PD) have revolved around the toxicity and spread of α-synuclein. Thus, α-synuclein would follow caudo-rostral propagation from the periphery to the central nervous system, first producing non-motor manifestations (such as constipation, sleep disorders and hyposmia), and subsequently impinging upon the mesencephalon to account for the cardinal motor features before reaching the neocortex as the disease evolves towards dementia. This model is the prevailing theory of the principal neurobiological mechanism of disease. Here, we scrutinize the temporal evolution of motor and non-motor manifestations in PD and suggest that, even though the postulated bottom-up mechanisms are likely to be involved, early involvement of the nigrostriatal system is a key and prominent pathophysiological mechanism. Upcoming studies of detailed clinical manifestations with newer neuroimaging techniques will allow us to more closely define, in vivo, the role of α-synuclein aggregates with respect to neuronal loss during the onset and progression of PD.

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease-modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood-brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease-modifying therapy in very-early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood-brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies-subthalamotomy and putaminal blood-brain barrier opening-could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) is a degenerative disorder of the brain characterized by the impairment of the nigrostriatal system. This impairment leads to specific motor manifestations (i.e., bradykinesia, tremor, and rigidity) that are assessed through clinical examination, scales, and patient-reported outcomes. New sensor-based and wearable technologies are progressively revolutionizing PD care by objectively measuring these manifestations and improving PD diagnosis and treatment monitoring. However, their use is still limited in clinical practice, perhaps because of the absence of external validation and standards for their continuous use at home. In the near future, these systems will progressively complement traditional tools and revolutionize the way we diagnose and monitor patients with PD.

Focal application of a relatively strong permanent magnet over the human cortex induces neurophysiological and behavioral effects. This discovery led to the inclusion of transcranial static magnetic field stimulation (tSMS) into the family of noninvasive brain stimulation (NIBS) techniques. The safety, simplicity, portability, and low-cost of tSMS make it particularly appealing for possible clinical and research applications. Similarly to all NIBS techniques, we are far from understanding the exact mechanisms by which tSMS produces its effects, but converging evidence suggests that modulation of ionic interchange across the membrane may be responsible for its physiological effects at the cellular level. There are no data yet supporting clear effects of tSMS in clinical applications, but a number of ongoing studies suggest that clinical results will become available soon.

Background The application of stimulators implanted directly over deep brain structures (i.e., deep brain stimulation, DBS) was developed in the late 1980s and has since become a mainstream option to treat several neurological conditions. Conventional DBS involves the continuous stimulation of the target structure, which is an approach that cannot adapt to patients’ changing symptoms or functional status in real-time. At the beginning of 2000, a more sophisticated form of stimulation was conceived to overcome these limitations. Adaptive deep brain stimulation (aDBS) employs on-demand, contingency-based stimulation to stimulate only when needed. So far, aDBS has been tested in several pathological conditions in animal and human models. Objective To review the current findings obtained from application of aDBS to animal and human models that highlights effects on motor, cognitive and psychiatric behaviors. Findings while aDBS has shown promising results in the treatment of Parkinson's disease and essential tremor, the possibility of its use in less common DBS indications, such as cognitive and psychiatric disorders (Alzheimer's disease, obsessive-compulsive disorder, post-traumatic stress disorder) is still challenging. Conclusions While aDBS seems to be effective to treat movement disorders (Parkinson's disease and essential tremor), its role in cognitive and psychiatric disorders is to be determined, although neurophysiological assumptions are promising.

Objective. Adaptive deep brain stimulation (aDBS) is a form of invasive stimulation that was conceived to overcome the technical limitations of traditional DBS, which delivers continuous stimulation of the target structure without considering patients’ symptoms or status in real-time. Instead, aDBS delivers on-demand, contingency-based stimulation. So far, aDBS has been tested in several neurological conditions, and will be soon extensively studied to translate it into clinical practice. However, an exhaustive description of technical aspects is still missing. Approach. in this topical review, we summarize the knowledge about the current (and future) aDBS approach and control algorithms to deliver the stimulation, as reference for a deeper undestending of aDBS model. Main results. We discuss the conceptual and functional model of aDBS, which is based on the sensing module (that assesses the feedback variable), the control module (which interpretes the variable and elaborates the new stimulation parameters), and the stimulation module (that controls the delivery of stimulation), considering both the historical perspective and the state-of-the-art of available biomarkers. Significance. aDBS modulates neuronal circuits based on clinically relevant biofeedback signals in real-time. First developed in the mid-2000s, many groups have worked on improving closed-loop DBS technology. The field is now at a point in conducting large-scale randomized clinical trials to translate aDBS into clinical practice. As we move towards implanting brain-computer interfaces in patients, it will be important to understand the technical aspects of aDBS.

The amplitude of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) is a common yet highly variable measure of corticospinal excitability. The tradeoff between maximizing the number of trials and minimizing experimental time remains a hurdle. It is therefore important to establish how many trials should be used. The aim of this study is not to provide rule-of-thumb answers that may be valid only in specific experimental conditions, but to offer a more general framework to inform the decision about how many trials to use under different experimental conditions. Specifically, we present a set of equations that show how the number of trials affects single-subject MEP amplitude, population MEP amplitude, hypothesis testing and test–retest reliability, depending on the variability within and between subjects. The equations are derived analytically, validated with Monte Carlo simulations, and representatively applied to experimental data. Our findings show that the minimum number of trials for estimating single-subject MEP amplitude largely depends on the experimental conditions and on the error considered acceptable by the experimenter. Conversely, estimating population MEP amplitude and hypothesis testing are markedly more dependent on the number of subjects than on the number of trials. These tools and results help to clarify the impact of the number of trials in the design and reproducibility of past and future experiments.

Tremor is a core feature of Parkinson's disease and the most easily recognized Parkinsonian sign. Nonetheless, its pathophysiology remains poorly understood. Here, we show that multispectral spiking activity in the posterior-dorso-lateral oscillatory (motor) region of the subthalamic nucleus distinguishes resting tremor from the other Parkinsonian motor signs and strongly correlates with its severity. We evaluated microelectrode-spiking activity from the subthalamic dorsolateral oscillatory region of 70 Parkinson's disease patients who underwent deep brain stimulation surgery (114 subthalamic nuclei, 166 electrode trajectories). We then investigated the relationship between patients' clinical Unified Parkinson's Disease Rating Scale score and their peak theta (4-7 Hz) and beta (13-30 Hz) powers. We found a positive correlation between resting tremor and theta activity (

In Parkinson's disease, striatal dopamine depletion produces profound alterations in the neural activity of the cortico-basal ganglia motor loop, leading to dysfunctional motor output and parkinsonism. A key regulator of motor output is the balance between excitation and inhibition in the primary motor cortex, which can be assessed in humans with transcranial magnetic stimulation techniques. Despite decades of research, the functional state of cortical inhibition in Parkinson's disease remains uncertain. Towards resolving this issue, we applied paired-pulse transcranial magnetic stimulation protocols in 166 patients with Parkinson's disease (57 levodopa-naïve, 50 non-dyskinetic, 59 dyskinetic) and 40 healthy controls (age-matched with the levodopa-naïve group). All patients were studied OFF medication. All analyses were performed with fully automatic procedures to avoid confirmation bias, and we systematically considered and excluded several potential confounding factors such as age, gender, resting motor threshold, EMG background activity and amplitude of the motor evoked potential elicited by the single-pulse test stimuli. Our results show that short-interval intracortical inhibition is decreased in Parkinson's disease compared to controls. This reduction of intracortical inhibition was obtained with relatively low-intensity conditioning stimuli (80% of the resting motor threshold) and was not associated with any significant increase in short-interval intracortical facilitation or intracortical facilitation with the same low-intensity conditioning stimuli, supporting the involvement of cortical inhibitory circuits. Short-interval intracortical inhibition was similarly reduced in levodopa-naïve, non-dyskinetic and dyskinetic patients. Importantly, intracortical inhibition was reduced compared to control subjects also on the less affected side (n = 145), even in de novo drug-naïve patients in whom the less affected side was minimally symptomatic (lateralized Unified Parkinson's Disease Rating Scale part III = 0 or 1, n = 23). These results suggest that cortical disinhibition is a very early, possibly prodromal feature of Parkinson's disease. Department of Economy, Industry and Competitiveness and Co-financed by the European Union (FEDER) “A way to make Europe” (grant SAF2017-86246-R MINECO/AEI/FEDER, UE), by “The Michael J. Fox Foundation” (grant 9205) and by Comunidad de Madrid (fellowship 2017-T2/BMD-5231). 13.501 JCR (2020) Q1, 6/208 Clinical Neurology 5.142 SJR (2020) Q1, 35/2446 Medicine (miscellaneous) No data IDR 2020 UEM

Focal application of a strong static magnetic field over the human scalp induces measurable local changes in brain function. Whether it also induces distant effects across the brain and how these local and distant effects collectively affect motor behavior remains unclear. Here we applied transcranial static magnetic field stimulation (tSMS) over the supplementary motor area (SMA) in healthy subjects. At a behavioral level, tSMS increased the time to initiate movement while decreasing errors in choice reaction-time tasks. At a functional level, tSMS increased SMA resting-state fMRI activity and bilateral functional connectivity between the SMA and both the paracentral lobule and the lateral frontotemporal cortex, including the inferior frontal gyrus. These results suggest that tSMS over the SMA can induce behavioral aftereffects associated with modulation of both local and distant functionally-connected cortical circuits involved in the control of speed-accuracy tradeoffs, thus offering a promising protocol for cognitive and clinical research., Pineda-Pardo et al. show that focal application of a strong permanent magnet over the supplementary motor area shifts the speed-accuracy tradeoff towards accuracy by modulating both cortical circuits and distant cortical networks. This study suggests the utility of transcranial static magnetic field stimulation for cognitive research.

Essential tremor is the most common movement disorder in adults. In patients who are not responsive to medical treatment, functional neurosurgery and, more recently, transcranial MR‐guided focused ultrasound thalamotomy are considered effective therapeutic approaches. However, the structural brain changes following a thalamotomy that mediates the clinical improvement are still unclear. In here diffusion weighted images were acquired in a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial MR‐guided focused ultrasound thalamotomy targeting at the posteroventral part of the VIM. Microstructural changes along the DRTT were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3‐months and at 1‐year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR‐guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello‐thalamo‐cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting.

The cortical reorganization after spinal cord injury (SCI) involves a series of physiological changes that drive the expansion of the intact cortical area to the deafferented cortical area. These changes have always been studied under a stimulus-response paradigm, which demonstrates that the deafferented cortex becomes more responsive to stimulation of body regions above the level of the lesion. However, less is known about how permanent large-scale deafferentation affects spontaneous activity in the somatosensory cortex, an important physiological feature related to the processing of peripheral inputs and perception. Here we studied the spontaneous activity at two sites of the somatosensory cortex, corresponding to forepaw and hindpaw, and at three different time points after SCI: acute SCI, one week post-SCI and chronic SCI (1–3 months after injury). Electrophysiological recordings from anesthetized rats were obtained in conditions of slow-wave activity in order to compare features of the neural populations in periods of cortical up-states. Our data demonstrate that acute SCI reduces the excitability of cortical neurons during up-states in both the forepaw and the hindpaw cortex. One week after SCI, the properties of cortical neurons were similar to those under control conditions, indicating a homeostatic plasticity. Finally, chronic SCI increased neural activity during up-states, while reduced up-state frequency in the cortex. We conclude that SCI induces different homeostatic changes in cortical slow-wave depending on the time after lesion. This temporal evolution of spontaneous activity could help better understand the cortical plasticity associated with acute or chronic SCI.

In Parkinson's disease, the progressive neurodegeneration of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNc) is associated with classic motor features, which typically have a focal onset. Since a defined somatotopic arrangement in the SNc has not been recognized, this focal motor onset is unexplained and hardly justified by current pathogenic theories of bottom-up disease progression (Braak's hypothesis, prionopathy). Here we propose that corticostriatal activity may represent a critical somatotopic "stressor" for nigrostriatal terminals, ultimately driving retrograde nigrostriatal degeneration and leading to focal motor onset and progression of Parkinson's disease. As a pathogenic mechanism, corticostriatal activity may promote secretion of striatal extracellular alpha-synuclein, favoring its pathological aggregation at vulnerable dopaminergic synapses. A similar pathogenic process may occur at corticofugal projections to the medulla oblongata and other vulnerable structures, thereby contributing to the bottom-up progression of Lewy pathology. This cortical pathogenesis may co-exist with bottom-up mechanisms, adding an integrative top-down perspective to the quest for the factors that impinge upon the vulnerability of dopaminergic cells in the onset and progression of Parkinson's disease.

ObjectivesTo assess the feasibility and clinical efficacy of local field potentials (LFPs)–based adaptive deep brain stimulation (aDBS) in patients with advanced Parkinson disease (PD) during daily activities in an open-label, nonblinded study.MethodsWe monitored neurophysiologic and clinical fluctuations during 2 perioperative experimental sessions lasting for up to 8 hours. On the first day, the patient took his/her daily medication, while on the second, he/she additionally underwent subthalamic nucleus aDBS driven by LFPs beta band power.ResultsThe beta band power correlated in both experimental sessions with the patient's clinical state (Pearson correlation coefficient r = 0.506, p < 0.001, and r = 0.477, p < 0.001). aDBS after LFP changes was effective (30% improvement without medication [3-way analysis of variance, interaction day × medication p = 0.036; 30.5 ± 3.4 vs 22.2 ± 3.3, p = 0.003]), safe, and well tolerated in patients performing regular daily activities and taking additional dopaminergic medication. aDBS was able to decrease DBS amplitude during motor “on” states compared to “off” states (paired t test p = 0.046), and this automatic adjustment of STN-DBS prevented dyskinesias.ConclusionsThe main findings of our study are that aDBS is technically feasible in everyday life and provides a safe, well-tolerated, and effective treatment method for the management of clinical fluctuations.Classification of evidenceThis study provides Class IV evidence that for patients with advanced PD, aDBS is safe, well tolerated, and effective in controlling PD motor symptoms.

The field of invasive brain-machine interfaces (BMIs) is typically associated with neuroprosthetic applications aiming to recover loss of motor function. However, BMIs also represent a powerful tool to address fundamental questions in neuroscience. The observed subjects of BMI experiments can also be considered as indirect observers of their own neurophysiological activity, and the relationship between observed neurons and (artificial) behavior can be genuinely causal rather than indirectly correlative. These two characteristics defy the classical object-observer duality, making BMIs particularly appealing for investigating how information is encoded and decoded by neural circuits in real time, how this coding changes with physiological learning and plasticity, and how it is altered in pathological conditions. Within neuroengineering, BMI is like a tree that opens its branches into many traditional engineering fields, but also extends deep roots into basic neuroscience beyond neuroprosthetics.