Transcranial static magnetic field stimulation of the supplementary motor area decreases corticospinal excitability in the motor cortex: a pilot study.

Transcranial static magnetic field stimulation (tSMS) is a non-invasive brain stimulation technique that is portable and easy to use. Long-term, home-based treatments with tSMS of the supplementary motor area (SMA) are promising for movement disorders and other brain diseases. The aim of the present work was to investigate the potential of SMA-tSMS for reducing corticospinal excitability. We completed an open pilot study in which twenty right-handed healthy subjects (8 females; age: 31.3 ± 5.4 years) completed two 30-min sessions (at least one week apart) of SMA-tSMS. We assessed corticospinal excitability by applying transcranial magnetic stimulation (TMS) over the primary motor cortex, recording 30 motor evoked potentials (MEPs) from either the left or right first dorsal interosseous (FDI, 'hotspot' muscle) and extensor carpi radialis (ECR, 'offspot' muscle) in each session before and after (up to 30 min) tSMS. We observed moderate-to-extreme level of Bayesian evidence for a reduction of MEP amplitude after 30 min of tSMS over SMA compared to baseline. Thus, tSMS applied over SMA may reduce corticospinal excitability. These findings, if confirmed with double-blind, placebo-controlled experiments, support the potential of targeting the SMA for neuromodulating a large motor network in future therapeutic applications of tSMS.

To be or not to be hallucinating: Implications of hypnagogic/hypnopompic experiences and lucid dreaming for brain disorders.

The boundaries between waking and sleeping-when falling asleep (hypnagogic) or waking up (hypnopompic)-can be challenging for our ability to monitor and interpret reality. Without proper understanding, bizarre but relatively normal hypnagogic/hypnopompic experiences can be misinterpreted as psychotic hallucinations (occurring, by definition, in the fully awake state), potentially leading to stigma and misdiagnosis in clinical contexts and to misconception and bias in research contexts. This Perspective proposes that conceptual and practical understanding for differentiating hallucinations from hypnagogic/hypnopompic experiences may be offered by lucid dreaming, the state in which one is aware of dreaming while sleeping. I first introduce a possible systematization of the phenomenological range of hypnagogic/hypnopompic experiences that can occur in the transition from awake to REM dreaming (including hypnagogic perceptions, transition symptoms, sleep paralysis, false awakenings, and out-of-body experiences). I then outline how metacognitive strategies used by lucid dreamers to gain/confirm oneiric lucidity could be tested for better differentiating hypnagogic/hypnopompic experiences from hallucinations. The relevance of hypnagogic/hypnopompic experiences and lucid dreaming is analyzed for schizophrenia and narcolepsy, and discussed for neurodegenerative diseases, particularly Lewy-body disorders (i.e. Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies), offering testable hypotheses for empirical investigation. Finally, emotionally positive lucid dreams triggered or enhanced by training/induction strategies or by a pathological process may have intrinsic therapeutic value if properly recognized and guided. The overall intention is to raise awareness and foster further research about the possible diagnostic, prognostic, and therapeutic implications of hypnagogic/hypnopompic experiences and lucid dreaming for brain disorders.

Oscillatory vs. non-oscillatory subthalamic beta activity in Parkinson's disease.

Parkinson's disease is characterized by exaggerated beta activity (13-35 Hz) in cortico-basal ganglia motor loops. Beta activity includes both periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and excitation/inhibition balance (i.e. non-oscillatory activity). However, the relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non-oscillatory beta activity remain unclear. We recorded, modelled and analysed subthalamic local field potentials in parkinsonian patients at rest while off or on medication. Autoregressive modelling with additive 1/f noise clarified the relationships between measures of beta activity in the time domain (i.e. amplitude and duration of beta bursts) or in the frequency domain (i.e. power and sharpness of the spectral peak) and oscillatory vs. non-oscillatory activity: burst duration and spectral sharpness are specifically sensitive to oscillatory activity, whereas burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non-oscillatory activity. Our experimental data confirmed the model predictions and assumptions. We subsequently analysed the effect of levodopa, obtaining strong-to-extreme Bayesian evidence that oscillatory beta activity is reduced in patients on vs. off medication, with moderate evidence for absence of modulation of the non-oscillatory component. Finally, specifically the oscillatory component of beta activity correlated with the rate of motor progression of the disease. Methodologically, these results provide an integrative understanding of beta-based biomarkers relevant for adaptive deep brain stimulation. Biologically, they suggest that primarily the oscillatory component of subthalamic beta activity is dopamine dependent and may play a role not only in the pathophysiology but also in the progression of Parkinson's disease. KEY POINTS: Beta activity in Parkinson's disease includes both true periodic fluctuations (i.e. oscillatory activity) and aperiodic fluctuations reflecting spiking activity and synaptic balance (i.e. non-oscillatory activity). The relative contribution, dopamine dependency and clinical correlations of oscillatory vs. non-oscillatory beta activity remain unclear. Burst duration and spectral sharpness are specifically sensitive to oscillatory activity, while burst amplitude and spectral power are ambiguously sensitive to both oscillatory and non-oscillatory activity. Only the oscillatory component of subthalamic beta activity is dopamine-dependent. Stronger beta oscillatory activity correlates with faster motor progression of the disease.

Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Decoding firings of a large population of human motor units from high-density surface electromyogram in response to transcranial magnetic stimulation.

We describe a novel application of methodology for high-density surface electromyography (HDsEMG) decomposition to identify motor unit (MU) firings in response to transcranial magnetic stimulation (TMS). The method is based on the MU filter estimation from HDsEMG decomposition with convolution kernel compensation during voluntary isometric contractions and its application to contractions elicited by TMS. First, we simulated synthetic HDsEMG signals during voluntary contractions followed by simulated motor evoked potentials (MEPs) recruiting an increasing proportion of the motor pool. The estimation of MU filters from voluntary contractions and their application to elicited contractions resulted in high (>90%) precision and sensitivity of MU firings during MEPs. Subsequently, we conducted three experiments in humans. From HDsEMG recordings in first dorsal interosseous and tibialis anterior muscles, we demonstrated an increase in the number of identified MUs during MEPs evoked with increasing stimulation intensity, low variability in the MU firing latency and a proportion of MEP energy accounted for by decomposition similar to voluntary contractions. A negative relationship between the MU recruitment threshold and the number of identified MU firings was exhibited during the MEP recruitment curve, suggesting orderly MU recruitment. During isometric dorsiflexion we also showed a negative association between voluntary MU firing rate and the number of firings of the identified MUs during MEPs, suggesting a decrease in the probability of MU firing during MEPs with increased background MU firing rate. We demonstrate accurate identification of a large population of MU firings in a broad recruitment range in response to TMS via non-invasive HDsEMG recordings. KEY POINTS: Transcranial magnetic stimulation (TMS) of the scalp produces multiple descending volleys, exciting motor pools in a diffuse manner. The characteristics of a motor pool response to TMS have been previously investigated with intramuscular electromyography (EMG), but this is limited in its capacity to detect many motor units (MUs) that constitute a motor evoked potential (MEP) in response to TMS. By simulating synthetic signals with known MU firing patterns, and recording high-density EMG signals from two human muscles, we show the feasibility of identifying firings of many MUs that comprise a MEP. We demonstrate the identification of firings of a large population of MUs in the broad recruitment range, up to maximal MEP amplitude, with fewer required stimuli compared to intramuscular EMG recordings. The methodology demonstrates an emerging possibility to study responses to TMS on a level of individual MUs in a non-invasive manner.

The Supplementary Motor Area and Automatic Cognitive Control: Lack of Evidence from Two Neuromodulation Techniques.

The SMA is fundamental in planning voluntary movements and execution of some cognitive control operations. Specifically, the SMA has been known to play a dominant role in controlling goal-directed actions as well as those that are highly predicted (i.e., automatic). Yet, the essential contribution of SMA in goal-directed or automatic control of behavior is scarce. Our objective was to test the possible direct role of SMA in automatic and voluntary response inhibition. We separately applied two noninvasive brain stimulation (NIBS) inhibitory techniques over SMA: either continuous theta-burst stimulation using repetitive transcranial magnetic stimulation or transcranial static magnetic field stimulation. Each NIBS technique was performed in a randomized, crossover, sham-controlled design. Before applying NIBS, participants practiced a go/no-go learning task where associations between stimulus and stopping behaviors were created (initiation and inhibition). After applying each NIBS, participants performed a go/no-go task with reversed associations (automatic control) and the stop signal task (voluntary control). Learning associations between stimuli and response initiation/inhibition was achieved by participants and therefore automatized during training. However, no significant differences between real and sham NIBS were found in either automatic (go/no-go learning task) or voluntary inhibition (stop signal task), with Bayesian statistics providing moderate evidence of absence. In conclusion, our results are compatible with a nondirect involvement of SMA in automatic control of behavior. Further studies are needed to prove a noncausal link between prior neuroimaging findings relative to SMA controlling functions and the observed behavior.

Amplitude and frequency modulation of subthalamic beta oscillations jointly encode the dopaminergic state in Parkinson's disease.

Brain states in health and disease are classically defined by the power or the spontaneous amplitude modulation (AM) of neuronal oscillations in specific frequency bands. Conversely, the possible role of the spontaneous frequency modulation (FM) in defining pathophysiological brain states remains unclear. As a paradigmatic example of pathophysiological resting states, here we assessed the spontaneous AM and FM dynamics of subthalamic beta oscillations recorded in patients with Parkinson's disease before and after levodopa administration. Even though AM and FM are mathematically independent, they displayed negatively correlated dynamics. First, AM decreased while FM increased with levodopa. Second, instantaneous amplitude and instantaneous frequency were negatively cross-correlated within dopaminergic states, with FM following AM by approximately one beta cycle. Third, AM and FM changes were also negatively correlated between dopaminergic states. Both the slow component of the FM and the fast component (i.e. the phase slips) increased after levodopa, but they differently contributed to the AM-FM correlations within and between states. Finally, AM and FM provided information about whether the patients were OFF vs. ON levodopa, with partial redundancy and with FM being more informative than AM. AM and FM of spontaneous beta oscillations can thus both separately and jointly encode the dopaminergic state in patients with Parkinson's disease. These results suggest that resting brain states are defined not only by AM dynamics but also, and possibly more prominently, by FM dynamics of neuronal oscillations.

Striatal Blood-Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: 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 ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: 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.

Static magnetic field stimulation over motor cortex modulates resting functional connectivity in humans.

Focal application of transcranial static magnetic field stimulation (tSMS) over the human motor cortex induces local changes in cortical excitability. Whether tSMS can also induce distant network effects, and how these local and distant effects may vary over time, is currently unknown. In this study, we applied 10 min tSMS over the left motor cortex of healthy subjects using a real/sham parallel design. To measure tSMS effects at the sensori-motor network level, we used resting-state fMRI. Real tSMS, but not sham, reduced functional connectivity within the stimulated sensori-motor network. This effect of tSMS showed time-dependency, returning to sham levels after the first 5 min of fMRI scanning. With 10 min real tSMS over the motor cortex we did not observe effects in other functional networks examined (default mode and visual system networks). In conclusion, 10 min of tSMS over a location within the sensori-motor network reduces functional connectivity within the same functional network.

Long-term directional deep brain stimulation: Monopolar review vs. local field potential guided programming.

BACKGROUND: Directional subthalamic stimulation in Parkinson's disease can increase stimulation threshold for adverse effects and widen the therapeutic window. However, selection of programming settings is time consuming, requiring a thorough monopolar clinical review. To overcome this, programming may be guided by intraoperatively recording local field potential beta oscillations (13-35 Hz). OBJECTIVES: 1) Evaluate whether the power of beta oscillations recorded intraoperatively can predict the clinically most effective directional contacts; and 2) assess long-term directional stimulation outcomes between patients programmed based on clinical monopolar review and patients programmed based on beta activity. METHODS: We conducted a non-randomized, prospective study with 24 Parkinson's disease patients divided into two groups. In group A (14 patients, 2016-2018), we investigated whether beta activity in the directional contacts correlated with clinical efficacy. Stimulating parameters were selected according to clinical monopolar review and mean follow-up was 27 months. In group B (10 patients, 2018-2019), stimulating parameters were selected according to beta activity and mean follow-up was 13 months. RESULTS: Neurophysiological results showed a strong correlation between clinical efficacy and the low-beta sub-band. Contacts with highest beta peaks increased the therapeutic window by 25%. Selecting the two contacts with highest beta peaks provided an 82% probability of selecting the best clinical contact. Clinical results showed similar improvements in group A (motor score, 72% reduction; levodopa-equivalent daily dose, 65% reduction) and B (72% and 63% reduction, respectively), maintained at long-term follow-up. CONCLUSIONS: Our results validate the long-term efficacy of directional stimulation guided by intraoperative local field potential beta oscillations.

Double-blind cross-over pilot trial protocol to evaluate the safety and preliminary efficacy of long-term adaptive deep brain stimulation in patients with Parkinson's disease.

INTRODUCTION: After 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). METHODS: The 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 DISSEMINATION: The trial was approved as premarket study by the Italian, Polish, and Dutch Competent Authorities: Bioethics Committee at National Oncology Institute of Maria Sklodowska-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 NUMBER: NCT04681534.

Brain oscillations and Parkinson disease.

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."

Motor and non-motor circuit disturbances in early Parkinson disease: which happens first?

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.

Deep brain stimulation: is it time to change gears by closing the loop?

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.

Clinical perspectives of adaptive deep brain stimulation.

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.

Blood-brain barrier opening with focused ultrasound in Parkinson's disease dementia.

MR-guided focused ultrasound (MRgFUS), in combination with intravenous microbubble administration, has been applied for focal temporary BBB opening in patients with neurodegenerative disorders and brain tumors. MRgFUS could become a therapeutic tool for drug delivery of putative neurorestorative therapies. Treatment for Parkinson's disease with dementia (PDD) is an important unmet need. We initiated a prospective, single-arm, non-randomized, proof-of-concept, safety and feasibility phase I clinical trial (NCT03608553), which is still in progress. The primary outcomes of the study were to demonstrate the safety, feasibility and reversibility of BBB disruption in PDD, targeting the right parieto-occipito-temporal cortex where cortical pathology is foremost in this clinical state. Changes in ß-amyloid burden, brain metabolism after treatments and neuropsychological assessments, were analyzed as exploratory measurements. Five patients were recruited from October 2018 until May 2019, and received two treatment sessions separated by 2-3 weeks. The results are set out in a descriptive manner. Overall, this procedure was feasible and reversible with no serious clinical or radiological side effects. We report BBB opening in the parieto-occipito-temporal junction in 8/10 treatments in 5 patients as demonstrated by gadolinium enhancement. In all cases the procedures were uneventful and no side effects were encountered associated with BBB opening. From pre- to post-treatment, mild cognitive improvement was observed, and no major changes were detected in amyloid or fluorodeoxyglucose PET. MRgFUS-BBB opening in PDD is thus safe, reversible, and can be performed repeatedly. This study provides encouragement for the concept of BBB opening for drug delivery to treat dementia in PD and other neurodegenerative disorders.

A framework to assess the impact of number of trials on the amplitude of motor evoked potentials.

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.