Adaptive Deep Brain Stimulation in Advanced Parkinson's Disease: Bridging the Gap beetween Concept and Clinical Application

Parkinson’s disease (PD) is a common neurodegenerative disorder. Recent evidence points towards increased synchronous neuronal oscillations of the cortico-thalamic-basal ganglia circuits in the beta band (12–30 Hz) as the main pathophysiological abnormality associated with PD. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for improving PD motor symptoms. However, the current DBS systems have several limitations, mainly related to the fixed and continuous application of stimulation. Especially in the long-term, DBS can only partially control clinical fluctuations and can exacerbate undesirable adverse effects often reversible with a change of stimulation parameters. A new strategy called adaptive DBS (aDBS) allows for continuous adaptation of STN stimulation to the patient’s clinical state by directly harnessing the recordings of the STN pathological oscillatory activity or local field potentials (LFPs). With this project, we aimed to accelerate the clinical translational process by suggesting a pathway to the clinical practice. To do so, we developed an external portable LFPs-based aDBS device for clinical investigations in acute experimental sessions. We then conducted a proof of concept study investigating the functioning of the device and comparing aDBS and conventional DBS (cDBS) and how they interacted with the concurrent pharmacological treatment. Then, we monitored the clinical and neurophysiological fluctuations over a period of eight hours with and without aDBS. We thus investigated the preservation of LFPs-clinical state correlation and the aDBS management of motor fluctuations during daily activities. Because in the clinical practice the DBS therapy is provided by means of implantable pulse generators (IPGs), we evaluated whether the proposed aDBS approach, based on real-time LFPs processing, fits the power constraints of implantable devices. Finally, we contextualized our results and proposed an overview of the possible pathways toward the clinical practice

Adaptive deep brain stimulation in a freely moving parkinsonian patient

The future of deep brain stimulation (DBS) for Parkinson\u2019s disease (PD) lies in new closed-loop systems that continuously supply the implanted stimulator with new settings obtained by analyzing a feedback signal related to the patient\u2019s current clinical condition

Adaptive deep brain stimulation controls levodopa-induced side effects in Parkinsonian patients

The potential superior benefits of adaptive deep brain stimulation (aDBS) approaches compared to classical, constantparameters DBS were already proven by scientific evidence from different research groups. aDBS provides better symptoms control in Parkinson\u2019s disease patients by adapting the stimulation parameters to the patient\u2019s clinical state estimated through the analysis of subthalamic neuronal oscillations (ie, local field potentials) in the beta band (13-30 Hz)

Eight-hours adaptive deep brain stimulation in patients with Parkinson disease

To 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. METHODS: We 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. RESULTS: The 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 7 medication p = 0.036; 30.5 \ub1 3.4 vs 22.2 \ub1 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. CONCLUSIONS: The 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 EVIDENCE: This study provides Class IV evidence that for patients with advanced PD, aDBS is safe, well tolerated, and effective in controlling PD motor symptoms

An external portable device for adaptive deep brain stimulation (aDBS) clinical research in advanced Parkinson's Disease

5noCompared to conventional deep brain stimulation (DBS) for patients with Parkinson's Disease (PD), the newer approach of adaptive DBS (aDBS), regulating stimulation on the basis of the patient's clinical state, promises to achieve better clinical outcomes, avoid adverse-effects and save time for tuning parameters. A remaining challenge before aDBS comes into practical use is to prove its feasibility and its effectiveness in larger groups of patients and in more ecological conditions. We developed an external portable aDBS system prototype designed for clinical testing in freely-moving PD patients with externalized DBS electrodes. From a single-channel bipolar artifact-free recording, it analyses local field potentials (LFPs), during ongoing DBS for tuning stimulation parameters, independent from the specific feedback algorithm implemented. We validated the aDBS system in vitro, by testing both its sensing and closed-loop stimulation capabilities, and then tested it in vivo, focusing on the sensing capabilities. By applying the aDBS system prototype in a patient with PD, we provided evidence that it can track levodopa and DBS-induced LFP spectral power changes among different patient's clinical states. Our system, intended for testing LFP-based feedback strategies for aDBS, should help understanding how and whether aDBS therapy works in PD and indicating future technical and clinical advances.reservedmixedArlotti, Mattia; Rossi, Lorenzo; Rosa, Manuela; Marceglia, Sara; Priori, AlbertoArlotti, Mattia; Rossi, Lorenzo; Rosa, Manuela; Marceglia, Sara; Priori, Albert

The adaptive deep brain stimulation challenge

Sub-optimal clinical outcomes of conventional deep brain stimulation (cDBS) in treating Parkinson's Disease (PD) have boosted the development of new solutions to improve DBS therapy. Adaptive DBS (aDBS), consisting of closed-loop, real-time changing of stimulation parameters according to the patient's clinical state, promises to achieve this goal and is attracting increasing interest in overcoming all of the challenges posed by its development and adoption. In the design, implementation, and application of aDBS, the choice of the control variable and of the control algorithm represents the core challenge. The proposed approaches, in fact, differ in the choice of the control variable and control policy, in the system design and its technological limits, in the patient's target symptom, and in the surgical procedure needed. Here, we review the current proposals for aDBS systems, focusing on the choice of the control variable and its advantages and drawbacks, thus providing a general overview of the possible pathways for the clinical translation of aDBS with its benefits, limitations and unsolved issues

Transcranial direct current stimulation modulates cortical neuronal activity in Alzheimer's disease

12noQuantitative electroencephalography (qEEG) showed that Alzheimer's disease (AD) is characterized by increased theta power, decreased alpha and beta power, and decreased coherence in the alpha and theta band in posterior regions. These abnormalities are thought to be associated with functional disconnections among cortical areas, death of cortical neurons, axonal pathology, and cholinergic deficits. Since transcranial Direct Current Stimulation (tDCS) over the temporo-parietal area is thought to have beneficial effects in patients with AD, in this study we aimed to investigate whether tDCS benefits are related to tDCS-induced changes in cortical activity, as represented by qEEG. A weak anodal current (1.5 mA, 15 min) was delivered bilaterally over the temporal-parietal lobe to seven subjects with probable AD (Mini-Mental State Examination, MMSE score >20). EEG (21 electrodes, 10-20 international system) was recorded for 5 min with eyes closed before (baseline, t0) and 30 min after anodal and cathodal tDCS ended (t1). At the same time points, patients performed a Word Recognition Task (WRT) to assess working memory functions. The spectral power and the inter- and intra-hemispheric EEG coherence in different frequency bands (e.g., low frequencies, including delta and theta; high frequencies, including alpha and beta) were calculated for each subject at t0 and t1. tDCS-induced changes in EEG neurophysiological markers were correlated with the performance of patients at the WRT. At baseline, qEEG features in AD patients confirmed that the decreased high frequency power was correlated with lower MMSE. After anodal tDCS, we observed an increase in the high-frequency power in the temporo-parietal area and an increase in the temporo-parieto-occipital coherence that correlated with the improvement at the WRT. In addition, cathodal tDCS produced a non-specific effect of decreased theta power all over the scalp that was not correlated with the clinical observation at the WRT. Our findings disclosed that tDCS induces significant modulations in the cortical EEG activity in AD patients. The abnormal pattern of EEG activity observed in AD during memory processing is partially reversed by applying anodal tDCS, suggesting that anodal tDCS benefits in AD patients during working memory tasks are supported by the modulation of cortical activity.openopenMarceglia, Sara; Mrakic-Sposta, Simona; Rosa, Manuela; Ferrucci, Roberta; Mameli, Francesca; Vergari, Maurizio; Arlotti, Mattia; Ruggiero, Fabiana; Scarpini, Elio; Galimberti, Daniela; Barbieri, Sergio; Priori, AlbertoMarceglia, SARA RENATA FRANCESCA; Mrakic Sposta, Simona; Rosa, Manuela; Ferrucci, Roberta; Mameli, Francesca; Vergari, Maurizio; Arlotti, Mattia; Ruggiero, Fabiana; Scarpini, Elio; Galimberti, Daniela; Barbieri, Sergio; Priori, Albert

Electric Fields Induced in the Brain by Transcranial Electric Stimulation: A Review of In Vivo Recordings

Transcranial electrical stimulation (tES) techniques, such as direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), cause neurophysiological and behavioral modifications as responses to the electric field are induced in the brain. Estimations of such electric fields are based mainly on computational studies, and in vivo measurements have been used to expand the current knowledge. Here, we review the current tDCS- and tACS-induced electric fields estimations as they are recorded in humans and non-human primates using intracerebral electrodes. Direct currents and alternating currents were applied with heterogeneous protocols, and the recording procedures were characterized by a tentative methodology. However, for the clinical stimulation protocols, an injected current seems to reach the brain, even at deep structures. The stimulation parameters (e.g., intensity, frequency and phase), the electrodes' positions and personal anatomy determine whether the intensities might be high enough to affect both neuronal and non-neuronal cell activity, also deep brain structures

A New Implantable Closed-Loop Clinical Neural Interface: First Application in Parkinson’s Disease

Deep brain stimulation (DBS) is used for the treatment of movement disorders, including Parkinson’s disease, dystonia, and essential tremor, and has shown clinical benefits in other brain disorders. A natural path for the improvement of this technique is to continuously observe the stimulation effects on patient symptoms and neurophysiological markers. This requires the evolution of conventional deep brain stimulators to bidirectional interfaces, able to record, process, store, and wirelessly communicate neural signals in a robust and reliable fashion. Here, we present the architecture, design, and first use of an implantable stimulation and sensing interface (AlphaDBSR System) characterized by artifact-free recording and distributed data management protocols. Its application in three patients with Parkinson’s disease (clinical trial n. NCT04681534) is shown as a proof of functioning of a clinically viable implanted brain-computer interface (BCI) for adaptive DBS. Reliable artifact free-recordings, and chronic long-term data and neural signal management are in place

Electromyography data in chronic migraine patients by using neurostimulation with the Cefaly^® device

The objective of this observational study is to report clinical and instrumental results obtained in 23 chronic migraine sufferers treated with transcutaneous neurostimulation with the Cefaly^® device. The electromyography (EMG) parameters of the patients monitored before and during neurostimulation with the Cefaly^® device showed a significant increase in the EMG amplitude and frequency values in the frontalis, anterior temporalis, auricularis posterior and middle trapezius muscles. The Cefaly^® device could act on the inhibitory circuit in the spinal cord thus causing a neuromuscular facilitation and may help reduce contraction of frontalis muscles