Mattia Arlotti

Cellular effects of acute direct current stimulation: somatic and synaptic terminal effects

•  The diversity of cellular targets of direct current stimulation (DCS), including somas, dendrites and axon terminals, determine the modulation of synaptic efficacy. •  Axon terminals of cortical pyramidal neurons are two–three times more susceptible to polarization than somas. •  DCS in humans results in current flow dominantly parallel to the cortical surface, which in animal models of cortical stimulation results in synaptic pathway‐specific modulation of neuronal excitability. •  These results suggest that somatic polarization together with axon terminal polarization may be important for synaptic pathway‐specific modulation of DCS, which underlies modulation of neuronal excitability during transcranial DCS.

Adaptive deep brain stimulation in a freely moving parkinsonian patient

The future of deep brain stimulation (DBS) for Parkinsons 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 patients current clinical condition.1 The most suitable feedback for PD is subthalamic local field potential (LFP) activity recorded from the stimulating electrode itself.2, 3, 4 This closed‐loop technology known as adaptive DBS (aDBS) recently proved superior to conventional open‐loop DBS (cDBS) in patients with PD.2

The adaptive deep brain stimulation challenge.

Sub-optimal clinical outcomes of conventional deep brain stimulation (cDBS) in treating Parkinsons 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 patients 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 patients 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.

Axon terminal polarization induced by weak uniform DC electric fields: A modeling study

Uniform steady state (DC) electric fields, like those generated during transcranial direct current stimulation (tDCS), can affect neuronal excitability depending on field direction and neuronal morphology. In addition to somatic polarization, subthreshold membrane polarization of axon compartments can play a significant role in modulating synaptic efficacy. The aim of this study is to provide an estimation of axon terminal polarization in a weak uniform subthreshold electric field. Simulations based on 3D morphology reconstructions and simplified models indicate that for axons having long final branches compared to the local space constant (L>;4λ) the terminal polarization converges to Eλ for electric fields oriented in the same direction as the branch. In particular we determined how and when analytical approximations could be extended to real cases when considering maximal potential polarization during weak DC stimulation.

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

Compared to conventional deep brain stimulation (DBS) for patients with Parkinsons Disease (PD), the newer approach of adaptive DBS (aDBS), regulating stimulation on the basis of the patients 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 patients 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.

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’s disease patients by adapting the stimulation parameters to the patient’s clinical state estimated through the analysis of subthalamic neuronal oscillations (ie, local field potentials) in the beta band (13-30 Hz). Because aDBS administration was never systematically assessed during prolonged stimulation sessions in more ecologic conditions, we tested unilateral aDBS delivered for 2 hours, with specific focus on the concurrent administration of levodopa treatment, in freely moving parkinsonian patients. We therefore randomly administered aDBS and cDBS through an external wearable prototype in 10 PD patients with DBS electrode implant in 2 different experimental sessions taking place the 5th and the 6th day after surgery (Fig. 1A). Each experimental session lasted 2 hours, during which the patient, after a baseline assessment (OFF DBS and OFF medication, stimOFF/medOFF), received both levodopa and stimulation (aDBS or cDBS), thus allowing one to study the interaction between electrical and pharmacological stimulation (ON DBS and ON medication, stimON/medON). The patient was blind to the type of DBS received during the session. The clinical effects were blindly evaluated through the UPDRS III (motor part) and the Unified Dyskinesia Rating Scale (UDysRS). According to the gold standard, the clinical assessment was performed by a blinded video rater (rigidity scores were excluded from the analysis). The total electrical energy delivered (TEED) was used for energy efficiency assessment and adverse events were collected for safety assessment. The clinical scores were not significantly different between the 2 experimental sessions at baseline (stimOFF/ medOFF UPDRS III, aDBS vs cDBS: 37.0 6 16.8 vs 36.6 6 16.2; F1,9 5 0.2, P > .05). When the patient was under the effect of both levodopa and DBS (stimON/medON), we observed a similar improvement on global motor symptoms regardless to the type of DBS (UPDRS III percent change from baseline, aDBS vs cDBS: 246.1% 6 10.5% vs 240.1% 6 17.5%; F1,9 5 0.6, P > .05; Fig. 1B). Conversely, in this condition, aDBS was more effective on dyskinesias than cDBS (UDysRS score, aDBS vs cDBS: 11.7 6 67 vs 15.0 6 8.7; F1,9 5 6.1, P 5 .02; Fig. 1C). These results were obtained with an average power saving of 73.6% 6 22.9% in aDBS compared with cDBS (mean TEED aDBS vs cDBS: 44.6 6 47.9 lW vs 158.7 6 69.7 lW; F1,8 5 30.4, P 5 .0005). Throughout the entire experiment, we did not observe any serious adverse event specifically linked to DBS. These results support the idea that aDBS, being effective, efficient, and safe, when administered concomitantly to levodopa could help clinicians limit the severity of side effects induced by the transient summation of DBS stimulation and pharmacological therapy. However, the acute experimental setting, characterized by a microlesional

Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease

Quantitative electroencephalography (qEEG) showed that Alzheimers 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.

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

Objectives 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 patients 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. 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.

Risk of Infection After Local Field Potential Recording from Externalized Deep Brain Stimulation Leads in Parkinson's Disease

OBJECTIVE Adaptive deep brain stimulation (aDBS) controlled by local field potentials (LFPs) is considered a promising treatment for advanced Parkinsons disease (PD). The clinical research investigating aDBS functioning is performed using external deep brain stimulation (DBS) systems that require LFP recording through the temporary externalization of DBS leads. Although research examining LFP was first undertaken more than 20 years ago, only a few studies concern lead externalization and LFP recording safety. In the present retrospective study, we assessed the risk of infection related to these procedures. METHODS A total of 105 patients with PD who underwent DBS surgery and lead externalization at our hospital from 2002 to 2014 were included in the present study. The medical records were used to collect clinical data and information concerning surgical site infections. We assessed the infection incidence in our cohort and the risk of infection related to the LFP recording procedure. RESULTS The incidence of infections in patients who underwent lead externalization was 2.8%, which was consistent with the postoperative infectious risk reported in the literature (Wilcoxon signed rank test; P > 0.05). Moreover, the LFP recording procedure did not significantly increase the infection risk (LFP recordings vs. no LFP recordings: 2.5% vs. 4.2%; Fisher exact test; P > 0.05). CONCLUSIONS DBS lead externalization and LFP recording are safe and do not increase the postoperative infection risk in patients with PD who undergo DBS surgery. Our retrospective study supported further clinical research in the field of LFP-based aDBS.

Cognitive safety of eight-hours adaptive deep brain stimulation (aDBS) in Parkinson's disease

Objective: The aim of this work is to evaluate clinimetric properties of a method for measuring Parkinson’s disease (PD) upper limb temporal irregularities during spiral drawing tasks.Background: B ...Basic Science Abstracts - Session Title: Parkinsons Disease: Pathophysiology: abstract no. 518