Using a virtual training program to train community neurologist on EEG reading skills.

BACKGROUND: EEG training requires iterative exposure of different patterns with continuous feedback from the instructor. This training is traditionally acquired through a traditional fellowship program, but only 28% of neurologists in training plan to do a fellowship in EEG. PURPOSE: The purpose of this study was to determine the value of online EEG training to improve EEG knowledge among general neurologists. METHODS: The participants were general neurologists invited through bulk e-mail and paid a fee to enroll in the virtual EEG program. A 40-question pretest exam was performed before training. The training included 4 online learning units about basic EEG principles and 40 online clinical EEG tutorials. In addition there were weekly live teleconferences for Q&A sessions. At the end of the program, the participants were asked to complete a posttest exam. RESULTS: Fifteen of 20 participants successfully completed the program and took both the pre- and posttest exams. All the subjects scored significantly higher in the posttest compared to their baseline score. The average score in the pretest evaluation was 61.7% and the posttest average was 87.8% (p = .0002, two-tailed). CONCLUSIONS: Virtual EEG training can improve EEG knowledge among community neurologists.

Subthalamic nucleus deep brain stimulation driven by primary motor cortex γ2 activity in parkinsonian monkeys.

In parkinsonism, subthalamic nucleus (STN) electrical deep brain stimulation (DBS) improves symptoms, but may be associated with side effects. Adaptive DBS (aDBS), which enables modulation of stimulation, may limit side effects, but limited information is available about clinical effectiveness and efficaciousness. We developed a brain-machine interface for aDBS, which enables modulation of stimulation parameters of STN-DBS in response to γ2 band activity (80-200 Hz) of local field potentials (LFPs) recorded from the primary motor cortex (M1), and tested its effectiveness in parkinsonian monkeys. We trained two monkeys to perform an upper limb reaching task and rendered them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Bipolar intracortical recording electrodes were implanted in the M1, and a recording chamber was attached to access the STN. In aDBS, the M1 LFPs were recorded, filtered into the γ2 band, and discretized into logic pulses by a window discriminator, and the pulses were used to modulate the interval and amplitude of DBS pulses. In constant DBS (cDBS), constant stimulus intervals and amplitudes were used. Reaction and movement times during the task were measured and compared between aDBS and cDBS. The M1-γ2 activities were increased before and during movements in parkinsonian monkeys and these activities modulated the aDBS pulse interval, amplitude, and dispersion. With aDBS and cDBS, reaction and movement times were significantly decreased in comparison to DBS-OFF. The electric charge delivered was lower with aDBS than cDBS. M1-γ2 aDBS in parkinsonian monkeys resulted in clinical benefits that did not exceed those from cDBS. However, M1-γ2 aDBS achieved this magnitude of benefit for only two thirds of the charge delivered by cDBS. In conclusion, M1-γ2 aDBS is an effective therapeutic approach which requires a lower electrical charge delivery than cDBS for comparable clinical benefits.

Highlights From AES2020, a Virtual American Epilepsy Society Experience.

Due to COVID-19 a live, in-person meeting was not possible for the American Epilepsy Society in 2020. An alternative, virtual event, the AES2020, was held instead. AES2020 was a great success with 4679 attendees from 70 countries. The educational content was outstanding and spanned the causes, treatments, and outcomes from epileptic encephalopathy to the iatrogenicity of epilepsy interventions to neurocognitive disabilities to the approach to neocortical epilepsies. New gene therapy approaches such as antisense oligonucleotide treatment for Dravet syndrome were introduced and neuromodulation devices were discussed. There were many other topics discussed in special interest groups and investigators' workshops. A highlight was having a Nobel prize winner speak about memory processing. Human intracranial electrophysiology contributes insights into memory processing and complements animal work. In a special COVID symposium, the impact of COVID on patients with epilepsy was reviewed. Telehealth has been expanded rapidly and may be well suited for some parts of epilepsy care. In summary, the epilepsy community was alive and engaged despite being limited to a virtual platform.

Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial.

PURPOSE: To evaluate topiramate (TPM) and phenytoin (PHT) monotherapy following rapid oral initiation in new-onset epilepsy. METHODS: Randomized, double-blind, 28-day trial of TPM (100 mg/day beginning on day 1) versus PHT (1,000 mg on day 1 followed by 300 mg/day maintenance dosing) in 261 patients with new-onset epilepsy. The primary end point was time to seizure, and the primary objective was to establish noninferiority of TPM to PHT in the risk of seizure. RESULTS: At day 28, the estimated seizure-free rate was 81.1% for TPM treatment in comparison with 90.3% for PHT treatment. Noninferiority of TPM to PHT (primary objective) could not be established [hazard ratio (HR) 2.0, 95% confidence interval (CI), 0.98 to 4.12, p = 0.366), and PHT could not be shown to be superior to TPM. A higher percentage discontinued with PHT compared to TPM for all reasons (21.1 vs. 12.8%) and due to adverse events (13.4 vs. 6.8%). The most common treatment-related adverse events in both groups were dizziness, paresthesia, and somnolence. A post hoc analysis showed that TPM was superior to PHT in time to discontinuation (retention rate) for all causes (89.4% vs. 80.3%, p = 0.047). CONCLUSION: This study was inconclusive in establishing noninferiority of TPM 100 mg/day compared to a standard regimen of oral PHT in seizure risk in this population of patients with new-onset epilepsy. Given the superiority of TPM in overall retention and favorable tolerability without titration, it may nonetheless be an appropriate option in some patients with new-onset epilepsy requiring rapid treatment initiation.

Physical Plasticity of the Brain and Deep Brain Stimulation Lead: Evolution in the First Post-operative Week.

Background: Deep brain stimulation (DBS) is a therapy for movement disorders and psychiatric conditions. In the peri-operative period, brain shift occurs as the consequence of events related to the brain surgery which results in post-operative lead deformation. Objective: To quantify post-operative 3-dimensional DBS lead deformation after implantation. Methods: In 13 patients who had DBS lead implantation, we performed preoperative magnetic resonance imaging (MRI), preoperative computed tomography (CT) scans after placement of fiducial markers, and post-operative CT scans immediately, 24-48 h, and 7 days after implantation. The MRI scans were used to define brain orientation and merged with CT scans. Lead deviation was determined relative to a theoretical linear lead path defined by the skull entry and target lead tip points. Results: In the sagittal plane, we distinguished an initial period after surgery (<48 h) characterized by a deviation of the lead toward the rostral direction and a late period (over 1 week) characterized by a lead deviation toward the caudal direction. In the coronal plane, there was higher probability of lead deviation in the lateral than medial direction. During 7 days after implantation, there was net movement of the center of the lead anteriorly, and the half of the lead close to the entry point moved medially. These deviations appeared normative since all patients included in this study had benefits from DBS therapy with total power of charged comparable to those described in literature. Conclusion: DBS lead deviation occurs during 7 days after implantation. The range of deviation described in this study was not associated to adverse clinical effects and may be considered normative. Future multicenter studies would be helpful to define guide lines on DBS lead deformation and its contribution to clinical outcome.

Novel in vivo Assessment of Unruptured Intracranial Aneurysm Inflammatory Factors.

Background and Purpose: The growth and eventual rupture of intracranial aneurysms may be due to an underlying inflammatory process as evidenced by pathological examination of aneurysm walls. We hypothesize that unruptured aneurysms have an increased inflammatory milieu within their lumen in comparison to the rest of the cerebral arterial vascular system. Methods: Blood was sampled from unruptured aneurysms in patients presenting for aneurysm coil embolization and C3 and C4 complement values from this serum were compared with complement values in the parent artery. Results: Ten patients were enrolled over 32 months with a mean aneurysm size of 9.1 mm. Compared to control samples drawn from peripheral circulation, there were significant decreases of both C3 (p = 0.0003) and C4 (p = 0.0063) levels in aneurysmal blood samples. Conclusions: A state of decreased complement indicative of classic pathway activation was found in all tested aneurysms, thus providing evidence of an ongoing process of complement activation in the blood of live, unruptured aneurysm sacs.

Local field potential dynamics in the primate cortex in relation to parkinsonism reveled by machine learning: A comparison between the primary motor cortex and the supplementary area.

The present study compares the cortical local field potentials (LFPs) in the primary motor cortex (M1) and the supplementary motor area (SMA) of non-human primates rendered Parkinsonian with administration of dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The dynamic of the LFPs was investigated under several mathematical frameworks and machine learning was used to discriminate the recordings based on these features between healthy, parkinsonian with off-medication and parkinsonian with on-medication states. The importance of each feature in the discrimination process was further investigated. The dynamic of the LFPs in M1 and SMA was affected regarding its variability (time domain analysis), oscillatory activities (frequency domain analysis) and complex patterns (non-linear domain analysis). Machine learning algorithms achieved accuracy near 0.90 for comparisons between conditions. The TreeBagger algorithm provided best accuracy. The relative importance of these features differed with the cortical location, condition and treatment. Overall, the most important features included beta oscillation, fractal dimension, gamma oscillation, entropy and asymmetry of amplitude fluctuation. The importance of features in discriminating between normal and pathological states, and on- or off-medication states depends on the pair-comparison and it is region-specific. These findings are discussed regarding the refinement of current models for movement disorders and the development of on-demand therapies.

Parkinsonism Differently Affects the Single Neuronal Activity in the Primary and Supplementary Motor Areas in Monkeys: An Investigation in Linear and Nonlinear Domains.

The changes in neuronal firing activity in the primary motor cortex (M1) and supplementary motor area (SMA) were compared in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The neuronal dynamic was characterized using mathematical tools defined in different frameworks (rate, oscillations or complex patterns). Then, and for each cortical area, multivariate and discriminate analyses were further performed on these features to identify those important to differentiate between the normal and the pathological neuronal activity. Our results show a different order in the importance of the features to discriminate the pathological state in each cortical area which suggests that the M1 and the SMA exhibit dissimilarities in their neuronal alterations induced by parkinsonism. Our findings highlight the need for multiple mathematical frameworks to best characterize the pathological neuronal activity related to parkinsonism. Future translational studies are warranted to investigate the causal relationships between cortical region-specificities, dominant pathological hallmarks and symptoms.

Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

PURPOSE: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE. METHODS: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process. RESULTS: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study). CONCLUSIONS: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

Development of a therapeutics curriculum to enhance knowledge of fourth-year medical students about clinical uses and adverse effects of drugs.

BACKGROUND: Enhanced clinical pharmacology and therapeutics education of medical students is important for improving effective and safe drug therapy. Increased education about pharmacovigilance is needed because serious drug-induced adverse effects are increasing. Fostering the needed scientific approach to prescribing requires knowledge of evidence-based drug therapy, based on understanding clinical trials. Therapeutic agents with novel mechanisms of action are increasingly available, and an unbiased understanding of the risks and benefits of novel agents is also important. These issues can be addressed in clinical pharmacology courses. However, many medical schools lack sufficient clinical pharmacologists to teach such courses. The Southern Illinois University Medical School faculty implemented an Advanced Therapeutics course to address these issues. DESCRIPTION: Development of this course involved defining appropriate content and organizing preclinical pharmacology and clinical faculty into teaching teams. The course was offered to 4th-year medical students and covered clinical trial information, and cutting-edge therapeutic developments. The "ABCs of Pharmacology" is a mental algorithm that was presented in the sophomore year and reintroduced in this course. This algorithm emphasizes pharmacovigilance, which stresses the balance between positive and negative effects of pharmacological agents. General principles of clinical pharmacology and therapeutics were covered by a clinical pharmacologist. Most sessions on specific disease treatment involved an integrated presentation by a preclinical pharmacologist and a clinician with expertise in that topic, often in the context of clinical cases. Other important topics were emphasized, which reinforce individualization of therapy, including pharmacogenomics that may determine idiosyncratic responses. Feedback during and following the course was obtained via questionnaires. EVALUATION: This approach was well received by participating students and graduates. Most students rated this course as a valuable experience. CONCLUSION: This approach appears useful for educating medical students about therapeutics at medical schools that lack sufficient clinical pharmacology faculty to mount such a course.

Computed tomographic method to quantify electrode lead deformation and subdural gap after lead implantation for deep brain stimulation.

BACKGROUND: Deep brain stimulation is an effective treatment for movement disorders and psychiatric conditions. Intra-operative and post-operative events can result in brain tissue deformation (i.e. subdural gaps) which may cause lead deformation and its displacement from optimal target. We developed a method to quantify postoperative lead deformation and we present two DBS cases to illustrate the phenomena of lead deformation resulting from the development of subdural gaps. NEW METHOD: We present a semi-automatic computational algorithm using Computed Tomography scanning with reconstruction to determine lead curvature relative to a theoretical straight lead between the skull entry site and lead tip. Subdural gap was quantified from the CT scan. RESULTS: In 2 patients who had leads implanted, analysis of CT scans was completed within 5 min each. The maximum deviation of the observed lead from the theoretical linear path was 1.1 and 2.6 mm, and the subdural gap was 5.5 and 9.6 mL, respectively. COMPARISON WITH EXISTING METHOD(S): This is the first method allowing a comprehensive characterization of the lead deformation in situ. CONCLUSIONS: The computational algorithms provide a simple, semiautomatic method to characterize in situ lead curvature related to brain tissue deformation after lead placement.

Glucose metabolites in the striatum of freely behaving rats following infusion of elevated potassium.

The outcome of patients with traumatic brain injury (TBI) can be predicted by the extracellular potassium concentration and the change in energy homeostasis. In this study, the authors investigated the effects of high potassium concentrations on extracellular levels of glucose, pyruvate and lactate in the rat striatum. Applying artificial cerebrospinal fluid (ACSF) enriched with 120 mM potassium by reverse microdialysis leads to an increase in lactate and reduction in glucose and pyruvate. Consequently, the lactate to pyruvate ratio was also increased. These data are discussed in the context of recent studies on lactate/pyruvate conversion and the potential mechanisms whereby high potassium could affect this equilibrium. We conclude that ischemic-like events are unlikely to explain these K(+)-induced changes.

Parkinsonian Balance Deficits Quantified Using a Game Industry Board and a Specific Battery of Four Paradigms.

This study describes a cost-effective screening protocol for parkinsonism based on combined objective and subjective monitoring of balance function. Objective evaluation of balance function was performed using a game industry balance board and an automated analyses of the dynamic of the center of pressure in time, frequency, and non-linear domains collected during short series of stand up tests with different modalities and severity of sensorial deprivation. The subjective measurement of balance function was performed using the Dizziness Handicap Inventory questionnaire. Principal component analyses on both objective and subjective measurements of balance function allowed to obtained a specificity and selectivity for parkinsonian patients (vs. healthy subjects) of 0.67 and 0.71 respectively. The findings are discussed regarding the relevance of cost-effective balance-based screening system as strategy to meet the needs of broader and earlier screening for parkinsonism in communities with limited access to healthcare.

Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

Metabolic changes in rat striatum following convulsive seizures.

Generalized convulsive seizures increase glucose utilization within the brain but their impact on metabolism is not well known. The striatum receives excitatory input from widespread sources in the brain and could potentially reflect energy depletion in the brain resulting from generalized seizures. We utilized multiprobe microdialysis in freely moving rats subjected to maximal electroshock to simultaneously measure glucose, lactate, and pyruvate levels in the interstitial space within striatum and in peripheral subcutaneous tissue. A brief convulsive seizure was associated with marked changes in striatal and peripheral metabolism during the post-ictal state that lasted up to 1 h. There were significant central and peripheral elevations of glucose, pyruvate, and lactate, reflecting increased glucose metabolism. Interestingly, the lactate-to-pyruvate ratio increased significantly in the periphery but remained unchanged in the striatum. Thus, there appears to be brain mechanisms that maintain adequate energy sources and prevent anaerobic shift during the post-ictal state.

The effect of vagus nerve stimulation on migraines.

Vagus nerve stimulation (VNS) inhibits nociceptive behavior in animals. VNS might reduce pain in patients with VNS device implanted for intractable seizures. One case report described possible benefits on migraines. We contacted all patients who received VNS therapy for intractable epilepsy between 1993 and 1999 at Southern Illinois University, Springfield, Illinois. Patients who had concomitant chronic pain were subsequently interviewed. Pain intensity before and after VNS implantation was rated by the patient as average, worst, and least and on numeric rating scale from 1 to 10. Current pain measurements were compared to preimplantation by using Global Pain Relief Rating Scale. Of 62 patients who received VNS, 27 patients were interviewed; 4 patients had common migraine, and no other chronic pain syndromes were identified. All patients with migraine reported reductions in headache frequency and numeric rating scale score for average and least headache intensity. One patient reported complete relief of headaches. Improvement was reported to start 1 to 3 months after initiation of therapy. On Global Pain Relief Rating Scale, 1 patient reported complete pain relief, 2 reported a lot of pain relief, and 1 reported slight pain relief. Concomitant antiepileptic drugs were decreased in 3 patients and slightly increased in 1. VNS might be beneficial for prophylactic therapy of migraine.

Acute vagus nerve stimulation does not suppress spike and wave discharges in genetic absence epilepsy rats from Strasbourg.

We evaluated the efficacy of vagus nerve stimulation (VNS) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a validated model for absence epilepsy. In the first experiment, we investigated whether VNS applied at seizure onset can interrupt spike and wave discharges (SWD). In the second experiment, we investigated whether SWD are suppressed or shortened in duration when VNS is applied several hours per day. Both control and VNS groups underwent EEG and VNS electrode implantation. For the first experiment, a randomized crossover design was used. Stimuli (amplitude: 3 V; frequency: 30 Hz; pulse duration: 500 micros) were given when an SWD occurred on the EEG. The experiment was repeated the next day. In the second experiment, treated animals were stimulated (amplitude: 1.5 mA; frequency: 30 Hz; pulse duration: 500 micros; on/off time cycle: 30 s / 5 min) for 3h per day, during five consecutive days. In the first experiment, the duration of the SWD was increased on day 1, (P < 0.05). There was no difference in SWD duration on Day 2. In the second experiment, no significant differences could be found in number, duration and EEG frequency of SWD. VNS applied at the onset of an SWD can prolong the duration of SWD in GAERS. As a 5-day stimulation protocol had no effect, long-term VNS might be necessary to affect SWD.

Self-inflicted vocal cord paralysis in patients with vagus nerve stimulators. Report of two cases.

Vagus nerve stimulation for treatment of epilepsy is considered safe; reports of severe complications are rare. The authors report on two developmentally disabled patients who experienced vocal cord paralysis weeks after placement of a vagus nerve stimulator. In both cases, traction injury to the vagus nerve resulting in vocal cord paralysis was caused by rotation of the pulse generator at the subclavicular pocket by the patient. Traumatic vagus nerve injury caused by patients tampering with their device has never been reported and may be analogous to a similar phenomenon reported for cardiac pacemakers in the literature. As the use of vagus nerve stimulation becomes widespread it is important to consider the potential for this adverse event.

An entropy-based model for basal ganglia dysfunctions in movement disorders.

During this last decade, nonlinear analyses have been used to characterize the irregularity that exists in the neuronal data stream of the basal ganglia. In comparison to linear parameters for disparity (i.e., rate, standard deviation, and oscillatory activities), nonlinear analyses focus on complex patterns that are composed of groups of interspike intervals with matching lengths but not necessarily contiguous in the data stream. In light of recent animal and clinical studies, we present a review and commentary on the basal ganglia neuronal entropy in the context of movement disorders.

Non-linear dynamics in parkinsonism.

Over the last 30 years, the functions (and dysfunctions) of the sensory-motor circuitry have been mostly conceptualized using linear modelizations which have resulted in two main models: the "rate hypothesis" and the "oscillatory hypothesis." In these two models, the basal ganglia data stream is envisaged as a random temporal combination of independent simple patterns issued from its probability distribution of interval interspikes or its spectrum of frequencies respectively. More recently, non-linear analyses have been introduced in the modelization of motor circuitry activities, and they have provided evidences that complex temporal organizations exist in basal ganglia neuronal activities. Regarding movement disorders, these complex temporal organizations in the basal ganglia data stream differ between conditions (i.e., parkinsonism, dyskinesia, healthy control) and are responsive to treatments (i.e., l-DOPA, deep brain stimulation). A body of evidence has reported that basal ganglia neuronal entropy (a marker for complexity/irregularity in time series) is higher in hypokinetic state. In line with these findings, an entropy-based model has been recently formulated to introduce basal ganglia entropy as a marker for the alteration of motor processing and a factor of motor inhibition. Importantly, non-linear features have also been identified as a marker of condition and/or treatment effects in brain global signals (EEG), muscular activities (EMG), or kinetic of motor symptoms (tremor, gait) of patients with movement disorders. It is therefore warranted that the non-linear dynamics of motor circuitry will contribute to a better understanding of the neuronal dysfunctions underlying the spectrum of parkinsonian motor symptoms including tremor, rigidity, and hypokinesia.