David Arkadir

Midbrain dopamine neurons encode decisions for future action

Current models of the basal ganglia and dopamine neurons emphasize their role in reinforcement learning. However, the role of dopamine neurons in decision making is still unclear. We recorded from dopamine neurons in monkeys engaged in two types of trial: reference trials in an instructed-choice task and decision trials in a two-armed bandit decision task. We show that the activity of dopamine neurons in the decision setting is modulated according to the value of the upcoming action. Moreover, analysis of the probability matching strategy in the decision trials revealed that the dopamine population activity and not the reward during reference trials determines choice behavior. Because dopamine neurons do not have spatial or motor properties, we conclude that immediate decisions are likely to be generated elsewhere and conveyed to the dopamine neurons, which play a role in shaping long-term decision policy through dynamic modulation of the efficacy of basal ganglia synapses.

Shaping of motor responses by incentive values through the basal ganglia.

The striatum is a key neural interface for cognitive and motor information processing in which associations between reward value and visual stimulus can be used to modify motor commands. It can guide action–selection processes that occur farther downstream in the basal ganglia (BG) circuit, by encoding the reward value of an action. Here, we report on the study of simultaneously recorded neurons in the dorsal striatum (input stage of the BG) and the internal pallidum (output stage of the BG) in two monkeys performing a center-out motor task in which the visual targets were associated with different reward probabilities. We show that the tuning curves of motor-related neurons in both structures are modulated by the value of the action before movement initiation and during its execution. The representations of values associated with different actions change dynamically during the task in the internal globus pallidus, with a significant increase in the number of encoding neurons for the chosen target at the onset of movement. This report sheds additional light on the functional differences between the input and output structures of the BG and supports the assertion that the dorsal basal ganglia are involved in movement-related decision-making processes based on incentive values.

Akineto-rigid vs. tremor syndromes in Parkinsonism

Purpose of reviewAkinesia, rigidity and low-frequency rest tremor are the three cardinal motor signs of Parkinsons disease and some Parkinsons disease animal models. However, cumulative evidence supports the view that akinesia/rigidity vs. tremor reflect different pathophysiological phenomena in the basal ganglia. Here, we review the recent physiological literature correlating abnormal neural activity in the basal ganglia with Parkinsons disease clinical symptoms. Recent findingsThe subthalamic nucleus of Parkinsons disease patients is characterized by oscillatory activity in the beta-frequency (∼15 Hz) range. However, Parkinsons disease tremor is not strictly correlated with the abnormal synchronous oscillations of the basal ganglia. On the other hand, akinesia and rigidity are better correlated with the basal ganglia beta oscillations. SummaryThe abnormal basal ganglia output leads to akinesia and rigidity. Parkinsons disease tremor most likely evolves as a downstream compensatory mechanism.

Independent Coding of Movement Direction and Reward Prediction by Single Pallidal Neurons

Associating action with its reward value is a basic ability needed by adaptive organisms and requires the convergence of limbic, motor, and associative information. To chart the basal ganglia (BG) involvement in this association, we recorded the activity of 61 well isolated neurons in the external segment of the globus pallidus (GPe) of two monkeys performing a probabilistic visuomotor task. Our results indicate that most (96%) neurons responded to multiple phases of the task. The activity of many (34%) pallidal neurons was modulated solely by direction of movement, and the activity of only a few (3%) pallidal neurons was modulated exclusively by reward prediction. However, the activity of a large number (41%) of single pallidal neurons was comodulated by both expected trial outcome and direction of arm movement. The information carried by the neuronal activity of single pallidal neurons dynamically changed as the trial progressed. The activity was predominantly modulated by both outcome prediction and future movement direction at the beginning of trials and became modulated mainly by movement-direction toward the end of trials. GPe neurons can either increase or decrease their discharge rate in response to predicted future reward. The effects of movement-direction and reward probability on neural activity are linearly summed and thus reflect two independent modulations of pallidal activity. We propose that GPe neurons are uniquely suited for independent processing of a multitude of parameters. This is enabled by the funnel-structure characteristic of the BG architecture, as well as by the anatomical and physiological properties of GPe neurons.

Statistical Properties of Pauses of the High-Frequency Discharge Neurons in the External Segment of the Globus Pallidus

The neurons of many basal ganglia nuclei, including the external and internal globus pallidus (GPe and GPi, respectively) and the substantia nigra pars reticulata (SNr) are characterized by their high-frequency (50–100 spikes/s) tonic discharge (HFD). However, the high firing rate of GPe neurons is interrupted by long pauses. We studied the extracellularly recorded spiking activity of 212 well-isolated HFD GPe and 52 GPi/SNr neurons from five monkeys during different states of behavioral activity. An algorithm that maximizes the surprise function was used to detect pauses and pauser cells (“pausers”). Only 6% of the GPi/SNr neurons versus as many as 56% of the GPe neurons were classified as pausers. The GPe average pause duration equals 0.62 s. The interpause intervals follow a Poissonian distribution with a frequency of 13 pauses/minute. No linear relationship was found between pause parameters (duration or frequency) and the firing rate of the cell. Pauses were preceded by various changes in firing rate but not dominantly by a decrease. The average amplitude and duration of the spike waveform was modulated only after the pause but not before it. Pauses of pairs of cells that were recorded simultaneously were not correlated. The probability of GPe cells to pause spontaneously was extremely variable among monkeys (30–90%) and inversely related to the degree of the monkeys motor activity. These findings suggest that spontaneous GPe pauses are related to low-arousal periods and are generated by a process that is independent of the discharge properties of the cells.

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.

Redundant dopaminergic activity may enable compensatory axonal sprouting in Parkinson disease

Neurodegenerative diseases become clinically apparent only after a substantial population of neurons is lost. This raises the possibility of compensatory mechanisms in the early phase of these diseases. The importance of understanding these mechanisms cannot be underestimated because it may guide future disease-modifying strategies. Because the anatomy and physiology of the nigrostriatal dopaminergic pathways have been well described, the study of Parkinson disease can offer insight into these early compensatory mechanisms. Collateral axonal sprouting of dopaminergic terminals into the denervated striatum is the most studied compensatory mechanism in animal (almost exclusively rodent) models of Parkinson disease and is correlated with behavioral recovery after partial lesions. This sprouting, however, does not respect the normal anatomy of the original nigrostriatal pathways and leads to aberrant neuronal networks. We suggest here that the unique physiologic property of the dopaminergic innervation of the striatum, namely redundancy of information encoding, is crucial to the efficacy of compensatory axonal sprouting in the presence of aberrant anatomical connections. Redundant information encoding results from the similarity of representation of salient and rewarding events by many dopaminergic neurons, from the wide axonal field of a single dopaminergic neuron in the striatum, and from the nonspecific spatial effect of dopamine on striatal neurons (volume conductance). Finally, we discuss the relevance of these findings in animal models to human patients with Parkinson disease.

Preliminary experience with the use of self-expanding stent as a thrombectomy device in ischemic stroke.

Abstract Objectives: Stent-based techniques may allow rapid arterial recanalization in acute stroke. We present our experience using a self-expanding stent to achieve a transient bypass, and then as a thrombectomy device, with no permanent stent implantation, in acute stroke. Materials and methods: Six patients (mean age 55 years, range 35-71 years) presented with major ischemic stroke secondary to large vessel occlusion. Patients had a National Institutes of Health Stroke Scale score of >17, no intracerebral hemorrhage or early infarction, and poor collateral supply to the affected parenchyma. Within 6 hours of symptom onset, a stent (Solitaire, ev3, Irvine, CA, USA) was deployed across the entire occluded segment. Repeat angiogram was performed to evaluate the reconstituted flow. The balloon of the guide catheter was inflated for proximal carotid occlusion. The partially deployed stent was slowly pulled back (mechanical thrombectomy step) under continuous aspiration. Suction was repeated to ensure the aspiration of any clot remnants. Results: In all the cases, complete recanalization (Thrombolysis in Myocardial Infarction Revascularization and Reperfusion Score of 3) was achieved in <60 minutes after femoral access, and a single thrombectomy attempt was sufficient to achieve clot removal. No stent was permanently implanted. Modified Rankin Scores were 0-2 in all patients at a mean 1-month follow-up. Conclusions: The presented approach allowed three desired effects: rapid endovascular revascularization, clot removal, and no need of leaving a permanent implant. In our preliminary experience this simple and rapid stent-based mechanical thrombectomy technique has had an unprecedented success rate.

Local vs. volume conductance activity of field potentials in the human subthalamic nucleus

Subthalamic nucleus field potentials have attracted growing research and clinical interest over the last few decades. However, it is unclear whether subthalamic field potentials represent locally generated neuronal subthreshold activity or volume conductance of the organized neuronal activity generated in the cortex. This study aimed at understanding of the physiological origin of subthalamic field potentials and determining the most accurate method for recording them. We compared different methods of recordings in the human subthalamic nucleus: spikes (300-9,000 Hz) and field potentials (3-100 Hz) recorded by monopolar micro- and macroelectrodes, as well as by differential-bipolar macroelectrodes. The recordings were done outside and inside the subthalamic nucleus during electrophysiological navigation for deep brain stimulation procedures (150 electrode trajectories) in 41 Parkinsons disease patients. We modeled the signal and estimated the contribution of nearby/independent vs. remote/common activity in each recording configuration and area. Monopolar micro- and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity. However, bipolar macroelectrode recordings inside the subthalamic nucleus can detect locally generated potentials. These results are confirmed by high correspondence between the model predictions and actual correlation of neuronal activity recorded by electrode pairs. Differential bipolar macroelectrode subthalamic field potentials can overcome volume conductance effects and reflect locally generated neuronal activity. Bipolar macroelectrode local field potential recordings might be used as a biological marker of normal and pathological brain functions for future electrophysiological studies and navigation systems as well as for closed-loop deep brain stimulation paradigms.NEW & NOTEWORTHY Our results integrate a new method for human subthalamic recordings with a development of an advanced mathematical model. We found that while monopolar microelectrode and macroelectrode recordings detect field potentials that are considerably affected by common (probably cortical) activity, bipolar macroelectrode recordings inside the subthalamic nucleus (STN) detect locally generated potentials that are significantly different than those recorded outside the STN. Differential bipolar subthalamic field potentials can be used in navigation and closed-loop deep brain stimulation paradigms.

Stent for temporary endovascular bypass and thrombectomy in major ischemic stroke.

Endovascular techniques for acute stroke have evolved from a pharmacological to a mechanical approach. We report illustrative cases of successful anterior circulation recanalization in patients with large arterial occlusions, using a stent-based technique to perform arterial recanalization and thrombectomy, without permanent stent implantation. Four patients (mean age 59 years), presented with National Institutes of Health Stroke Scale (NIHSS) scores of 18 to 24, from 2 hours to 6 hours after stroke onset, with middle cerebral artery (MCA), MCA branch, internal carotid artery (ICA) terminus, or tandem ICA-MCA occlusions. A closed-cell stent was temporarily inserted to achieve temporary endovascular bypass, and then used as a thrombectomy device during withdrawal. Rapid and complete recanalization with successful thrombectomy was achieved in all patients within 28 minutes to 52 minutes. One week after treatment patients achieved NIHSS scores of 2 to 5, with no hemorrhagic complications. This approach allowed rapid endovascular revascularization and thrombectomy, without permanent stent implant. Stent-based thrombectomy devices may become a valuable tool in the management of acute ischemic stroke.