Subcortical Neuronal Ensembles: An Analysis of Motor Task Association, Tremor, Oscillations, and Synchrony in Human Patients

Department of Neurobiology, Duke University, Durham, North Carolina 27710, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2012; 32(25):8620-32. DOI: 10.1523/JNEUROSCI.0750-12.2012
Source: PubMed


Deep brain stimulation (DBS) has expanded as an effective treatment for motor disorders, providing a valuable opportunity for intraoperative recording of the spiking activity of subcortical neurons. The properties of these neurons and their potential utility in neuroprosthetic applications are not completely understood. During DBS surgeries in 25 human patients with either essential tremor or Parkinson's disease, we acutely recorded the single-unit activity of 274 ventral intermediate/ventral oralis posterior motor thalamus (Vim/Vop) neurons and 123 subthalamic nucleus (STN) neurons. These subcortical neuronal ensembles (up to 23 neurons sampled simultaneously) were recorded while the patients performed a target-tracking motor task using a cursor controlled by a haptic glove. We observed that modulations in firing rate of a substantial number of neurons in both Vim/Vop and STN represented target onset, movement onset/direction, and hand tremor. Neurons in both areas exhibited rhythmic oscillations and pairwise synchrony. Notably, all tremor-associated neurons exhibited synchrony within the ensemble. The data further indicate that oscillatory (likely pathological) neurons and behaviorally tuned neurons are not distinct but rather form overlapping sets. Whereas previous studies have reported a linear relationship between power spectra of neuronal oscillations and hand tremor, we report a nonlinear relationship suggestive of complex encoding schemes. Even in the presence of this pathological activity, linear models were able to extract motor parameters from ensemble discharges. Based on these findings, we propose that chronic multielectrode recordings from Vim/Vop and STN could prove useful for further studying, monitoring, and even treating motor disorders.

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Available from: Mikhail A Lebedev
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    • "ith most task - related modulations occurring during button pressing . This agrees with observations that STN neurons are modulated during voluntary movements , which reflects regulation of basal ganglia inhibition around movement initiation ( Matsumura et al . , 1992 ; Wichmann et al . , 1994 ; Hutchison et al . , 1998 ; Williams et al . , 2005 ; Hanson et al . , 2012 ) . Few STN neurons were modulated during the imaginary gait epoch , suggesting that the STN may not be specifically active during gait , consist - ent with the lack of STN modulation during functional imaging of imaginary ( Snijders et al . , 2011 ; Crémers et al . , 2012 ; Karachi et al . , 2012 ) or real gait ( Hanakawa et al . , 199"
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    ABSTRACT: The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans.
    Full-text · Article · May 2015 · Brain
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    • "These sites have in common the presence of pathological activities (dysrhythmia and/or hyperactivity) as shown by recordings in patients both at the single neuron level (via microelectrode probes during surgery) and at the population level (via implanted DBS leads or imaging studies). There are examples of pathological activity in rhythmic oscillations and pairwise synchrony in the ventral thalamus Vim/Vop of patients suffering from essential tremor (Hanson et al., 2012); augmented synchrony of neuronal firing, loss of specificity of the receptive fields, and increased firing rates with bursts in the STN and GPi of Parkinson's disease (PD) patients (Hutchison et al., 1998); rhythmic oscillations in the Vop of patients suffering from Tourette syndrome (Marceglia et al., 2010); high-frequency discharge with bursting in the limbic STN (Welter et al., 2011) or in the ventral caudate nucleus of patients showing OCD episodes during surgery (Guehl et al., 2008); increased activation of regional cerebral blood flow that may be reversed by several anti-depressant therapies in the subcallosal cingulate gyrus (SCG) in patients with depression (Hamani et al., 2012) and in areas specifically activated in patients experiencing acute cluster headaches but not in other causes of head pain (May et al., 1998). This review aims at examining why it has been so difficult to discern the mechanisms underlying the HFS-mediated clinical improvements. "
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    ABSTRACT: High-frequency deep brain stimulation is used to treat a wide range of brain disorders, like Parkinson's disease. The stimulated networks usually share common electrophysiological signatures, including hyperactivity and/or dysrhythmia. From a clinical perspective, HFS is expected to alleviate clinical signs without generating adverse effects. Here, we consider whether the classical open-loop HFS fulfills these criteria and outline current experimental or theoretical research on the different types of closed-loop DBS that could provide better clinical outcomes. In the first part of the review, the two routes followed by HFS-evoked axonal spikes are explored. In one direction, orthodromic spikes functionally de-afferent the stimulated nucleus from its downstream target networks. In the opposite direction, antidromic spikes prevent this nucleus from being influenced by its afferent networks. As a result, the pathological synchronized activity no longer propagates from the cortical networks to the stimulated nucleus. The overall result can be described as a reversible functional de-afferentation of the stimulated nucleus from its upstream and downstream nuclei. In the second part of the review, the latest advances in closed-loop DBS are considered. Some of the proposed approaches are based on mathematical models, which emphasize different aspects of the parkinsonian basal ganglia: excessive synchronization, abnormal firing-rate rhythms, and a deficient thalamo-cortical relay. The stimulation strategies are classified depending on the control-theory techniques on which they are based: adaptive and on-demand stimulation schemes, delayed and multi-site approaches, stimulations based on proportional and/or derivative control actions, optimal control strategies. Some of these strategies have been validated experimentally, but there is still a large reservoir of theoretical work that may point to ways of improving practical treatment.
    Full-text · Article · Dec 2013 · Frontiers in Systems Neuroscience
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    • "Robust oscillatory synchronization patterns of STN spiking activity have been reported in the 6-hydroxydopamine rodent model of Parkinsonism (Machado et al., 2006; Mallet et al., 2008a,b; Lintas et al., 2012). In human PD patients, oscillatory synchronization of spiking activity has been reported in several studies (Levy et al., 2000, 2002a,b; Amirnovin et al., 2004; Weinberger et al., 2006; Hanson et al., 2012; Alavi et al., 2013; Lourens et al., 2013) but there have been no detailed descriptions of the dependence of the neuronal synchronization on the oscillatory activity or the spatial properties of the neuronal pairs (e.g., simultaneous recording of neurons from the oscillatory and non-oscillatory regions of the STN, see below). "
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    ABSTRACT: Beta-band synchronous oscillations in the dorsolateral region of the subthalamic nucleus (STN) of human patients with Parkinson's disease (PD) have been frequently reported. However, the correlation between STN oscillations and synchronization has not been thoroughly explored. The simultaneous recordings of 2390 multi-unit pairs recorded by two parallel microelectrodes (separated by fixed distance of 2 mm, n = 72 trajectories with two electrode tracks >4 mm STN span) in 57 PD patients undergoing STN deep brain stimulation surgery were analyzed. Automatic procedures were utilized to divide the STN into dorsolateral oscillatory and ventromedial non-oscillatory regions, and to quantify the intensity of STN oscillations and synchronicity. Finally, the synchronicity of simultaneously vs. non-simultaneously recorded pairs were compared using a shuffling procedure. Synchronization was observed predominately in the beta range and only between multi-unit pairs in the dorsolateral oscillatory region (n = 615). In paired recordings between sites in the dorsolateral and ventromedial (n = 548) and ventromedial-ventromedial region pairs (n = 1227), no synchronization was observed. Oscillation and synchronicity intensity decline along the STN dorsolateral-ventromedial axis suggesting a fuzzy border between the STN regions. Synchronization strength was significantly correlated to the oscillation power, but synchronization was no longer observed following shuffling. We conclude that STN long-range beta oscillatory synchronization is due to increased neuronal coupling in the Parkinsonian brain and does not merely reflect the outcome of oscillations at similar frequency. The neural synchronization in the dorsolateral (probably the motor domain) STN probably augments the pathological changes in firing rate and patterns of subthalamic neurons in PD patients.
    Full-text · Article · Nov 2013 · Frontiers in Systems Neuroscience
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