title: The nature of tremor circuits in parkinsonian and essential tremor.
abstract: Tremor is a cardinal feature of Parkinson's disease and essential tremor, the two most common movement disorders. Yet, the mechanisms underlying tremor generation remain largely unknown. We hypothesized that driving deep brain stimulation electrodes at a frequency closely matching the patient's own tremor frequency should interact with neural activity responsible for tremor, and that the effect of stimulation on tremor should reveal the role of different deep brain stimulation targets in tremor generation. Moreover, tremor responses to stimulation might reveal pathophysiological differences between parkinsonian and essential tremor circuits. Accordingly, we stimulated 15 patients with Parkinson's disease with either thalamic or subthalamic electrodes (13 male and two female patients, age: 50-77 years) and 10 patients with essential tremor with thalamic electrodes (nine male and one female patients, age: 34-74 years). Stimulation at near-to tremor frequency entrained tremor in all three patient groups (ventrolateral thalamic stimulation in Parkinson's disease, P=0.0078, subthalamic stimulation in Parkinson's disease, P=0.0312; ventrolateral thalamic stimulation in essential tremor, P=0.0137; two-tailed paired Wilcoxon signed-rank tests). However, only ventrolateral thalamic stimulation in essential tremor modulated postural tremor amplitude according to the timing of stimulation pulses with respect to the tremor cycle (e.g. P=0.0002 for tremor amplification, two-tailed Wilcoxon rank sum test). Parkinsonian rest and essential postural tremor severity (i.e. tremor amplitude) differed in their relative tolerance to spontaneous changes in tremor frequency when stimulation was not applied. Specifically, the amplitude of parkinsonian rest tremor remained unchanged despite spontaneous changes in tremor frequency, whereas that of essential postural tremor reduced when tremor frequency departed from median values. Based on these results we conclude that parkinsonian rest tremor is driven by a neural network, which includes the subthalamic nucleus and ventrolateral thalamus and has broad frequency-amplitude tolerance. We propose that it is this tolerance to changes in tremor frequency that dictates that parkinsonian rest tremor may be significantly entrained by low frequency stimulation without stimulation timing-dependent amplitude modulation. In contrast, the circuit influenced by low frequency thalamic stimulation in essential tremor has a narrower frequency-amplitude tolerance so that tremor entrainment through extrinsic driving is necessarily accompanied by amplitude modulation. Such differences in parkinsonian rest and essential tremor will be important in selecting future strategies for closed loop deep brain stimulation for tremor control.
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK.
authors.forename: Hayriye
authors.initials: H
authors.lastname: Cagnan
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Little
authors.affiliation: 2 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.affiliation: 2 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Limousin
authors.affiliation: 2 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Ludvic
authors.initials: L
authors.lastname: Zrinzo
authors.affiliation: 2 Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, WC1N 3BG, UK.
authors.forename: Marwan
authors.initials: M
authors.lastname: Hariz
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK.
authors.forename: Binith
authors.initials: B
authors.lastname: Cheeran
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK 3 Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: James
authors.initials: J
authors.lastname: Fitzgerald
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK 3 Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Green
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK 3 Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
authors.forename: Tipu
authors.initials: T
authors.lastname: Aziz
authors.affiliation: 1 Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, West Wing Level 6, OX3 9DU, Oxford, UK peter.brown@ndcn.ox.ac.uk.
authors.forename: Peter
authors.initials: P
authors.lastname: Brown
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D046690:Deep Brain Stimulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009069:Movement Disorders / Q000503:physiopathology / Q000628:therapy; D010300:Parkinson Disease / Q000503:physiopathology / Q000628:therapy*; D020531:Subthalamic Nucleus / Q000503:physiopathology*; D013788:Thalamus / Q000503:physiopathology*; D016896:Treatment Outcome; D014202:Tremor / Q000503:physiopathology / Q000628:therapy*
keywords: basal ganglia; clinical neurophysiology; deep brain stimulation; thalamus; tremor