title: Phase dependent modulation of tremor amplitude in essential tremor through thalamic stimulation.
abstract: High frequency deep brain stimulation of the thalamus can help ameliorate severe essential tremor. Here we explore how the efficacy, efficiency and selectivity of thalamic deep brain stimulation might be improved in this condition. We started from the hypothesis that the effects of electrical stimulation on essential tremor may be phase dependent, and that, in particular, there are tremor phases at which stimuli preferentially lead to a reduction in the amplitude of tremor. The latter could be exploited to improve deep brain stimulation, particularly if tremor suppression could be reinforced by cumulative effects. Accordingly, we stimulated 10 patients with essential tremor and thalamic electrodes, while recording tremor amplitude and phase. Stimulation near the postural tremor frequency entrained tremor. Tremor amplitude was also modulated depending on the phase at which stimulation pulses were delivered in the tremor cycle. Stimuli in one half of the tremor cycle reduced median tremor amplitude by ∼10%, while those in the opposite half of the tremor cycle increased tremor amplitude by a similar amount. At optimal phase alignment tremor suppression reached 27%. Moreover, tremor amplitude showed a non-linear increase in the degree of suppression with successive stimuli; tremor suppression was increased threefold if a stimulus was preceded by four stimuli with a similar phase relationship with respect to the tremor, suggesting cumulative, possibly plastic, effects. The present results pave the way for a stimulation system that tracks tremor phase to control when deep brain stimulation pulses are delivered to treat essential tremor. This would allow treatment effects to be maximized by focussing stimulation on the optimal phase for suppression and by ensuring that this is repeated over many cycles so as to harness cumulative effects. Such a system might potentially achieve tremor control with far less power demand and greater specificity than current high frequency stimulation approaches, and may lower the risk for tolerance and rebound.
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.forename: John-Stuart
authors.initials: JS
authors.lastname: Brittain
authors.forename: Simon
authors.initials: S
authors.lastname: Little
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.forename: Patricia
authors.initials: P
authors.lastname: Limousin
authors.forename: Ludvic
authors.initials: L
authors.lastname: Zrinzo
authors.forename: Marwan
authors.initials: M
authors.lastname: Hariz
authors.forename: Carole
authors.initials: C
authors.lastname: Joint
authors.forename: James
authors.initials: J
authors.lastname: Fitzgerald
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Green
authors.forename: Tipu
authors.initials: T
authors.lastname: Aziz
authors.forename: Peter
authors.initials: P
authors.lastname: Brown
mesh_terms: D000328:Adult; D000368:Aged; D046690:Deep Brain Stimulation / Q000379:methods; D020329:Essential Tremor / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D009473:Neuronal Plasticity / Q000502:physiology*; D013788:Thalamus / Q000503:physiopathology*; D016896:Treatment Outcome
keywords: deep brain stimulation; entrainment, plasticity; essential tremor; thalamus
references.citation: J Neurol. 2011 Mar;258(3):434-9
references.pmid: 20927533
references.citation: Brain. 1960;83:337-50
references.pmid: 13852002
references.citation: Neurology. 2003 Oct 14;61(7):919-25
references.pmid: 14557560
references.citation: Eur J Neurosci. 1995 Apr 1;7(4):521-34
references.pmid: 7620604
references.citation: Neurology. 2002 Sep 10;59(5):706-13
references.pmid: 12221161
references.citation: World Neurosurg. 2012 Nov;78(5):554.e1-5
references.pmid: 22381301
references.citation: Curr Biol. 2013 Mar 4;23(5):436-40
references.pmid: 23416101
references.citation: Lancet. 1991 Feb 16;337(8738):403-6
references.pmid: 1671433
references.citation: Neural Comput. 1995 Mar;7(2):307-37
references.pmid: 8974733
references.citation: Eur J Neurosci. 2009 Oct;30(7):1306-17
references.pmid: 19788577
references.citation: Nature. 2002 Mar 28;416(6879):433-8
references.pmid: 11919633
references.citation: Nat Neurosci. 1999 Dec;2(12):1098-105
references.pmid: 10570487
references.citation: Lancet. 2001 Feb 17;357(9255):519-23
references.pmid: 11229671
references.citation: J Clin Neurophysiol. 1996 Mar;13(2):133-44
references.pmid: 8849968
references.citation: Philos Trans R Soc Lond B Biol Sci. 2010 Aug 12;365(1551):2407-22
references.pmid: 20603361
references.citation: J Comp Neurol. 1986 Oct 1;252(1):32-50
references.pmid: 3025270
references.citation: Biol Cybern. 1994;71(3):271-80
references.pmid: 7918804
references.citation: Ann Neurol. 2012 Nov;72(5):816-20
references.pmid: 23280797
references.citation: J Neurosci. 1998 Dec 15;18(24):10464-72
references.pmid: 9852584
references.citation: J Neurosci. 1988 Mar;8(3):754-64
references.pmid: 3346719
references.citation: Exp Neurol. 2009 May;217(1):171-6
references.pmid: 19233174
references.citation: Neurology. 2000;54(11 Suppl 4):S14-20
references.pmid: 10854347
references.citation: Biol Cybern. 2006 Jan;94(1):58-66
references.pmid: 16284784
references.citation: Neuroscience. 1999 Jan;88(1):201-12
references.pmid: 10051201
references.citation: Biol Cybern. 2003 Aug;89(2):81-8
references.pmid: 12905037
references.citation: J Physiol. 1984 Apr;349:227-47
references.pmid: 6737293
references.citation: Annu Rev Physiol. 2002;64:355-405
references.pmid: 11826273
references.citation: Science. 1991 Jan 25;251(4992):432-5
references.pmid: 1824881
references.citation: Nature. 2000 Nov 30;408(6812):584-8
references.pmid: 11117745
references.citation: J Comput Neurosci. 2004 May-Jun;16(3):211-35
references.pmid: 15114047
references.citation: Front Hum Neurosci. 2012 Mar 20;6:58
references.pmid: 22454622
references.citation: Science. 1997 Jan 10;275(5297):213-5
references.pmid: 8985014
references.citation: Mov Disord. 2004 Aug;19(8):933-6
references.pmid: 15300659
references.citation: J Neurophysiol. 2005 Jan;93(1):117-27
references.pmid: 15317839
references.citation: Mov Disord. 2000 Sep;15(5):919-24
references.pmid: 11009200
references.citation: Chaos. 2008 Sep;18(3):037112
references.pmid: 19045486
references.citation: Neurosurgery. 2010 Dec;67(2 Suppl Operative):437-47
references.pmid: 21099570
references.citation: J Physiol. 1984 Apr;349:205-26
references.pmid: 6737292
references.citation: Brain. 1994 Jun;117 ( Pt 3):531-43
references.pmid: 8032863
references.citation: J Neurol Neurosurg Psychiatry. 1993 Aug;56(8):868-73
references.pmid: 8350102
references.citation: J Neurol Neurosurg Psychiatry. 1998 Feb;64(2):273-6
references.pmid: 9489548
references.citation: Brain Res. 1995 Feb 13;671(2):345-50
references.pmid: 7743228
references.citation: Neural Comput. 1996 Jul 1;8(5):979-1001
references.pmid: 8697231
references.citation: J Neurol Neurosurg Psychiatry. 2001 Aug;71(2):215-9
references.pmid: 11459896
references.citation: J Neurosurg. 2004 Jul;101(1):43-7
references.pmid: 15255250