Sage Journals: Discover world-class research

Abstract

Background:

Tremor is present in almost half of multiple sclerosis (MS) patients. The lack of understanding of its pathophysiology is hampering progress in development of treatments.

Objectives:

To clarify the structural and functional brain changes associated with the clinical phenotype of upper limb tremor in people with MS.

Methods:

Fifteen healthy controls (46.1 ± 15.4 years), 27 MS participants without tremor (46.7 ± 11.6 years) and 42 with tremor (46.6 ± 11.5 years) were included. Tremor was quantified using the Bain score (0–10) for overall severity, handwriting and Archimedes spiral drawing. Functional magnetic resonance imaging activations were compared between participants groups during performance of a joystick task designed to isolate tremulous movement. Inflammation and atrophy of cerebello-thalamo-cortical brain structures were quantified.

Results:

Tremor participants were found to have atrophy of the cerebellum and thalamus, and higher ipsilateral cerebellar lesion load compared to participants without tremor (p < 0.020). We found higher ipsilateral activation in the inferior parietal lobule, the premotor cortex and supplementary motor area in MS tremor participants compared to MS participants without tremor during the joystick task. Finally, stronger activation in those areas was associated with lower tremor severity.

Conclusion:

Subcortical neurodegeneration and inflammation along the cerebello-thalamo-cortical and cortical functional neuroplasticity contribute to the severity of tremor in MS.

Keywords

Multiple sclerosis functional magnetic resonance imaging magnetic resonance imaging

Get full access to this article

View all access options for this article.

References

Browne

Chandraratna

Angood

, et al. Atlas of multiple sclerosis 2013: A growing global problem with widespread inequity. Neurology 2014; 83(11): 1022–1024.

Rinker

2nd Salter

Walker

, et al. Prevalence and characteristics of tremor in the NARCOMS multiple sclerosis registry: A cross-sectional survey. BMJ Open 2015; 5(1): e006714.

Deuschl

Bain

Brin

Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13(Suppl 3): 2–23.

Koziarska

Krol

Nocon

, et al. Prevalence and factors leading to unemployment in MS (multiple sclerosis) patients undergoing immunomodulatory treatment in Poland. PLoS ONE 2018; 13(4): e0194117.

Julian

Vella

Vollmer

, et al. Employment in multiple sclerosis: Exiting and re-entering the work force. J Neurol 2008; 255(9): 1354–1360.

Pittock

McClelland

Mayr

, et al. Prevalence of tremor in multiple sclerosis and associated disability in the Olmsted County population. Mov Disord 2004; 19(12): 1482–1485.

Labiano-Fontcuberta

Benito-Leon

Understanding tremor in multiple sclerosis: Prevalence, pathological anatomy, and pharmacological and surgical approaches to treatment. Tremor Other Hyperkinet Mov 2012; 2: tre-02-109-765-2.

Nakamura

Kamakura

Tadano

, et al. MR imaging findings of tremors associated with lesions in cerebellar outflow tracts: Report of two cases. Mov Disord 1993; 8(2): 209–212.

Fahn

What is it? Case 1 1986. Presentation of a case. Mov Disord 1986; 1(4): 275–280.

10.

Feys

Maes

Nuttin

, et al. Relationship between multiple sclerosis intention tremor severity and lesion load in the brainstem. NeuroReport 2005; 16(12): 1379–1382.

11.

Boonstra

Florescu

Evans

, et al. Tremor in multiple sclerosis is associated with cerebello-thalamic pathology. J Neural Transm 2017; 124(12): 1509–1514.

12.

Reddy

Narayanan

Arnoutelis

, et al. Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 2000; 123(Pt 11): 2314–2320.

13.

Reddy

Narayanan

Woolrich

, et al. Functional brain reorganization for hand movement in patients with multiple sclerosis: Defining distinct effects of injury and disability. Brain 2002; 125(Pt 12): 2646–2657.

14.

Kurtzke

JF.

Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurology 1983; 33(11): 1444–1452.

15.

Van Der Walt

Sung

Spelman

, et al. A double-blind, randomized, controlled study of botulinum toxin type A in MS-related tremor. Neurology 2012; 79(1): 92–99.

16.

Bain

Findley

Atchison

, et al. Assessing tremor severity. J Neurol Neurosur Ps 1993; 56(8): 868–873.

17.

Alusi

Worthington

Glickman

, et al. A study of tremor in multiple sclerosis. Brain 2001; 124(Pt 4): 720–730.

18.

Boonstra

FMC

Perera

Noffs

, et al. Novel functional MRI task for studying the neural correlates of upper limb tremor. Front Neurol 2018; 9: 513.

19.

Smith

Jenkinson

Woolrich

, et al. Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 2004; 23(Suppl 1): S208–S219.

20.

Lotze

Flor

Grodd

, et al. Phantom movements and pain: An fMRI study in upper limb amputees. Brain 2001; 124(Pt 11): 2268–2277.

21.

Buma

Raemaekers

Kwakkel

, et al. Brain function and upper limb outcome in stroke: A cross-sectional fMRI study. PLoS ONE 2015; 10(10): e0139746.

22.

Avants

Tustison

Song

, et al. A reproducible evaluation of ANTs similarity metric performance in brain image registration. NeuroImage 2011; 54(3): 2033–2044.

23.

Schmidt

Gaser

Arsic

, et al. An automated tool for detection of FLAIR-hyperintense white-matter lesions in Multiple Sclerosis. NeuroImage 2012; 59(4): 3774–3783.

24.

Liu

Miall

Aziz

, et al. Analysis of action tremor and impaired control of movement velocity in multiple sclerosis during visually guided wrist-tracking tasks. Mov Disord 1997; 12(6): 992–999.

25.

Miall

Weir

Wolpert

, et al. Is the cerebellum a smith predictor. J Mot Behav 1993; 25(3): 203–216.

26.

Carpenter

Hanna

GR.

Effects of thalamic lesions upon cerebellar dyskinesia in the rhesus monkey. J Comp Neurol 1962; 119: 127–147.

27.

Wilms

Sievers

Deuschl

Animal models of tremor. Mov Disord 1999; 14(4): 557–571.

28.

Foote

Seignourel

Fernandez

, et al. Dual electrode thalamic deep brain stimulation for the treatment of posttraumatic and multiple sclerosis tremor. Neurosurgery 2006; 58(4 Suppl 2) ONS-280–ONS-285; discussion ONS-285–ONS-6.

29.

Yap

Kouyialis

Varma

TR.

Stereotactic neurosurgery for disabling tremor in multiple sclerosis: Thalamotomy or deep brain stimulation?

Br J Neurosurg 2007; 21(4): 349–354.

30.

Anderson

Fox

Miller

DH.

Magnetic resonance imaging measures of brain atrophy in multiple sclerosis. J Magn Reson Imaging 2006; 23(5): 605–618.

31.

Rocca

Filippi

Functional MRI in multiple sclerosis. J Neuroimaging 2007; 17: 36S–41S.

32.

Broersma

van der Stouwe

AMM

Buijink

AWG

, et al. Bilateral cerebellar activation in unilaterally challenged essential tremor. Neuroimage Clin 2016; 11: 1–9.

33.

Buijink

Broersma

van der Stouwe

, et al. Rhythmic finger tapping reveals cerebellar dysfunction in essential tremor. Parkinsonism Relat Disord 2015; 21(4): 383–388.

34.

Neely

Kurani

Shukla

, et al. Functional brain activity relates to 0-3 and 3-8 Hz force oscillations in essential tremor. Cereb Cortex 2015; 25(11): 4191–4202.

35.

VanMeter

Maisog

Zeffiro

, et al. Parametric analysis of functional neuroimages: Application to a variable-rate motor task. NeuroImage 1995; 2(4): 273–283.

36.

Svoboda

Neural mechanisms of movement planning: Motor cortex and beyond. Curr Opin Neurobiol 2018; 49: 33–41.

37.

Blakemore

Sirigu

Action prediction in the cerebellum and in the parietal lobe. Exp Brain Res 2003; 153(2): 239–245.

38.

Clower

West

Lynch

, et al. The inferior parietal lobule is the target of output from the superior colliculus, hippocampus, and cerebellum. J Neurosci 2001; 21(16): 6283–6291.

39.

Shum

Shiller

Baum

, et al. Sensorimotor integration for speech motor learning involves the inferior parietal cortex. Eur J Neurosci 2011; 34(11): 1817–1822.

40.

Claeys

Lindsey

De Schutter

, et al. A higher order motion region in human inferior parietal lobule: Evidence from fMRI. Neuron 2003; 40(3): 631–642.

41.

Mallol

Barros-Loscertales

Lopez

, et al. Compensatory cortical mechanisms in Parkinson’s disease evidenced with fMRI during the performance of pre-learned sequential movements. Brain Res 2007; 1147: 265–271.

42.

Meador

Salter

Rinker

2nd . Symptomatic management of multiple sclerosis–associated tremor among participants in the NARCOMS registry. Int J MS Care 2016; 18(3): 147–153.

43.

Schapiro

RT.

Pharmacologic options for the management of multiple sclerosis symptoms. Neurorehabil Neural Repair 2002; 16(3): 223–231.

44.

Koch

Mostert

Heersema

, et al. Tremor in multiple sclerosis. J Neurol 2007; 254(2): 133–145.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.15 MB

Functional neuroplasticity in response to cerebello-thalamic injury underpins the clinical presentation of tremor in multiple sclerosis