Tremor in Motor Neuron Disease May Be Central Rather Than Peripheral in Origin

Home , Essential tremor, Intention tremor, Tremor

This article isThis article by protected copy 10.1111/ene.13743doi: differences to lead between the of thisversion citethisa and Version Record.Please copyediting, paginationbeen throughthe andproofreadingtypesetting, process,may which This article acceptedhas been for publication andundergone fullpeer revie [email protected] 8723 44(0) Tel: 20 3448 Office UCL, Clinical of Neurology Professor Kailash Prof author: Corresponding Article :Original Article type : 0000 (OrcidID BERARDELLI DR. ALFREDO ID: 0000 (Orcid LATORRE DR. ANNA 3 Department of Bettina Balint

Accepted ArticleAnna Latorre MD 1

Sobell Disorders, DepartmentMotorMovement ofNeuroscienceCollege and University London(UCL) of Institute 33 Tremor in motorneuron disease

Queen Square, London, WC1N3BG London, Square, Queen 6 DepartmentClinical of UCL Neurology, Neuroscience, of Institute RowlandHill London, Street, UK Bhatia, FRCP Bhatia, Neurology, PhilippsMarburg, University, ofNeurology,Attikon Germany; Department Hospital, University MD 4 DepartmentNeurology, of FatebenefratelliASST Hospital, Sacco, Milan 7 2 Istituto eCura aCarattere Ricovero Scientifico(IRCCS) di Neuromed,Pozzilli,Italy IS, DepartmentNeurology of andPsychiatry, Sapienza, UniversityRome, of Italy 1 1,2 ,5

, , Lorenzo, Rocchi MD

Katie Sidle 5 DepartmentNeurology, of UniversityH

, PhD, right. All rightsreserved. Neurology,London, United Kingdom peripheral - 0001 1 6 , Maria Stamelou , Alfredo Berardelli MD of Athens, Athens, Greece - -

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4 , This article isThis article by protected copy with healthy frequency change peak acceleromet A tremor. kinetic simple also ofthemshowed Two asymmetry. degree of withasmall bilateral frequency, constant and amplitude oflow tremor postural Results: was calculated. rectified of spectra Power weightload. variable bilaterally recorded tremor Methods: in can occur in neuron motor Background: A c of Disclosure cerebellum Key words: title: Running bstract

Accepted Article phenotyp the performed and no other movement disorders disorders othermovement no and

Action tremor was present in about 10% of our population. A population. our about10%of present in was tremor Action

120

To investigate a possible cerebellar involvement, e cerebellarinvolvement, a possible investigate To Motor ric MND,

volunteers Motor neuron disease Motor neuron

s tremor in motor neuron disease neuron motor in tremor consecutive consecutive onflict ofi

recordings ranging recordings in in e

R .

ecent c ecent five Rhythmic involuntary oscillations of the hands during action, resembling tremor, resembling action, during ofthehands oscillations Rhythmic involuntary neuron disease, tr disease, neuron but its pathophysiology has not hasnot pathophysiology its but

using surface surface using

patients. , patients in either the either in nterest: nterest: linical and postmortem observations observations postmortem and linical MND

patients were patients had None electromyography electromyography right. All rightsreserved. from 4 from

(MND) electromyograp emor, a

smaller smaller

Hz were found

refers to refers power spectrum power

to 12Hz

screened screened num electromyography yet ber ber a hic and

was found in all patients foundin was . Ten spectrum of degenerative diseases diseases ofdegenerative spectrum been investigated. been

or or of

for tremor. for triaxial accelerometer triaxial

conditioned responses responses conditioned accelerometric accelerometric

took part in took part , eye blink eye ,

ye blink classic condition classic blink ye have revealed have

peak the at peak

and accelerometric signal were signal and accelerometric

Twelve patients with with patients Twelve ll patients showed distal distal showed patients ll

classic

the study. the study.

power spectra power electrom

considerable variability variability considerable conditioning, conditioning, .

, Loading did not didnot Loading

with during during T remor was was remor yography

and without and ing ing . Compared . Compared EBCC affecting affecting action action (EBCC) (EBCC)

and .

This article isThis article by protected copy tremor. resembling thus to fasciculations, associated and not during acti hands the of oscillations rhythmic involuntary show were palpable amplitudes with irregular movements, ( MND postmortem sig (ALS) sclerosis (PMA). muscular atrophy toprogressive sclerosis lateral primary from spans variably Motor Introduction tremor action andthat disease neurodegenerative multisystem possibly Conclusion 2 - ns combined ns combined Accepted4 Article ) .

then then should should

neuron In 1970 affect the affect

due to due movements attributed to fasciculations fasciculations to attributed s :

be observations our data suggest datasuggest our

is disease (MND) disease , a cerebellar dysfunction. This evidence supports the novel idea of of novel idea the supports evidence This dysfunction. a cerebellar with regarded as regarded

Spiro Spiro the most common subtype of MND MND subtype of common the most

upper (UMN) upper

degreeof a of used the term minipolymyoclonus to clinicallydescribe minipolymyoclonus the term used

the joints" the

demonstrate

refers to refers widespread widespread that that

and lower motor neurons (LMN neurons lowermotor and pyramidal signs pyramidal right. All rightsreserved.

observed in childhood spinalmusc childhood in observed MND (

just sufficient to produce visible and visibleand produce to sufficient just 6 a d )

spectrum of progressive degenerative diseases diseases degenerative ofprogressive spectrum patients can present with action tremor action with can present patients . that

However, in our clinical experience MND patients often patients often MND experience clinical our in However, degenerative disease degenerative

other other

due to to due neural structures neural structures and itis UMNs involvement

characterized

on, with a fairly constant frequency frequency fairlyconstant with a on,

can be can of the central nervous system system (CNS) nervous the central of ), and includes a continuum which which a continuum includes ), and ular atrophy (SMA) (SMA) ular atrophy can be involved, indicating that that indicating beinvolved, can part ofth part

(

1 Amyot

) "intermittent predominant LMN LMN predominant .

C is

linical and linical and of of MND

condition rophi a central origin, origin, a central

as a a as which which c lateral lateral c ( 5

) and and ; .

these

This article isThis article by protected copy twelve London andNeurosurgery, Neurology for Hospital National One h Participants Methods in inertial movements in MND tremor action observed learning an associative tremors types of (6 frequency out. be cannot ruled givendif the However, factors, CNS changes mechanical by affected decrease onajoint loads inertial consequently, ( short enhanced 7 ) a subgroup of a subgroup Accepted Article.

M ( 9 undred andtw undred echanical )

months’ . loading

In this MND Tremor in Tremor such as

through - 40Hz) 40Hz) study, study, . Moreover, toexplore . Moreover,

–

- weakness weakness recognizes different pathophysiological mechanisms, such as as such mechanisms, pathophysiological different recognizes period

reflex tremulous MND tremulous or or ( 7 , long oscillations 9

e The power spectrum analysis and measured andmeasured analysis spectrum power we - nty nty 11

fus . tremor paradigm known as eye blink classical conditioning classical blink aseye known paradigm Twelve patients with action tremor with action patients Twelve - might havediverse might

latency reflexes, and central oscillations oscillations central and reflexes, latency ) sought sought cerebellum cerebellum . e damage to the to e damage consecutive consecutive

caused Dysfunctions Dysfunctions

of the neocortex the of . , to characterize the clinical and and clinical the characterize to influenced influenced

To as

patients by right. All rightsreserved.

t do so

hey are hey denervation or spasticity or denervation and and

a possible involvement of the cerebellum, cerebellum, ofthe involvement possible a MND MND of theof oliv the the ,

and compared the results with healthy volunteers healthy with the results compared and CNS we by the inertial and elastic properties of the body of elasticproperties theinertialand by origin. origin. patients attending the MND outpatients’ MND the outpatients’ attending patients produce oliv

confirmed the tremulous nature of the involuntary oftheinvoluntary nature tremulous the confirmed

during the course of the disease, a central origin acentralorigin ofthedisease, course the during its its

, o

and and - o frequency frequency One possibility is possibility One cerebellar cerebellar - cerebellar cerebellar d they

by a rhythmic activity generated within the the within generated activity rhythmic by a , likely and no other movement disorders disorders othermovement no and

were examined for tremor, examined for were ( possible network

8 resulting from resulting network network ) neurophysiological features of features neurophysiological .

pl caused by a by caused By contrast ay

that that it

frequency changes changes frequency a

critical re presumed todrive re presumed can can

(EBCC) is be investigated through through be investigated

, central tremors are not are tremors central , due todue UMN damage. damage. UMN mechani network dysfunction network

role in pacing s in pacing role we performed EBCC we performed

( 12

peripheral peripheral ) c . cal

linic at the at linic over a over resonance due to to due ; .

high

everal

the were

, This article isThis article by protected copy Electronic Design Cambridge sampling digitized ata a through werecollected signals at armsoutstretched with seated were subjects while hand, most affected ltd.). toolbox Neurospec inthe contained functions 2 of segments and linear bipolar from bilaterally recorded Tremor was Tremor recording posture dynamometer ( radialis (tabl body si weakest handedness, duration, tremor duration, w data clinical and demographic about Information Clinical examination guidelines. safety to international according Helsinki and the by approved w found,

Accepted Article ere e

Tremor was also recorded bya also was Tremor excluded

1 and ten of them tenofthem and Ag ).

( ECR

arms arms Muscle strength was assessed was strength Muscle ly - AgCl cupelectrodes AgCl

detrend ) muscles ) 14 outstretche . ranging ranging

P points was used was points UCL Research Ethics Committee Ethics Research UCL articipants gav articipants

bilaterally

rate of rate from 0 to 90kg 0 from prior to further analysis. A analysis. tofurther prior w ere recruited. ere d )

and action (finger action and ( Cambridge, UK). Cambridge, 5 KHz 5 KHz . e their written informed consent. A consent. written informed e their Continuous Continuous

for frequency decomposition. Autospectra w Autospectra decomposition. frequency for using the MRC the scale using CED 1401 CED right. All rightsreserved. and fed to a computer for data fordata computer fed to a and triaxial accelerometer FCR

(

JAMAR

Parkinsonism clinically clinically

and

interface ( interface EMG

( ® - ECR ECR Tremor was recorded was Tremor 13 to

hydraulic , in in signal was bandpass filtered(3 bandpass was signal -

, conducted ina conducted fast fast nose test nose 14 through as the the . Grip strength . Gripstrength

Cambridge Electronic Design, Cambridge, UK), Cambridge, Design, Electronic Cambridge )

and o collected, including

Fourier transform using non using transform Fourier written for MATLAB software (Mathworks (Mathworks MATLAB software written for flexor carpi radialis ( radialis carpi flexor de and body side most affected by tremor by affected sidemost body de and

) .

(

ther ther , Tremor was evaluated at rest, during rest,during at evaluated was Tremor surface surface ACC

when possible). possible). when

) s

greement econda placed on the dorsal surface ofthe surface the dorsal on placed ll experimental procedures were procedures ll experimental electromyography ( electromyography storage using using storage w

for at least 60 seconds atleast for as measured measured as r

y cause y age at onset, atonset, age

the with the Declaration of the Declaration with FCR

shoulder level shoulder

) - measured using measured

s 100 Hz), rectified Hz),rectified 100 and

Spike2 software by software Spike2 of of - by overlapping overlapping action

extensor carpi extensor a hand a hand EMG disease disease

tremor tremor in two in )

. using using These These

This article isThis article by protected copy and Accepted responses EBCC conditioned of number the compare and muscles examined the four across strength in muscle rig the between frequency tremor peak on load effects of possible to investigate Several t analysis Statistical from obtained occurring 200 as were considered oculi muscle orbicularis 11 CS consisted of consisted block Each blocks. acquisition Article 400 nerve right supraorbital to tw sq (US) a was stimulus unconditioned loud enough 400 tone lasting a was (CS) stimulus The conditioning EBCC conditioning Eye classic blink gr)500 weight without conditions: loading HS ice ice was performed performed was ). Spearman’s correlation coefficient was used to used was coefficient correlation ). Spearman’s

based onp based that - tests were used to compare to wereused tests

(70 to obtain a motor response in the orbicularis oculi of 50 oculi of orbicularis inthe response amotor to obtain - 600 12 healthy subjects 12 healthy ht and left side left ht and - 80 dB; -

atients’ muscle power (“weight”) muscle power atients’

ms only trials to measure extinction to measure trials only

conditioned responses (CRs) responses conditioned in a in after the CS were considered CRs. considered the CSwere after . 2

All the EMG bursts occurrin bursts the EMG All sub kHz) to inconsistently produce produce inconsistently kHz) to

ms after theCS. ms after

group of 5 patients patients of5 group . Wilcoxon’s signed rank test signedrank Wilcoxon’s right. All rightsreserved. (HS) (“no weight”) (“no

uare ele uare differences in peak frequency in peak differences .

of 9CS of

Pairs of CS and US CSand of Pairs ctrical pulse pulse ctrical - US pairs, 1US US pairs,

in CS in according to to according

and with a variable load variable weight with a and .

g at least 200 at g least located Surface EMG was was EMG Surface

in each block in the two groups two inthe block in each ms, delivered via binaural headphones via binaural ms, delivered - US trial

investigate Patients results were compared with those those with compared were results Patients an “al an Mann of of

was used to disclose possible differences possible differences disclose to used was on the metacarpal region of the hands. the region of metacarpal the on 200 -

s a on pha blink” within 200ms within blink” pha .

previously described described previously at 400 at - For CS For

Whitney test Whitney and to compare grip strength grip strength compare to and ly 

ms after the CS but before the US before CS but the ms after s

and

duration a possible correlation between between correlation a possible (PF) - 100

- recorded bilaterally from the from bilaterally recorded ms ISI were de ISI ms

only 1 CS 1

recorded by EMG and ACC, ACC, EMG and by recorded 

V - trials only trial only , delivered over the over delivered , and and s

w ere ,

(100gr, 200gr or (100gr, 200gr an EMG bursts EMG

intensity performed performed

protocol livered in6 livered ( ; a MND

( 7th 15

)

patients patients . block

and

The

equal equal ( 15 to

) .

This article isThis article by protected copy > 0.05) p values (all musclesexamined the four across strength (t 0.758). measured change PF didnot Loading either Hz). (average 7.3±2.6 from4.6 Hz)and (average 7.3±2.4 condition weight” “weight weight”and the “no 4.0 ranged from All patientsshowed Tremor recording t tookin who part of criteria two fitthe observed. not were tremor intention ofthemwith andtwo tremor, with postural presented Action Results by means variables. clinical and neurophysiologic 9

Accepted= 0.475) p = 0.745, Article in the “no weight” (t weight” “no in the

t remor was present in about presentinabout was remor

There

of Shapiro of

was no difference in average grip strength between right and left left side and right between strength average grip in no difference was

Hz to 9.5 Hz he study are study he

a consistent peak consistent a - Wilks’ test. Wilks’ , and PMA T - tests did not disclose any significant anysignificant disclose not did tests

Hz (average 7.2±2.1 Hz) and from4.0 and Hz) Hz (average 7.2±2.1

and progressive bulbar palsy respectively. respectively. palsy bulbar and progressive Wilcoxon’s signed rank test did not disclose disclose not did ranktest signed Wilcoxon’s 9 = 0.371, p = 0.720) =0.720) p 0.371, = ”

condition

summarized in table in summarized

All p values < 0.05 were considered significant. significant. were considered <0.05 pvalues All right. All rightsreserved. 10% o 10%

either E in ight ight When using t When using

respectively the EMG and ACC and EMG the f our MND population MND f our of the patients of with EMG (t with or or in the “weight” (t “weight” in the

1 .

- Hz to 12.8 Hz to

tests, n ACC and 2

both 9 =

PF had had - recording recording . 1.682, p = 0.127) p=0.127) 1.682,

differences in in differences postural and kinetic tremokinetic and postural

ormal distribution of data was assessed assessed datawas of distribution ormal v

aried from 4.3 from aried a diagnosis of ALS, while the other theother ofALS,while diagnosis a .

Hz in the “weight” condition condition inthe“weight” Hz Hz to 10.4 Hz

All the patient All 9 = C (Figure 1 - linical features of patients ofpatients features linical any 0.434, p = 0.674) condition. condition. = 0.674) p 0.434,

PF between EMG and ACC andACC EMG between PF Hz (average (average 7.5±2.4 Hz significant differences in differences significant

or or Hz Hz to 12.2

and 2 and ACC (tACC s

recruited recruited )

. EMG . EMG in MNDpatients in 9 r. = 0.318, p = 0.318, =

Hz the“no Hz in

Rest and and Rest PF

Hz ) in

This article isThis article by protected copy its tremor on oscillator muscles to the phasicimpulses of a essential tremor counterpart oscillations patients MND showed consistently rang recording showed ACC and theEMG of analysis Spectral pairs. co or alternating (i.e. pattern wasaclear there patients and amplitude low them twoof moment disorders; We describe Discussion muscles and orECR FCR inthe atrophy of presence p=0.004 2.680, inblock EBCC

Acceptedclear Article ing peak in the EMG EMG peak inthe

from A There was Compared s

pure , or a combination of , or a combination

, the frequency of which of , the frequency

kinetic d (

16 s 4 to12 own

10 patients with MND who presented with with presented who with MND 10 patients

present with present ly 3 ( ) )

mechanical mechanical (ET) (Figure 3 (Figure Z = Z By contrast By ,

a positive positive correlat a

with if its constant frequency, frequency, constant tremor (r = 0.676, p = 0.032). = 0.032). p (r 0.676, = tremor

fewer - Hz and Parkinsonian tremor) tremor) Parkinsonian and 2.472, p=0.014 2.472,

, w gain healthy healthy power power ) hich was was hich

. CR

tremor tremor is tremor, , in

during increased by a relative increased spectrum the two two the volunteers showed p , athologic right. All rightsreserved. wh probably due to a central oscillator. oscillator. a central to due probably

not affected by external loading. external by affected not depend

ion

such as EBCC compared to compared HS. EBCC ich might originate might originate ich ), 4 ( ), 4

tremor power tremor bilateral bilateral (

(Spearman’s rank) (Spearman’s 17

also also ( 16 Z = Z , ) al s . MND ,

physiologic The muscle stret muscle The on inertia and stiffness andstiffness inertia on tremors simple 17 - 2.638, p =0.007 2.638, motor unit entrainment is unitentrainment motor ) with a with . No correlation was found between foundbetween was correlation No

patients patients This means that means This kinetic

measured in the in measured (such as enhanced physiologic enhanced (such as

- small small amount amount small al contracting) of EMG activation in FCR/ECR inFCR/ECR activation EMG of contracting) from unstable stretch reflex loops, central reflexloops, stretch unstable from bilateral bilateral

tremor, tremor, had fewer fewer had

between tremor duration and the durationand tremor between tremor.

Overall, Overall,

degree ofasymmetry. degree ch reflex reflex ch

a consistent peak consistent a ), 5, ( ), 5,

postural postural the the is induced

Z = Z = Postural tremor Postural

of theof these findings findings these Lastly, Lastly, conditioned responses responses conditioned ( 18 CNS ACC c -

an 2.830, p = 0.004 p 2.830, ) , and , and strong enough to produce produce to enough strong

induce pathologic induce joint provides a regular series series aregular provides tremor signal. MND

by passive mechanic passive by can easily reinforce reinforce easily can , with no clear EMG clear , withno

of frequency frequency of

patients patients

and no other no other and

suggest suggest In none of theof none In

al the was distal was

tremor, tremor, ) and 6 ( and ) degree that that during during al ,

of of Z = Z our our al

- This article isThis article by protected copy Accepted C9orf72 inthe expansions repeat abnormal patients with ALS in studies, especially in abnormalities dysfunction. acerebellar to isdue tremor MND action found action of pathophysiology critical roleinthe to playa CR that a learning paradigm the to acontributor might be cerebellum muscle the tremulous activating rhythmically acentral loop reflexes support m influenced excitability in MND and myoclonus) as changes Article generators of neurons rhythmic spontaneously longsuspected been which rhythmicity generators is frequency CNS, whose specifically muscle of recruitment tremor an ongoing ( 23

structural or functional impairment o impairment functional or structural ) to be to . Dysfunctions of of . Dysfunctions

A s thespectrum in aclear peak showed EMG analysis patients, In all our

is likely to be of central origin. We origin. central of tobe is likely with mechanical loading mechanical with

econd finding in our study ourstudy finding in econd t can can ( 9 he so called mechanical socalled he abnormal in ET in abnormal , 17 be of two types: an unstable loop circuit or a circuit a or loop unstable an types: oftwo be

ALS has been recently demonstrated by demonstrated hasbeen recently ALS , 21 d

that depends on on that depends mechanic as a consequence of aconsequence as rives ) to be .

force otor unitentrainment otor circuits involving the cerebellum and cerebellum the circuits involving

independent of mechanical limbproperties mechanical of independent an otherwise normal circuit circuit normal an otherwise

the generator of both P both of the generator (

( 24 al 17

) or mechanical or )

and dystonic tremor dystonic and . , excluding , excluding Hence, Hence, right. All rightsreserved. the integrity of the oliv the integrity of the - several nuclei several reflex reflex is an abnormal EBCC in our patients, patients, our in EBCC abnormal is an

t he

the central circuit driving driving tremor circuit central

did not assess whether abnormal stretch reflex reflex stretch whether abnormal assess not did tremor

f the cerebellum leads to abnormalities in acquisition of in acquisition to abnormalities leads the cerebellum f inevitable delay between application of stretch and ofstretch between delay application inevitable fasciculatio s - reflex tretch reflex tretch , t hus we cannot exclude that exclude we cannot hus ( are arkinsonian arkinsonian 9

) tremor.

, - ( (

induced tremors tremors induced and 7

15 t Structural and functional cerebellar functional and Structural he principal candidates candidates he principal ) ns . The cerebello The .

, imaging imaging

23 , arrhythmic involuntary movements (such (such movements involuntary , arrhythmic central tremor central o can contribute can

- ) We neuronal ensemble neuronal cerebellar circ . Similarly, we might speculate tha we speculate might . Similarly,

the inferior olives have been reported reported havebeen inferior olives the tremor tremor

therefore therefore ( 25

- ( 27 17 and . - ( thalamo EBCC is an associative anassociative is EBCC 11 ) ,

s and and 19

, originatin to ) conclude that thetremor that conclude suggest ET uit

and EBCC has been been has EBCC and ,

enhanced stretch stretch enhanced all pathological tremors, tremors, pathological all (

( 22

pathological pathological and no frequency nofrequency and ( 7 as 12 ) ) - )

cortical network has network cortical with spontaneous spontaneous with . and the and

) c

Central tremor Central , and it is known itisknown , and ing entral tremors tremors entral ( 30 g

that the the that

, within the within 31 ) (

and 28 , 29 t the the )

This article isThis article by protected copy Accepted 60 seconds. different worsen implies tremor, intention of to thepresence inmost of what it is seen kinetictremor of the presence Curiously, ofthem. most in performance motor the poor by waslimited evaluation this tremor, but mutation tremor, including diagnosis. from 3years of survival median hasa usually notre progression, rateof slow anda duration disease ArticleTherefore, th mechanisms, pathogenetic havedifferent ETmight ALS and that variant identified inm degeneration one patient tested ataxin - 2 gene 2 fo s a higher a Some limitations in our study should be acknowledged be should inourstudy Some limitations I along suchas tremor, from apart features atypical with other presented Our patients cou ALS and tremor between link A possible

n two n two with disease progression. progression. disease with r s loading loading as

intermediate ATXN2expansions intermediate

( p 41

s carried a mutation in SOD1 gene, whose gene, whose SOD1 in carried a mutation Unfortunately, because of the severe disability and the poor general condition that this condition general thepoor and disability the of severe because Unfortunately, ossible ossible

a in the s ,

risk factorfor of of (ATXN2) 42

severity ofET severity weights

our ) ha ice . I FUS overlapping overlapping t is t is ve

patients ( 33

been described in some families with ALS type 8 caused by VAPB gene gene by VAPB caused type8 ALS with in some families been described

thus thus ( gene are associate with ET with gene are associate 27 ) , and the .

32 possible to presume that that presume to possible both familial and sporadic ALS andsporadic both familial

tremo

also kinetic tremor was noticed noticed was kinetic tremor also ( these were selected selected were these ) positively positively 44 .

FUS None of our MND patients MND ourpatients None of ) . right. All rightsreserved.

Using rs. In ET, for instance, disease duration has been correlated correlated only been has duration disease instance, for InET, rs.

mutations but

it has been suggested that the presence of kinetic tremor kinetic of presence that the suggested been it has correlated with disease duration, which is different different from which is duration, with disease correlated

the same analogy, we may argue that tremor in MND in thattremor argue wemay analogy, the same ,

but

in in in

the two condition the one

( accordi 37 ld be ld overexpression leads to Purkinje cells Purkinjecells leadsto overexpression

th - patient C9orf72 mutation was not found and and notfound was mutation patient C9orf72 sembling the “classical” form of ALS, which ALS, formof sembling the “classical” 39 Interestingly, Interestingly, ose patients ose ) bythe explained . ng to their ng

( Although th Although presented with cerebellar signsor cerebellar with presented 34

is ( - . 43 36 First, patients were studied studied patientswere First, has not not has ) ) . None see . None

and s

represent a represent cannot be excluded. be cannot the same characteristics the same ability to hold the hold the weight to ability

e there is yet yet

finding

FUS been demonstrated been med to have intention intention have tomed

gene. growing evidence growing evidence s

variant variant suggest that that suggest

This gene This of MND of

with with ,

FUS were

was for for

( . 40

in in

) . This article isThis article by protected copy nerve. 2001;24(6):716 9. 357 p. BV;2003. Science Elsevier York: New neurophysiology. 8. 1:S118 7. 2015;18(2):249 Acad Neurol. AnnIndian muscularatrophy. bulbospinal in minipolymyoclonus 6. Neurology. 1970;20(11):1124 5. 2014;10(11):661 Neurology. Nature reviews 4. 14. lateral sclerosis 3. 51. 2. sclerosis. 1. References thecondition. tremorispartof action suggests that support This evidence of 10% MND. tremorof in origin central a support might tremorpower and muscle atrophy however, tremor; to mightcontribute Denervation recording. reason to recruit able we not were causes, disease

Accepted Article - , we could , wecould not our our 22. Deuschl G, Raethjen J, Lindemann M, Krack P. The pathophysiology of tremor. Muscle & Muscle & oftremor. pathophysiology The M,Krack P. J,Lindemann G, Raethjen Deuschl clinical of Handbook editor. MH, In: tremor. physiologic enhanced and RJ. E.Physiologic Halle as masquerading Fasciculations S. E, Chokroverty Kozochonok MaW, Bhat S, Minipolymyoclonus Spiro AJ. sclerosis. lateral ofamyotrophic variability phenotypic The W. B,Robberecht Swinnen K.Amyotrophic DelTredici JQ, Trojanowski VM, AC,Lee J, Ludolph H, Brettschneider Braak 1994;124:38 Sci. JNeurol sclerosis. lateral in amyotrophic pathological findings J.New Lowe lateral amyotrophic of heterogeneity and genetic M.Clinical A, Zollino M, Sabatelli Conte I n conclusion, n conclusion, Clinical genetics. 2013;83(5):408 genetics. Clinical

MND patientsand MND for online only E online for tt M. Tremor: pathophysiology. Parkinsonism & related disorders. 2014;20 Suppl 2014;20 disorders. & related Parkinsonism pathophysiology. Tremor: tt M. -- a mod

assess assess s - the present the present

35. el of corticofugal axonal spread. Nature reviews Neurology. 2013;9(12):708 reviewsNeurology. Nature spread. axonal corticofugal el of the novel idea of MND as amultisystem as ofMND idea the novel

stretch reflex reflex stretch excitability - extra publication extra -

&. has a central origin, origin, central a has

study demonstrate study right. All rightsreserved. -

a Neglect a - 16. control - 70.

ed Sign in Childhood Spinal Muscular Atrophy. Muscular Atrophy. Spinal Childhood ed in Sign possibly possibly patients without tremor. Moreover, for the same the same for Moreover, tremor. without patients

s and denervation at the time of the tremor the tremor thetime at of denervation and

that action that resulting from a cerebellar dysfunction. a from resulting –

the absence of of the absence 64.

neurod

tremor tremor egenerative disease disease egenerative occurs in approximately approximately in occurs correlation between between correlation

and and - 51.

- This article isThis article by protected copy 1976;22(3):147 cybernetics. 22. 2013;241:156 neurology. Experimental 21. 1992;116(3):355 neurology. Experimental 20. 1993;56(10):1085 psychiatry. neurology, of Journal mimicking tremor. subjects and normal disease Parkinson's tremor, essential shocks in nerve median electrical bysupramaximal at the wrist tremors postural 19. 1998;402:421 physiology. of Journal The vibration. niuscle 18. Mo 17. 1987;50(5):568 psychiatry. and neurosurgery, neurology, of Journal tremor. pathological and onphysiological limb properties 16. 2016;31:23 disorders. &related Parkinsonism tremor. without with and patients dystonic distinguishes conditioning 15. 1995;64(2 biology. molecular and in biophysics Progress electromyograms. discharges and unit motor tremor, single physiological the 14. 1993;470:127 physiology. of The Journal inman. contraction isometric voluntary during studied motoneurones to inputs synaptic common 13. 2007;6(1):38 Cerebellum. conditioning. 12. 2012;123(1):61 theInternation of : journal official neurophysiology 11. 2014;34(22):7501 Neuroscience. the Society of for journal physiologica human on stimulation transcranial 10.

Accepted Article

vement disorders : official journal of the Movement Disorder Society. 1998;13 Suppl 3:24 Suppl 1998;13 Society. Disorder the Movement of journal :official disorders vement analysis of mixed time series/point process data process series/point time mixed of analysis Stein RB, Oguztoreli MN. Tremor and other oscillations in neuromuscular systems. Biological Biological systems. inneuromuscular oscillations other and Tremor MN. Oguztoreli Stein RB, awindow oftremor: somatotopy The distributed RC. Helmich tremor. essential of entrainment frequency and resetting L. Phase Hughes C, RJ,Higgins Elble Britt with feed movement studied foiearm inhuman TP. Instability A Prochazka system. nervous in central the oscillators ofpossible and anatomy Physiology JC. Rothwell eff HJ.Differential K,Freund Reiners Hefter H, V, Homberg F, Stasio E, Di Antelmi for framework A SF. Farmer BA, P,Conway Breeze AmjadAM, JR, Rosenberg Halliday DM, JA. Stephens JR, Rosenberg DM, FD,Halliday Bremner Farmer SF, eyeblink cerebellumin thehuman of involvement The D. KolbFP,Timmann M, Gerwig Clinical tremor. ofEssential network central oscillating G.The J, Deuschl Raethjen cerebellar versus cortical rhythmic of influence selective The P. JS, Brittain Brown AR, Mehta on TC, Thompson PD, Day BL, Rothwell JC, Findley LJ, Marsden CD. Modulation of Modulation CD. Marsden LJ, JC, Findley Rothwell DayBL, PD, Thompson TC, on - 4.

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3):237 9. Rocchi L, Erro R, Liguori R, Ganos C, et al. Impaired eye blink classical blink classical eye etImpaired C, al. R,Ganos Erro R,Liguori L, Rocchi

right. All rightsreserved. - 78. - - 8. 57.

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l tremor. The Journal of neuroscience : the official :the neuroscience of TheJournal l tremor. al Federation of Clinical Neurophysiology. Neurophysiology. ofClinical Federation al -- theory and application to the study of the study to application theory and - - 8. 42.

ects of changes in mechanical inmechanical changes ects of into the motor system. the motor system. into

The frequency content content of frequency The

neurosurgery, and neurosurgery, - back - controlled controlled - 8.

This article isThis article by protected copy 2010;42(2):170 Muscle & nerve. sclerosis. lateral amyotrophic andsporadic in familial mutations Fus gene 35. 2009;323(5918):1208 6.Science. type sclerosis lateral amyotrophic familial cause protein, processing RNA FUS, an 34. 2017;11:22. neuroanatomy. in Frontiers Mouse. inthe Architecture theCerebellar in Defects Discrete Leadsto SOD1 Human 33. ofaging. 201 Neurobiology counseling. and testing genetic Implication for phenotype? riskfactor orvariant sclerosis: lateral with amyotrophic patients Italian length in 32. 2012;32(5):505 ofNeuropathology. Society theJapanese of : journal official Neuropathology decline. cognitive associated but without cerebellum and hippocampus cortex, cerebral expans repeat with C9orf72 associated 31. 2011;72(2):257 Neuron. 9p21 chromosome of cause is the inC9ORF72 expansion repeat hexanucleotide 30. J Sci. 1993;120(1):15 Neurol lateral sclerosis. amyotrophic with familial patient in a degeneration 29. 2004;107(4):359 neuropathologica. Acta spectrum. clinicopathological broad with cases offiveautopsy analysis ubiquitin 28. 2016;79(2):295 ofneurology. Annals repeat expansions. intermediate cases with ATXN2 sclerosis lateral in loss amyotrophic neuronal 27. 2005;252(8):944 neurology. of Journal lateralsclerosis. inamyotrophic compensation 26. BMCn sclerosis. lateral amyotrophic imaging in 25. 6):1538 2007;130(Pt neurology. of a journal Brain: tremor. essential in subjectswith 24. 2013;38(1):2166 neuroscience. of journal The European practice. rTMS and by normalized are dystonia primary in deficits learning associative dependent 23.

Accepted Article Rademakers R, Stewart H, Dejesus H, R, Stewart Rademakers Rogelj Vance C, Rahimi X, AshtariN,Jiao P, Afshar T Gellera C, phenotype MND/ALS An L,Belletal. C, B,Siklos Rogelj L, S,Wijesekera Maekawa C, Troakes Waite A,Simon E, Majounie AE, Renton Oyanag H, Takahashi ubiquitin of E.Expression Ohama K, Nakashima T,Nakaso Nakano M,Mas Hassani McGinleyC, KrilJJ, Tan RH, motor Functional JM,et al. DuzelE,Hopf GR, C,Kuhnel Gaul C, MA,Tempelmann Schoenfeld tensor diffusion Longitudinal J. Grosskreutz R, V,Dengler T, Keil Peschel Hartung PrellT, C, condit D.Eyeblink F, Timmann B,Block GerwigM,Brol M, Kronenbuerger KP, Roth JT, M,Teo Bhatia P,Bologna Kassavetis BS, Hoffland - immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis with dementia: with dementia: sclerosis lateral inamyotrophic inclusions intraneuronal immunoreactive - 6. - 64.

icozzi N, Pensato V, Nanetti L, Castucci A, Castellotti B, et al. ATAXIN2 CAG ATAXIN2 et al. Castellotti B, A, L, Castucci V,Nanetti Pensato N, icozzi

- 11.

B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in in Mutations J, et al. AL,Sreedharan KJ, Nishimura Vos T, De Hortobagyi B, - 68.

i K, Ikuta F, Tanaka M, Yuasa T, Miyatake T. Widespread multiple system multiple system Widespread T. Miyatake T, M,Yuasa Tanaka IkutaF, i K, right. All rightsreserved. - 305. ion: abundant p62 abundant ion:

- - Balaei M, Zhang X, Yaganeh B, et al. Overexpression of of B,etal.Overexpression Yaganeh X, M, Zhang Balaei Hernandez M, Krieger M,Krieger C, Hernandez euroscience. 2012;13:141. euroscience. - Sanchez J, Rollinson S, Gibbs JR, eta JR, S,Gibbs J,Rollinson Sanchez uda - Suzukake M, Hasegawa M, et al. Cerebellar Cerebellar M,etal. M,Hasegawa Suzukake - 71. - positive, TDP positive,

Graff well JC, et al. Cerebellum JC, et al. well - 43 -

2;33(8):1847 e15 2;33(8):1847 Radford N, Fabros M,etal. N, Fabros Radford - negative inclusions in inclusions negative - bin - ding protein p62 in p62 protein ding linked ALS ioning is impaired impaired is ioning l. A l. A - 51. - 52.

- - FTD. 21. - 14. - - repeat repeat

- 21.

This article isThis article by protected copy study: for Funding sources Acknowledgment t of journal :official disorders Movement study. electrophysiological and Aclinical tremor? postural kinetic a or 44. 3:2 Suppl Society. 1998;13 Disorder the Mov of journal :official disorders Movement Committee. Hoc Scientific Tremor. Ad 43. 2016;263(2):263 neurology. aCh tremor in or pain of initial symptoms 42. 2004;75(5):822 genetics. ofhuman journal American lateral sclerosis. amyotrophic inthe vesicle mutation 41. 2012;91(2):313 identifi 40. 2014;21(2):361 neurology. of journal European tremor. in essential FUS p.R377W 39. e3 2013;34(8):2078 ofaging. Neurobiology tremor. with essential Han patients in gene Chinese sarcoma 38. tremor. in essential FUSgene inthe variant 37. 2010;20(6):1069 pathology. patho immunoreactive 36. -

Accepted Article 4.

es FUS mutations as a cause of essential tremor. American journal of human genetics. genetics. human of journal American tremor. ofessential acause as mutations es FUS Brennan KC, Jurewicz EC, Ford B, Pullman SL, Louis ED. Is essential tremor predominantly a predominantly tremor Is ED. essential SL,Louis B,Pullman Ford Jurewicz EC, KC, Brennan on Society Disorder Movement the statement of Consensus M. P,Brin G, Deuschl Bain with lateralsclerosis amyotrophic familial XM.Atypical Shen S, Y,Wang H,Da Di L,Chen Mitne AL, Nishimura sequencing etExome RiviereJB, al. BelzilVV, CV, H, Bourassa Catoire Girard SL, ND, Merner Rajp Rajput AH, A, Rajput thein of fused al. Genetic Y,analysis K, Yang et Gao H, SongZ, X, Liang Deng Zheng W, novelrisk ofa etIdentification YC, al. Chen KM, Prakash CM, Chen LC, JN,Tan Foo Wu YR, FUS Extensive et al. DW, Dickson JB, JQ, Strober Trojanowski F, Geser J, Zhang EJ, Huang he Movement Disorder Society.2002;17(2):313 Disorder Movement he - 9.

: None - logy in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Brain inclusions. basophilic with sclerosis lateral amyotrophic in juvenile logy trafficking protein VAPB causes late causes VAPB protein trafficking

- - None 76. - 8. Neto M, Silva HC, Richieri HC, M, Silva Neto

ut ML, Encarnacion M, Bernales CQ, Ross JP, et al. Identification of of JP, et Identification al. CQ,Ross M, Bernales Encarnacion ut ML, right. All rightsreserved. - 23.

inese family harboring VAPB harboring inese family Neurology. 2013;81(6):541 Neurology. - Costa A, Middleton S, Cascio D, et A et al. D, S, Cascio A, Middleton Costa - - 6. onset spinal muscular atrophy and atrophy and muscular spinal onset

- - P56S mutation. Journal of Journal mutation. P56S 4.

- 3. - 31.

ement - This article isThis article by protected copy arms non carpi radialis; FCR:flexor carpi radialis; extensor ECR: D: dominant; Table 2. di in superoxide mutations SOD1: atrophy; muscular progressive PMA: palsy; bulbar progressive diseaseduration DD: lateral sclerosis; ALS: amyotrophic Table 1. in post differences significant indicate error.Asterisks indicate bars standard 6.Error blocks3to than HSin Figure 3. (with weight: Figure weight: (with conditions loading Figure 1. Figure captions

Accepted duration. TD: tremor 1; smutase Article - dominant; muscle atrophy. atrophy. muscle - 2. An example of ACC power spectrum showing a peak at 6.7 Hz in the two loading conditions conditions loading the two Hzin 6.7 at a peak showing powerspectrum ACC example of An 2. hoc comparisons (p <0.05). (p comparisons hoc

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R: right; R: ssic conditioning result. Conditioned responses were lower in MND patients inMND werelower responses Conditioned result. conditioning ssic

riables TS: body side most affected by tremor; WS: weakest body side; *: degree side;*:degree of body weakest WS: by tremor; affected most bodyside TS:

dash and and dash right. All rightsreserved.

; without weight: weight: without ; cal data cal data dot grey line grey dot

continuous black line continuous ; without weight: ; without

at tremor registration tremor at

L: left; L: left; continuous blackline continuous NA: not available; ND: not available; NA: ). ).

; M: male; PBP: PBP: ).

SD AV 10 9 8 7 6 5 4 3 2 1 Pt

This article isThis article by protected copy 12.4 64 76 72 63 68 55 74 46 43 61 78 Age

Accepted Article

M M M M M M M M M M Gender

right. All rightsreserved. ALS ALS ALS PBP (SOD1) ALS ALS ALS ALS PMA ALS Diagnosis

Upper limbsUpper Bulbar hand Left Bulbar foot Left hand Left hand Left hand Left limbsUpper Righ hand ofonset Site

7 2 3 6 9 4 10 7 6 6 (yr) DD 2.5 6

2.3 2.1 0.5 1 2.5 3 3 0.3 8 1 1 1 (yr) T D

SD AV 10 9 8 7 6 5 4 3 2 1 Pt M

power scale power 3 2 3 5 1 4 2 5 4 2 FCR

This article isThis article by protected copy - D Accepted Article

3 2 2 5 0 5 2 4 4 2 ECR

- D

3 3 2 5 1 4 2 5 4 3 FCR

- ND

3 3 2 5 0 4 2 5 4 3 ECR

- ND right. All rightsreserved.

5.3 4.4 2 1 1 11 0 NA 4 NA 14.5 2 D (Kg) strength Grip

10 0 12 0 NA 2 NA 11 7 ND 5.1 5.5 2

500 200 5 2 5 1 500 500 500 (gr) Load 100

00 00 00 00

R L R = R L = L R WS =

L L L R R R L R R TS L

severe severe absent severe mild severe absent mild severe Atrophy severe

- - - + - - + - - - tremor Kinetic

This article isThis article by protected copy Accepted Article right. All rightsreserved.