Speed

Variability

and

Timing

of

Motor

Output

in

ADHD

Which

Measures

are

Useful

for

Endophenotypic

Research

Attention-Deficit/Hyperactivity

Disorder

-LRB-

ADHD

-RRB-

shares

a

genetic

basis

with

motor

coordination

problems

and

probably

motor

timing

problems

In

line

with

this

comparable

problems

in

motor

timing

should

be

observed

in

first

degree

relatives

and

might

therefore

form

a

suitable

endophenotypic

candidate

This

hypothesis

was

investigated

in

ADHD-families

-LRB-

children

-RRB-

and

control-families

-LRB-

children

-RRB-

A

motor

timing

task

was

administered

in

which

children

had

to

produce

a

ms

interval

In

addition

to

this

task

two

basic

motor

tasks

were

administered

to

examine

speed

and

variability

of

motor

output

when

no

timing

component

was

required

Results

indicated

that

variability

in

motor

timing

is

a

useful

endophenotypic

candidate

It

was

clearly

associated

with

ADHD

it

was

also

present

in

non-affected

siblings

and

it

correlated

within

families

Accuracy

-LRB-

under

versus

over-production

-RRB-

in

motor

timing

appeared

less

useful

Even

though

accuracy

was

associated

with

ADHD

-LRB-

probands

and

affected

siblings

had

a

tendency

to

under-produce

the

ms

interval

compared

to

controls

-RRB-

non-affected

siblings

did

not

differ

from

controls

and

sibling

correlations

were

only

marginally

significant

Slow

and

variable

motor

output

without

timing

component

also

appears

present

in

ADHD

but

not

in

non-affected

siblings

suggesting

these

deficits

not

to

be

related

to

a

familial

vulnerability

for

ADHD

Deficits

in

motor

timing

could

not

be

explained

by

deficits

already

present

in

basic

motor

output

without

a

timing

component

This

suggests

abnormalities

in

motor

timing

were

predominantly

related

to

deficient

motor

timing

processes

and

not

to

general

deficient

motor

functioning

The

finding

that

deficits

in

motor

timing

run

in

ADHD-families

suggests

this

to

be

a

fruitful

domain

for

further

exploration

in

relation

to

the

genetic

underpinnings

of

ADHD

Introduction

It

has

become

apparent

from

twin

and

adoption

studies

that

the

development

of

the

Attention-Deficit/Hyperactivity

Disorder

-LRB-

ADHD

-RRB-

-LRB-

American

Psychiatric

Association

-RRB-

is

strongly

genetically

based

-LRB-

Faraone

et

al.

Willcutt

in

press

-RRB-

Overall

heritability

estimates

exceed

-LRB-

Faraone

and

Doyle

Smalley

-RRB-

and

are

fairly

constant

across

studies

conducted

worldwide

-LRB-

Faraone

et

al.

-RRB-

Research

aimed

at

the

molecular

genetic

basis

of

the

disorder

-LRB-

genotype

-RRB-

has

had

success

in

identifying

some

susceptibility

genes

by

using

information

from

behaviorally

observable

symptoms

-LRB-

phenotype

-RRB-

-LRB-

Faraone

et

al.

-RRB-

However

the

current

knowledge

about

the

genetic

basis

of

the

disorder

is

still

limited

and

the

causal

pathway

-LRB-

s

-RRB-

leading

from

genotype

to

phenotype

have

yet

to

be

revealed

Both

issues

have

been

the

aims

of

investigation

in

endophenotypic

research

Endophenotypes

are

defined

as

heritable

vulnerability

traits

that

mark

a

risk

for

the

development

of

the

disorder

-LRB-

Almasy

and

Blangero

Castellanos

and

Tannock

Doyle

et

al.

Gottesman

and

Gould

Skuse

Waldman

Zobel

and

Maier

-RRB-

They

are

conceptualized

as

forming

an

intermediate

link

between

the

genotype

and

phenotype

and

are

presumably

genetically

less

complex

compared

to

phenotypic

symptoms

-LRB-

Gottesman

and

Gould

Waldman

-RRB-

Because

of

these

characteristics

it

is

thought

that

compared

to

phenotypic

symptoms

endophenotypes

are

more

suitable

for

detecting

disease

genes

and

for

unraveling

the

modes

of

actions

of

these

disease

genes

Several

criteria

have

been

proposed

to

discriminate

an

endophenotype

from

other

biological

markers

that

are

not

causally

involved

in

the

disorder

but

are

merely

associated

with

the

disorder

-LRB-

Durston

et

al.

Gottesman

and

Gould

-RRB-

Although

these

criteria

do

not

appear

to

be

universally

agreed

upon

several

key

criteria

have

emerged

from

the

literature

-LRB-

Almasy

and

Blangero

Castellanos

and

Tannock

Doyle

et

al.

Gottesman

and

Gould

Skuse

Waldman

Zobel

and

Maier

-RRB-

First

an

endophenotype

should

co-occur

with

the

disorder

although

given

the

heterogeneity

of

ADHD

it

is

unlikely

that

a

single

endophenotype

will

occur

in

all

patients

with

ADHD

-LRB-

Doyle

et

al.

-RRB-

Second

non-affected

relatives

should

also

exhibit

the

endophenotype

to

some

extent

indicating

that

the

endophenotype

contributes

to

a

familial

susceptibility

for

the

disorder

Because

non-affected

relatives

share

on

average

of

their

genes

with

the

affected

family

member

it

is

theorized

that

they

also

carry

some

of

the

susceptibility

genes

of

ADHD

which

translate

into

subtle

abnormalities

in

the

endophenotype

-LRB-

Gottesman

and

Gould

Waldman

-RRB-

Third

the

endophenotype

should

show

familial

resemblance

reflected

by

significant

sibling

correlations

for

the

endophenotypic

measure

In

addition

to

these

criteria

several

other

important

characteristics

of

an

endophenotype

have

been

put

forward

such

as

reliability

of

measurement

stability

over

time

-LRB-

i.e.

expressed

regardless

whether

or

not

the

disorder

is

currently

manifested

-RRB-

and

acting

as

a

mediator

and/or

moderator

between

genes

and

disorder

-LRB-

Doyle

et

al.

Waldman

-RRB-

The

focus

of

our

study

lies

on

the

first

three

key

criteria

of

an

endophenotype

Possible

endophenotypic

candidates

might

be

found

in

the

deficits

in

motor

output

associated

with

ADHD

Fine

motor

coordination

problems

as

well

as

gross

motor

coordination

problems

are

frequently

observed

in

co-occurrence

with

ADHD

-LRB-

Carte

et

al.

Korkman

and

Pesonen

Marcotte

and

Stern

Piek

et

al.

Pitcher

et

al.

Whitmont

and

Clark

-RRB-

Because

of

this

highly

frequent

co-occurrence

it

is

feasible

that

motor

problems

might

be

genetically

related

to

the

risk

for

developing

ADHD

-LRB-

Gillberg

-RRB-

which

has

indeed

been

reported

recently

-LRB-

Martin

et

al.

-RRB-

This

might

make

motor

measures

useful

endophenotypic

candidates

which

was

underlined

by

the

findings

of

motor

control

difficulties

in

non-affected

siblings

of

children

with

ADHD

-LRB-

Rommelse

et

al.

Slaats-Willemse

et

al.

-RRB-

A

specific

aspect

of

motor

output

that

might

serve

as

a

candidate

endophenotype

is

temporal

organization

-LRB-

Castellanos

and

Tannock

Waldman

et

al.

-RRB-

Temporal

organization

of

motor

output

refers

to

the

timing

of

movements

-LRB-

i.e.

motor

timing

-RRB-

and

seems

to

be

predominantly

mediated

by

the

cerebellum

and

basal

ganglia

and

their

reciprocal

connections

with

the

cerebral

cortex

-LRB-

Handy

et

al.

Harrington

et

al.

Ivry

Nenadic

et

al.

-RRB-

The

timing

of

motor

output

is

hypothesized

to

consist

of

two

components

a

clock

component

which

reflects

central

time

keeping

operations

and

a

motor

delay

component

which

reflects

random

variability

due

to

response

implementation

processes

-LRB-

Harrington

et

al.

Keele

et

al.

Wing

and

Kristofferson

-RRB-

Children

with

ADHD

seem

to

be

predominantly

impaired

in

the

clock

component

as

evidenced

by

paradigms

specifically

assessing

timing

operations

independent

of

motor

operations

such

as

duration

discrimination

tasks

-LRB-

Keele

et

al.

see

for

review

Toplak

et

al.

-RRB-

The

motor

component

is

possibly

best

assessed

using

simple

reaction

time

tasks

and

free

Tapping

tasks

in

which

timing

is

minimized

Some

have

found

no

impairments

in

children

with

ADHD

-LRB-

Kalff

et

al.

Seidman

et

al.

-RRB-

others

have

-LRB-

Kalff

et

al.

-RRB-

By

combining

both

components

one

can

assess

timing

that

is

predominantly

related

to

motor

output

which

reflects

the

interplay

between

timing

and

motor

skills

Studies

using

these

motor

timing

tasks

have

however

not

revealed

consistent

results

of

impairments

in

children

with

ADHD

possibly

due

to

inconsistencies

in

methodological

approaches

across

studies

-LRB-

Toplak

et

al.

-RRB-

However

greater

variability

in

motor

output

when

a

timing

component

is

required

is

a

frequently

reported

finding

in

children

with

ADHD

-LRB-

Leth-Steensen

et

al.

Pitcher

et

al.

Rubia

et

al.

Toplak

et

al.

Van

Meel

et

al.

-RRB-

of

these

studies

however

used

a

measure

of

basic

motor

speed/variability

-LRB-

without

requirements

regarding

timing/rhythm

-RRB-

in

addition

to

the

motor

timing

measure

Therefore

it

remains

unclear

whether

the

variability

in

motor

timing

is

primarily

due

to

variability

of

motor

processes

or

due

to

variability

of

timing

processes

or

both

Here

we

administered

two

simple

motor

tasks

in

addition

to

the

motor

timing

task

in

order

to

investigate

whether

deficits

were

specifically

related

to

the

timing

of

motor

output

or

whether

deficits

were

also

observed

in

tasks

that

do

not

require

timing

of

motor

output

The

current

study

is

to

our

knowledge

the

first

to

examine

motor

timing

abilities

in

not

only

children

with

ADHD

but

also

in

their

siblings

in

order

to

investigate

whether

motor

timing

measures

might

be

suitable

endophenotypic

candidates

Previous

studies

on

related

topics

have

shown

that

non-affected

siblings

of

children

with

ADHD

have

comparable

problems

in

time

reproduction

skills

as

their

affected

siblings

-LRB-

Rommelse

et

al.

-RRB-

and

that

variability

in

reaction

time

shows

familial

overlap

with

ADHD

-LRB-

Andreou

et

al.

-RRB-

giving

support

to

the

hypothesis

that

motor

timing

measures

may

be

suitable

endophenotypic

candidates

It

was

expected

that

-LRB-

-RRB-

children

with

ADHD

would

be

impaired

on

motor

timing

measures

and

not

-LRB-

or

to

a

lesser

extent

-RRB-

on

motor

measures

without

a

timing

component

indicating

an

association

between

ADHD

and

motor

timing

deficits

Furthermore

we

expected

-LRB-

-RRB-

to

find

similar

findings

in

the

non-affected

siblings

of

the

children

with

ADHD

suggesting

motor

timing

deficits

are

not

merely

associated

with

the

disorder

Last

we

expected

-LRB-

-RRB-

to

find

correlations

between

siblings

indicating

familial

resemblance

on

motor

timing

measures

Method

Participants

Families

with

at

least

one

child

with

the

combined

subtype

of

ADHD

-LRB-

proband

-RRB-

and

at

least

one

additional

sibling

-LRB-

regardless

of

possible

ADHD-status

-RRB-

were

recruited

in

order

to

participate

in

the

Dutch

part

of

the

International

Multicenter

ADHD

Genes

study

-LRB-

IMAGE

-RRB-

The

IMAGE

project

is

an

international

collaborative

study

that

aims

to

identify

genes

that

increase

the

risk

for

ADHD

using

QTL

linkage

and

association

strategies

-LRB-

Brookes

et

al.

-RRB-

Additional

control

families

were

recruited

from

primary

and

high

schools

from

the

same

geographical

regions

as

the

participating

ADHD-families

Controls

and

their

first

degree

relatives

had

no

formal

or

suspected

ADHD

diagnosis

A

total

of

ADHD-families

and

control-families

fulfilled

inclusion

and

exclusion

criteria

Within

the

ADHD-families

probands

-LRB-

all

with

combined

subtype

of

ADHD

-RRB-

affected

siblings

-LRB-

with

combined

subtype

with

inattentive

subtype

and

with

hyperactive-impulsive

subtype

of

ADHD

-RRB-

and

non-affected

siblings

participated

Control-families

consisted

of

children

For

control

children

no

additional

control

sibling

could

be

recruited

for

the

study

-LRB-

see

for

an

overview

Tables

-RRB-

Table

of

family

sizesNumber

of

siblings

within

a

familyADHDControlFamilies

-LRB-

n

-RRB-

Individuals

-LRB-

n

-RRB-

Families

-LRB-

n

-RRB-

Individuals

-LRB-

n

-RRB-

ADHD

Attention-Deficit/Hyperactivity

DisorderTable

of

affected

and

non-affected

siblings

within

ADHD-familiesTotal

number

of

children

within

a

familyDiagnostic

statusADHD-families

-LRB-

n

-RRB-

Proband

-LRB-

n

-RRB-

Affected

siblings

-LRB-

n

-RRB-

Non-affected

siblings

-LRB-

n

-RRB-

ADHD

Attention-Deficit/Hyperactivity

Disorder

All

children

were

between

the

ages

of

and

years

and

were

of

European

Caucasian

descent

Participants

were

excluded

if

they

had

an

IQ

a

diagnosis

of

autism

epilepsy

brain

disorders

or

known

genetic

disorders

such

as

Down

syndrome

or

Fragile-X-syndrome

Within

an

ADHD-family

both

proband

and

siblings

were

similarly

screened

using

the

standard

procedures

of

the

IMAGE

project

described

by

Brookes

et

al.

-LRB-

-RRB-

Briefly

screening

questionnaires

-LRB-

parent

and

teacher

Conners

long

version

rating

scales

-LSB-

Conners

-RSB-

and

parent

and

teacher

Strengths

and

Difficulties

Questionnaires

-LSB-

SDQ

Goodman

-RSB-

-RRB-

were

used

to

identify

children

with

ADHD

symptoms

T-scores

on

the

Conners

N-scale

-LRB-

DSM-IV

total

symptom

score

-RRB-

and

scores

percentile

on

the

SDQ-hyperactivity

scale

were

considered

as

clinical

For

all

children

within

a

family

scoring

clinically

on

any

of

the

questionnaires

a

semi-structured

standardized

investigator-based

interview

was

administered

separately

for

each

child

the

Parental

Account

of

Children

's

Symptoms

-LRB-

PACS

Taylor

-RRB-

The

PACS

covers

DSM-IV

symptoms

of

ADHD

conduct

disorder

oppositional

defiant

disorder

anxiety

mood

and

other

internalizing

disorders

The

section

on

autistic

behaviour

traits

was

administered

if

a

clinical

score

-LRB-

raw

score

-RRB-

was

obtained

on

the

Social

Communication

Questionnaire

-LRB-

SCQ

Berument

et

al.

-RRB-

A

standardised

algorithm

was

applied

to

the

PACS

and

parent

rated

Conners

to

derive

each

of

the

DSM-IV

ADHD

items

providing

operational

definitions

for

each

behavioural

symptom

These

were

combined

with

items

that

were

scored

-LRB-

pretty

much

true

-RRB-

or

-LRB-

very

much

true

-RRB-

in

the

teacher

rated

Conners

ADHD

subscale

to

generate

the

total

number

of

hyperactive-impulsive

and

inattentive

symptoms

of

the

DSM-IV

Situational

pervasiveness

was

defined

as

at

least

one

symptom

occurring

within

two

or

more

different

situations

as

indicated

by

the

parents

in

the

PACS

interview

as

well

as

the

presence

of

at

least

one

symptom

scoring

or

on

the

ADHD

subscale

as

indicated

by

teachers

on

the

Conners

Siblings

were

regarded

as

non-affected

if

they

obtained

scores

in

the

non-clinical

range

on

both

the

parent

and

teacher

questionnaires

-LRB-

Conners

N-scale

T-score

SDQ

percentile

-RRB-

No

PACS

interview

was

administered

concerning

non-affected

siblings

The

Conners

long

version

for

both

parents

and

teachers

was

completed

for

control

children

Control

children

had

to

obtain

non-clinical

scores

on

both

the

parent

and

teacher

version

-LRB-

Conners

N-scale

T-score

-RRB-

Table

provides

the

characteristics

of

the

four

groups

Table

characteristicsProbandsAffected

siblingsNon-affected

siblingsNormal

Contrastsn

in

ns

Right

nsa

full

scale

parent

DSM-IV

teacher

DSM-IV

diagnosis

Inattentive

Hyperactive-impulsive

Note

Probands

Affected

siblings

Non-affected

siblings

Normal

controlsADHD

Attention-Deficit/Hyperactivity

Disorder

DSM-IV

Diagnostic

and

Statistical

Manual

for

Mental

Disorders

-LRB-

edition

-RRB-

P

a

χ2

Contrasts

based

on

p-values

of

Measures

Motor

Timing

Task

This

task

was

designed

to

measure

the

accuracy

and

variability

of

motor

timing

-LRB-

Van

Meel

et

al.

-RRB-

Subjects

were

instructed

to

press

a

button

with

their

preferred

index

finger

when

they

thought

a

time

interval

had

elapsed

The

start

of

the

interval

was

announced

by

a

tone

After

the

subject

's

response

visual

feedback

concerning

the

accuracy

of

the

response

was

presented

on

the

screen

indicating

whether

the

response

was

correct

too

short

or

too

long

A

response

was

regarded

as

correct

if

it

fell

between

the

lower

and

upper

boundary

set

by

a

dynamic

tracking

algorithm

Boundaries

were

set

at

to

ms

at

the

beginning

of

the

task

If

the

response

fell

within

these

boundaries

the

boundaries

of

the

subsequent

trial

were

narrowed

by

ms.

Likewise

the

boundaries

of

the

subsequent

trial

were

widened

with

ms

if

the

response

on

the

previous

trial

fell

outside

the

boundaries

The

practice

session

consisted

of

trials

the

experimental

session

of

trials

Both

sessions

were

preceded

by

presenting

times

a

cartoon

figure

for

exactly

s

on

the

screen

to

demonstrate

the

duration

of

s

-LRB-

Van

Meel

et

al.

-RRB-

Dependent

measures

were

accuracy

-LRB-

median

of

productions

in

ms

which

reflects

under

versus

over-production

-RRB-

and

variability

-LRB-

SD

of

productions

in

ms

-RRB-

Baseline

Speed

task

This

task

was

designed

to

measure

the

speed

and

variability

of

motor

output

in

response

to

an

external

cue

and

comparable

to

a

simple

reaction

time

task

-LRB-

De

Sonneville

-RRB-

Subjects

were

required

to

press

a

key

as

quickly

as

possible

when

a

fixation

cross

in

the

centre

of

a

computer

screen

changed

into

a

white

square

Immediately

following

the

response

the

white

square

changed

back

into

the

fixation

cross

The

time

interval

between

a

response

and

the

emergence

of

the

next

white

square

varied

randomly

between

and

ms

in

order

to

prevent

anticipation

strategies

A

practice

session

-LRB-

trials

-RRB-

and

an

experimental

session

-LRB-

trials

-RRB-

were

administered

for

both

hands

separately

The

task

was

first

practised

and

executed

with

the

index

finger

of

the

non-preferred

hand

thereafter

practised

and

executed

with

the

index

finger

of

the

preferred

hand

Dependent

measures

were

the

speed

-LRB-

mean

reaction

time

in

ms

-RRB-

and

variability

-LRB-

SD

of

reaction

times

in

ms

-RRB-

of

responses

Tapping

task

This

task

measured

the

speed

and

variability

of

self-generated

motor

output

-LRB-

without

internal

or

external

cues

-RRB-

-LRB-

De

Sonneville

-RRB-

Subjects

were

required

to

tap

as

frequently

as

possible

within

an

interval

of

s

The

beginning

and

end

of

the

interval

were

announced

by

a

tone

During

tapping

the

number

of

taps

was

continuously

counted

and

displayed

on

the

screen

A

practice

session

-LRB-

s

-RRB-

and

an

experimental

session

-LRB-

s

-RRB-

were

administered

for

both

hands

separately

The

task

was

first

practised

and

executed

with

the

index

finger

of

the

non-preferred

hand

thereafter

practised

and

executed

with

the

index

finger

of

the

preferred

hand

Dependent

measures

were

speed

-LRB-

mean

intertap

interval

in

ms

-RRB-

and

variability

-LRB-

SD

of

intertap

intervals

in

ms

-RRB-

of

motor

output

Intelligence

Full-scale

IQ

was

estimated

by

four

subtests

of

the

WISC-III

-LRB-

Wechsler

-RRB-

or

WAIS-III

-LRB-

Wechsler

-RRB-

-LRB-

depending

on

the

child

's

age

-RRB-

Vocabulary

Similarities

Block

Design

and

Picture

Completion

These

subtests

are

known

to

correlate

between

with

the

Full-scale

IQ

-LRB-

Groth-Marnat

-RRB-

Procedure

Testing

of

ADHD

children

and

their

siblings

took

place

at

the

VU

University

Amsterdam

or

at

the

Radboud

University

Nijmegen

Medical

Centre

and

was

conducted

simultaneously

for

children

within

a

family

Psychostimulants

were

discontinued

for

at

least

h

before

testing

took

place

-LRB-

Pelham

et

al.

-RRB-

Participants

that

took

other

medication

than

stimulants

to

suppress

their

symptoms

of

ADHD

were

also

off

medication

during

testing

The

medication

of

these

children

was

gradually

decreased

in

line

with

standard

procedures

to

allow

for

sufficient

wash-out

Children

were

motivated

with

small

breaks

At

the

end

of

the

session

a

gift

worth

approximately

was

given

Control

children

were

tested

in

a

similar

way

in

a

quiet

room

at

their

school

The

study

had

medical-ethical

approval

Analyses

The

percentage

of

missing

data

was

less

than

for

each

of

the

dependent

variables

Missing

data

were

replaced

by

using

the

Estimation

Maximization

procedure

-LRB-

Tabachnick

and

Fidell

-RRB-

of

the

dependent

variables

was

normally

distributed

Therefore

variables

were

successfully

normalized

by

applying

a

Van

der

Waerden

transformation

-LRB-

Statistical

Package

for

the

Social

Sciences

-LSB-

SPSS

-RSB-

version

-RRB-

The

Van

der

Waerden

transformation

transforms

raw

scores

into

z-scores

corresponding

to

the

estimated

cumulative

proportion

of

the

distribution

corresponding

to

a

particular

rank

It

is

defined

by

the

formula

r

-LRB-

w

-RRB-

in

which

w

is

the

sum

of

the

case

weights

and

r

is

the

rank

ranging

from

to

w

-LRB-

Lehmann

-RRB-

Cases

are

given

different

weights

by

means

of

simulated

replication

The

value

of

the

new

standardized

variable

equals

the

sum

of

case

weights

-LRB-

SPSS

version

-RRB-

This

transformation

has

two

important

advantages

It

handles

the

-LRB-

extreme

-RRB-

influence

outliers

may

have

on

the

data

by

ranking

them

as

-LRB-

very

-RRB-

high

or

low

within

the

normal

distribution

and

the

comparison

between

the

variables

was

facilitated

since

the

variables

were

all

depicted

on

the

same

scale

Homogeneity

of

variance

was

tested

by

calculating

Fmax

-LRB-

ratio

of

the

largest

cell

variance

to

the

smallest

-RRB-

Since

sample

sizes

were

relatively

equal

-LRB-

i.e.

within

a

ratio

of

to

or

less

-RRB-

an

Fmax

of

and

lower

was

acceptable

-LRB-

Tabachnick

and

Fidell

-RRB-

For

all

six

normalized

variables

the

ratio

was

well

within

acceptable

limits

-LRB-

all

below

-RRB-

Alpha

was

set

at

for

all

tests

Following

Cohen

's

guidelines

-LRB-

Cohen

-RRB-

effect

sizes

were

defined

in

terms

of

the

percentage

of

explained

variance

and

were

used

to

define

small

medium

and

large

effects

These

figures

translate

into

of

and

Linear

mixed

models

were

used

for

the

analyses

The

linear

mixed

model

expands

the

general

linear

model

so

that

the

data

are

permitted

to

exhibit

correlated

variability

This

model

allows

for

the

investigation

of

group

differences

while

correcting

for

the

non-independency

of

data

-LRB-

i.e.

more

than

one

child

participated

per

family

which

resulted

in

related

measurements

within

groups

and

between

groups

-RRB-

In

first

instance

we

tested

the

main

effects

of

possible

confounders

-LRB-

hand

gender

IQ

and

age

-RRB-

on

performance

on

the

three

different

tasks

This

was

done

within

the

control

group

to

avoid

dependency

with

the

factor

group

Thereafter

interactions

between

group

and

the

confounders

were

examined

to

investigate

whether

effects

of

possible

confounders

were

comparable

across

groups

In

second

instance

we

investigated

whether

group

differences

existed

for

each

task

measure

Group

was

used

as

factor

-LRB-

four

groups

proband

affected

sibling

non-affected

sibling

and

control

-RRB-

age

-LRB-

linear

and/or

curvilinear

-RRB-

as

covariate

-LRB-

s

-RRB-

and

family

as

random

effect

to

account

for

within

family

correlation

Pairwise

comparisons

were

used

to

compare

groups

and

it

was

analyzed

whether

a

linear

trend

was

present

in

polynomial

group

contrasts

It

was

expected

that

probands

and

affected

siblings

performed

worse

than

controls

-LRB-

mainly

on

the

motor

timing

measures

but

not

or

to

a

lesser

extent

on

the

other

motor

measures

-RRB-

indicating

an

association

between

motor

timing

deficits

and

ADHD

It

was

also

expected

that

the

non-affected

siblings

performed

worse

than

controls

and

formed

an

intermediate

group

in

between

their

affected

siblings

and

controls

suggesting

motor

timing

deficits

were

related

to

a

familial

susceptibility

to

the

disorder

The

Conners

Total

ADHD

scale

-LRB-

averaged

across

parents

and

teachers

-RRB-

was

used

as

an

additional

covariate

in

the

analyses

to

rule

out

that

possible

deficits

in

the

non-affected

siblings

group

could

be

attributed

to

sub-clinical

ADHD

symptoms

in

this

group

Correlations

-LRB-

with

confidence

intervals

-RRB-

were

calculated

between

siblings

to

test

the

familial

resemblance

of

the

motor

measures

-LRB-

Statistical

Analysis

for

Genetic

Epidemiology

-LSB-

S.A.G.E

-RSB-

-RRB-

Results

Testing

of

possible

confounders

Main

effects

of

hand

gender

IQ

and

age

We

tested

for

the

effects

of

hand

gender

IQ

and

age

within

the

control

group

to

avoid

dependency

with

the

factor

group

No

significant

effect

of

hand

was

found

on

the

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

but

there

was

a

significant

effect

on

the

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Control

children

were

faster

and

less

variable

when

performing

the

Tapping

task

with

their

right

hand

than

their

left

hand

likely

reflecting

an

effect

of

hand

dominance

The

Motor

Timing

task

was

only

performed

with

the

preferred

hand

Gender

had

no

effect

on

the

Motor

Timing

task

and

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

but

had

an

effect

on

the

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Control

boys

were

faster

and

less

variable

in

their

tapping

performance

than

control

girls

No

effect

of

IQ

was

found

on

the

Motor

Timing

task

Baseline

Speed

task

or

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

In

order

to

assess

whether

age

could

be

best

modeled

in

linear

and/or

curvilinear

terms

we

first

analyzed

the

linear

effect

of

age

and

then

in

a

second

model

analyzed

the

quadratic

effect

of

age

while

keeping

the

linear

term

for

age

in

the

model

In

this

manner

the

incremental

contribution

of

the

curvilinear

relation

with

age

over

and

above

the

linear

relation

was

tested

Age

-LRB-

in

linear

terms

-RRB-

had

a

strong

effect

on

the

Motor

Timing

task

Baseline

Speed

task

and

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

Older

control

children

were

more

accurate

faster

and

less

variable

in

their

motor

output

Results

indicated

that

when

both

age

terms

were

implemented

in

the

model

no

curvilinear

effect

of

age

was

present

on

the

Motor

Timing

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

but

there

was

on

the

Baseline

Speed

task

and

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

No

significant

interactions

were

present

between

gender

and

age

whether

age

was

modelled

in

linear

or

curvilinear

terms

Interactions

between

group

and

possible

confounders

Group

did

not

interact

with

hand

on

the

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

but

did

interact

marginally

significantly

with

hand

on

the

Tapping

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Group

did

not

interact

with

gender

on

the

Motor

Timing

Baseline

Speed

or

Tapping

tasks

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

nor

with

IQ

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

nor

with

linear

age

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

nor

with

curvilinear

age

-LRB-

F

-LRB-

-RRB-

P

F

-LRB-

-RRB-

P

and

F

-LRB-

-RRB-

P

respectively

-RRB-

Based

on

the

results

of

these

analyses

it

was

decided

to

average

the

measures

across

hands

to

simplify

results

since

no

group

differences

were

found

for

the

percentage

of

right

and

left-handed

-LRB-

Table

-RRB-

and

since

there

was

only

a

marginal

significant

interaction

of

small

effect

between

group

and

hand

for

one

of

the

tasks

-LRB-

Tapping

-RRB-

Furthermore

not

included

as

covariates

were

IQ

-LRB-

had

no

effect

on

motor

performance

and

did

not

interact

with

group

-RRB-

and

gender

-LRB-

had

only

a

small

effect

on

one

of

the

tasks

and

even

in

the

opposite

direction

i.e.

boys

performing

better

than

girls

and

gender

did

not

interact

with

group

-RRB-

Both

the

linear

and

curvilinear

effects

of

age

were

included

as

covariates

in

the

analyses

for

the

Baseline

Speed

task

and

Tapping

task

Only

the

linear

effect

of

age

was

included

as

covariate

in

the

analyses

for

the

Motor

Timing

task

Raw

means

and

SDs

are

presented

in

Table

Table

and

standard

deviations

of

the

motor

measures

in

msDependent

variableProbandAffected

siblingNon-affected

siblingControlηp2ContrastsMSDMSDMSDMSDMotor

timing

Speed

ns

nsNote

Probands

Affected

Siblings

Non-Affected

Siblings

Controls

ns

not

significantScores

were

averaged

across

hands

for

the

Baseline

Speed

and

TappingOutliers

-LRB-

z

-RRB-

were

removed

Endophenotypic

analyses

Motor

Timing

task

A

significant

small

effect

of

group

was

found

for

accuracy

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Pairwise

comparisons

indicated

that

probands

and

affected

siblings

did

not

differ

from

each

other

-LRB-

P

-RRB-

Both

differed

significantly

from

controls

-LRB-

P

and

P

respectively

-RRB-

probands

and

-LRB-

to

a

lesser

extent

-RRB-

affected

siblings

tended

to

under-produce

the

ms

interval

-LRB-

M

ms

and

M

ms

respectively

-RRB-

compared

to

controls

-LRB-

M

ms

-RRB-

A

tendency

to

under

reproduce

appeared

to

be

associated

with

ADHD

but

was

not

convincingly

related

to

a

familial

predisposition

for

the

disorder

since

non-affected

siblings

did

not

show

this

tendency

they

differed

significantly

from

probands

-LRB-

P

-RRB-

marginally

significantly

from

affected

siblings

-LRB-

P

-RRB-

but

not

from

controls

-LRB-

P

-RRB-

-LRB-

see

Fig.

-RRB-

Using

the

Conners

Total

ADHD

score

as

covariate

did

not

change

the

difference

between

non-affected

siblings

and

controls

-LRB-

P

-RRB-

However

a

polynomial

group

contrast

indicated

a

linear

trend

to

be

present

-LRB-

Contrast

Estimate

-LSB-

CE

-RSB-

P

-RRB-

suggesting

probands

performed

most

abnormal

followed

by

affected

siblings

then

non-affected

siblings

and

then

controls

Siblings

marginally

significantly

resembled

each

other

-LRB-

r

confidence

interval

-LSB-

CI

-RSB-

P

-RRB-

Fig.

and

variability

of

motor

timing

-LRB-

adjusted

for

the

linear

effect

of

age

-RRB-

in

probands

affected

siblings

non-affected

siblings

and

control

children

Error

bars

represent

standard

error

from

the

mean

Groups

also

differed

with

respect

to

the

variability

of

motor

timing

-LRB-

medium

effect

-RRB-

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Pairwise

comparisons

indicated

that

probands

and

affected

siblings

were

equally

variable

-LRB-

P

-RRB-

and

both

were

more

variable

than

controls

-LRB-

both

P

-RRB-

suggesting

ADHD

and

variability

in

motor

timing

were

associated

Moreover

variability

in

motor

timing

appeared

related

to

a

familial

predisposition

for

the

disorder

since

non-affected

siblings

formed

an

intermediate

group

They

significantly

differed

from

probands

affected

siblings

and

controls

-LRB-

P

P

and

P

respectively

-RRB-

Using

the

Conners

Total

ADHD

score

as

covariate

did

not

change

the

difference

between

non-affected

siblings

and

controls

-LRB-

P

-RRB-

A

linear

group

contrast

was

present

-LRB-

CE

P

-RRB-

A

significant

familial

resemblance

was

found

for

variability

-LRB-

r

-LSB-

CI

-RSB-

P

-RRB-

These

findings

lend

support

for

variability

of

motor

timing

as

endophenotype

though

the

accuracy

of

motor

timing

appears

only

to

be

associated

with

ADHD

and

not

conclusively

related

to

a

familial

susceptibility

for

the

disorder

-LRB-

Fig.

-RRB-

Baseline

Speed

task

A

small

but

significant

effect

of

group

was

found

for

speed

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Pairwise

comparisons

revealed

that

probands

and

affected

siblings

did

not

differ

from

each

other

-LRB-

P

-RRB-

and

both

were

slower

than

controls

-LRB-

P

and

P

respectively

-RRB-

indicating

a

relationship

between

speed

and

ADHD

It

appeared

that

speed

was

not

related

to

a

familial

vulnerability

for

ADHD

since

non-affected

siblings

differed

from

probands

and

affected

siblings

-LRB-

P

and

P

respectively

-RRB-

but

not

from

controls

-LRB-

P

-RRB-

Using

the

Conners

Total

ADHD

score

as

covariate

did

not

change

the

difference

between

non-affected

siblings

and

controls

-LRB-

P

-RRB-

Nevertheless

polynomial

group

contrasts

indicated

a

linear

trend

-LRB-

CE

P

-RRB-

suggesting

probands

to

perform

most

abnormal

followed

by

affected

siblings

then

non-affected

siblings

and

then

controls

A

significant

correlation

between

siblings

was

found

-LRB-

r

-LSB-

CI

-RSB-

P

-RRB-

Groups

differed

somewhat

-LRB-

small

effect

size

-RRB-

in

the

variability

on

the

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

Pairwise

comparisons

indicated

that

probands

and

affected

siblings

were

equally

variable

-LRB-

P

-RRB-

and

both

groups

were

more

variable

than

normal

controls

-LRB-

P

and

P

respectively

-RRB-

signaling

an

association

between

ADHD

and

variability

in

self

generated

motor

output

Again

non-affected

siblings

did

differ

from

probands

-LRB-

P

-RRB-

and

affected

siblings

-LRB-

P

-RRB-

but

not

from

controls

-LRB-

P

-RRB-

Using

the

Conners

Total

ADHD

score

as

covariate

did

not

change

the

difference

between

non-affected

siblings

and

controls

-LRB-

P

-RRB-

Nevertheless

a

linear

group

contrast

was

present

-LRB-

CE

P

-RRB-

Variability

correlated

between

siblings

-LRB-

r

-LSB-

CI

-RSB-

P

-RRB-

These

findings

suggest

slow

and

variable

motor

output

in

response

to

an

external

cue

is

associated

with

ADHD

but

probably

not

related

to

a

familial

vulnerability

for

ADHD

since

motor

output

of

non-affected

siblings

resembles

that

of

normal

controls

more

than

that

of

their

affected

siblings

-LRB-

Fig.

-RRB-

Fig.

and

variability

of

Baseline

Speed

-LRB-

adjusted

for

the

linear

and

curvilinear

effects

age

-RRB-

in

probands

affected

siblings

non-affected

siblings

and

control

children

Error

bars

represent

standard

error

from

the

mean

Scores

were

averaged

across

hands

Tapping

Task

No

significant

effect

of

group

was

found

for

speed

-LRB-

F

-LRB-

-RRB-

P

-RRB-

or

variability

-LRB-

F

-LRB-

-RRB-

P

-RRB-

No

significant

linear

trend

was

present

in

polynomial

group

contrasts

for

speed

or

variability

-LRB-

CE

P

and

CE

P

respectively

-RRB-

Siblings

did

resemble

each

other

in

the

speed

and

variability

of

tapping

-LRB-

speed

r

-LSB-

CI

-RSB-

P

variability

r

-LSB-

CI

-RSB-

P

-RRB-

These

findings

indicated

that

speed

and

variability

in

self

generated

motor

output

were

not

familially

associated

with

ADHD

-LRB-

Fig.

-RRB-

Fig.

and

variability

of

tapping

-LRB-

adjusted

for

the

linear

and

curvilinear

effects

of

age

-RRB-

in

probands

affected

siblings

non-affected

siblings

and

control

children

Error

bars

represent

standard

error

from

the

mean

Scores

were

averaged

across

hands

Since

there

were

group

differences

for

speed

and

variability

of

externally

cued

motor

output

-LRB-

Baseline

Speed

task

-RRB-

the

issue

was

raised

whether

the

deficits

found

on

the

Motor

Timing

task

were

primarily

related

to

these

group

differences

in

basic

motor

output

Therefore

analyses

were

undertaken

whereby

the

speed

on

the

Baseline

Speed

task

was

used

as

an

additional

covariate

in

the

analyses

on

accuracy

on

the

Motor

Timing

task

The

variability

on

the

Baseline

Speed

task

was

used

as

additional

covariate

for

the

analyses

on

variability

on

the

Motor

Timing

task

The

effect

of

group

on

accuracy

on

the

Motor

Timing

task

remained

significant

after

accounting

for

speed

on

the

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

The

unadjusted

means

of

the

raw

-LRB-

unstandardized

-RRB-

data

of

the

accuracy

on

the

Motor

Timing

task

for

probands

affected

siblings

non-affected

siblings

and

controls

were

and

ms

respectively

The

adjusted

means

after

covarying

for

speed

on

the

Baseline

Speed

task

were

and

ms

respectively

The

same

was

true

for

variability

of

motor

timing

the

medium

effect

of

group

remained

significant

after

accounting

for

variability

on

the

Baseline

Speed

task

-LRB-

F

-LRB-

-RRB-

P

-RRB-

The

unadjusted

means

of

the

raw

-LRB-

unstandardized

-RRB-

data

of

the

variability

on

the

Motor

Timing

task

for

probands

affected

siblings

non-affected

siblings

and

controls

were

and

ms

respectively

The

adjusted

menas

after

covarying

for

the

variability

on

the

Baseline

Speed

task

were

and

ms

respectively

Group

contrasts

for

accuracy

and

variability

as

reported

above

also

remained

unchanged

These

findings

suggest

that

the

deficits

found

on

the

Motor

Timing

task

can

not

be

explained

by

the

deficits

found

in

basic

motor

output

Discussion

There

was

investigated

whether

accuracy

and

variability

of

motor

timing

were

viable

endophenotypic

candidates

as

reflected

by

poor

performance

on

these

measures

in

children

with

ADHD

-LRB-

i.e.

indicating

an

association

between

the

deficits

and

the

disorder

-RRB-

reflected

by

poor

performance

in

non-affected

siblings

in

between

their

affected

siblings

and

controls

-LRB-

i.e.

suggesting

a

relation

between

the

deficits

and

a

familial

susceptibility

for

the

disorder

-RRB-

and

reflected

by

sibling

correlations

-LRB-

i.e.

signalling

familial

resemblance

for

deficits

-RRB-

We

administered

two

motor

tasks

in

addition

to

a

motor

timing

task

in

order

to

investigate

whether

deficits

were

specifically

related

to

the

timing

of

motor

output

or

whether

deficits

were

also

observed

in

tasks

requiring

motor

output

without

any

timing

demands

Probands

and

affected

siblings

were

dissociated

from

controls

with

respect

to

accuracy

of

motor

timing

Both

groups

tended

to

under-produce

the

ms

compared

to

control

children

-LRB-

who

tended

to

over-produce

the

interval

-RRB-

This

finding

has

been

reported

previously

using

exactly

the

same

task

-LRB-

Van

Meel

et

al.

-RRB-

and

is

comparable

to

some

other

studies

documenting

on

under

estimation

-LRB-

re

-RRB-

production

in

patients

with

ADHD

compared

to

controls

-LRB-

see

for

review

Toplak

et

al.

-RRB-

These

findings

suggest

a

relation

between

under

reproduction

-LRB-

possibly

reflecting

a

somewhat

speeded

internal

clock

and/or

impulsivity

-RRB-

and

ADHD

The

findings

were

less

convincing

with

respect

to

non-affected

siblings

despite

a

linear

trend

in

group

contrasts

their

accuracy

of

motor

timing

was

more

like

controls

than

that

of

affected

siblings

Furthermore

correlations

between

siblings

on

accuracy

were

also

modest

suggesting

familial

resemblance

for

accuracy

was

present

but

not

strongly

Therefore

accuracy

of

motor

timing

seems

not

to

be

a

strong

endophenotypic

candidate

Variability

of

motor

timing

however

convincingly

met

all

characteristics

of

an

endophenotype

as

investigated

in

our

study

Probands

and

affected

siblings

were

clearly

more

variable

in

their

motor

output

than

controls

non-affected

siblings

also

differed

significantly

from

controls

and

had

variability

scores

in

between

their

affected

siblings

and

controls

and

greater

variability

in

motor

timing

was

evidently

familial

Greater

variability

in

motor

timing

in

children

with

ADHD

compared

to

controls

concurs

with

previous

studies

-LRB-

Pitcher

et

al.

Rubia

et

al.

Toplak

et

al.

Van

Meel

et

al.

-RRB-

and

suggests

variability

in

motor

timing

is

characteristic

of

ADHD

Our

study

adds

important

knowledge

to

this

topic

showing

that

non-affected

siblings

portray

a

similar

type

of

variability

in

their

motor

timing

and

that

siblings

resemble

each

other

in

the

variability

of

motor

timing

These

findings

suggest

the

variability

in

motor

timing

is

not

only

associated

with

the

disorder

but

is

related

to

familial

vulnerability

for

ADHD

which

may

make

it

a

useful

tool

in

future

studies

aimed

at

unraveling

the

genetic

underpinnings

of

ADHD

All

in

all

variability

of

motor

timing

may

form

a

fruitful

endophenotypic

candidate

However

group

differences

were

also

present

on

motor

measures

that

did

not

require

a

timing

component

suggesting

motor

deficits

not

to

be

specifically

related

to

timing

but

to

be

more

generalized

Probands

and

affected

siblings

were

significantly

slower

and

more

variable

than

controls

concerning

motor

output

in

response

to

an

external

cue

-LRB-

Baseline

Speed

-RRB-

These

findings

of

slow

and

variable

responding

are

in

line

with

a

study

using

the

same

task

in

young

children

at

risk

for

ADHD

-LRB-

Kalff

et

al.

-RRB-

and

suggests

slow

and

variable

responding

are

characteristic

of

ADHD

However

in

contrast

to

variability

of

motor

timing

non-affected

siblings

did

not

differ

from

controls

with

respect

to

speed

and

variability

of

externally

cued

motor

output

So

despite

the

finding

that

slow

and

variable

motor

output

is

associated

with

ADHD

it

does

not

appear

to

be

convincingly

associated

with

a

familial

vulnerability

for

the

disorder

Given

that

poor

motor

output

was

observed

in

probands

and

affected

siblings

-LRB-

Baseline

Speed

-RRB-

it

was

surprising

that

no

such

abnormalities

were

found

in

self-generated

motor

output

-LRB-

Tapping

-RRB-

Probands

and

affected

siblings

had

a

normal

speed

and

variability

in

self

generated

motor

output

The

discrepancy

in

results

between

both

tasks

may

lie

in

the

suggestion

that

Baseline

Speed

may

have

required

some

form

of

cognitive

processing

-LRB-

i.e.

registering

a

stimulus

and

responding

to

it

-RRB-

whereas

Tapping

only

required

executing

a

motor

action

The

normal

performance

of

children

with

ADHD

on

the

Tapping

task

is

in

line

with

some

studies

-LRB-

Seidman

et

al.

-RRB-

but

in

contrast

with

others

-LRB-

Toplak

et

al.

-RRB-

This

might

be

explained

by

the

important

difference

in

timing

requirements

necessary

in

the

Tapping

task

used

here

and

in

some

previous

studies

Here

no

timing

was

required

to

execute

the

Tapping

task

The

instruction

was

simply

to

press

the

button

as

often

as

possible

within

a

certain

time

interval

However

in

other

studies

the

child

was

required

to

modify

his/her

tapping

rate

to

be

in

synchrony

with

the

stimulus

and

maintain

the

rhythm

in

the

absence

of

the

stimulus

-LRB-

Rubia

et

al.

Toplak

et

al.

-RRB-

These

tasks

load

differently

on

timing

processes

Our

findings

suggest

that

self-generated

motor

output

does

not

form

a

viable

area

of

endophenotypic

research

even

though

speed

and

variability

of

self-generated

motor

output

correlate

within

families

Since

group

differences

were

not

only

present

on

measures

of

motor

timing

but

also

on

measures

of

motor

output

-LRB-

Baseline

Speed

-RRB-

it

was

investigated

whether

motor

timing

impairments

may

be

due

to

deficits

in

basic

motor

output

This

appeared

not

to

be

the

case

Even

when

speed

and

variability

of

basic

motor

output

were

used

as

covariates

in

the

analyses

on

motor

timing

group

differences

for

motor

timing

remained

These

findings

suggest

abnormalities

in

the

accuracy

and

variability

of

motor

timing

are

relatively

independent

of

general

deficits

in

basic

motor

output

-LRB-

Keele

et

al.

-RRB-

and

suggest

abnormalities

in

motor

timing

are

predominantly

related

to

timing

operations

and

not

to

motor

functioning

Since

motor

timing

appears

predominantly

regulated

by

the

cerebellum

basal

ganglia

and

their

reciprocal

connections

with

the

cerebral

cortex

-LRB-

Handy

et

al.

Harrington

et

al.

Ivry

Nenadic

et

al.

-RRB-

subcortical

regions

in

addition

to

cortical

regions

might

be

important

in

the

etiology

of

ADHD

-LRB-

Halperin

and

Schulz

-RRB-

Limitations

We

did

not

administer

the

PACS

interview

for

nonaffected

siblings

This

might

have

resulted

in

undetected

ADHD

cases

in

the

nonaffected

sibling

group

which

in

turn

might

explain

the

deficits

of

this

group

However

we

do

not

believe

this

to

be

the

case

because

-LRB-

-RRB-

all

siblings

were

thoroughly

screened

and

if

they

scored

clinically

on

any

of

the

screening

questionnaires

the

PACS

interview

was

administered

and

-LRB-

-RRB-

even

when

symptom

severity

was

used

as

a

covariate

group

differences

between

nonaffected

siblings

and

controls

remained

significant

Furthermore

including

measures

aimed

at

isolating

aspects

of

timing

performance

such

as

time

estimation

and

reproduction

paradigms

in

addition

to

the

measure

of

time

production

would

have

enhanced

the

comprehensiveness

of

our

findings

with

respect

to

the

internal

clock

Some

previous

studies

using

time

estimation

and

reproduction

tasks

have

reported

that

children

with

ADHD

performed

abnormally

-LRB-

see

for

review

Toplak

et

al.

-RRB-

We

documented

previously

on

time

reproduction

deficits

present

in

both

children

with

ADHD

as

well

as

their

non-affected

siblings

-LRB-

Rommelse

et

al.

-RRB-

suggesting

familial

deficits

in

timing

in

ADHD

generalize

across

timing

paradigms

and

extent

beyond

motor

timing

as

reported

in

the

current

study

Conclusions

Variability

in

motor

timing

appears

a

useful

endophenotypic

candidate

It

is

clearly

associated

with

ADHD

it

is

also

present

in

non-affected

siblings

and

it

correlates

within

families

Accuracy

-LRB-

under

versus

over

production

-RRB-

in

motor

timing

appears

less

useful

even

though

accuracy

is

associated

with

ADHD

-LRB-

probands

and

affected

siblings

have

a

tendency

to

under-produce

compared

to

controls

-RRB-

non-affected

siblings

did

not

exhibit

this

tendency

and

sibling

correlations

were

only

marginally

significant

There

were

group

differences

in

motor

speed

and

variability

-LRB-

Baseline

Speed

task

-RRB-

probands

and

affected

siblings

were

slower

and

more

variable

in

their

motor

output

as

response

to

an

external

cue

Even

though

siblings

resembled

each

other

in

their

speed

and

variability

non-affected

siblings

performed

more

like

controls

These

findings

suggest

that

speed

and

variability

of

externally

cued

motor

output

are

associated

with

having

ADHD

but

probably

not

related

to

a

familial

vulnerability

for

the

disorder

Interestingly

the

speed

and

variability

in

self-generated

motor

output

-LRB-

Tapping

-RRB-

is

normal

in

probands

and

affected

siblings

making

it

unsuitable

to

unravel

underlying

vulnerabilities

leading

up

to

ADHD

Deficits

in

motor

timing

can

not

be

explained

by

deficits

already

present

in

basic

motor

output

without

a

timing

component

-LRB-

Baseline

Speed

-RRB-

suggesting

abnormalities

in

motor

timing

are

predominantly

related

to

deficient

timing

operations

but

not

to

deficient

motor

functioning

The

finding

that

deficits

in

motor

timing

run

in

ADHD-families

suggests

this

to

be

a

fruitful

domain

for

further

exploration

in

relation

to

the

genetic

underpinnings

of

ADHD

O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O B O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O B I O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B O O O O O B O O O O O O B I O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O O O O O O O O B O B I O O O O O O O O O O O O O O O O B O O O O B O O B I O O O O O O O O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O B O O O O O O O O O O O O O B O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O B I O O O O O O O B I O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O B I O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O B I O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B I O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O B I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O B O O O O O O O O O O O O O B O O O O O O O O B I O O B O O O O O O O B I O O O O O O O B I O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O B O O O O O O O B I O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O B I O O O O O O O O O O B O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O 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adhd
siblings
endophenotype
motor timing
motor speed