Deficit

of

social

cognition

in

subjects

with

surgically

treated

frontal

lobe

lesions

and

in

subjects

affected

by

schizophrenia

The

ability

of

humans

to

predict

and

explain

other

people

's

behaviour

by

attributing

independent

mental

states

such

as

desires

and

beliefs

to

them

is

considered

to

be

due

to

our

ability

to

construct

a

Theory

of

Mind

Recently

several

neuroimaging

studies

have

implicated

the

medial

frontal

lobes

as

playing

a

critical

role

in

a

dedicated

mentalizing

or

Theory

of

Mind

network

in

the

human

brain

In

this

study

we

compare

the

performance

of

patients

with

right

and

left

medial

prefrontal

lobe

lesions

in

theory

of

mind

and

in

social

cognition

tasks

with

the

performance

of

people

with

schizophrenia

Introduction

Social

cognition

refers

to

the

ability

to

perceive

interpret

and

provide

an

adequate

response

to

affective

and

other

interpersonal

cues

-LSB-

-RSB-

Pioneering

studies

have

found

that

schizophrenic

subjects

show

social

cognitive

impairments

in

particular

in

modifying

their

behaviour

when

interacting

with

other

people

and

in

recognizing

social

information

cues

-LSB-

-RSB-

People

with

schizophrenia

also

show

a

great

deal

of

social

naivety

in

interpersonal

situations

-LSB-

-RSB-

The

ability

to

engage

in

competent

social

relations

and

to

understand

social

information

depends

on

the

adequate

functioning

of

a

mental

mechanism

termed

Theory

of

Mind

-LRB-

ToM

-RRB-

that

allows

people

to

understand

and

interpret

their

own

and

other

people

's

mental

states

and

hence

to

predict

and

explain

their

behaviour

-LSB-

-RSB-

Evidence

from

neuroimaging

and

neuropsychological

studies

has

led

researchers

to

conclude

that

ToM

is

subserved

by

dedicated

brain

systems

including

the

amygdala

the

temporo-parietal

junction

the

orbital

frontal

cortex

and

in

particular

the

medial

frontal

lobes

-LSB-

-RSB-

The

results

of

these

studies

have

been

used

to

argue

that

the

medial

frontal

lobes

play

a

critical

role

in

a

dedicated

mentalizing

system

-LSB-

-RSB-

Neuropsychological

literature

specifically

relevant

to

the

medial

frontal

cortex

is

scarce

Actually

only

three

studies

have

included

patients

with

relatively

focal

medial

frontal

lobe

damage

and

have

sought

to

investigate

correlations

between

specific

frontal

brain

areas

and

performance

in

ToM

tasks

-LSB-

-RSB-

However

there

are

important

limitations

to

these

investigations

Stuss

et

al.

-LSB-

-RSB-

reported

that

patients

with

right

frontal

and

bilateral

frontal

lobe

damage

were

impaired

in

their

ability

to

infer

visual

experience

in

others

The

authors

conclude

that

acquired

brain

damage

to

the

medial

frontal

lobes

does

impact

on

ToM

ability

but

aetiology

of

brain

damage

for

each

patient

is

not

reported

the

text

implies

that

most

of

the

bifrontal

group

had

suffered

head

traumas

It

is

often

very

difficult

to

assess

the

extent

of

brain

damage

reliably

after

head

trauma

as

widespread

damage

can

often

occur

through

axonal

shearing

and

other

effects

-LRB-

e.g.

-LSB-

-RSB-

-RRB-

The

second

neuropsychological

study

-LSB-

-RSB-

reports

that

patients

with

left

and

right-sided

lesions

were

equally

impaired

while

lesion

size

was

unrelated

to

performance

and

no

effect

of

lesion

location

was

found

when

comparing

patients

with

focal

dorsolateral

medial

or

orbital

frontal

lesions

Also

a

recent

group

study

of

empathy

in

patients

-LSB-

-RSB-

included

an

assessment

of

performance

on

the

Faux

Pas

Test

a

probe

of

ToM

ability

Patients

with

frontal

lobe

lesions

were

impaired

in

this

task

Specifically

patients

with

ventromedial

frontal

lobe

damage

made

significantly

more

errors

than

patients

with

posterior

lesions

or

healthy

controls

in

the

Faux

Pas

Test

However

a

detailed

analysis

of

lesion

sites

associated

with

ToM

deficits

in

these

previous

studies

revealed

a

particularly

important

role

for

the

right

ventromedial

prefrontal

frontal

lobe

-LSB-

-RSB-

Damage

in

these

areas

induces

behavioural

changes

affecting

personality

-LRB-

indifference

-RRB-

impaired

social

judgement

reduced

affect

and

goal-directed

behaviour

self-monitoring

deficits

-LSB-

-RSB-

More

recent

studies

have

provided

evidence

that

is

in

disagreement

with

a

single

area

hypothesis

involved

in

ToM

processing

In

fact

the

neural

network

involving

the

right

and

left

temporo-parietal-junction

-LRB-

TPJ

R

and

L

-RRB-

the

posterior

cingulated

-LRB-

PC

-RRB-

and

medial

prefrontal

cortex

-LRB-

MPFC

-RRB-

seems

to

be

crucial

in

processing

the

complex

reasoning

involved

in

mentalizing

-LSB-

-RSB-

Bird

et

al.

-LSB-

-RSB-

studied

a

patient

affected

by

extensive

damage

of

the

medial

frontal

lobes

reporting

interestingly

a

dysexecutive

syndrome

with

confabulation

with

preserved

performance

on

some

ToM

tasks

Saxe

and

Wexler

-LSB-

-RSB-

in

an

fMRI

study

in

normal

subjects

described

an

equally

selective

profile

of

activation

of

the

above-mentioned

areas

in

a

multicomponent

pattern

of

activation

fMRI

methodology

Frontal

lobe

damage

in

patients

has

long

been

linked

to

impairments

in

social

behaviour

-LSB-

-RSB-

in

fact

they

have

been

described

as

presenting

diminished

social

awareness

and

a

lack

of

concern

for

social

rules

-LSB-

-RSB-

An

interesting

approach

to

social

competence

deficits

in

schizophrenic

people

may

be

represented

by

the

Machiavellian

Intelligence

Hypothesis

-LRB-

MIH

-LSB-

-RSB-

-RRB-

According

to

this

hypothesis

in

the

development

of

intelligence

social

rather

than

technical

efficiency

represents

the

main

selective

pressure

of

human

evolution

-LSB-

-RSB-

Social

efficiency

is

represented

by

the

ability

to

understand

the

intentions

and

beliefs

of

others

with

the

aim

of

deceiving

and

manipulating

them

to

achieve

relevant

objectives

such

as

control

of

food

sources

or

sexual

partners

-LSB-

-RSB-

Recent

literature

fosters

that

these

abilities

are

localised

in

the

ventromedial

prefrontal

cortex

selective

damage

to

these

areas

causes

a

relevant

impairment

of

interpersonal

relationships

and

in

regulating

behaviour

according

to

social

rules

-LSB-

-RSB-

Patients

with

lesions

to

the

orbitofrontal

cortex

also

have

disinhibited/socially

inappropriate

behaviour

Grafman

interpreted

the

patient

's

impairment

in

terms

of

an

inability

to

access

social

schema

knowledge

stored

in

the

frontal

lobes

-LSB-

-RSB-

Social

schema

knowledge

is

thought

to

inhibit

aberrant

behaviour

Patients

with

orbitofrontal

cortex

lesions

who

can

not

access

social

schema

knowledge

fail

to

inhibit

aberrant

behaviour

such

as

physical

threats

and

aggression

The

prediction

of

a

similar

cognitive

profile

in

terms

of

ToM

abilities

and

social

competence

between

frontal

lesion

subjects

and

schizophrenic

people

has

been

investigated

and

confirmed

-LSB-

-RSB-

An

extensive

and

careful

review

recently

published

-LSB-

-RSB-

reported

a

general

agreement

about

the

nature

and

extension

of

ToM

dysfunctions

in

people

affected

by

schizophrenia

These

dysfunctions

are

symptoms

related

-LSB-

-RSB-

disease

specific

and

state

independent

The

neural

architecture

of

the

social

cognitive

dysfunction

of

schizophrenia

is

of

paradigmatic

importance

for

the

understanding

of

social

cognitive

dysfunction

and

more

importantly

for

the

understanding

of

the

consequences

at

the

behavioural

level

-LSB-

-RSB-

A

previous

seminal

study

provided

evidence

that

structural

orbitofrontal

cortex

abnormalities

are

related

to

social

dysfunction

in

schizophrenic

people

-LSB-

-RSB-

Moreover

this

prefrontal

area

has

been

unequivocally

involved

in

the

social

cognitive

deficits

associated

with

this

disorder

-LSB-

-RSB-

However

empirically

controlled

investigations

in

which

the

cognitive

profile

of

brain

damaged

patients

was

compared

with

schizophrenic

subjects

with

an

appropriate

set

of

ToM

and

social

intelligence

tasks

are

lacking

thus

leaving

several

crucial

questions

largely

unresolved

In

the

current

study

we

examined

the

performance

of

stabilized

schizophrenic

outpatients

inpatients

with

focal

damage

of

left

and

right

ventromedial

prefrontal

lobes

and

healthy

controls

in

ToM

abilities

in

social

competence

and

tactical

strategy

-LRB-

Machiavellian

Intelligence

-RRB-

to

clarify

whether

schizophrenic

patients

demonstrate

impairment

similar

to

ventromedial

prefrontal

lesion

patients

and

whether

their

performance

in

these

tasks

can

be

differentiated

from

their

performance

in

tasks

sensitive

to

neuropsychological

dysfunction

including

executive

functions

Our

prediction

is

that

an

overlapping

dysfunctional

cognitive

profile

should

emerge

between

brain

damaged

and

schizophrenic

subjects

when

compared

to

healthy

subjects

We

also

addressed

several

methodological

issues

raised

by

earlier

studies

using

social

cognition

tasks

created

for

adults

and

not

for

children

Methods

Participants

The

subjects

for

this

study

included

adult

neurosurgical

patients

with

unilateral

frontal

lobe

lesions

who

had

undergone

surgery

at

the

Department

of

Neurosurgery

of

S.

Salvatore

Hospital

L'Aquila

Italy

The

patients

were

consecutively

enrolled

in

the

study

from

January

to

September

Only

patients

with

exclusive

frontal

lesions

were

identified

and

brain

damage

was

confirmed

through

neuroimaging

with

pre

and

postoperative

CT

scanning

and

MRIs

Nine

subjects

with

left

side

medial

prefrontal

cortex

-LRB-

LMPFC

-RRB-

lesions

and

nine

subjects

with

right

side

medial

prefrontal

cortex

-LRB-

RMPFC

-RRB-

lesions

were

studied

and

underwent

neuropsychological

examinations

-LRB-

Fig.

B

-RRB-

Fig.

-LRB-

A

-RRB-

MRI

weight

-LRB-

axial

view

-RRB-

with

gadolinium

showing

low

density

abnormalities

-LRB-

meningioma

excised

patients

L.F.

-RRB-

orbitofrontal

cortex

on

the

left

side

-LRB-

B

-RRB-

CT

scan

image

showing

low

density

abnormalities

-LRB-

meningioma

excised

patients

L.G.

-RRB-

orbitofrontal

cortex

on

right

sides

Thirteen

subjects

had

intra

or

extra-axial

tumours

-LRB-

-RRB-

had

spontaneous

haemorrhage

-LRB-

-RRB-

and

-LRB-

-RRB-

had

intracerebral

haemorrhage

from

ruptured

aneurysms

In

the

RMPFC

group

seven

patients

had

a

tumour

removed

-LRB-

four

had

a

meningioma

excised

had

a

high

grade

glioma

excised

and

had

an

oligodendroglioma

excised

-RRB-

one

had

a

right

anterior

communicating

artery

-LRB-

ACoA

-RRB-

aneurysm

clipped

following

rupture

and

one

had

spontaneous

intracerebral

haemorrhage

with

no

evidence

of

arterial

malformations

Of

the

LMPFC

patients

six

had

a

tumour

removed

-LRB-

five

had

a

meningioma

excised

and

one

had

a

high

grade

astrocytoma

excised

-RRB-

two

had

spontaneous

intracerebral

haemorrhage

with

no

evidence

of

arterial

malformations

and

one

had

a

left

ACoA

aneurysm

clipped

following

rupture

The

location

of

the

experimental

group

's

lesions

were

defined

anatomically

as

medial

-LRB-

Broadman

area

and

-RRB-

and

orbital

-LRB-

Broadman

areas

and

-RRB-

and

further

classified

according

to

the

prefrontal

sectors

of

functional

significance

into

which

the

lesions

encroached

-LRB-

Tables

-RRB-

Table

details

of

subjects

with

ventromedial

frontal

lobe

lesionsSubjectsSiteAgeEducationAetiologyM.DRight

frontal

frontal

frontal

frontal

frontal

grade

IIIE.GRight

frontal

intracerebral

haemorrhageS.MRight

frontal

grade

IVA.URight

frontal

haemorrhage

from

aneurismal

sac

ruptureM.URight

frontal

frontal

frontal

frontal

intra-cerebral

haemorrhageM.M.Left

frontal

intra-cerebral

haemorrhageR.MLeft

frontal

frontal

frontal

grade

IIIA.CLeft

frontal

frontal

haemorrhage

from

aneurismal

sac

ruptureTable

of

the

RMPFC

and

LMPFC

experimental

group

according

to

the

prefrontal

sectors

of

functional

significance

into

which

the

lesions

encroachedPatientSexAge

-LRB-

years

-RRB-

AetiologyLesion

grade

III+RF

grade

IV+RF

grade

III+LF

SIH

spontaneous

intracerebral

haemorrhage

IhAsc

intracerebral

haemorrhage

from

aneurismal

sac

rupture

Subjects

were

assessed

with

neuropsychological

test

batteries

days

after

surgery

A

control

group

of

schizophrenic

subjects

and

a

control

group

of

psychiatrically

and

neurologically

healthy

subjects

were

studied

as

well

Twenty

male

patients

all

native

Italian

speakers

whose

symptoms

satisfied

the

DSM-IV

criteria

for

schizophrenia

-LSB-

-RSB-

participated

in

the

study

They

were

all

patients

of

the

Department

of

Psychiatry

of

the

University

of

L'Aquila

and

diagnosis

was

re-confirmed

on

admission

to

-LRB-

and

months

after

discharge

from

-RRB-

the

Day-Hospital

-LRB-

DH

-RRB-

using

a

non-structured

interview

conducted

by

two

psychiatrists

-LRB-

M.C.

R.R

-RRB-

referring

to

DSM-IV

criteria

All

the

subjects

whose

assessment

took

place

when

clinically

stable

within

a

month

of

admission

to

the

DH

and

establishment/confirmation

of

diagnosis

were

treated

with

maintenance

antipsychotic

drugs

The

mean

daily

dose

was

-LRB-

SD

-RRB-

mg/equivalents

of

Chlorpromazine

-LSB-

-RSB-

this

dose-equivalence

with

a

typical

antipsychotic

is

necessary

in

order

to

compare

the

different

antipsychotic

drugs

as

their

strength

may

be

different

when

administered

to

patients

Twenty

neurologically

and

psychiatrically

healthy

control

subjects

-LRB-

matched

for

age

and

education

-RRB-

were

included

Exclusion

criteria

were

history

of

neurological

disease

including

epilepsy

head

trauma

or

mental

retardation

All

subjects

provided

informed

consent

to

participate

in

the

study

Materials

and

procedure

Clinical

assessment

Clinical

assessment

in

the

sample

with

MPFC

lesions

was

performed

by

using

a

non-structured

clinical

interview

and

Brief

Psychiatric

Rating

Scale

-LRB-

BPRS

-RRB-

version

translated

into

Italian

by

-LSB-

-RSB-

and

through

the

neuropsychiatric

Inventory

-LRB-

NPI

-RRB-

a

semistructured

clinicians

interview

using

the

protocol

described

by

-LSB-

-RSB-

For

the

schizophrenic

sample

frequency

and

severity

of

current

symptomatology

was

registered

by

using

a

non-structured

clinical

interview

and

Brief

Psychiatric

Rating

Scale

-LRB-

BPRS

-RRB-

version

-LRB-

Modified

version

translated

into

Italian

by

-LSB-

-RSB-

and

Clinical

Global

Impression

scale

-LRB-

CGI

-RRB-

-LSB-

-RSB-

The

prevalent

symptomatology

was

also

investigated

using

the

Scale

for

the

assessment

of

Positive

Symptoms

-LRB-

SAPS

-LSB-

-RSB-

-RRB-

and

Scale

for

the

assessment

of

Negative

Symptoms

-LRB-

SANS

-LSB-

-RSB-

-RRB-

The

SAPS

consists

of

items

and

is

divided

into

four

subscales

hallucinations

delusions

bizarre

behaviour

and

formal

thought

disorder

The

SANS

consists

of

items

and

is

designed

to

measure

five

domains

affective

flattening

or

blunting

alogia

apathy

asociality

and

impaired

attention

We

also

evaluated

social

function

with

AD-Disability

Assessment

-LSB-

-RSB-

Socio-demographic

and

clinical

data

are

reported

in

Table

Table

demographic

clinical

details

in

the

total

sampleSchizophrenia

-LRB-

no.

-RRB-

Right

medial

prefrontal

cortex

lesion

-LRB-

no.

-RRB-

Left

medial

prefrontal

cortex

lesion

-LRB-

no.

-RRB-

Healthy

controls

-LRB-

no.

-RRB-

Sex

-LRB-

M

F

-RRB-

Age

-LRB-

years

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Education

-LRB-

years

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Day

since

surgery

-LRB-

-RRB-

-LRB-

-RRB-

IQ

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

NPI

total

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Duration

of

illness

-LRB-

years

-RRB-

-LRB-

-RRB-

BPRS

total

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

C.G.I.

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Social

function

-LRB-

AD

-RRB-

-LRB-

-RRB-

The

values

are

means

standard

deviation

are

in

parenthesis

Neuropsychological

assessment

All

the

schizophrenic

subjects

with

the

exception

of

two

positive

schizophrenics

were

also

administered

three

neuropsychological

tests

for

assessment

of

executive

functions

the

WCST

the

Tower

of

London

Test

and

a

Phonemic

Verbal

Fluency

Test

-LRB-

Table

-RRB-

Table

detailed

of

total

sampleSchizophrenia

-LRB-

no.

-RRB-

Right

medial

prefrontal

cortex

lesion

-LRB-

no.

-RRB-

Left

medial

prefrontal

cortex

lesion

-LRB-

no.

-RRB-

Healthy

controls

-LRB-

no.

-RRB-

Verbal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Tower

of

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

WCST

no

of

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

WCST

of

perseverative

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Verbal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

The

values

are

means

standard

deviation

are

in

parenthesis

The

WCST

-LRB-

cards

-RRB-

was

administered

with

standard

instructions

as

described

by

Spreen

and

Strauss

-LSB-

-RSB-

whereas

scoring

followed

Heaton

's

-LSB-

-RSB-

rules

Scoring

and

administration

instructions

for

the

Tower

of

London

Test

were

those

described

by

Krikorian

et

al.

-LSB-

-RSB-

Scoring

and

administration

instructions

of

the

Phonemic

Verbal

Fluency

Test

were

those

described

by

Novelli

et

al.

-LSB-

-RSB-

Visuo-spatial

intellectual

level

was

assessed

by

means

of

Raven

's

Progressive

Matrices

-LSB-

-RSB-

Theory

of

mind

tasks

Four

stories

were

read

to

the

participants

individually

to

assess

ToM

competence

The

stories

were

structured

to

assess

the

ability

to

understand

first

and

second

order

false

beliefs

in

adult

subjects

-LSB-

-RSB-

First

order

false

beliefs

require

a

subject

to

make

an

inference

about

the

state

of

the

world

To

assess

first

order

ToM

two

stories

were

used

The

washing

machine

task

-LSB-

-RSB-

and

The

Cigarette

Task

-LSB-

-RSB-

Second

order

stories

measure

the

capacity

to

understand

other

people

's

false

beliefs

To

assess

second

order

ToM

two

stories

were

used

The

Burglar

-LSB-

-RSB-

and

The

Wallpaper

Story

-LSB-

-RSB-

These

stories

were

presented

to

the

subjects

in

a

series

of

cartoons

in

which

the

various

actions

of

the

characters

are

depicted

in

sequences

All

the

subjects

were

asked

a

ToM

question

and

three

control

questions

False

belief

test

question

This

was

designed

to

elicit

a

response

that

demonstrated

the

ability

to

make

inferences

about

another

individual

's

mental

state

namely

that

a

character

in

the

story

holds

a

false

belief.Fact

question

This

was

posed

to

determine

whether

subjects

understood

the

actual

sequence

of

relevant

events

that

had

occurred

in

the

story

which

is

in

contrast

with

the

sequence

as

understood

by

one

of

the

characters

in

the

story

and

that

leads

to

his

coming

to

a

false

conclusion.Memory

question

This

was

used

to

assess

whether

memory

for

story

details

was

approximately

intact

The

stories

were

the

same

for

all

the

subjects

examined

Each

subject

obtained

a

score

ranging

from

to

in

the

case

of

a

correct

answer

to

a

False-belief

question

to

the

fact

question

and

to

the

memory

question

where

incorrect

answer

correct

answer

If

the

subject

gave

a

correct

answer

to

both

the

first

order

stories

s/he

had

a

global

score

for

first

order

ToM

equal

to

-LRB-

non-casual

performance

-RRB-

For

second

order

false

belief

stories

we

followed

the

same

methods

Social

cognition

tasks

The

following

tasks

addressed

two

aspects

of

social

cognition

The

ability

to

process

the

appropriateness

of

behaviour

in

different

social

contexts

-LSB-

-RSB-

and

the

ability

to

use

tactical

strategy

-LRB-

Machiavellian

Intelligence

-RRB-

Social

situations

task

This

task

investigates

the

capacity

to

judge

the

appropriateness

of

behaviour

that

may

induce

anger

in

observers

Procedure

Nine

short

stories

describing

social

situations

incorporating

behaviour

were

read

by

the

patient

At

various

points

in

each

story

the

patient

was

asked

to

comment

on

how

appropriate

the

behaviour

was

giving

a

score

from

A

to

D.

A

scores

meant

that

he

judged

the

situation

as

normative

B

to

D

scores

meant

that

he

judged

the

situation

as

a

norm

violation

and

indexed

the

extent

of

the

violation

-LRB-

B

scores

being

mild

and

D

being

serious

-RRB-

Blair

and

Cipollotti

-LSB-

-RSB-

report

that

previous

piloting

on

a

large

independent

sample

of

healthy

controls

had

resulted

in

the

identification

of

a

set

of

consistently

identified

normative

situations

and

violations

Two

scores

were

obtained

for

this

task

one

referring

to

the

number

of

normative

situations

and

the

other

to

the

number

of

violations

correctly

identified

The

third

refers

to

the

extent

to

which

the

patient

judged

the

violations

to

be

socially

inappropriate

For

each

situation

the

participant

obtained

a

score

between

and

matching

their

response

of

A

to

D

-LRB-

i.e.

A

D

-RRB-

Mach

IV

Scale

We

used

the

Mach

IV

Scale

to

assess

the

Machiavellian

Intelligence

of

participants

-LSB-

-RSB-

This

is

a

self-report

Likert

scale

with

scores

ranging

from

to

-LRB-

where

I

totally

disagree

no

opinion

I

totally

agree

-RRB-

composed

of

items

each

consisting

of

a

statement

The

Mach

IV

scale

is

a

method

for

assessing

awareness

and

social

functioning

in

a

social

context

characterised

by

interpersonal

deception

-LRB-

Machiavellianism

-RRB-

From

the

statements

of

the

Mach

IV

Scale

we

extracted

two

groups

of

items

-LRB-

-RRB-

items

describing

duplicity

tactics

e.g.

It

is

wise

to

flatter

important

people

-LRB-

tactics

-RRB-

and

-LRB-

-RRB-

items

describing

a

disagreements

with

tactics

duplicity

e.g.

When

you

ask

someone

to

do

something

for

you

it

is

best

to

give

the

real

reason

-LRB-

tactics

-RRB-

The

items

were

labelled

for

coding

as

follows

Positive

tactics

-LRB-

tactics

-RRB-

subjects

must

agree

with

statements

reporting

the

ability

to

manipulate

other

people

's

intentions

and

actions

according

to

Niccolò

Machiavelli

's

beliefs

Negative

tactics

-LRB-

tactics

-RRB-

subjects

must

agree

with

statements

reporting

judgements

of

correct

and

honest

behaviour

for

this

reason

they

can

not

use

intentional

deception

mechanisms

involved

in

the

Machiavellian

Intelligence

Hypothesis

These

features

depend

on

an

accurate

interpretation

of

even

the

most

particular

intention

of

respondents

-LSB-

-RSB-

Human

nature

components

referring

to

people

's

knowledge

in

particular

the

degree

of

cynicism

concerning

other

people

's

intentions

and

decisions

are

strictly

related

to

the

ability

to

interpret

other

people

's

mental

states

Statistical

analysis

One-way

ANOVA

was

used

to

compare

demographic

clinical

information

and

neuropsychological

Assessment

and

social

cognition

tasks

The

Kruskaal

Wallis

test

was

used

to

analyse

the

level

of

significance

of

patients

scores

on

ToM

tasks

Results

No

differences

among

groups

emerged

for

age

-LSB-

F

-LRB-

-RRB-

P

-RSB-

years

of

education

-LSB-

F

-LRB-

-RRB-

P

-RSB-

and

estimated

IQ

-LSB-

F

-LRB-

-RRB-

P

-RSB-

-LRB-

Table

-RRB-

Clinical

assessment

Neither

were

differences

found

between

the

four

subgroups

in

age

-LSB-

F

-LRB-

-RRB-

P

sex

ratio

standard

of

education

-LSB-

F

-LRB-

-RRB-

P

-RSB-

IQ

-LSB-

F

-LRB-

-RRB-

P

-RSB-

in

BPRS

total

scores

-LSB-

F

-LRB-

-RRB-

P

-RSB-

and

in

NPI

total

score

-LSB-

F

-LRB-

-RRB-

P

-RSB-

Executive

function

The

three

groups

differed

significantly

in

the

planning

Tower

of

London

task

-LSB-

F

-LRB-

-RRB-

P

-RSB-

Verbal

Fluency

-LSB-

F

-LRB-

-RRB-

P

-RSB-

and

No

of

categories

achieved

in

the

WCST

-LSB-

F

-LRB-

-RRB-

P

-RSB-

and

perseverative

errors

-LSB-

F

-LRB-

-RRB-

P

-RSB-

The

performance

data

for

the

four

groups

on

the

tests

of

executive

functioning

are

shown

in

Table

The

LSD

method

was

used

for

post

hoc

comparisons

This

revealed

that

in

Verbal

Fluency

both

frontal

groups

-LRB-

LMPFC

and

RMPFC

-RRB-

performed

significantly

worse

than

the

schizophrenic

group

and

control

subjects

Bonferroni

tests

on

the

Tower

of

London

task

showed

impaired

performance

for

the

LMPFC

group

only

when

compared

to

both

the

schizophrenic

and

healthy

subjects

control

groups

The

LMPFC

group

performed

significantly

worse

than

the

RMPFC

subjects

First-order

false

belief

tasks

False-belief

test

question

Groups

differed

significantly

on

the

non-parametric

Kruskall

Wallis

test

χ2

-LRB-

-RRB-

df

P

Post

hoc

-LRB-

Bonferroni

methods

-RRB-

comparisons

showed

that

the

RMPFC

group

's

performance

differed

significantly

from

that

of

the

LMPFC

-LRB-

RMPFC

vs.

LMPFC

mean

differences

P

-RRB-

but

not

from

schizophrenic

subgroups

and

that

the

overall

percentage

of

correct

scores

for

patient

groups

was

significantly

lower

than

those

of

the

normal

control

group

Fact

questions

The

percentage

of

correct

scores

revealed

no

significant

overall

differences

between

groups

Memory

questions

The

percentage

of

correct

scores

showed

no

significant

group

differences

-LRB-

Fig.

-RRB-

Fig.

of

study

groups

-LRB-

schizophrenics

Right

Medial

Prefrontal

Cortex

RMPFC

Lesion

Subjects

Left

Medial

Prefrontal

Cortex

LMPFC

Lesion

Subjects

and

healthy

controls

-RRB-

on

First-order

False

Belief

tasks

Second

order

theory

of

mind

False-belief

test

question

Groups

differed

significantly

Kruskall

Wallis

χ2

-LRB-

-RRB-

df

P

-RRB-

Post

hoc

-LRB-

Bonferroni

methods

-RRB-

analyses

revealed

the

most

impaired

performance

for

the

RF

and

schizophrenia

groups

when

compared

to

LMPFC

-LRB-

LMPFC

vs.

RMPFC

mean

differences

P

LMPFC

vs.

schizophrenics

mean

differences

P

-RRB-

However

the

overall

percentage

of

correct

scores

for

patient

groups

was

significantly

lower

than

those

of

the

normal

control

group

Fact

questions

The

percentage

of

correct

scores

revealed

no

significant

overall

difference

between

the

groups

Memory

questions

The

percentage

of

correct

scores

showed

no

significant

group

differences

-LRB-

Fig.

-RRB-

Fig.

of

study

groups

-LRB-

schizophrenics

Right

Medial

Prefrontal

Cortex

RMPFC

Lesion

Subjects

Left

Medial

Prefrontal

Cortex

LMPFC

Lesion

Subjects

and

healthy

controls

-RRB-

on

second-order

False

Belief

tasks

Social

situation

task

The

ANOVA

comparison

between

RMPFC

LMPFC

schizophrenics

and

healthy

controls

showed

statistically

significant

differences

in

the

ability

to

identify

normative

situations

-LSB-

F

-LRB-

-RRB-

P

-RSB-

Post

hoc

-LRB-

Bonferroni

methods

-RRB-

comparisons

showed

that

the

RMPFC

group

's

performance

differed

significantly

from

that

of

the

LMPFC

-LRB-

RMPFC

vs.

LMPFC

mean

differences

P

LMPFC

vs.

schizophrenics

mean

differences

P

-RRB-

and

healthy

controls

but

not

from

schizophrenics

There

were

no

significant

differences

between

the

four

groups

in

the

total

score

of

the

norm

violations

-LRB-

Fig.

-RRB-

Fig.

on

social

situation

task

in

all

groups

-LRB-

schizophrenics

Right

Medial

Prefrontal

Cortex

RMPFC

Lesion

Subjects

and

Left

Medial

Prefrontal

Cortex

LMPFC

Lesion

Subjects

-RRB-

The

figure

reports

the

scores

in

correct

identification

of

normative

situation

and

the

mean

scores

of

norm

violations

Mach

IV

scale

The

ANOVA

comparison

between

RMPFC

LMPFC

schizophrenics

and

healthy

controls

showed

statistically

significant

differences

on

the

following

Mach

IV

items

-LRB-

tactics

-RRB-

item

Trusting

someone

means

getting

into

trouble

-LSB-

F

-LRB-

-RRB-

P

-RSB-

-LRB-

tactics

-RRB-

It

's

hard

to

be

successful

without

taking

short-cuts

-LSB-

F

-LRB-

-RRB-

P

-RSB-

-LRB-

tactics

-RRB-

There

is

no

need

to

deceive

anyone

-LSB-

F

-LRB-

-RRB-

P

-RSB-

-LRB-

tactics

-RRB-

It

is

possible

to

be

good

in

all

situations

-LSB-

F

-LRB-

-RRB-

P

-RSB-

Post

hoc

multiple

comparison

-LRB-

Bonferroni

methods

-RRB-

showed

that

RMPFC

score

lower

for

items

indicating

agreement

in

strategic

thinking

-LRB-

tactics

-RRB-

than

LMPFC

schizophrenics

and

controls

showed

higher

scores

for

items

indicating

disagreement

with

strategic

thinking

-LRB-

Tactics

-RRB-

Results

are

displayed

in

Fig.

Fig.

on

items

of

Mach

IV

Scale

in

the

four

groups

for

strategic

thinking

Correlation

analyses

No

significant

correlations

were

found

between

ToM

first

order

and

ToM

second

order

questions

and

executive

functions

-LRB-

verbal

fluency

WCST

number

of

categories

and

perseverative

errors

Tower

of

London

-RRB-

in

normal

controls

and

in

subjects

with

left

and

right

frontal

lesions

No

significant

correlations

were

found

between

the

Mach

IV

scales

-LRB-

good

tactical

strategy

and

negative

tactical

strategy

-RRB-

and

executive

functions

-LRB-

verbal

fluency

WCST

no

of

categories

and

perseverative

errors

Tower

of

London

-RRB-

in

normal

controls

and

in

subjects

with

left

and

right

MPFC

There

was

a

significant

correlation

between

first

order

ToM

scores

and

duration

of

illness

-LRB-

r

P

-RRB-

between

first

order

ToM

scores

and

SANS

total

scores

-LRB-

r

P

-RRB-

between

first

order

and

second

order

ToM

scores

and

social

functioning

total

scores

-LRB-

AD

-RRB-

-LRB-

first

order

P

second

order

r

P

-RRB-

The

significant

correlation

was

also

found

in

the

schizophrenic

sample

between

ToM

performances

and

verbal

fluency

-LRB-

r

P

-RRB-

No

significant

correlations

were

found

between

the

Mach

IV

scale

and

social

cognition

task

and

psychopathological

and

clinical

variable

-LRB-

SANS

SAPS

and

CGI

-RRB-

Discussion

One

of

the

distinctive

attributes

of

human

social

cognition

is

our

propensity

to

build

models

of

other

people

's

minds

to

make

inferences

about

the

mental

states

of

others

Several

neuroimaging

studies

have

attempted

to

elucidate

the

neural

substrates

that

support

this

distinctively

human

ability

that

is

impaired

in

people

with

schizophrenia

The

main

aim

of

the

present

paper

is

to

establish

whether

patients

affected

by

schizophrenia

show

an

impairment

in

several

social

cognitive

tasks

as

demonstrated

in

other

researches

-LSB-

-RSB-

and

if

this

cognitive

profile

is

comparable

to

patients

with

a

unilateral

brain

lesion

involving

orbito-ventromedial

areas

of

the

frontal

lobes

Our

results

are

in

line

with

other

studies

in

people

with

schizophrenia

there

was

an

impairment

of

social

cognitive

abilities

and

this

deficit

appears

to

be

related

to

negative

symptomatology

-LSB-

-RSB-

and

to

be

a

key

determinant

of

functional

outcome

including

social

outcome

-LSB-

-RSB-

It

has

been

suggested

that

theory

of

mind

deficit

make

unable

schizophrenic

subjects

to

interact

effectively

with

their

social

environment

but

that

a

lack

of

certain

aspects

of

social

cognition

will

lead

to

social

misperceptions

In

addition

to

these

clinical

and

outcome

goals

there

is

increasing

interest

in

identifying

the

neural

substrates

that

underlie

social

cognitive

deficits

in

schizophrenia

For

all

of

these

reasons

we

compared

the

performances

on

social

cognition

tasks

of

schizophrenic

subjects

with

the

performances

of

MPFC

subjects

Among

the

several

studies

which

investigated

the

effects

of

frontal

lobe

lesions

-LRB-

dorsolateral

and

ventromedial/orbital

-RRB-

on

performance

in

ToM

tasks

-LSB-

-RSB-

some

of

these

including

patients

with

bilateral

frontal

lobe

damage

are

limited

because

of

a

lack

of

detailed

anatomical

specification

of

lesion

location

-LSB-

-RSB-

Moreover

most

of

patients

with

bilateral

lesions

had

suffered

head

trauma

an

aetiology

associated

with

rather

diffuse

brain

damage

that

is

particularly

likely

to

impinge

on

orbitofrontal

brain

areas

Thus

the

present

study

strictly

tests

the

hypothesis

that

the

unilateral

-LRB-

right

or

left

-RRB-

medial

frontal

cortex

is

implicated

in

the

neural

network

sub

serving

ToM

-LSB-

-RSB-

which

is

based

on

well

established

evidences

suggesting

the

implication

of

the

ventromedial

frontal

lobe

areas

in

playing

a

critical

role

in

a

dedicated

mentalizing

or

ToM

network

in

human

brains

-LRB-

-LSB-

-RSB-

for

a

review

-RRB-

We

found

out

that

subjects

with

RMPFC

lesion

are

impaired

in

ToM

tasks

of

false

beliefs

showing

thus

a

very

similar

cognitive

dysfunctional

profile

to

people

affected

by

schizophrenia

in

all

Theory

of

Mind

tasks

and

in

all

social

cognition

tasks

A

normal

performance

on

control

questions

indicates

an

unimpaired

comprehension

of

stories

and

suggest

that

the

task

was

sensitive

in

detecting

TOM

impairments

In

addition

schizophrenics

and

subjects

with

RMPFC

lesion

also

showed

impairment

in

the

social

cognition

tasks

in

fact

they

both

failed

to

discriminate

in

judging

inappropriate

behaviour

likely

to

induce

anger

in

observers

This

was

unlike

patients

with

LMPFC

who

showed

no

impairment

on

any

of

these

tasks

This

is

clear

evidence

that

the

medial

frontal

cortex

plays

a

critical

role

in

a

dedicated

mentalizing

brain

network

that

underpins

ToM

ability

-LSB-

-RSB-

Our

findings

are

in

agreement

with

previous

lesional

studies

showing

the

association

between

right

medial

area

damage

and

more

severe

ToM

deficits

-LSB-

-RSB-

Siegal

et

al.

-LSB-

-RSB-

reported

that

ToM

impairments

seem

to

be

associated

with

right

hemisphere

damage

In

the

present

study

we

report

a

dissociation

in

RMPFC

damage

patients

who

displayed

a

defective

ToM

performance

in

contrast

to

LMPFC

patients

LMPCF

subjects

show

lower

performances

than

RMPCF

subjects

in

other

cognitive

competences

but

have

normal

performance

in

ToM

competences

and

our

results

confirm

the

results

obtained

by

Siegal

and

Surian

-LSB-

-RSB-

In

addition

when

a

more

sophisticated

social

ability

is

required

in

order

to

perform

second

order

false

belief

tasks

correctly

also

LMPFC

damaged

subjects

fail

to

perform

at

a

normal

level

and

show

a

statistically

significant

impairment

even

though

to

a

lesser

degree

when

compared

to

subjects

with

RMPFC

and

schizophrenic

people

A

possible

explanation

is

that

LMPFC

is

involved

in

more

sophisticated

mentalizing

tasks

and

that

an

intact

right

hemisphere

structure

is

nevertheless

required

-LSB-

-RSB-

Normal

subjects

and

neurosurgical

subjects

with

unilateral

LMPFC

lesions

perform

fairly

well

on

tasks

related

to

tactical

strategy

showing

correspondingly

low

scores

on

the

ingenuity

aspect

of

thinking

The

present

study

also

provides

further

data

on

the

neural

prefrontal

areas

involved

in

social

cognition

tasks

and

in

strategic

thinking

-LSB-

-RSB-

Social

efficiency

is

represented

by

the

ability

to

understand

the

intentions

and

beliefs

of

others

with

the

aim

of

deceiving

and

manipulating

them

to

achieve

relevant

objectives

such

as

control

of

food

sources

or

sexual

partners

-LSB-

-RSB-

Recent

literature

fosters

that

these

abilities

are

localised

in

the

frontal

cortex

-LSB-

-RSB-

the

ability

to

recognise

and

manipulate

hierarchical

states

to

achieve

some

advantage

would

be

localised

in

the

amygdala

and

right

hemisphere

-LSB-

-RSB-

Schizophrenic

people

and

subjects

with

RMPFC

lesion

showed

impaired

performance

on

tactical

strategy

associated

with

relatively

high

levels

of

social

ingenuity

and

have

an

impaired

ability

to

access

social

schema

knowledge

which

is

stored

in

the

frontal

lobes

-LSB-

-RSB-

Such

patients

can

not

access

social

schema

knowledge

and

fail

to

inhibit

aberrant

behaviour

such

as

physical

threats

and

aggression

-LSB-

-RSB-

Interestingly

a

completely

reversed

pattern

characterizes

the

performance

of

LMPFC

lesion

subjects

and

healthy

controls

in

fact

we

found

out

a

complete

disassociation

of

the

neural

prefrontal

areas

located

in

the

medial

part

of

the

hemisphere

in

sub

serving

human

ability

to

think

strategically

indicating

that

the

cortical

organization

related

to

tactical

aspects

of

Machiavellian

Intelligence

is

lateralized

to

the

right

hemisphere

-LSB-

-RSB-

Our

results

are

at

slight

variance

with

the

pioneering

study

of

Rowe

et

al.

-LSB-

-RSB-

who

found

a

significantly

impaired

performance

of

both

the

RMPFC

and

LMPFC

subjects

in

first

and

second

order

ToM

tasks

In

this

study

cortical

lesions

were

non-exclusive

medial

hemisphere

but

includes

subjects

with

dorsolateral

prefrontal

cortex

-LRB-

DLPC

-RRB-

damage

Studies

of

normal

subjects

have

used

a

variety

of

imaging

techniques

designs

and

test

materials

but

especially

PET

and

fMRI

to

define

brain

regions

specifically

activated

during

a

ToM

task

-LSB-

-RSB-

Such

studies

have

consistently

shown

activation

of

the

medial

prefrontal

gyrus

-LRB-

MPFG

-RRB-

and

the

Temporo

Parietal

Junction

Frith

and

Frith

-LSB-

-RSB-

reporting

data

on

studies

carried

out

in

adults

have

revealed

an

MPFC

system

of

three

components

that

are

consistently

activated

during

both

implicit

and

explicit

mentalizing

tasks

This

brain

region

is

probably

the

basis

of

the

decoupling

mechanism

that

distinguishes

mental

state

representations

from

physical

state

representations

We

can

speculate

according

to

the

Edelman

model

-LSB-

-RSB-

that

a

hierarchical

organization

of

mental

operation

when

disrupted

at

a

specified

level

impairs

the

integrity

of

final

output

via

an

interruption

of

the

chain

of

events

required

to

perform

a

task

This

study

is

limited

by

the

small

number

of

patients

with

unilateral

frontal

lobe

lesions

due

to

the

rarity

of

such

lesion

Despite

this

limitation

this

study

provides

further

evidence

that

social

competence

is

compromised

in

RMPFC

subjects

very

closely

to

schizophrenics

and

these

data

seem

to

elucidate

the

possible

neuroanatomic

structure

alteration

present

in

schizophrenia

However

we

are

confident

that

there

is

a

wide

range

of

behavioural

manifestations

of

frontal

lobe

dysfunction

and

ToM

impairments

clearly

can

not

account

for

all

of

these

nor

is

it

likely

to

be

responsible

for

all

reported

difficulties

in

social

cognition

In

contrast

ToM

tests

are

designed

with

the

aim

of

isolating

those

aspects

of

social

cognition

associated

with

two-way

reciprocal

interactions

that

rely

crucially

on

ToM

ability

and

false

belief

tasks

have

facilitated

the

demonstration

of

a

mentalizing

impairment

in

subjects

with

lesions

of

the

prefrontal

cortex

which

is

independent

of

non-mental

state

inference

In

conclusion

our

findings

provide

evidence

that

lesions

to

the

right

MPCF

determine

an

incapacity

to

understand

ToM

false

belief

stories

and

to

use

tactical

strategy

and

understanding

of

social

schema

Other

authors

have

reported

the

same

results

subjects

with

right

hemisphere

damage

but

not

subjects

with

left

hemisphere

damage

had

difficulties

in

performing

simple

theory

of

mind

tasks

-LSB-

-RSB-

The

difficulties

shared

by

subjects

with

right

hemisphere

damage

and

young

children

on

ToM

tasks

may

have

a

similar

origin

-LSB-

-RSB-

These

may

both

derive

from

a

pragmatic

deficit

that

prevents

subjects

from

interpreting

the

implicit

questions

correctly

rather

than

from

a

conceptual

deficit

concerning

the

ability

to

represent

mental

states

The

response

pattern

of

subjects

with

ventromedial

prefrontal

damage

on

ToM

tasks

adds

new

evidence

to

the

growing

literature

on

the

effects

of

the

right

hemisphere

on

various

pragmatic

aspects

of

language

production

and

comprehension

-LSB-

-RSB-

The

good

performance

of

subjects

with

RMPCF

lesions

in

executive

function

and

verbal

memory

tasks

suggests

that

their

difficulties

are

due

to

a

reduced

sensitivity

to

the

constraints

that

guide

the

interpretation

and

production

of

contextually

appropriate

utterances

-LSB-

-RSB-

It

may

be

concluded

that

the

ToM

disorder

in

RMPCF

subjects

does

not

stem

from

executive

function

or

memory

deficits

and

that

deficits

in

ToM

and

executive

functioning

in

subjects

with

frontal

lobe

lesions

are

not

causally

related

even

though

our

findings

are

in

disagreement

with

Channon

and

Crawford

-LSB-

-RSB-

who

found

a

relationship

between

executive

functioning

and

ToM

ability

in

adults

with

damage

to

the

frontal

lobes

-LSB-

-RSB-

We

support

two

positions

first

that

a

specialized

discrete

ToM

module

or

set

of

modules

is

located

in

the

frontal

lobes

but

is

functionally

independent

and

second

that

these

deficits

can

co-occur

on

the

basis

of

the

proximity

of

the

respective

underlying

neural

areas

O O B I O O O O O B I I 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 B I 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 B I 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 B I I O O B I O O O O 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 O O O O O O O O O O O O O O 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 I 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 B I 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 B I 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 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 B I 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 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 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 O O O O B I 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 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 I O O O O O O O O O O O O O O O O O O O O B I 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 B O O B I I 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 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 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 B I 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 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 I 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 B I 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 B I 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

schizophrenia
frontal lobe lesions
theory of mind
social cognition


Modulation

in

voluntary

neural

drive

in

relation

to

muscle

soreness

The

aim

of

this

study

was

to

investigate

whether

-LRB-

-RRB-

spinal

modulation

would

change

after

non-exhausting

eccentric

exercise

of

the

plantar

flexor

muscles

that

produced

muscle

soreness

and

-LRB-

-RRB-

central

modulation

of

the

motor

command

would

be

linked

to

the

development

of

muscle

soreness

Ten

healthy

subjects

volunteered

to

perform

a

single

bout

of

backward

downhill

walking

exercise

-LRB-

duration

min

velocity

ms

negative

grade

load

of

body

weight

-RRB-

Neuromuscular

test

sessions

-LSB-

H-reflex

M-wave

maximal

voluntary

torque

-LRB-

MVT

-RRB-

-RSB-

were

performed

before

immediately

after

as

well

as

days

after

the

exercise

bout

Immediately

after

exercise

there

was

a

decrease

in

MVT

of

the

plantar

flexors

partly

attributable

to

an

alteration

in

contractile

properties

-LRB-

in

electrically

evoked

mechanical

twitch

-RRB-

However

MVT

failed

to

recover

before

the

third

day

whereas

the

contractile

properties

had

significantly

recovered

within

the

first

day

This

delayed

recovery

of

MVT

was

likely

related

to

a

decrement

in

voluntary

muscle

drive

The

decrease

in

voluntary

activation

occurred

in

the

absence

of

any

variation

in

spinal

modulation

estimated

from

the

H-reflex

Our

findings

suggest

the

development

of

a

supraspinal

modulation

perhaps

linked

to

the

presence

of

muscle

soreness

Introduction

In

an

exercise

inducing

muscle

damage

inadequate

neural

drive

can

be

an

attempt

of

the

neuromuscular

system

to

protect

the

muscle-tendon

unit

from

additional

damage

-LRB-

Strojnik

and

Komi

Nicol

et

al.

-RRB-

This

inadequate

neural

drive

could

be

the

result

from

a

combination

of

three

factors

the

conscious

and

unconscious

will

of

the

subject

to

reduce

the

exercise

intensity

an

inability

of

the

motor

cortex

to

generate

sufficient

output

to

maximally

activate

the

muscle

and/or

a

decreased

transmission

of

the

supraspinal

input

to

the

muscle

by

the

spinal

motor

axons

A

decrement

in

H-reflex

amplitude

has

been

observed

immediately

after

an

exhausting

voluntary

contraction

of

a

single

muscle

group

-LRB-

i.e.

Duchateau

et

al.

Garland

and

McComas

Kuchinad

et

al.

-RRB-

It

has

been

proposed

that

this

decline

in

the

transmission

of

the

action

potentials

from

the

Ia

afferent

to

the

α-motoneuron

may

be

a

consequence

of

a

presynaptic

inhibition

mediated

by

group

III

and

IV

afferents

-LRB-

Bigland-Ritchie

et

al.

Duchateau

et

al.

Garland

and

McComas

Garland

Woods

et

al.

-RRB-

induced

by

muscle

damage

-LRB-

Avela

et

al.

-RRB-

Furthermore

increased

group

III

and

IV

muscle

afferent

inputs

could

induce

H-reflex

depression

when

muscle

soreness

progresses

as

muscle

pain

is

believed

to

reflect

activity

in

group

III

and

IV

muscle

afferents

-LRB-

O'Connor

and

Cook

-RRB-

But

only

a

few

studies

have

observed

a

decrease

in

H-reflex

amplitude

after

exercise

of

multiple

muscle

groups

as

occurs

for

example

in

running

-LRB-

Avela

et

al.

Bulbulian

and

Bowles

Racinais

et

al.

-RRB-

raising

the

question

of

whether

spinal

modulation

occurs

after

whole

body

exercise

Recently

it

has

been

shown

that

walking

backward

induces

muscle

soreness

in

the

muscles

of

the

lower

limb

-LRB-

Nottle

and

Nosaka

-RRB-

Accordingly

this

exercise

model

allows

the

study

of

the

effects

of

muscle

soreness

on

alteration

in

neural

drive

Thus

the

goal

of

this

study

was

to

determine

whether

the

impaired

exercise

performance

of

muscles

with

delayed

onset

muscle

soreness

-LRB-

DOMS

-RRB-

is

due

to

an

alteration

in

neural

drive

related

to

spinal

modulation

Methods

Subjects

Ten

healthy

subjects

-LRB-

eight

males

and

two

females

age

years

weight

kg

height

cm

data

in

mean

SEM

-RRB-

gave

informed

written

consent

to

participate

in

this

study

The

procedures

complied

with

the

Helsinki

declaration

for

human

experimentation

and

were

approved

by

the

local

Ethics

Committee

of

the

subjects

suffered

from

muscle

soreness

or

ankle

injuries

Subjects

were

asked

to

avoid

caffeine

intake

within

the

preceding

the

test

and

to

avoid

all

vigorous

activity

during

the

preceding

the

test

Subjects

were

also

asked

to

refrain

from

analgesic

intake

all

along

the

protocol

which

could

have

disturbed

DOMS

perception

Experimental

procedures

Subjects

visited

our

laboratory

on

four

consecutive

days

-LRB-

Fig.

-RRB-

The

first

day

consisted

of

a

neuromuscular

test

session

-LRB-

described

subsequently

-RRB-

followed

by

a

backward

walking

exercise

-LRB-

description

below

-RRB-

followed

by

further

neuromuscular

testing

On

the

second

third

and

fourth

days

subjects

returned

to

the

laboratory

at

the

same

hour

of

day

that

they

had

finished

the

walking

exercise

and

performed

the

neuromuscular

testing

Fig.

design

Thin

arrow

indicates

stimulation

at

Hmax

intensity

simple

thick

arrow

indicates

stimulation

at

Mmax

intensity

double

thick

arrow

indicates

doublet

at

Mmax

intensity

Neuromuscular

tests

The

neuromuscular

tests

are

described

in

Fig.

All

the

neuromuscular

tests

began

with

the

determination

of

the

stimulation

intensity

required

to

elicit

a

maximal

H-reflex

-LRB-

Hmax

-RRB-

Afterwards

three

Hmax

-LRB-

interspaced

by

s

-RRB-

and

three

maximal

M-wave

amplitudes

-LRB-

Mmax

-RRB-

interspaced

by

s

were

elicited

from

the

relaxed

muscle

The

amplitude

of

the

three

twitches

evoked

at

Hmax

and

Mmax

intensities

were

averaged

for

subsequent

analysis

in

both

the

soleus

and

gastrocnemius

medialis

Thereafter

subjects

were

instructed

to

perform

three

maximal

voluntary

torque

-LRB-

MVT

-RRB-

contractions

of

the

plantar

flexor

muscles

each

for

s.

Subjects

were

verbally

encouraged

to

perform

maximally

A

superimposed

stimulus

-LRB-

Hmax

intensity

-RRB-

was

evoked

during

each

MVT

plateau

to

obtain

the

H-reflex

during

contraction

-LRB-

Hsup

-RRB-

Then

another

superimposed

stimulus

-LRB-

Mmax

intensity

-RRB-

was

evoked

in

order

to

obtain

a

superimposed

M-wave

-LRB-

Msup

-RRB-

during

voluntary

contraction

Finally

a

doublet

-LRB-

two

electrically

evoked

twitches

ms

apart

Mmax

intensity

-RRB-

was

evoked

during

each

plateau

-LRB-

superimposed

twitch

-RRB-

and

another

doublet

was

evoked

s

after

each

MVT

-LRB-

potentiated

twitch

-RRB-

The

ratio

of

the

amplitude

of

the

superimposed

twitch

torque

over

the

amplitude

of

a

twitch

evoked

at

rest

s

after

the

MVT

was

used

to

assess

the

level

of

voluntary

activation

-LRB-

VA

-RRB-

-LRB-

Allen

et

al.

-RRB-

According

to

the

twitch

interpolation

method

-LRB-

Allen

et

al.

-RRB-

the

percentage

of

VA

was

calculated

as

follow

VA

-LRB-

-RRB-

-LRB-

Superimposed

Twitch/Potentiated

Twitch

-RRB-

Muscle

soreness

assessment

A

subjective

evaluation

of

the

extent

of

DOMS

in

the

plantar

flexor

muscles

was

performed

before

each

neuromuscular

test

by

completing

two

subjective

scales

for

evaluation

of

DOMS

The

first

was

a

visual

scale

of

cm

without

any

graduation

-LRB-

horizontal

line

ranging

from

no

pain

at

the

left

to

extreme

pain

at

the

right

-RRB-

The

second

was

a

Lickert

scale

with

seven

items

-LRB-

from

no

pain

to

severe

pain

limiting

movement

Vickers

-RRB-

Backward

downhill

walking

exercise

Subjects

exercised

by

walking

on

a

motorized

treadmill

-LRB-

HEF

Techmachine

France

-RRB-

for

at

a

constant

velocity

of

ms

with

a

negative

grade

of

To

increase

the

eccentric

loading

on

the

plantar

flexor

muscles

the

walk

was

performed

backward

-LRB-

Nottle

and

Nosaka

-RRB-

whilst

wearing

a

vest

loaded

with

an

additional

weight

equivalent

to

of

body

weight

Measurement

and

calculations

Torque

measurement

The

MVT

of

the

plantar

flexor

muscles

was

recorded

by

a

dynamometric

pedal

-LRB-

Captels

St

Mathieu

de

Treviers

France

-RRB-

Subject

position

was

standardized

with

hip

knee

and

ankle

angulations

of

and

foot

securely

strapped

on

the

pedal

Evoked

potentials

The

tibial

nerve

was

stimulated

with

a

cathode

electrode

with

a

diameter

of

mm

placed

in

the

popliteal

cavity

-LRB-

Contrôle

Graphique

Medical

Brie-Comte-Robert

France

-RRB-

Subjects

were

in

a

standardized

position

with

motionless

head

-LRB-

Zehr

-RRB-

and

a

standardized

environment

-LRB-

i.e.

same

time-of-day

silent

room

constant

lighting

-RRB-

Furthermore

a

constant

pressure

was

applied

to

the

electrode

with

the

use

of

a

strap

This

was

controlled

by

an

air

pressure-recorder

-LRB-

Kikuhime

TT

MediTrade

Soro

Denmark

-RRB-

located

under

the

strap

The

anode

-LRB-

cm

cm

Medicompex

Ecublens

Switzerland

-RRB-

was

positioned

distal

to

the

patella

Electrical

stimulations

-LRB-

V

rectangular

pulse

of

ms

-RRB-

were

delivered

by

a

high-voltage

stimulator

-LRB-

Digitimer

Digitimer

Hertfordshire

England

-RRB-

The

amperage

was

adjusted

for

each

subject

during

the

familiarization

session

During

this

first

session

the

amperage

was

increased

progressively

-LRB-

mA

increment

-RRB-

until

a

plateau

in

twitch

mechanical

response

-LSB-

peak

twitch

-LRB-

Pt

-RRB-

-RSB-

and

Mmax

were

observed

With

increasing

stimulation

intensity

the

H-reflex

response

initially

increased

progressively

before

decreasing

and

then

disappearing

Thereafter

the

intensity

needed

to

obtain

Hmax

was

adjusted

by

mA

The

stimulation

intensity

needed

to

obtain

Hmax

was

determined

before

each

test

session

but

with

a

simplified

procedure

based

on

the

knowledge

of

the

intensity

used

during

the

first

test

session

This

adjustment

seemed

necessary

for

the

H-reflex

in

view

of

the

important

variation

occurring

in

Hmax

for

a

small

variation

in

stimulation

conditions

-LRB-

e.g.

intensity

localization

of

the

cathode

-RRB-

Recordings

Evoked

Pt

torque

was

recorded

in

relaxed

muscle

by

the

same

ergometer

than

MVT

Both

MVT

and

Pt

were

measured

with

the

knee

at

to

reflect

the

changes

occurring

in

the

soleus

Reflex

waves

for

both

the

soleus

which

provides

the

highest

responses

due

to

the

activation

of

the

slow

twitch

fibre

by

H-reflex

-LRB-

Buchthal

and

Schmalbruch

-RRB-

and

the

gastrocnemius

medialis

which

is

particularly

susceptible

to

be

affected

by

the

walking

exercise

were

recorded

with

mm

diameter

bipolar

Ag/AgCl

electrodes

-LRB-

Contrôle

Graphique

Medical

Brie-Comte-Robert

France

-RRB-

with

an

inter-electrode

distance

of

mm

The

reference

electrode

was

placed

on

the

wrist

Low

impedance

between

the

two

electrodes

-LRB-

kΩ

-RRB-

was

obtained

by

abrading

and

washing

the

skin

with

emery

paper

and

cleaning

with

alcohol

Signals

were

amplified

and

filtered

-LRB-

band

pass

Hz

gain

-RRB-

and

recorded

at

high

frequency

-LRB-

Hz

-RRB-

The

compound

muscle

action

potentials

were

recorded

using

hardware

-LRB-

Biopac

Systems

Inc.

Santa

Barbara

CA

USA

-RRB-

and

dedicated

software

-LRB-

BSL

Pro

Version

Biopac

Systems

Inc.

Santa

Barbara

CA

USA

-RRB-

The

same

equipment

was

also

used

to

drive

the

stimulator

Calculation

The

Pt

may

be

considered

as

an

index

of

the

contractile

properties

and

Mmax

amplitude

represents

an

index

of

sarcolemmal

excitability

Because

no

evidence

exists

to

show

that

data

recorded

at

rest

reflects

the

responses

of

the

neuromuscular

system

during

contraction

Hsup

amplitude

was

recorded

during

MVT

to

complement

Hmax

amplitude

at

rest

To

ensure

that

any

changes

in

the

evoked

Hmax

and

Hsup

amplitudes

were

not

due

to

changes

at

the

muscle

fiber

membrane

or

neuromuscular

junction

-LRB-

Cupido

et

al.

-RRB-

we

normalized

these

recordings

to

the

M-wave

amplitude

recorded

under

the

same

testing

conditions

that

is

the

Hmax/Mmax

and

Hsup/Msup

ratios

These

ratios

may

be

considered

as

a

global

index

of

the

spinal

modulation

produced

by

presynaptic

inhibition

motoneuron

excitability

collision

in

antidromically

activated

axons

and

Renshaw

cell

inhibition

acting

individually

or

in

concert

Statistical

analysis

Each

variable

was

tested

for

normality

using

the

Skewness

and

Kurtosis

tests

with

acceptable

Z

values

not

exceeding

With

the

assumption

of

normality

confirmed

parametric

tests

could

be

performed

The

effect

of

the

walking

exercise

was

analyzed

for

each

variable

by

a

one-way

analysis

of

variance

for

repeated

measures

-LRB-

five

test

sessions

-RRB-

The

contrast

method

was

applied

as

post

hoc

to

further

investigate

the

effect

of

both

the

exercise

and

the

recovery

Because

VA

level

failed

to

display

a

normal

distribution

a

Friedman

test

was

used

instead

of

the

ANOVA

Statistical

analyses

were

performed

with

Systat

software

-LRB-

Systat

Evanston

IL

USA

-RRB-

Data

are

reported

as

mean

SEM

and

the

level

of

statistical

significance

was

set

at

P

Results

Maximal

voluntary

torque

voluntary

activation

and

contractile

properties

The

MVT

significantly

changed

across

the

days

following

the

walking

test

-LRB-

P

Fig.

-RRB-

Post

hoc

analysis

showed

a

significant

decrease

in

MVT

after

the

walking

exercise

and

which

persisted

during

the

next

two

days

-LRB-

P

-RRB-

A

significant

recovery

in

MVT

was

observed

on

the

third

day

-LRB-

versus

after

P

-RRB-

Fig.

of

voluntary

torque

-LRB-

a

-RRB-

voluntary

activation

-LRB-

b

-RRB-

electrically

evoked

peak

twitch

-LRB-

c

-RRB-

and

subjective

delayed

onset

muscle

soreness

-LRB-

d

black

rectangle

analogic

visual

scale

white

rectangle

Lickert

scale

-RRB-

across

the

experimental

sessions

Data

in

mean

SEM

Asteriskindicates

value

or

group

of

values

significantly

different

from

the

other

values

of

the

graph

-LRB-

P

-RRB-

In

line

with

the

evolution

observed

in

MVT

post

hoc

analysis

showed

a

significant

decrease

in

VA

level

after

the

walking

exercise

-LRB-

pre

versus

post-exercise

P

Fig.

-RRB-

which

failed

to

recover

by

-LRB-

post-exercise

versus

and

after

exercise

NS

-RRB-

However

there

was

a

significant

recovery

by

-LRB-

post-exercise

versus

after

P

-RRB-

The

electrically

evoked

Pt

also

displayed

a

significant

variation

following

walking

exercise

-LRB-

P

Fig.

-RRB-

Post

hoc

analysis

revealed

a

significant

decrease

in

Pt

after

the

exercise

-LRB-

P

-RRB-

followed

by

a

significant

recovery

thereafter

-LRB-

P

-RRB-

Subjective

DOMS

The

subjects

feeling

of

DOMS

increased

significantly

in

the

days

following

the

walking

exercise

-LRB-

P

for

both

scales

used

Fig.

-RRB-

Post

hoc

analysis

displayed

significantly

higher

subjective

DOMS

for

the

days

following

exercise

compared

to

the

termination

of

exercise

-LRB-

P

for

both

scales

-RRB-

Muscle

soreness

reached

a

maximum

after

exercise

and

began

to

recover

by

-LRB-

versus

after

exercise

P

for

both

scales

-RRB-

Evoked

potentials

An

example

of

evoked

potentials

recorded

in

a

representative

subject

is

displayed

in

Fig.

and

the

mean

values

are

displayed

in

Table

The

walking

exercise

failed

to

induce

significant

changes

in

the

evoked

potentials

both

at

rest

-LRB-

Mmax

and

for

soleus

and

gastrocnemius

medialis

respectively

NS

-RRB-

and

during

the

voluntary

contraction

-LRB-

Msup

and

for

soleus

and

gastrocnemius

medialis

respectively

NS

-RRB-

Furthermore

the

reflex

waves

calculated

both

at

rest

-LRB-

Hmax/Mmax

ratio

-RRB-

and

during

contraction

-LRB-

Hsup/Msup

ratio

-RRB-

also

did

not

change

significantly

-LRB-

all

NS

Table

-RRB-

Fig.

of

evoked

potentials

recorded

in

a

representative

subject

Each

drawing

represents

the

average

of

three

recordings

obtained

on

a

relaxed

muscleTable

of

maximal

compound

action

potential

electrically

evoked

at

rest

-LRB-

Mmax

-RRB-

and

during

MVT

-LRB-

Msup

-RRB-

normalized

H-reflex

at

rest

-LRB-

Hmax/Mmax

-RRB-

and

during

MVT

-LRB-

Hsup/Msup

-RRB-

ExerciseRecoveryStatistical

-LRB-

mV

-RRB-

Msup

-LRB-

mV

-RRB-

Hmax/Mmax

Hsup/Msup

Gastrocnemius

medialisMmax

-LRB-

mV

-RRB-

Msup

-LRB-

mV

-RRB-

Hmax/Mmax

Data

in

mean

SEM

Discussion

The

downhill

walking

exercise

induced

a

significant

decrease

in

the

MVT

of

the

plantar

flexor

muscles

Immediately

after

the

walking

exercise

the

torque

decrement

of

-LRB-

Fig.

-RRB-

appeared

to

be

caused

partly

by

an

alteration

in

muscle

contractile

properties

-LRB-

i.e.

for

Pt

Fig.

-RRB-

This

alteration

is

typically

referred

to

as

peripheral

fatigue

-LSB-

for

a

review

see

Millet

and

Lepers

-RSB-

Furthermore

this

peripheral

fatigue

was

also

associated

with

a

decrease

in

VA

-LRB-

i.e.

Fig.

-RRB-

suggesting

the

concomitant

existence

of

a

central

modulation

-LSB-

for

a

review

see

Gandevia

-RSB-

The

first

finding

of

this

study

is

that

the

maximum

voluntary

torque

failed

to

recover

before

the

third

day

-LRB-

i.e.

and

after

and

of

recovery

respectively

Fig.

-RRB-

whereas

the

measure

of

the

-LRB-

peripheral

-RRB-

contractile

properties

had

recovered

significantly

within

the

first

h

after

exercise

-LRB-

P

Fig.

-RRB-

This

delayed

recovery

in

MVT

appeared

to

be

mainly

associated

with

a

decrease

in

voluntary

muscle

activation

-LRB-

Fig.

-RRB-

The

time

course

of

change

in

VA

presents

similarities

with

the

time

course

of

torque

changes

A

significant

decrease

in

the

VA

reaching

the

muscle

has

previously

been

observed

after

prolonged

-LRB-

Millet

et

al.

-RRB-

and

short-duration

-LRB-

Racinais

et

al.

-RRB-

fatiguing

exercise

but

our

data

showed

that

a

backward

downhill

walking

exercise

did

produce

a

decrease

in

muscle

activation

persisting

for

a

few

days

after

the

exercise

It

has

been

suggested

that

this

central

component

could

explain

as

well

the

reduction

in

force

production

by

the

respiratory

muscles

after

heavy

exercise

-LRB-

Verin

et

al.

-RRB-

and

represents

a

protective

mechanism

in

order

that

peripheral

muscle

fatigue

does

not

exceed

a

critical

threshold

-LRB-

Amann

et

al.

-RRB-

This

central

protection

of

the

muscle

from

further

peripheral

fatigue

and

damage

will

be

performed

at

the

expense

of

a

truly

maximal

performance

in

which

all

the

motor

units

are

activated

-LRB-

Gandevia

et

al.

-RRB-

It

has

recently

been

suggested

that

a

central

governor

in

the

brain

regulates

the

extent

of

skeletal

muscle

recruitment

during

exercise

-LRB-

Noakes

et

al.

-RRB-

According

to

this

theory

the

sensation

of

fatigue

is

the

conscious

interpretation

of

these

homoeostatic

control

mechanisms

during

prolonged

exercise

-LRB-

Noakes

et

al.

-RRB-

Our

results

could

partly

support

this

theory

but

with

the

proviso

that

the

modulation

of

central

activation

in

this

experiment

appears

to

be

related

not

only

to

fatigue

immediately

after

exercise

but

also

to

the

development

of

DOMS

the

days

following

the

exercise

However

regulation

of

muscle

recruitment

by

the

brain

-LRB-

i.e.

supraspinal

regulation

-RRB-

is

not

the

only

system

that

could

explain

the

observed

decrease

in

skeletal

muscle

activation

since

reflex

pathways

need

also

to

be

considered

-LRB-

i.e.

spinal

modulation

-RRB-

Previous

results

showed

impairment

in

VA

after

eccentric

exercise

when

VA

was

estimated

by

nerve

stimulation

but

not

by

cortical

stimulation

-LRB-

Prasartwuth

et

al.

-RRB-

That

suggests

that

the

VA

deficit

lies

within

these

two

site

of

stimulations

i.e.

in

the

motor

cortex

or

at

spinal

level

-LRB-

Prasartwuth

et

al.

-RRB-

rather

than

a

governor

upstream

to

the

motor

cortex

In

the

present

study

we

used

H-reflex

amplitude

as

a

tool

to

evaluate

the

spinal

modulation

-LRB-

Aagaard

et

al.

Schieppati

-RRB-

to

provide

a

differentiation

within

these

possible

regulatory

mechanisms

The

DOMS

produced

by

our

experimental

protocol

would

have

induced

an

increased

discharge

of

group

III

and

IV

muscle

afferents

-LRB-

Avela

et

al.

-RRB-

and

thus

a

pre-synaptic

inhibition

of

the

transmission

from

the

Ia

afferent

stimulation

to

the

α-motoneurons

-LRB-

Avela

et

al.

Bigland-Ritchie

et

al.

Duchateau

et

al.

Garland

and

McComas

Garland

Woods

et

al.

-RRB-

The

extent

to

which

this

inhibition

occurs

will

depend

on

whether

the

input

producing

the

inhibition

is

ongoing

or

has

ceased

But

in

theory

increased

group

III

and

IV

muscle

afferent

input

induced

by

the

DOMS

should

induce

H-reflex

depression

as

the

soreness

progresses

Indeed

muscle

pain

is

believed

to

reflect

activity

in

group

III

and

IV

muscle

afferents

-LRB-

O'Connor

and

Cook

-RRB-

However

our

results

failed

to

show

significant

variations

in

the

evoked

reflex-wave

amplitudes

throughout

the

experiment

-LRB-

i.e.

Hmax/Mmax

and

Hsup/Msup

ratios

-RRB-

suggesting

that

the

motoneuron

pool

excitability

was

well

preserved

A

number

of

previous

studies

have

demonstrated

a

significant

H-reflex

decrease

in

the

exercised

muscle

group

after

an

exhausting

voluntary

contraction

of

that

muscle

group

-LRB-

i.e.

Duchateau

et

al.

Garland

and

McComas

Kuchinad

et

al.

-RRB-

But

only

a

few

studies

have

observed

this

decrease

after

more

generalized

muscular

exercise

such

as

running

-LRB-

Avela

et

al.

Bulbulian

and

Bowles

Racinais

et

al.

-RRB-

Our

results

support

these

findings

by

showing

that

after

a

downhill

walking

exercise

electrically

evoked

reflex-wave

activity

was

not

decreased

Thus

we

conclude

that

non-exhausting

walking

exercise

sufficient

to

induce

significant

DOMS

seems

not

to

induce

alteration

of

the

spinal

modulation

Since

the

persistence

of

a

decrease

in

VA

during

several

days

in

this

study

could

not

be

explained

by

spinal

modulation

it

seems

likely

that

a

supraspinal

component

must

have

played

a

part

Accordingly

the

changes

in

VA

that

occurred

at

the

same

time

that

the

subjective

symptoms

of

DOMS

suggest

a

supraspinal

regulation

of

muscle

recruitment

Indeed

it

has

been

known

for

some

time

that

exercise

performance

is

regulated

at

least

in

part

by

supraspinal

factors

For

example

Bigland-Ritchie

-LRB-

-RRB-

showed

that

central

fatigue

during

repeated

isometric

contraction

is

minimized

by

exhorting

the

subject

to

produce

a

super

effort

at

the

end

of

each

voluntary

contraction

Our

results

add

to

that

interpretation

by

suggesting

the

possibility

that

supraspinal

modulation

can

also

occurs

after

locomotory

activity

such

as

walking

even

without

exhaustion

As

we

have

already

argued

the

observed

increase

in

DOMS

could

represent

the

conscious

interpretation

of

an

increased

discharge

of

group

III

and

IV

muscle

afferents

-LRB-

O'Connor

and

Cook

-RRB-

Even

though

we

failed

to

observe

a

significant

alteration

of

the

spinal

modulation

at

the

time

of

increased

muscle

soreness

this

would

not

prove

that

the

discharge

of

these

afferents

had

not

increased

since

it

is

still

unclear

whether

group

III

and

IV

muscle

afferents

induce

a

post-exercise

decrease

in

motoneurons

excitability

in

healthy

humans

Indeed

previous

studies

have

shown

that

maintained

firing

of

ischaemically

sensitive

group

III

and

IV

muscle

afferents

does

not

influence

the

altered

muscle

responses

to

cortical

or

corticospinal

stimulation

observed

after

fatiguing

exercise

-LRB-

Andersen

et

al.

Gandevia

et

al.

Taylor

et

al.

-RRB-

All

these

findings

might

suggest

that

after

exercise

increased

output

from

group

III

and

IV

muscle

afferents

may

not

directly

inhibit

the

motoneurons

but

may

act

upstream

of

the

motor

cortex

to

impair

voluntary

descending

motor

drive

-LRB-

Taylor

et

al.

-RRB-

Accordingly

a

novel

contribution

of

this

study

is

that

VA

significantly

recovered

on

the

third

day

when

the

DOMS

displayed

also

a

significant

decrement

-LRB-

P

for

the

both

scales

-RRB-

Although

this

temporal

relationship

does

not

prove

causality

this

finding

could

suggest

a

relationship

between

the

persistence

of

the

decrease

in

VA

and

the

subjective

symptoms

of

DOMS

in

these

subjects

This

observation

is

consistent

with

the

data

of

Le

Pera

et

al.

-LRB-

-RRB-

showing

that

muscle

pain

could

induce

a

long-lasting

depression

in

motor

activation

Their

data

suggest

that

this

inhibition

in

motor

system

excitability

could

be

linked

to

a

decreased

excitability

of

the

motor

cortex

as

well

as

spinal

modulation

-LRB-

Le

Pera

et

al.

-RRB-

However

Prasartwuth

et

al.

-LRB-

-RRB-

observed

a

different

time

course

in

muscle

soreness

after

eccentric

exercise

and

changes

in

VA

leading

these

authors

to

suggest

that

muscle

pain

did

not

directly

cause

the

change

in

voluntary

drive

These

different

data

emphasised

the

complexity

of

the

relation

within

muscle

soreness

and

voluntary

muscle

drive

It

has

been

recently

observed

that

motoneuron

excitability

in

elbow

flexors

but

not

extensors

was

able

to

recover

when

ischemia

is

maintained

after

fatiguing

contractions

-LRB-

Martin

et

al.

-RRB-

a

finding

that

suggests

differential

influences

of

group

III

and

IV

muscle

afferents

on

different

motoneuron

pools

-LRB-

Martin

et

al.

-RRB-

In

this

study

concerning

the

plantar

flexors

we

observed

some

statistical

similarities

within

DOMS

and

VA

-LRB-

i.e.

lowest

value

of

VA

at

when

DOMS

was

the

highest

and

significant

recovery

for

the

both

at

-RRB-

However

from

a

functional

point

of

view

VA

returned

at

control

level

at

whereas

DOMS

at

was

not

less

than

DOMS

at

and

VA

decreased

after

exercise

when

DOMS

was

weak

That

suggests

that

subjective

DOMS

of

the

plantar

flexors

can

not

be

considered

as

an

objective

indicator

of

VA

capability

Conclusion

It

was

recently

reported

that

a

min

bout

of

flat

running

exercise

produced

a

modification

in

spinal

modulation

-LRB-

Racinais

et

al.

-RRB-

The

present

study

showed

that

a

downhill

walking

exercise

failed

to

induce

the

same

modification

However

there

was

a

significant

decrease

in

VA

during

maximal

voluntary

contractions

performed

during

the

days

after

eccentric

exercise

that

produced

DOMS

This

suggested

the

occurrence

of

a

supraspinal

modulation

of

muscle

activation

during

this

period

when

muscle

contractile

properties

had

fully

recovered

following

the

eccentric

exercise

Furthermore

the

persistence

of

the

decrement

for

several

days

suggests

that

this

modulation

was

not

caused

by

an

acute

exercise-related

physiological

or

biochemical

alteration

in

the

motor

cortex

so-called

central

fatigue

but

more

likely

represents

a

modulation

which

may

be

partly

linked

to

the

muscle

soreness

O O O O 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 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 O 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 O O O O O O O O O O O O O O O O O O O O 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 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 O O O O O 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 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 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 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 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 B 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 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 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 B 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 O O O O O O O O B 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 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 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 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 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 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 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 O O O O O O O O O O O O O O O O O O O O O O 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 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 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 O O O O O O O O O O O B 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 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 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 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 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 O O O O O O O O O O O O O O O O O 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 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 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 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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 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 O O O O O O B O O O O O O B O O O O O O O B 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 B 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 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 B 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 I O O O O O O O O O O O O O O O O

exercise
neuromuscular
central fatigue
eccentric
doms