La Stimolazione magnetica transcranica nel trattamento del dolore

La Stimolazione magnetica
transcranica nel
trattamento del dolore
neuropatico
Quale ruolo per la Dorsolateral
Prefrontal Cortex (DLPFC)?
Filippo Brighina, Brigida Fierro
Background:
.
Chronic motor cortex stimulation in patients with
thalamic pain.
T. Tsubokawa, Yoichi Katayama, T. Yamamoto,
T. Hirayama, S. Koyama.
J Neurosurg. 1993 Mar;78(3):393-401
Pain
Processing
Treatment
Motor
Cortex
Transcranial magnetic stimulation: TMS
Barker AT, Jalinous R, Freeston IL. (1985).
NonNon-invasive magnetic stimulation of human motor cortex..
cortex.
Lancet 1: 1106-1107.
TMS: principles
rTMS
Modulation of cortical activity
>1 Hz: facilitation ≤ 1 Hz:inhibition
Direct cortical
stimulation
Induction of long-lasting plastic changes ?
Repeated sessions of TMS trains
Therapeutic options ?
Transcranial magnetic coil stimulation of motor
cortex in patients with central pain.
Migita K, Uozumi T, Arita K, Monden S.
Neurosurgery. 1995 May;36(5):1037-9;
Two patients with deafferentation pain secondary to central nervous system lesions evaluated
by noninvasive magnetic coil stimulation of the motor cortex followed by electrical motor cortex
stimulation with epidural electrode array implantation.
Our first patient was a 52-year-old man who experienced a left putamenal hemorrhage at the
age of 48. Two years later, he had paresthesias and intractable pain in the extremities and
face on the right side. Pain was resistant to barbiturates but responded to magnetic coil
stimulation of the motor cortex. Electrical motor cortex stimulation provided excellent relief from
the pain.
The second patient was a 43-year-old man who was suffering from congenital cerebral palsy
for which left thalamotomy was performed two times, at the ages of 9 and 13. He began to
experience intractable pain on the right side 20 years later. Although barbiturate administration
was effective for pain relief, neither magnetic coil stimulation nor electrical stimulation of the
motor cortex gave relief from pain.
Background:
Background:
1.
2.
3.
4.
Only M1 stimulation
gives consistent
amelioration of pain
Motor Area: M1
Somatosentive Area: S1
Premotor Area: PMA
Supplementar Motor Area: SMA
Background:
Background:
1 Hz rTMS over right
motor cortex
decreases capsaicine
induced pain
Background:
Why motor cortex
stimulation is effective
for treatment of pain
?
Background:
Background:
Recovery of SICI
by 10 Hz rTMS that..
…correlates with
pain reduction
Background:
1 Hz
Increased
20 Hz threshold for
cold sensation
Increased
threshold for
pain
Slight increase
in threshold for
cold sensation
Riduzione del MEP
dopo 20’
20’ e 30‘
30‘
Background:
Lorenz et al. (2003), in a PET study
during capsaicine induced pain, showed
that DLPFC activation (specially on the
left side) significantly correlated to
dampening of pain together with the
reduced activation of Anterior Cingulate
Cortex and medial thalamus, structures
intensely active during maximum pain
sensation.
Top-down control on pain system
Background:
rTMS of left DLPFC
Background:
Background:
Low-frequency rTMS of R-DLPFC exerts bilateral anti-nociceptive control,
significantly increasing threshold to cold pressor test
Background:
Background:
Objectives:
Experiment I
To study the effects of DLPFC rTMS on pain control
in a model of capsaicine induced pain in healthy
subjects.
To explore the role of right and left DLPFC in pain
control
To evaluate the effects of capsaicine induced pain
on motor intracortical circuits
Experiment II
To evaluate the effects of DLPFC rTMS on motor
cortex activation during capsaicine induced pain
Methods: Experiment 1
16 healthy subjects (9M/7F; age range : 25-50 yrs)
Capsaicin was applied over the
dorsal surface of right and left
hand (area of 2 x 2 cm).
2 cm
VAS evaluation of spontaneous pain every 10 minutes
along the time of capsaicine application (1 hr).
In baseline and after rTMS.
Methods:
VAS (visuo-analogic scale)
100
0
Methods:
rTMS
Left DLPFC
Site:
Stimuli:
DPLFC
n° 1800 in 12 trains with
10 sec. inter-train intervals
Right DLPFC
5 cm
Hot-spot of
APB muscle
Frequency: 5 Hz
Intensity:
90% MT
Timing:
10 or 20 min. after capsaicine application
Methods: flow-chart
0
10
20
30
40
50
60
X
X
X
X
X
X
Baseline
VAS
X
min.
Methods: design
16 subjects
8 subjects 10’ rTMS
The order of the
sessions was
balanced across
subjects .
8 subjects 20’ rTMS
1
baseline r-hand
1
2
baseline l-hand
2
3
L-DLPFC rTMS r-hand
3
4
L-DLPFC rTMS l-hand
4
5
R-DLPFC rTMS r-hand
5
6
L-DLPFC rTMS l-hand
6
Methods: Experiment Ib
Sham Left DLPFC stimulation
Left DLPFC
Coil rotated 45°on scalp
5 cm
Hot-spot of
APB muscle
5 Subjects (3M/2 F)
1
10’ rTMS
Baseline r-hand
Capsaicin on
2
Real L-DLPFC rTMS
3
Sham L-DLPFC rTMS
Right hand
Methods: Experiment II
Motor cortex activity
7 Subjects (4M/3 F);
Motor Threshold (MT) over hot-spot for right
APB activation by focal TMS
Paired pulse paradigm:
Conditioning Stimulus (CS) :
Test Stimulus (TS):
2 interstimulus intervals (ISI):
80% MT
120% MT
2 msec: ICI
10 msec: ICF
10 stimuli for each condition (CS, TS, ICI, ICF)
Capsaicine was applied on the right hand
Motor cortex activity ealuated in baseline and every 10
min after capsaicine application with and without rTMS
Results: Experiment 1
10’ rTMS, effects on spontaneus pain
Capsaicin
Right Hand
mean VAS +/- SE
Capsaicin +
L- DLPFC rTMS
*
*
Capsaicin +
R -DLPFC rTMS
*
Time (min.)
Left Hand
mean VAS +/- SE
*
Time (min.)
*
*
Results: Experiment 1
20’ rTMS, effects on spontaneus pain
Capsaicin
Right Hand
mean VAS +/- SE
Capsaicin +
L- DLPFC rTMS
*
*
*
*
Capsaicin +
R -DLPFC rTMS
*
*
Time (min.)
Left Hand
mean VAS +/- SE
*
Time (min.)
*
*
Results: Experiment Ib
Effects of sham 10 ‘ rTMS on left DPLFC
Capsaicin
mean VAS +/- SE
Capsaicin +
L- DLPFC rTMS
*
*
Time (min.)
*
Capsaicin +
Sham L -DLPFC rTMS
Motor
cortex
changes
Results: Experiment II
Test MEP
Capsaicin
*
*
Capsaicin + rTMS
*
Results: Experiment II
Intra-cortical Inhibition
Capsaicin
% of test MEP (mean +/- SE)
Motor
cortex
changes
Capsaicin + rTMS
*
*
*
Time
(min)
*
*
Results: Experiment II
Intracortical Facilitation
Capsaicin
Capsaicin + rTMS
% of test MEP (mean +/- SE)
Motor
cortex
changes
Time
min
Motor
cortex
changes
Without
capsaicin
Results: Experiment Iib
DLPFC rTMS without capsaicin
MEP
Motor
cortex
changes
Without
capsaicin
Results: Experiment Iib
DLPFC rTMS without capsaicin
SICI, ICF
Conclusions: Effects on Pain
rTMS of left DLPFC significantly decreases
capsaicine induced pain, in both hands:
The effect occurs at both rTMS stimulation times
used 10’ and 20’ after capsaicin application
rTMS of right DLPFC was ineffective as well
as sham rTMS
Conclusions: Effects on Pain
Diffuse effects of unilateral stimulation
Background:
Conclusions: Effects on Pain
Facilitation of left-side vs inhibition of right side
5 Hz rTMS
facilitation
1 Hz rTMS
inhibition
=
L
R
L
R
Conclusions: Effects on motor
cortical excitability
Capsaicine-induced pain affects motor
cortex excitability:
Significant decrease of MEP amplitude from 20 to 40
min after capsaicine application, in agreement with
previous studies.
Significant decrease of intracortical inhibition at 20
to 60 min after capsaicine
No significant changes of intracortical facilitation
after capsaicine
All these changes can be reverted by left
DLPFC rTMS, that exerts specific effects
with nociceptive activation: no modulation
in without-capsaicin condition
Conclusions:
Left DLPFC seems to exert a bilateral
control on pain system
Capsaicine-induced pain affects motor
intracortical circuits determining changes
that can be reverted by left DLPFC
stimulation together with pain control
Left DLPFC could represent an alternative
target for pain treatment protocols and to
explore pain motor cortex relationship
Results in direct inhibition of regions of brain involved in
emotional response of pain (ACC)
Triggers descending inhibitory pathway to act at the dorsal horn
level
Induces placebo effect
TMS: applications
Evaluation of cortical excitability
Motor threshold
Phosphene threshold
Interference
with ongoing
cortical activity
Functional role
of specific
cortical areas
Modulation
of cortical
activity
Direct cortical >1 Hz: facilitation
≤1
stimulation
Hz:inhibition
Induction of long-lasting plastic changes ?
Repeated sessions of TMS trains
Therapeutic options ?