1. The talk will propose an historical point of view
Specifically for the case of Major Depressive Episode, the first
major therapeutic goal set for TMS
With 3 historical steps
From
Step 1 18th Century: Historical Background
Electrical Brain “Stimulation” in Psychiatry
P
L
A
N
Step 2 End of the 20th Century :
Validation of rTMS treatment as a focal brain stimulation
To
Step 3
21-22th Century: Future Proposition
Electrical Brain “Interaction” in Psychiatry

2. In 1993, first use of TMS in patient with Depression
Two cases reports of a single pulse
TMS (not repetitive) applied over
the whole cortex with a circular coil
250 single pulses / day
10 days
5-30 % motor threshold
S
T
Depression intensity
E
P
Possible antidepressant effect for
one patient 2
50% efficacy!
Encouraging result!
But did not stimulate a specific
focal brain region
Höflich et al. 1993

3. Why to stimulate a focal brain region in depression ?
Sadness Happiness
More happy
TMS may affect mood states
Less sad
☐ DLPFC Right ☐ DLPFC Right
Studies of rTMS to prefrontal structures
have shown a lateralized effect on mood in
normal (healthy) volunteers
Less happy
George et al. 1996, Pascual Leone et al. 1996.
More sad
 DLPFC Left  DLPFC Left
S
T
E
P
Left frontal lobe is involved in the L R L R
2
pathogenesis of depression
Lesion and imaging studies suggest that left
prefrontal lobe dysfunction is linked to
depression
George et al. 1994.
Healthy Depressed
Martinot et al. 1990

4. In 1995, first proof of efficacy of rTMS in depression
The “George Team”
Open study of 6 patients
rTMS applied over the left DLPFC
20 2s trains of rTMS at 20 Hz
800 pulses / day S
T
Continued if response after 5 days E
P
80 % motor threshold
Depression intensity
2
Significant improvement
One complete improvement :
Encouraging result!
George et al. 1995

5. In 1996, first controlled study of rTMS in depression
The “Pascual Leone Team”
Multiple cross-over, randomized,
placebo-controlled trial with 17
patients
rTMS applied over the left DLPFC
Depressed
20 10s trains of rTMS at 10 Hz
S
 2000 pulses / day T
E
P
5 days (5 conditions)
2
90 % motor threshols
Significant improvement
Less
depressed
6 non responders patients (35 %)
Pascual-Leone et al. 1996

6. Many controlled studies and 11 Meta analysis
since 1996 Pascual-Leone trial
2007
rTMS is an efficacy and sure focal brain
stimulation treatment
The U.S. Food and Drug Administration
(FDA) has approved rTMS for patients
who have not responded to one adequate trial of
2010
antidepressant medication (2007)
S
T
Thus 2007
E
P
The question is not 2
Is rTMS effective for the treatment of
depression ? 2008
But
Why rTMS is not effective for all
patients with depression ? 2011

7. Why rTMS is not effective for some patients with
depression ?
There are two classical But we will focus on two less
factors of variability classical factors of variability
a c  
Clinical Stimulation Neuro-anatomical Neuro-functional
variability Parameters variability variability S
variability T
Age  E
 P
Motor threshold
Treatment
refractoriness Number of pulse Anatomical … 2
precision on the Step 3
Duration of Frequency
EDM left DLPFC ?

MRI guided rTMS
Micoulaud-Franchi et al., submitted
Micoulaud-Franchi and Vion-Dury, 2011

8. Neuro-anatomical variability: the 5 cm standard method
5 cm method
5 cm anterior on a
parasagital line 5cm
Optimal surface site for
activation of the controlateral
Abductor Policis Brevis (APB)
S
T
rTMS is supposed to be E
P
applied to the left DLPFC
2
according to a method
based on a presumed
coordinates (Talairach 45°
Atlas)
George et al. 1995
Pascual Leone et al. 1996

9. 5 cm standard method  Neuro-anatomical variability
The small black dots indicate the optimal sites
for abductor pollicis brevis muscle
stimulation over the motor cortex
The larger dots indicate the
rostral coil positions
S
T
E
P
2
Herwig et al., 2001
A considerable variability occurs with the 5cm standard method

10. Neuro anatomical variability  MRI guided rTMS
(Neuronavigated rTMS)
Camera
Spatial mark
Personal MRI of the patient with
the dorso prefrontal targeted
Szekely©
Note that subject can see in real time
if the coil stimulates the target and Szekely©
Szekely©
Szekely©
move his head to the right position
(beginning of the rTMS interaction…) From David Szekely
« Club rTMS et Psychiatrie »

11. Future rTMS should probably use MRI guided rTMS in
order to limit neuro anatomical variability
The “Fitzgerald Team”
Randomized trial of 51 patients
rTMS applied over the left DLPFC
with either standard 5cm method
or using a neuronavigational
method (BA9 and 46)
S
30 5s trains of rTMS at 10 Hz T
 1500 pulses / day
Depression intenstity
E
Standar
d rTMS P
3 weeks
2
100 % motor threshold MR
I gu
ided
rTM
S
Significantly better improvement
for the MRI guided rTMS group
Fitzgerald et al. 2009

12. Second step :
Neuro-anatomical MRI guided rTMS
Electrical Brain Focal Electrical Brain More
Stimulation in Focal Stimulation in
psychiatry psychiatry
S
T
E
P
2
Electrical Brain Global
Camphor Stimulation in
Metrazole psychiatry