1. Why rTMS is not effective for some patients with
depression ?
There are two classical We will focus on two less classical
factor of variability factor 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
Interaction

MRI guided rTMS
Micoulaud-Franchi et al., submitted
Micoulaud-Franchi and Vion-Dury, 2011

2. 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

3. Why stimulate a focal brain region in depression ?
Sadness Happiness
More happy
TMS may affect mood states
Less sad
☐ DLPFC Right ☐ DLPFC Right
Less happy
More sad
George et al. 1996, Pascual Leone et al. 1996.
 DLPFC Left  DLPFC Left
S
T
E
P
Left frontal lobe is involved in the L R L R
2
pathogenis of depression
George et al. 1994.
Healthy Depressed
Martinot et al. 1990

4. “Hypometabolic brain region is variable in depression!”
Left frontal lobe is involved in the L R L R
pathogenesis of depression
BUT
PET studies show divergent results.
The hemispheric asymmetry in brain metabolism
in the prefrontal cortex can favor right or the left S
side. Other studies have found a general T
Healthy Depressed E
hypofrontality.
P
Iidaka et al. 1997, Nikolaus et al. 2000. 3
These divergent findings might be due to the phenotypic and
pathophysiological heterogeneity of depression

rTMS should probably target specific hypometabolic brain regions
to interact with each different phenotypic depressed patients

5. Why rTMS is not effective for some patient with
depression ?
There are two classical We will focus on two less
factor of variability classical possible variability
ac  
Clinical Stimulation Neuro-anotomical Neuro-functional
variability Parameters variability variability S
variability T
Age ar i E
 P
Motor threshold
Treatment Target
refractoriness Number of pulse Anatomical 3
precision on the hypometabolism
Duration of Frequency
left DLPFC brain region
EDM
 r
MRI guided rTMS PET fMRI
Micoulaud-Franchi et al., submitted
Guided rTMS
Micoulaud-Franchi and Vion-Dury, 2011

6. Neuro-functional factor of variability 
Target definition according to functional activity
Brain hypometabolism
• PET guided rTMS treatment (PET)
R L
The DLPFC with lower metabolic activity was
selected.
A neuronavigational system was used to place
the magnetic coil above each individuals’
selected cortical region.
Results did not support the hypothesis of S
increased antidepressant effect T
E
Herwig et al. 2003 P
Paillere Martinot et al. 2010
3
• fMRI guided rTMS treatment Brain
hyperactivity
Encouraging results for the (BOLD)
treatment of hallucinations.
Jardri et al. 2008,
Montagne Larmurier et al. 2009

7. Why stimulate a focal brain region in depression ?
Sadness Happiness
More happy
TMS may affect mood states
Less sad
☐ DLPFC Right ☐ DLPFC Right
Less happy
More sad
George et al. 1996, Pascual Leone et al. 1996.
 DLPFC Left  DLPFC Left
S
T
E
P
Left frontal lobe is inolved in the L R L R
2
pathogenis of depression
George et al. 1994.
Healthy Depressed
Martinot et al. 1990

8. “Surprising lateralized mood effect in healthy subject!”
TMS may affect mood states Sadness Happiness
More happy
Less sad
BUT ☐ DLPFC Right ☐ DLPFC Right
The lateralized effect in healthy subject is
opposed to depressed patients…
Stimulation to the left side induce
Less happy
More sad
“depression” in healthy subjects!
S
 DLPFC Left  DLPFC Left
And an improvement of depression in T
E
depressed patients… P
George et al. 1996, Pascual Leone et al. 1996. 3
These TMS studies raise the possibility that stimulation may impact
differently healthy subject as compared to depressed patients

The reasons could be
specific interactions of rTMS with mood state and specific brain activity

9. rTMS has a brain network effect
Coil position
rTMS stimulates a focal region
But
has an effect on many regions
These “network effects” could depend
on the connected brain activity context Activation of S
of each stimulus connected T
E
brain areas P
This context is determining by :
3
1 - Brain electrophysiological activity
2 – Neuro-Cognitive activity of the
subject during stimulation
And could influence the therapeutic
efficacy of rTMS

10. Why rTMS is not effiacy for some patient with depression
?
There are two classical We will focus on two less
factor of variability classical possible variability
ac  
Clinical Stimulation Neuro-anotomical Neuro-functional
variability Parameters variability variability S
variability T
Age ar i E
 P
Motor threshold
Treatment Target Controlled
refractoriness Number of pulse Anatomical 3
precision on the hypometabolism network
Duration of Frequency
left DLPFC brain region effect of rTMS
EDM
 r f
PET IRMf Cognitive EEG
MRI guided rTMS
priming contingent
Guided rTMS rTMS
Micoulaud-Franchi et al., submitted rTMS
Micoulaud-Franchi and Vion-Dury, 2011

11. Controlling the network effect of rTMS with
electrophysiological measurement
It is possible to combine EEG recording with rTMS
Each pulse of rTMS can be applied in response to a
selected pattern of background EEG activity
analyzed in real time
Price named this rTMS: Najib et al.
2011
EEG contingent rTMS S
T
or Interactive rTMS E
P
3
The intention is to stimulate an activated network in
the hope that will reinforce the activation
It is feasible in an rTMS clinical trial
A trend toward a greater clinical effect than the
standard rTMS was found Price et al.
2010

12. Controlling the network effect of rTMS with
neurocognitive activity MEP
during rTMS
amplitude
Experimental studies found that specific
neurocognitive activity can modify the effect
of a TMS pulse on motor cortex

What is the effect of positive and negative
guided mood activity (by cognitive
emotional procedure) during rTMS Bonnard
Let go Resist S
stimulation in depression ? et al. T
E
2003 P
Depression intenstity
Isserles et al. found that negative guided Negative 3
mood activity in depressed patients during
rTMS treatment disrupts the therapeutic Positive
Neutre
effect
Neural networks mediating negative
emotions may disrupt the therapeutic Isserles et al.
network effect of rTMS 2011

13. Finger et al. Electrical Brain More
Third step : Focal Stimulation in
Electrical Brain Interaction psychiatry
Electrical Brain Focal
Stimulation in
psychiatry
Electrical Brain
Focal/Global
Interaction in
psychiatry
S
T
E
P
The stimulation has to be focalized BUT the effect of 3
stimulation interact with the global activity of the brain.
Electrical Brain Global
Camphor Stimulation in
Metrazole psychiatry

14. The talk has proposed an historical point of view
From
Step 1 18th Century: Historical Background
Electrical Brain “Stimulation” in Psychiatry
To
Step 3
21-22th Century: Future Proposition C
O
Electrical Brain “Interaction” in Psychiatry N
C
L
Future Electrical Brain Interaction Treatment in Psychiatry will
necessitate collaboration between
Neuro-computational, Experimental, and Clinical approaches
And … an active patient

15. Brain stimulation:
Neuro-computational, Experimental, and Clinical approaches
May 31st – June 1st 2012
Thank you for your attention
Special thank you to:
Dr Agnes Trebuchon
Dr Aileen McGonigal
Dr Raphaëlle Richieri
Pr Christophe Lançon
Dr Jean Vion-Dury

16. 4th Annual
Computational
Neurosciences
Workshop
Marseille
Brain stimulation:
Neuro-computational, Experimental, and Clinical approaches
May 31st – June 1st 2012
rTMS Treatment in Psychiatry:
Stimulation or Interaction?
Jean-Arthur MICOULAUD-FRANCHI
M.D. Chef de Clinique - Assistant
Ph.D. Student in Neuroscience