How to design neurostimulation studies? Mandana Modirrousta MD PhD FRCPC

Fundamentals of Research and Scholarship
Grand Rounds
How to design neurostimulation
studies?
Mandana Modirrousta
MD PhD FRCPC
Assistant Professor, Department of
Psychiatry, University of Manitoba
Brain and Behaviour correlation
Other Brain-Behavior Techniques
• Lesion Studies
– experimental models in animals
– Single or few case studies
– might be more than a single lesion
– lesion may be larger than the brain area under study
– Cognitive abilities may be globally impaired
– Given brain plasticity, connections might be modified
following lesions
Other Brain-Behavior Techniques
• Cortical Stimulation
– Invasive
– Limited to the study of patients with brain
pathologies requiring neurosurgical
interventions
– Stressful situation in the OR and medications
might condition subject’s performance
– Time constraints limit the experimental
paradigms
– Retesting is not possible
Other Brain-Behavior Techniques
• Neuroimaging (Brain Mapping)
– Non-invasive identification of the
brain injury correlated with a given
behavior
– Association of brain activity with
behavior - cannot rule out
epiphenomenon
– Cannot demonstrate the necessity of
given region to function
– Neuroimaging techniques are usually
only good either temporally or
spatially, not both (e.g. Pet & fMRI
lack temporal resolution, EEG lacks
spatial resolution)
TMS in the Study of Brain-Behavior Relations
• Study of normal subjects eliminates the potential confounds of
additional brain lesions and pathological brain substrates
• Acute studies minimize the possibility of plastic reorganization
of brain function
• Repeated studies in the same subject
• Study multiple subjects with the same experimental paradigm
• Study the time course of network interactions
• When combined with PET or fMRI, can build a picture of not
only which areas of brain are active in a task, but also the time
at which each one contributes to the task performance.
Advantages of TMS: Virtual Patients
causal link between brain activity and behaviour
Braille Alexia
Real lesion
Hamilton et al., 2000.
Reported case of blind
woman who lost ability to
read braille following
bilateral occipital lesions
TMS lesion
Cohen et al., 1997.
Occipital TMS
disrupts braille
reading in early blind,
but not control
subjects
Blue = sighted; Red = E blind
Advantages of TMS: Chronometry
“Chronometry”:
timing the
contribution of focal
brain activity to
behavior
Role of “visual” cortex
in tactile information
processing in early
blind subjects
Hamilton and PascualLeone, 1998
Functional connectivity- relate behaviour to the
interaction between elements of a neural network
Paus et al.
TMS/PET
TMS to FEF - correlation between
TMS and CBF at
i) stimulation site
ii) distal regions consistent with
known anatomical connectivity of
monkey FEF
Electromagnetic Induction
Introduces disorder into a normally ordered system
Summary: What can TMS add to Cognitive
Neuroscience ?
• “Virtual Patients”: causal link between brain activity
and behavior
• “Chronometry”: timing the contribution of focal
brain activity to behavior
• “Functional connectivity”: relate behavior to the
interaction between elements of a neural network
• Map and modulate neural plasticity
To consider while designing an
experiment
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Sham stimulation
On-line vs. off-line paradigm
TMS parameters: When and How to stimulate
Intensity of stimulation
Scalp to Brain Target Distance
Frequency of Stimulation
Duration of Stimulation
Stimulation Parameters and Behavioral Task
Where?
What are you stimulating?
Practical
considerations
Coil shape
The geometry of the
coil determines the
focality of the
magnetic field and of
the induced current hence also of the
targeted brain area.
T
Practical Considerations - stimulation depth
70x60
5mm
55x45
40x30
0
15mm
20mm
25mm
Cannot stimulate medial or sub-cortical areas
Stimulation techniques and possible effects
-
+
Expected effect
Single pulse
rTMS (low/high fr.)
Connected effects
Paired pulse
+
Paradoxical effects
Paired pulse
Control Conditions
Real
Different hemisphere
Different
effect or
no effect
Sham
Different site
Or interleave TMS with no TMS trials
Safety
Seizure induction
Hearing loss
Heating of the brain Engineering safety
Safety
Scalp burns from EEG electrodes
Effect on cognition Local neck pain and headaches
Effect on Mood in normals
Safety
Follow published safety guidelines for rTMS
Maximum safe duration of single rTMS train at 110% MT
Frequency (Hz)
Max. duration (s)
1
1800+
5
10
10
5
20
1.6
25
.84
Caution: Guidelines not perfect
+ minimum inter-train
interval
e.g. at 20Hz @1.0-1.1
T leave >5s inter train
Contraindications
•Metallic hardware near coil
–Pacemakers
–implantable medical pumps
–ventriculo-peritoneal shunts
(case studies with implanted brain stimulators and
abdominal devices have not shown complications)
•History of seizures or history of epilepsy in first degree
relative
•Medicines which reduce seizure threshold
Contraindications
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Subjects who are pregnant
(case studies have not shown complications)
History of serious head trauma
History of substance abuse
Stroke
Status after Brain Surgery
Other medical/neurologic conditions either
associated with epilepsy or in whom a seizure
would be particularly hazardous (e.g. increased
intracranial pressure)
Ethics Guidelines
• Informed Consent - disclosure of all significant
risks, both those known and those suspected
possible
• Potential Benefit must outweigh risk
• Equal distribution of risk - Particularly vulnerable
patient populations should be avoided
Major advantages summary
Reversible lesions without plasticity changes
Repeatable
High spatial and temporal resolution
Can establish causal link between brain activation and behaviour
Can measure cortical plasticity
Can modulate cortical plasticity
Therapeutic benefits
Major limitations summary
Only regions on cortical surface can be stimulated
Can be unpleasant for subjects
Risks to subjects and esp. patients
Stringent ethics required (can’t be used by some
institutions)
Localisation uncertainty
Stimulation level uncertainty
Question time