neurostimulation studies Mandana Modirrousta MD PhD FRCPC Assistant Professor Department of Psychiatry University of Manitoba Fundamentals of Research and Scholarship Grand Rounds Brain and ID: 275858
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How to design neurostimulation studies?
Mandana Modirrousta MD PhD FRCPCAssistant Professor, Department of Psychiatry, University of Manitoba
Fundamentals of Research and Scholarship Grand Rounds Slide2
Brain and Behaviour correlationSlide3
Lesion Studies
experimental models in animalsSingle or few case studiesmight 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 TechniquesSlide4
Cortical Stimulation
InvasiveLimited 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 TechniquesSlide5
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)Slide6
TMS in the Study of Brain-Behavior Relations
Study of normal subjects eliminates the potential confounds of additional brain lesions and pathological brain substratesAcute 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.Slide7
Real lesion
Blue = sighted; Red = E blind
Cohen et al., 1997. Occipital TMS disrupts braille reading in early blind, but not control subjects
Hamilton et al., 2000. Reported case of blind woman who lost ability to read braille following bilateral occipital lesions
Advantages of TMS: Virtual Patients
causal link between brain activity and behaviour
TMS lesion
Braille AlexiaSlide8
Advantages of TMS: Chronometry
Role of “visual” cortex in tactile information processing in early blind subjects
Hamilton
and Pascual-Leone, 1998
“Chronometry”:
timing the contribution of focal brain activity to behaviorSlide9
Paus et al.
TMS
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
Functional connectivity-
relate behaviour to the interaction between elements of a neural networkSlide10
Electromagnetic Induction
Introduces disorder into a normally ordered systemSlide11
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 plasticitySlide12
To consider while designing an experiment
Sham stimulationOn-line vs. off-line paradigmTMS parameters: When and How to stimulateIntensity of stimulationScalp to Brain Target DistanceFrequency of StimulationDuration of
Stimulation
Stimulation Parameters and Behavioral
Task
Where?What are you stimulating?Slide13
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
Coil shapeSlide14
25mm
15mm
20mm
70x60
55x45
40x30
0
5mm
Practical Considerations
- stimulation depth
Cannot stimulate medial or sub-cortical areasSlide15
-
-
-
+
+
Stimulation techniques and possible effects
Single pulse
rTMS (low/high fr.)
Paired pulse
Paired pulse
Paradoxical effects
Connected effects
Expected effectSlide16
Real
Sham
Control Conditions
Different hemisphere
Different site
Different effect or no effect
Or interleave TMS with no TMS trialsSlide17Slide18
Safety
Seizure induction
Hearing loss
Heating of the brain
Engineering safetySlide19
Safety
Scalp burns from EEG electrodes
Effect on cognition
Local
neck pain and
headaches
Effect on Mood in
normalsSlide20
+ minimum inter-train interval
e.g. at 20Hz @1.0-1.1 T leave >5s inter train
Frequency (Hz)
Max. duration (s)
1
1800+
5
10
10
5
20
1.6
25
.84
Maximum safe duration of single rTMS train at 110% MT
Follow published safety guidelines for rTMS
Caution: Guidelines not perfect
SafetySlide21
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
thresholdSlide22
Subjects who are pregnant (case studies have not shown complications)
History of serious head traumaHistory of substance abuseStrokeStatus after Brain SurgeryOther medical/neurologic conditions either associated with epilepsy or in whom a seizure would be particularly hazardous (e.g. increased intracranial pressure)
ContraindicationsSlide23
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 avoidedSlide24
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
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 benefitsSlide25
Question time