Fundamentals of Neuroscience Neuroimaging in Cognitive Neuroscience James Danckert PAS 4040 jdancker@watarts.ca

Functional Neuroimaging Electrical activity Event-related potentials (ERP), visual evoked potentials (VEP) all derivative from EEG Stimulation Trans-cranial magnetic stimulation – single vs. rapid pulse TMS Metabolism Positron Emission Tomography (PET) and Blood Oxygenated Level Dependent (BOLD) functional MRI (fMRI)

EEG Large populations of neurons firing produce electrical potentials that can be measured at the scalp Signals are passively conducted through the skull and scalp and can be amplified and measured Difference between reference (ground) and recording electrodes are measured to give the electrical potential – electroencephalogram (EEG)

ERPs and VEPs EEG tends to record global brain activity ERPs (and VEPs) are a special case of EEG average EEG trace from a large number of trials align signal to onset of a stimulus or response – hence event-related potential (ERP)

Pros and cons of ERPs. Good temporal resolution Linked to specific physiological markers (e.g., N1, P3 etc. which in turn can be linked to known cognitive processes) Cons Poor spatial resolution Difficult to get at some brain regions (OFC, temporal cortex)

Transcranial Magnetic Stimulation (TMS) Thompson (1910) placed head between two coils and stimulated at ~ 42 Hz saw flashing lights – magnetophosphenes was probably stimulating the retina and not the visual cortex Cowey and Walsh, 2001

TMS TMS applies a magnetic pulse to a certain brain region to temporarily modulate the function of that region

TMS circular coil induced current the induced current in the tissue is in the opposite direction to that of the coil the intensity of the signal drops off towards the centre and outside of the coil Cowey and Walsh, 2001

TMS little or no change maximum hyperpolarization maximum depolarization the flow of the current must cross the axon to cause stimulation or interruption of function (N3 will not be stimulated) Cowey and Walsh, 2001

TMS

Spatial extent of TMS spatial extent of induced electric field drops ~ 75% within 10 mm affects 600 mm2 of neural tissue

Rapid vs. Single Pulse TMS for single pulse TMS duration of stimulation = 1 msec, but affects motor cortex for up to 100 msec for rapid or repetitive pulse TMS stimuli are delivered in trains with frequencies from 1 to 25 Hz (1 – 25 times per second) duration of after-effects for rapid pulse TMS anywhere from msec to several seconds

Transcranial magnetic stimulation (TMS / rTMS) excitatory or inhibitory reversible effects depending on site and parameters of stimulation (e.g. frequency of pulses) -> facilitates or slows down cognitive process/behavior when inhibitory, referred to as ‘virtual lesion technique’ can give precise timing information (msec level) due to transient nature of effects rTMS is beginning to be used as a treatment for depression (focus is on DLPFC)

TMS Poor spatial localisation – how focal is the stimulation? Can’t stimulate certain areas (e.g., temporal lobe) and can only stimulate cortical surface Good temporal resolution Can presumably disrupt individual processes within a task. Distance effects – changed interactions due to stimulation Can induce seizures (particularly rTMS)

Frameless stereotaxy and fMRI areas can be identified functionally and then used to position the coil in a TMS study using the frameless stereotaxy method Paus is attempting to directly combine fMRI and TMS – with TMS pulses delivered in between fMRI runs

Metabolic Imaging Two main techniques – positron emission tomography (PET) and functional MRI (fMRI) Activity in cells requires energy (oxygen and glucose) Increased neural activity will lead to changes in cerebral blood volume (CBV), cerebral blood flow (CBF) and the rate of metabolism of glucose and oxygen (CRMGl and CRMO) These changes in blood flow and metabolism can be measured using PET and fMRI

Positron Emission Tomography (PET) Measures local changes in cerebral blood flow (CBF) or volume and can also be used to trace certain neurotransmitters (but can only do one of these at a time) Radioactive isotopes are used as tracers The isotopes rapidly decay emitting positrons When the positrons collide with electrons two photons (or gamma rays) are emitted The two photons travel in opposite directions allowing the location of the collision to be determined

Positron Emission Tomography (PET)

PET and subtraction Run two conditions – stimulation (e.g., look at visual images) vs. control (e.g., look at blank screen) Measure the difference in activation between the two images (i.e., subtract control from stimulation) This provides a picture of regional cerebral blood flow relative to visual stimulation.

Motion vs. colour. Subject views coloured screen (left) vs. moving random black and white dots (right) Both task activate early visual areas (V1 and V2) Subtracting the two images reveals different brain areas for colour (V4) vs. motion (V5) processing

PET vs. fMRI PET allows you to track multiple metabolic processes so long as the emitted photon can be detected – allows imaging of some neurotransmitters PET is invasive – radioactive isotopes can only be administered (at experimental levels) every 4 – 5 years fMRI has much greater spatial resolution (~ mms) fMRI has greater temporal resolution – can detect activation to stimuli appearing for less than a second (PET is limited by the half life of the isotope used)

fMRI

Magnet safety very strong magnetic fields – even large and heavy objects can ‘fly’ into the magnet bore

Cerebral blood supply. Arterioles Capillaries Y=95% at rest. Y=100% during activation. 25 mm diameter. <15% blood volume of cortical tissue. Venules Y=60% at rest. Y=90% during activation. 25-50 mm diameter. 40% blood volume of cortical tissue. Red blood cell 6 mm wide and 1-2 mm thick. Delivers O2 in form of oxyhemoglobin. Capillaries Y=80% at rest. Y=90% during activation. 8 mm diameter. 40% blood volume of cortical tissue. Primary site of O2 exchange with tissue. Transit Time = 2-3 s

Cerebral blood supply.

fMRI Deoxyhaemoglobin is paramagnetic When neural activity increases more oxygenated blood than is needed is delivered to the site This leads to an imbalance in oxyhaemoglobin and deoxyhaemoglobin – more oxy than deoxy fMRI is able to measure this difference due to the different magnetic properties of oxy and deoxyhaemoglobin

fMRI and BOLD blood oxygenated level dependent (BOLD) signal is actually a complex combination of: rate of glucose and oxygen metabolism CBV CBF same subtraction logic used in PET is used in fMRI

fMRI – block design fMRI (like PET) began examining brain activity using block designs colours rest motion

fMRI – event-related design allows randomization of stimuli (not possible in PET)

fMRI – event-related design BOLD response has a predictable form In rapid event-related designs the signal to a given trial type is deconvolved using models of the BOLD response

Linearity of BOLD response Dale & Buckner, 1997 Linearity: “Do things really add up?” red = 2 - 1 green = 3 - 2 Sync each trial response to start of trial Not quite linear but good enough !

Fixed vs. Random Intervals If trials are jittered,  ITI  power Source: Burock et al., 1998

fMRI spatial resolution images can be co-registered to the subject’s own brain (not an average brain as in PET) PET fMRI

red = wrist; orange = shoulder fMRI and topologies Using fMRI to “map” different brain functions Penfield’s maps Servos et al., 1998 red = wrist; orange = shoulder

Retintopy 8 Hz flicker (checks reverse contrast 8X/sec) EXPANDING RINGS ROTATING WEDGES 8 Hz flicker (checks reverse contrast 8X/sec) good stimulus for driving visual areas subjects must maintain fixation (on red dot) Source: Jody Culham

EXPECTED RESPONSE PROFILE OF AREA RESPONDING TO STIMULUS To analyze retinotopic data: Analyze the data with a set of functions with the same profile but different phase offsets. For any voxels that show a significant response to any of the functions, color code the activation by the phase offset that yielded maximum activation (e.g., maximum response to foveal stimulus = red, maximum response to peripheral stimulus = pink) time = 0 time = 20 sec time = 40 sec 20 40 60 STIMULUS time = 60 sec TIME  Source: Jody Culham

Retintopy: Eccentricity calcarine sulcus left occipital lobe right occipital lobe foveal area represented at occipital pole peripheral regions represented more anteriorly

Retinotopy Source: Sereno et al., 1995

Other Sensory “-topies” Audition: Tonotopy cochlea Sylvian fissure temporal lobe

Marty Sereno’s web page Saccadotopy delayed saccades move saccadic target systematically around the clock Source: Sereno et al., 2001 http://kamares.ucsd.edu/~sereno/LIP/both-closeup+stim.mpg Marty Sereno’s web page

Break

Finding the human homologue of monkey area X! recent research has used monkey neurophys to guide fMRI in humans Dukelow et al. 2001

Problems with the search for homologues Absence of activation doesn’t mean the absence of function Presence of activation doesn’t imply sole locus of function But our brains are different! Confirmatory hypotheses Dukelow et al. 2001

fMRI and diagnosis fMRI is starting to be used in patients with epilepsy one goal is to use this as a tool to localise language, memory etc. prior to surgery another goal would be to use fMRI to study the propogation of seizures in stroke patients fMRI can be used to chart recovery of function

Patient SP – congenital porencephalic cyst Left Right

SP - motor strip motor strip sequential tapping alternating tapping

SP – somatosensory strip sequential tapping alternating tapping

superior parietal sequential tapping alternating tapping e g n a h c l 6.0 6 4 2 -1 1 3 5 % s i g n a l c h e images g n a 4.0 h c l 2.0 a n g 0.0 s i % -2.0 1 21 41 images

Broca’s area? name animals name objects non-word sounds (‘ba’) e h c l % s i g n a l c h e images 1 21 41 2 -1

left occipital name animals name objects non-word sounds (‘ba’) e h c % s i g n a l c h e images 1 21 41 2 -1

fMRI and cognition What not to do – poorly designed tasks! What is the right inferior parietal lobe’s contribution to movement control? spatial component of movements compare imagined movements with only a spatial component vs. movements with a sequential component

spatial only complex sequence

Bilateral FEF

Supplementary Motor Area (SMA)

Bilateral superior parietal

Inferior parietal cortex Left Right Anterior Posterior L R complex sequence only alternation only both

Design Problems Boy, you must be rich then!!! What could the right vs. left parietal difference be due to? Attention? – possibly! Differences in eye movements? – maybe! Were the tasks really different in the intended way? Perhaps – both tasks were spatial in nature and both tasks had a sequential component, so… So did you just test task difficulty? Maybe, what of it? Why is right parietal more active for less difficult tasks then? I don’t know and I don’t care, piss off! I’m gonna start again! Boy, you must be rich then!!!

Confirming modularity Nancy Kanwisher and the parahippocampal recliner region!

Is that all there is to it? Alex Martin and co. suggest that the FFA responds to other kinds of objects too Isabelle Gauthier and co. suggest that it is expertise with faces which drives the activation

Exploring behaviours Prism adaptation ameliorates neglect – how? First, explore the direct effects of prism adaptation in the healthy brain. Clower et al 1996 used PET to do this but reversed the direction of prismatic shift every 5 trials.

Prism Adaptation – Rossetti and colleagues prisms shift world further to the right (into the patient’s ‘good’ field) patient’s movements compensate for the prismatic shift – in the opposite direction after effects lead to better processing of previously neglected stimuli

Setup.

Protocol I. 2 sec 2 sec 0.5 sec 11.5 sec 2 sec 5 runs with prisms (50 trials) 5 runs without prisms (50) 2 sec

Protocol II. 2 sec volumes – so 2 sec for critical stimulus (the target) and 12 sec for post stimulus return to baseline (a la Bandettini).

Protocol III. 4T scanner at Robarts 17 pseudo-axial slices 5 mm thick TR 2 sec 2-shot EPI sequence Co-registered to 128 slice anatomical

Adapting in the magnet. mean shift = 27.73 mm

Finding ROIs. med frontal (SMA) right sup par left sup par

Modeling the peak activation across trials. Linear Logarithmic

Left and right superior parietal cortices. Left Superior Parietal -0.5 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 trial max % signal change r2=0.13 Right Superior Parietal -0.5 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 trial max % signal change r2=0.15

Cerebellar ROIs. Medial Cerebellum r2=0.14 Right Lateral Cerebellum -0.5 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 trial max % signal change r2=0.14 Right Lateral Cerebellum -0.5 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 trial max % signal change r2=0.42

SMA. transverse sagittal r2 = 0.37 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 trial max % signal change (group mean) 2 3 4 5 6 7 8 9 10 r2 = 0.37

Bottom line? Difficult to image the direct effects of adaptation in normals. Image “good adaptors” OR change protocol to look at after effects of adaptation – with all its problems…

I wonder if fMRI could be used to cure cancer? Conclusions? fMRI should be used for good and not evil! I wonder if fMRI could be used to cure cancer?

Acknowledgements fMRI of epilepsy patient fMRI of prism adaptation Stacey Danckert Seyed Mirsitari David Carey Mel Goodale Ravi Menon Jody Culham fMRI of prism adaptation Susanne Ferber Stacey Danckert Mel Goodale Yves Rossetti fMRI of imagined movements it was all my fault!

End of Lecture