Functional MRI: Physiology and Methodology Seong-Gi Kim Department of Radiology and Neurobiology Univ. of Pittsburgh Supported by NIH (NS44589, EB003324, EB003375), and McKnight Foundation

Mapping Brain Functions Stimulation/Task Functional Map (MRI) Neural Activity As you know very well, functional brain mapping relies on many events from stimulation to detecting signal changes in brain. Stimulation induces neural activity at the localized brain area, then induces hemodynamic changes in blood vasculature such as blood flow, -> detect signal changes using MRI or PET. Pre-synaptic activity Post-synaptic activity Action potentials Blood flow Blood volume Blood oxygenation Vascular Response

Blood oxygenation level Vascular Structure Arteries Capillaries Veins Blood oxygenation level ~1.0 ~0.6 Distance

Blood oxygenation level Vascular Structure Arteries Capillaries Veins (Task -> oxygen supply overcompensates oxygen utilization) Blood oxygenation level ~1.0 ~0.6 Distance (Fox et al., 1988)

Lab’s Research Facility MR Laboratory 9.4 Tesla, 31-cm bore MR instrument Visual and electrical stimulation equipment MR-compatible EEG Life-supporting equipment Access to human 3 and 7 T MR systems Physiology Lab 5 mm 25 x 12 x 2 µm ~ 20ms/frame Tail tail vein of GFP mice was catheterized for the administration of rhodamine-B dextran (MW of 70 kDa), an intra-vascular fluorescent plasma dye (Figure 2A). -green: neurites (dendrites and axons, not cell bodies because of upper cortical layers) Invitrogen, Texas Red: excitation/emission maxima of ~595/615 nm Two-photon laser scanning microscope Intrinsic optical imager 16-channel multi-unit recording system Laser Doppler flowmeter Oxygen polarographer 230 x 230 µm

Lab’s Research Direction Quantification of fMRI Signals Anatomical source of fMRI: Intra- vs. extravascular large vs. small vessels; arterial vs. venous vessels 2. Physiological source of fMRI: neural activity, metabolic response, hemodynamic response Technological Advances Development and characterization of various fMRI techniques (SE BOLD, CBF, CBV, arterial CBV, CMRO2, diffusion, etc) Pushing limits of spatial and temporal resolution

Cortical Column Model in V1 Single-neuron Activities Ocular Dominance Columns Color sensitive regions Gray matter (1.5 – 3 mm) Orientation columns Hubel & Wiesel, 1968

fMRI without and without contrast agent (Cat visual stimulation, 156 x156 x 1000 m) 2 mm Conventional BOLD fMRI 0.3 3.0 % With contrast agent, iron oxide particle Reduce large vessel signals (Zhao, Wang, Hendrich, Ugurbil & Kim, Neuroimage, 30, 1149-60, 2006)

Coronal plane Left Right mg WM 5 mm A 2 mm L LS Marginal gyrus (mg) Lateral sulcus (LS) Marginal gyrus (mg) mg LS WM 5 mm A 2 mm L -30 -180 (a.u.) (Zhao, Wang, Hendrich & S-G. Kim, Neuroimage, 27, 416-24, 2005)

fMRI vs. Invasive Optical Imaging Left Right LS mg SUPS SPL 1 cm Optical imaging 5 mm M A ( 570 nm) MRI M A 5 mm Comparison between fMRI and optical imaging is not trivial. 1-mm thick fMRI slice is selected in the middle of the cortex (dashed rectangles), while optical imaging data is acquired at the surface of the cortex. (note mg, maginal gyrus where visual cortex exists; LS, lateral sulcus). To coregister images acquired by fMRI and optical imaging, pial vascular pattern just above the fMRI imaging slice was used. (move to a next slide) In vessel-weighted MRI, you can see pial vessels as well as intracortical veins (dark spots). It is quite straightforward to obtain vessel-weighted optical images. (move to a next slide) After moving around images to match vessel patterns, we can find vessel pattern in the ROI is well-matched. (move to a next). Expand ROIs (move to a next), trace vessel tress in optical image (move to a next) overlay on MRI data. Vessel patterns are well-matched. This is how we can coregister between MRI and optical data. Note that 6 cats were compared to OIS. M A 1 mm (Fukuda, Moon, Wang & Kim, J Neurosci, 26:11821–11832, 2006)

Iso-orientation maps measured by fMRI vs. optical imaging (in the same cat) +1 fMRI Signal intensity (arbitrary unit) optical imaging This is one animal data. Dark spots indicate CBV increase during the stimulation shown in right corner orientation. 45, 90, 135, 0 degree. (just in case, the bright spots indicates the orthogonal stimulation-induced area). Both maps are quite similar. To help comparison between these two, we marked patched and bothers based on fMRI, and then overlain on optical images (move to a next). This clearly shows that both maps agree very well, indicating that larger plasma-volume change area co-register larger RBC volume change. -1 1 mm (Fukuda, Moon, Wang & Kim, J Neurosci, 26:11821–11832, 2006)

Iso-orientation maps in the medial area using CBV-weighted fMRI 5 mm D A P SPL: spleinal sulcus V SPL -10 +10 Signal intensity (arbitrary unit)

3D architecture of orientation columns V M L A P 1 mm With Shigeru Tanaka at RIKEN, sfn 366.22, 2008

My future plan and interest Collaborative Research Efforts Implementation of new fMRI methodologies into human fMRI research 2. Clinical neuroimaging research

Physiology/Optical Imaging Research Staff Hiro Fukuda Alberto Vazquez Kristy Hendrich Ping Wang Michelle Tasker Shafiq Abedin MRI/Biophysics External Collaborators Tao Jin Tae Kim Paul Schornack Cecil Yen Yuquang Meng Justin Crowley at CMU Shigeru Tanaka at RIKEN Peter Strick at Pitt

Multi-slice imaging of orientation columns #0 #1 #2 #3 #4 #5 #6 #7 2.0x2.0 cm^2 3.125 mm Midline Coronal view Left Right 3.5x2.2 cm2 #0 #1 #2 #3 #4 #5 #6 #7 Orientation column-resolution fMRI was performed on cat visual cortex at 9.4T. The normal adult cat was anesthetized with isoflurane (0.8-1.0%) and immobilized with pancuronium bromide (0.2 mg·kg-1·hr-1, i.v.). The imaging positions were selected in the region of dorsal surface and less large surface veins, based on high-resolution 3D anatomical images. fMRI data were acquired using the multi-slice 2D gradient-echo EPI sequence with parameters: TR =2.0s, TE =10ms, matrix=128×128, and FOV=2×2cm2, following an intravascular bolus injection of a dextran-coated monocrystalline iron oxide nanoparticles (MION) contrast agent (20mg Fe/kg body weight). Eight overlapping 0.5-mm thick slices (0.4mm inter-slice gap) covered a 2.8mm slab. For visual stimulation, high-contrast square-wave full-field moving gratings (0.15cpd, 2Hz, movement direction reversal per 0.5s) were presented binocularly with 8 consecutive orientations (22.5º increments, 10s each) presented without a gap between different orientations for one cycle (80s). One stimulation cycle was repeated ten times continuously (total 800s per run). Twenty fMRI runs were performed for signal averaging. With Shigeru Tanaka at RIKEN sfn 366.22, 2008

Electric Activity Measurements