2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Peter Pazmany Catholic University Faculty of Information Technology BIOMEDICAL IMAGING Functional Magnetic Resonance Imaging (fMRI) -the BOLD method www.itk.ppke.hu (Orvosbiológiai képalkotás) (Funkcionális Mágneses Rezonancia-a BOLD módszer) ISTVÁN KÓBOR, VIKTOR GÁL Biomedical Imaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu Functional Magnetic Resonance Imaging FunctionalMagneticResonanceImaging(fMRI)referstodifferenttypesofspecializedMRIscanswithacommongoal: tomeasurethedynamicsoflocalneuralactivityinthebrainorspinalcordofhumansorotheranimals. methods:endogenousorexogenouscontrastagentscanbeusedtodirectlyorindirectlydetectneuralaction.•Blood-oxygen-leveldependentimaging(BOLD)isthemostfrequentlyusedtechnique,wherethecontrastagentistheblooddeoxyhemoglobin. G:\vision_projects\st_mem\col_square\fmri\_results\parietal.png Biomedical Imaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu Sources of theBOLDsignal • Auto(vaso)regulationinCNScontrolsthelocaloxygensupplyaccordingtothelocalactivity. • Changesinthehemoglobin(oxygencarriermolecule)concentrationcanbedetectedbyMRI. Neuronal activity BOLD signal Local concentration of deoxy- hemoglobin Local Autoregulation in CNS Biomedical Imaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 www.itk.ppke.hu Metabolic requirements of neural activity Neural mechanisms require external sources of energy (glucose) and oxygen to support metabolic processes (e.g. restoration of the concentration gradients following changes in membrane potential). Direct source of energy at the cell level are the ATP molecules (adenosin-triphosphate). ATP is produced via oxidation of glucose (glycolysis) in the cell• When oxygen supply is appropriate: aerobic glycolysis (90%) • When oxygen supply is inadequate: anaerobic glycolysis (very fast, 10% ) Iron-containing Hemoglobin (Hb) in the blood is what transports oxygen from the lungs to the rest of the body (i.e. the tissues), where it releases the oxygen for cell use. 2 forms depending on O2binding:• oxyhemoglobin (oxyHb) is saturated with O2 • deoxyhemoglobin (deoxyHb) binds no O2 For imaging purposes, the main vasculature concerned are the capillaries networks –where glucose and oxygen exchanges happen BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 www.itk.ppke.hu Metabolic rates of the different components of neuronal activity Attwell and LaughlinJof Cerebral Blood Flow & Metabolism(2001) BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu How does the brain cope with the increasedmetabolicdemands? Activity dependent changes in CBF & CMRO2: autoregulation Cerebral Blood Flow (CBF) and Cerebral Metabolic Rate of Oxygen (CMRO2) are coupled under baseline conditions– PET measures CBF well, CMRO2poorly – fMRImeasures CMRO2well, CBF poorly CBF about .5 ml/g/min under baseline conditions– Increases to max of about .7-.8 ml/g/min under activation conditions CMRO2only increases slightly with activation– Note: A large CBF change may be needed to support a small change in CMRO2 BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 www.itk.ppke.hu Energy Consumption and blood supply O2 consumption: 20% of the total body (Brain tissue is 2-3% of body weight) Most of the energy is spent maintaining action potentials and in post-synaptic signaling: post-synaptic activity probably dominates in human Inhibitory synapses use less energy than excitatory ones Neural activity use locally available glucose and Hbbound O2• Glucose, oxyHb • deoxyHb, pH, CO2 BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 www.itk.ppke.hu Autoregulation: Energy Consumption Theory Increased CBF provides higher concentration of glucose and Hbbound O2:• Glucose, oxyHb • deoxyHb,pH, CO2 CBF Increases to max of about .7-.8 ml/g/min under activation conditions Initial thoughts were that increase of blood flow is directly linked tothe elevated metabolic rate (and thus increase in energy and O2requirements) of the active tissue. Candidate signal substrates:• Lactate, pH, CO2, O2, But this is not true! BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu Thenhowdoes the brain cope with the increase in glucose and O2demands? Glutamate-generated Calcium influx at post-synaptic level releases potent vasodilators:• Nitric Oxide • Adenosine • ArachidonicAcid metabolites Blood flow is increased over an area larger than the one with elevatedneuralactivity Global blood flow changes also associated with dopamine, noradrenalineand serotonin – Not related with regional energy utilisation at all!! Attwell, D. , Iadecola, C. 2002. “The neural basis of functional brain imaging signals”. Trends in Neuroscience. 25 (12) 621-625 Energy utilisation and increase in blood flow are processes that occur in parallel and are not causally related Autoregulation of the blood flow BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 www.itk.ppke.hu Factors defining local deoxyhemoglobin-concentration Local neuronal activity Local concentration of deoxy- hemoglobin Vasodilators Blood flow Blood volume Metabolic changes Diffuse projections Vasoconstrictors BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 www.itk.ppke.hu 0 Time Relativeconcentration Hb dHb 0 14 • Quite distinct changes in oxygenated(Hb)and deoxygenated hemoglobin(dHb)following neuronal activation. • Unlike weak deoxygenated hemoglobin signal spatial pattern of oxygenated hemoglobin does not reflect the pattern of neuronal activity Activity dependent changes in deoxy-and oxyhemoglobin levels BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 www.itk.ppke.hu Depending on blood oxygen level: deoxyHb is paramagnetic, increases local inhomogeneity of magnetic field oxyHb diamagnetic – local homogeneity of magnetic field increased Oxygen and Field homogeneity BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 www.itk.ppke.hu Impact of local inhomogeneity: attenuation of MR signal Reversible+irreversible, origin: spin-spin (molecular) interaction and within-voxel inhomogeneities of the magnetic field BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 15 www.itk.ppke.hu Contrastagents Irreversible: dynamically changing difference in frequency/dephasing of the spin precessions –dephasing is not constant. Source: molecular motion and spin-spin interaction. Reversible: constant difference in frequency (within one slice acquisition), dephasing speed is not changing, refocusing RF pulse can recover phase coherence. Origin: local magnetic field non-uniformities. BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 16 www.itk.ppke.hu T2 relaxation time: irreversible dephasing, molecular interaction T2* relaxation time:MR signal attenuation due to irreversible+reversible dephasing. Local magnetic field non-uniformity is a major component of the effect: it correlates with local deoxyHb concentration. Impact of local inhomogeneity on T2* BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 17 www.itk.ppke.hu Signal decay is sensitive to magnetic field inhomogeneities =>• Sensitive to signal difference based on deoxyHB concentration Optimal read-out time: When signal difference is highest between different deoxyHB levels• TE=25-35ms at 3Tesla (depends on anatomical region as well) How to detect BOLD contrast signal TE optimal TE Rest activation BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 18 www.itk.ppke.hu Link betweenBOLD and neuralactivity: Neurovascularcoupling Local neuronal activity Local concentration of deoxy- hemoglobin Vasodilators Blood flow Blood volume Metabolic changes Diffuse projections Vasoconstrictors BOLD signal Field inhomogeneity BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 19 www.itk.ppke.hu Neuronal Origins of BOLD: proof of concept •BOLD response correlates primarily with Local Field Potentialthat reflects activity in the neuropil(dendritic activity) •Increased neuronal activity results in increased MR (T2*) signal LFP: Local Field PotentialMUA: Multi-Unit ActivitySDF: Spike-Density Function LogothetisJournal of Neuroscience, 2003, BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 20 www.itk.ppke.hu Most frequently used sequence in fMRI:• Gradient Echo Planar Imaging (gradient EPI) Why Gradient? Requires relatively long read-out time=>• Very sensitive to magnetic field inhomogeneities =>• Sensitive to signal difference based on deoxyHB concentration Signal decay is characterized by T2* relaxation Why EPI? Relatively high temporal resolution: required time for a whole brain acquisition typically 2-3sec At higher magnetic fields (4.5T, 7T, 9.4T) can be combined with spin-echo sequence Gradient EPI: benefits BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 21 www.itk.ppke.hu Low contrast and spatial resolution Serious distortions near to air/tissue borders (e.g. amygdala/inner ear) High water-fat shift Signal instability over time Gradient EPI: disadvantages BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 22 www.itk.ppke.hu Spatial Resolution and specificity of BOLD response •In general: high spatial resolution because changes in BOLD response rely on changes in perfusion of capillaries (o 5-10µm) • Influencing factors: • Voxel size (depending on region to scan 1-5mm) -attention! reduced voxel size reduced signal compared with noise and increased acquisition time, but less diversity in tissue content • Concordance of neural activity and vascular response– Arteries are fully oxygenated – Venous blood has increased proportion of dHb – Difference between Hb and dHb states is greater for veins – Therefore BOLD is the result of venous blood changes Signal can arisefrom larger and more distant blood vessels!!! BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 23 www.itk.ppke.hu Temporal resolutionof fMRI Typical sampling time of a volume: 2-3sec Temporal resolution is inversely related to– Spatial resolution – Imaging volume size – TE (sensitivity to BOLD) Stimuli can be detected:– Minimum duration : < 16 ms – Minimum onset diff: 100 ms to 2 sec– Above 2 sec, linear summation of responses – Below 2 sec: nonlinear interactions BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 24 www.itk.ppke.hu Stability of the BOLD signal •Low frequency drifts and temporal autocorrelation is an inherent characteristic BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. 25 Initial Dip Baseline Rise Undershoot -5 0 5 Baseline Undershoot Peak Initialdip S1 Stimulus: Initial Dip Baseline Rise Undershoot -5 0 5 Baseline Undershoot Peak S1 S2 S3……………….SN Stimuli: 25 (msec) Initialdip TÁMOP –4.1.2-08/2/A/KMR-2009-0006 www.itk.ppke.hu Sustainedresponse 25 (msec) BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 26 www.itk.ppke.hu Initial Dip (Hypo-oxicPhase) •Initial Dip (1-2sec)may result from initial oxygen extraction before later overcompensatory response • Transient increase in oxygen consumption, before change in blood flow – Menonet al., 1995; Hu, et al., 1997 • Shown by optical imaging studies– Malonek& Grinvald, 1996 • Smaller amplitude than main BOLD signal– 10% of peak amplitude (e.g., 0.1% signal change) • Potentially more spatially specific– Oxygen utilization may be more closely associated with neuronal activity than perfusion response BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 27 www.itk.ppke.hu Rise (HyperoxicPhase) •Results from vasodilationof arterioles, resulting in a large increase in cerebral blood flow • Inflection point can be used to index onset of processing Peak –Overshoot •Over-compensatoryresponse– More pronounced in BOLD signal measures than flow measures • Overshoot found in blocked designs with extended intervals– Signal saturates after ~10s of stimulation BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 28 www.itk.ppke.hu Sustained Response •Blocked design analyses rest upon presence of sustained response– Comparison of sustained activity vs. baseline – Statistically simple, powerful • Problems– Difficulty in identifying magnitude of activation – Little ability to describe form of hemodynamic response – May require detrendingof raw time course Undershoot •Cerebral blood flow more locked to stimuli than cerebral blood volume– Increased blood volume with baseline flow leads to decrease in MR signal • More frequently observed for longer-duration stimuli (>10s)– Short duration stimuli may not evidence – May remain for 10s of seconds BiomedicalImaging: fMRI -the BOLD method TÁMOP –4.1.2-08/2/A/KMR-2009-0006 29 www.itk.ppke.hu Normalization of responses: Percent Signal Change •Peak / mean(baseline) • Basic assumption: signal is proportional to mean baseline. • Question: mean baseline depends on what? • Amplitude variable across subjects, age groups, etc. • Peak signal change dependent on:– Brain region – activation parameters – Voxel size – Field Strength Initial Dip Baseline Rise Undershoot 0 5 Baseline Undershoot Initialdip 15 (msec) Initial Dip Baseline Rise Undershoot 0 5 Baseline Undershoot Initialdip 15 (msec) 1% 1% 205 200 505 500 BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 30 www.itk.ppke.hu Issues: what are we actually measuring? •Inputs or Outputs?– BOLD responses correspond to intra-cortical processing and inputs, not outputs – Aligned with previous findings related to high activity and energy expenditure in processing and modulation • Excitation or inhibition circuits?– Excitation increases blood flow, but inhibition might too –ambiguous data – Neuronal deactivation is associated with vasoconstriction and reduction in blood flow (hence reduction in BOLD signal) • And what about the awake, but resting brain? – Challenges in interpreting BOLD signal – Presence of the signal without neuronal spiking BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 31 www.itk.ppke.hu 90.000 to 100.000 neurons per 1mm3 of brain tissue 109synapses, depending on cortical thickness What is in a Voxel? Volume of 55mm3 – Using a 9-16 mm2plane resolution and slice thickness of 5-7 mm Only 3% of vessels and the rest are….(be prepared!!) – 5.5 million neurons – 2.2-5.5 x 1010synapses – 22km of dendrites – 220km of axons Issues: what are we actually measuring? BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 32 www.itk.ppke.hu Relative vs. Absolute Measures •BOLD fMRI provides relativechange over time– Signal measured in “arbitrary MR units” – Percent signal change over baseline – Direct longitudinal or intersubject comparisons are impossible – within subject interregional (different cortical areas) comparisons : only qualitative or indirect • Arterial spin labeling (another type of fMRI method discussed later) or PET provides absolutesignal – Measures biological quantity in real units CBF: cerebral blood flow CMRGlc: Cerebral Metabolic Rate of Glucose CMRO2: Cerebral Metabolic Rate of Oxygen CBV: Cerebral Blood Volume BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 33 www.itk.ppke.hu Why the Growth of fMRI? •Powerful– Improved ability to understand cognition – Better spatial resolution than PET – Allows new forms of analysis • High benefit/risk ratio– Non-invasive (no contrast agents) – Repeated studies (multisession, longitudinal) • Accessible– Uses clinically prevalent equipment – No isotopes required – Little special training for personnel BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 34 www.itk.ppke.hu What fMRI Can Do Help in understanding healthy brain organization – map networks involved with specific behavior, stimulus, or performance – characterize changes over time (seconds to years) – determine correlates of behavior (response accuracy, etc…) Current Clinical Applications – presurgical mapping – better understanding mechanism of pathology for focused therapy – drug effect assessment – assessment of therapy progress, biofeedback – epileptic foci mapping – neurovascular physiology assessment Current Clinical Research – assessment of recovery and plasticity – clinical population characterization with probe task or resting state BiomedicalImaging: fMRI -the BOLD method 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 35 www.itk.ppke.hu What fMRICan’t Do •Too low SNR for routine clinical use (takes too long) • Requires patient cooperation (too sensitive to motion) • Too low spatial resolution (each voxelhas several million neurons) • Too low temporal resolution (hemodynamicsare variable and sluggish) • Too indirectly related to neuronal activity • Too many physiologic variables influence signal • Requires a task (BOLD cannot look at baseline maps) • Too confined space and high acoustic noise.