The (Human) Brain Basic neurophysiology and imaging techniques - - PDF document

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The (Human) Brain Basic neurophysiology and imaging techniques - - PDF document

The (Human) Brain Basic neurophysiology and imaging techniques Peter Bossaerts 1 Contents 1. Neurons 2. Neurotransmitters, neuromodulators 3. Some important brain regions 4. Single-unit (neuron) recording 5. EEG 5.1. Frequency analysis


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The (Human) Brain

Basic neurophysiology and imaging techniques

Peter Bossaerts

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Contents

  • 1. Neurons
  • 2. Neurotransmitters, neuromodulators
  • 3. Some important brain regions
  • 4. Single-unit (neuron) recording
  • 5. EEG

5.1. Frequency analysis 5.2.Time-Frequency analysis

  • 6. fMRI

6.1.BOLD signal 6.2.Statistical analysis: GLM

  • 7. Pharmacology

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  • 1. Neurons

Cells in the brain that carry “information” are called neurons (There are other cells, such as glial cells like astrocytes,...) Information carried within cell body (dendrites, nucleus, axon) is electrical (ions) Across neurons, through synapse (synaptic cleft) it is chemical

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  • 2. Neurotransmitters

... carry information from one neuron to another Upstream cell emits neurotransmitter that attached to receptors of downstream cell – if not blocked by an “antagonist” – and causes downstream cell to “fire” (a temporary charge surge traveling through the cell) Upstream cells emit particular neurotransmitters, eg GABA, dopamine, serotonin, norepinephrine, acetylcholine, histamine,...

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Some are really “neuromodulators”

These neurotransmitters don’t really relay information but regulate information transmission Eg dopamine

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Example: Dopamine

Gives sensation of “arousal” Sub-cortical neurons (brain stem!), with extensive projections, including to prefrontal cortex Affected by cocaine, alcohol, amphetamines,... and L-Dopa

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  • 3. Some Important

Brain Regions

“Gray matter” = cell bodies (nucleus); “white matter” = “connections” (axons) Cortex, subcortical regions, brainstem

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mm

7 9

view)

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SLIDE 5

More...

mPFC = medial Prefrontal Cortex ACC = Anterior Cingulate Cortex IFG = Inferior Frontal Gyrus IPS = Interparietal Sulcus TPJ = Temporo-Parietal Junction pSTS = posterior Superior Temporal Sulcus AI = anterior Insula

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  • 4. Single-Unit Recording

Electrode is inserted and tip located close to neuron of interest Invasive, so mostly done on animals (eg monkeys) Record “firing” of neurons (surges of voltage within neuron)

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Typical Results

... from Wolfram Schultz’ lab Recordings from dopamine neurons in substantia nigra

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Can Provide Very Detailed Info:

“Adaptive Encoding:” Firing

  • f dopamine neurons at

reward delivery is SCALED by risk (reward VARIANCE) ... which is the optimal way to encode prediction errors! (Fiorillo, Tobler, Schultz, Science 2005)

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  • 5. EEG

Record electric activity at nodes positioned on scalp (10 to more than 100) Current recorded is small – millivolts, even microvolts – but significant (Since electric current creates magnetic field, could also record magnetic field: MEG)

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to the first electrode (see Fig 3).

  • 5.1. Frequency Analysis

Disentangle EEG time series at a node in terms of amplitudes for different frequencies (Frequency BANDS)

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  • Table 1 . Type of Brain wave
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SLIDE 8

Frequency Analysis: The Principle

Every time series can be written as the sum of sine waves with different periodicity (frequency) and amplitude...

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But Often The Amplitudes Change...

Need to do LOCAL analysis ... use time- frequency analysis!

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SLIDE 9

5.2. Time-Frequency Analysis

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(About Localization)

Previous slide: localization of source of EEG signal displayed Very tricky to determine this... one needs to solve an inverse problem: many sources could potentially give rise to signal at scalp! (In previous slide: use fMRI localization results as PRIOR in Bayesian analysis of EEG signals at multiple electrodes) While EEG has superb time resolution (ms), it is difficult to perform source localization. For that, we may want to use fMRI. But fMRI:

  • 1. Has bad time resolution
  • 2. Only reveals signals in high-frequency bands (so misses out on the

lower frequency electric activity)

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SLIDE 10
  • 6. functional Magnetic

Resonance Imaging

Exploits “resonance” of atoms with odd number of protons/neurons (eg Oxygen) when exposed to a magnetic pulse Done in “layers” across the brain, within ~2s, each layer presenting “voxels” Resulting BOLD (Blood Oxygen Level Dependent) time series, per voxel, is analyzed using GLM (General Linear Model) Only voxels with significant effects are retained and plotted against a structural scan of the brain: “Statistical Parametric Map”

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Not Invasive, But:

Noisy Claustrophobic Magnetic field is dangerous (3 Tesla usually) (Coolant is too!)

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6.1. The BOLD Signal

... comes with a delay after neuronal activity because it reveals oxygenated blood that moves to neurons that have “worked” - it reflects metabolic activity rather than neuronal activity (Another way to put this: it reflects activity of astrocytes rather than neurons) The delay is called “hemodynamic response” ... and depends on the brain regions (but that we usually ignore in the analysis) Fortunately, the effect of sustained neuronal activity is LINEAR - see picture (rCBF = regional Cerebral Blood Flow)

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Characterizing the Dynamic Perfusion Response to Stimuli of Short Duration

  • K. L. Mikrt,
  • W. M. Luh, T. T. Liu, A. Martinez, T. Obata, E. C. Wang, L. R. Frank and R. B. Buxton

University of California ut San Diego, and +Stanford University, California

Introduction: Recent advances in perfusion imaging en- able fMRl studies of the regional cerebral blood flow (rCBF) response to brain activation. One important char- acteristic of this response is its relationship to stimulus

  • duration. In particular, a linear time-invariant relation-

ship would indicate that the flow response is a convo- lution of the presented stimulus with a hemodynamic (impulse) response. The accuracy of such a model has implications for the general characterization of the cere- bral response, as well as for the design and analysis of fMRI studies [l]. Using a linearity analysis, we compare the rCBF response to visual stimuli of short duration to previously reported data in the motor cortex [Z]. Methods: In each of two experiments (motor and visual stimuli) arterial spin labeling (ASL) data was collected in 3 subjects using PICORE QUIPSS II [3] with an EPI acquisition (TR=Zs, TE=30ms, T11=700ms, T12=1400ms, FOV=24 cm, slice thickness=8mm, matrix=64x64). Data for the motor experiment was collected on a GE Signa 1.5T scanner fitted with a local gradient head coil; data for the visual experiment was collected on a Siemens Vi- sion 1.5T scanner fitted with a receive-only surface coil centered over the occipital cortex. Stimulus presenta- tion consisted of 8 cycles of either 2,6 or 18 s of stimulus (finger tapping or radial checkerboard flicker) followed by 19 s without stimulus. Two runs of each stimulus du- ration were collected in each subject. An additional run

  • f the 18 s stimulus pattern was used for identification
  • f activated voxels. The rCBF response was calculated

by subtracting magnetically tagged images from control images acquired at the same timepoint in the stimulus cycle, resulting in a flow measurement at each second of the stimulus. This response to a single cycle of stimu- lus presentation was then temporally smoothed to a 2 s time resolution and expressed as a percent change from

  • baseline. Response linearity was analyzed by summing

shifted replicas of the measured rCBF response to short stimuli to match the duration of longer stimuli. Results: The results of the linearity analysis are shown in Figure 1. As previously reported [2], the flow response in the motor cortex appears to be fairly consistent with a linear relationship to stimulus duration, although the 2 s response makes a slight overprediction of the 6 s re-

  • sponse. In contrast, the flow response in the visual cor-

tex exhibits a strong, consistent nonlinearity: an over- prediction of the long duration response by the short duration response. This nonlinearity is very similar to previously reported findings of the BOLD response [4]. Modeling: We tested whether the observed nonlineari- ties are consistent with a simple nonlinear model for the neural response to a block stimulus followed by a linear transformation from the neural response to rCBF response (see Figure 2). This model takes into account habituation effects of neural firing rates [4]. The neural response model takes parameters TV, a decay time con- stant; td, an onset delay; and a, the amount the initial response overshoots the steady-state response. To test

2s “s. 6s 2s YS. 18s 6s YS. 18s

Figure 1: Linearity analysis of motor and visual flow data.

Titles indicate the short-term response used in prediction (gray) and measured long-term responses (black).

if the measured flow responses were consistent with a linear transformation of such a neural response, we con- volved the neural response model with a simple model for the hemodynamic response (a gamma-variate func- tion with width parameter (FWHM) wh). We found that a single set of parameters was able to describe all 3 du- ration responses for each stimulus type: in the motor

COl-tt?X,

Tn=o.%,td=o.65S, P0.75, wh=5.&; in the ViSUti

cortex (see Figure 3), Tn=0.5S,td=1.5S, a=3, wh=6.2s. Figure 2: Stimulus response model. Displayed models fit

motor data (dashed) and visual cortex (solid).

Figure 3: Flow model fit (black) for visual data (gray). Conclusion: The rCBF response to brief stimuli exhibits different dynamics in the motor and visual cortices. Flow in the motor cortex is fairly consistent with a lin- ear relationship to stimulus presentation pattern; flow in the visual cortex appears nonlinear. Both rCBF re- sponses are consistent with a linear transformation of a simple nonlinear neural response model. References: 111 Dale, A. et al., EZBM,

5:329 (1997).

[21 Miller, K.L et al., Proc., 7th ISMRM, 381 (1999). [31 Wong, E.C. et al., MRM, 39:855 (1998). [41 Boynton, et al., J. Neuroscience, 16(13):4207 (1996).

  • Proc. Intl. Sot. Mag. Reson. Med. 8 (2000)

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6.2. Statistical Analysis: GLM

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GLM

Y data are BOLD data filtered for low-frequency effects and normalized X data are adjusted for hemodynamic response Errors are AR(1), hence appropriate estimation is GLS

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Inference

... has to take into account that we are looking at LOTS of t statistics, and there will always be a fraction that will be significant So, correct for multiple comparisons

  • 1. Rudimentary: choose low p level (0.001) and minimum size of

cluster (say, 50 voxels)

  • 2. Formal statistics:
  • Whole brain correction (tough!)
  • Small volume correction (usually when you look at regions of

interest; center around coordinates where others found significant effects)

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Further “Sanity” Checks

If you know there are behavioral differences, then hope to see corresponding effects in signal strength across subjects Use cross-validation whenever possible: estimate GLM

  • n all subjects except one at hand, and then predict

BOLD for that subject; then plot predicted BOLD against subject characteristics for all subjects and report correlation strength

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Example

Task... Localize activation correlating with p and p^2 (p = probability of reward) Differentiate between short effect (“phasic”, 1s) and (subsequent) long effect (“tonic”, 6s)

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1s! ~6s!

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Localization

LEFT: activation correlating with p, phasic RIGHT: activation correlating with p^2, tonic (notice: NEGATIVE correlation)

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Now Look At Exact Shape

1.Pick voxel within these locales with maximum t-stat 2.Take average BOLD across (18) subjects (diamonds) and plot against p, to see whether effect is really:

  • Linear (reflecting expected reward)
  • Inverse U shaped (reflecting reward variance)
  • 3. Plot range (2 standard deviations)

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p

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p^2

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  • 7. Pharmacology

(From slides that Benedetto de Martino passed on; Benedetto is at UCL, UK)

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Why should I care?

Computations in the brain are modulated by neurotransmitters and they are at the core of many computational theories (e.g. DA - prediction error) You can use drugs to complement your experiments and study causality rather than only correlation (fMRI) All the genetic studies in cognitive neuroscience involve polymorphisms of proteins well studied in pharmacology When you pop a pill or drink a coffee you have a rough idea on what is going on in your body

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Temporal characteristics of a drug effect

Duration of action averse response no therapeutical effect Therapeutic window peak effect Drug Effect (plasma concentration) Time

  • nset

effect lag period

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General principal for a metabolism of a drug

  • Drugs often have to

be lipophilic or hydrophobic in order to be accessible to cells and reach their site

  • To be eliminated (excrete) drugs

need to change this physical property and become hydrophilic

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How do you convince a drug to love water and hate oil?

Original state Phase I Phase II

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Where are drugs metabolised?

Phase I Phase II

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Drug metabolism interaction

Be wary of the apparently innocuous grapefruit! Anti-cholesterol Anxiolytic Anti-histaminic Seldane

(retired from the market)

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Repeated administration

(Reaching the Steady-State)

CSS = Fidose CLiT

Think carefully about the half-life of the drug you administer for a study since it may take longer than you think to metabolize a substance with a long half-life !

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BBB transport :An example : Dopamine vs. L-Dopa

Pass the BBB Does not pass the BBB

using the amino acid transporters

Blood-Brain-Barrier

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The Dopaminergic system

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Dopamine receptors

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Parkinson’s disease

Why they degenerate?

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Anti-Parkinson drugs

Thalamus Tractus pyramidalis Globus pallidus medialis Globus pallidus lateralis Nucleus caudatus putamen Nucleus subthalamicus Reticularis Substantia nigra Compacta 1 2 3 2 Anti-Parkinson Drugs. Figure 1 Extrapyramidal wiring diagram of the basal ganglia in Parkinson’s disease. Arrow heads: activation; arrow beams: inhibition; solid lines: normal neurotransmission; double lines: increased neurotransmission; broken lines, diminished neurotransmission; red: glutamate excitatory; blue: GABA inhibitory; green: dopamine excitatory (D1 receptors, 2) and inhibitory (D2 receptors, 1, 3); yellow: acetylcholine. (from Feuerstein TJ. Antiparkinsonmittel, Pharmakotherapie des Morbus Parkinson. In: 5).

Precursor: L-DOPA DA-Agonist: Pergolide and Cabergoline MAO- inhibitors: Selegiline Ach agonist: Benzatropine

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Cocaine

Target: Block the Reuptake

  • f DA

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