Cognitive neurobiology
HC1: Neurobiological techniques
MRI and fMRI:
Electrical induction = a moving magnetic field induces an electric field (and vice versa)
which causes measurable electric current to flow through e.g., a wire.
MRI (Magnetic Resonance Imaging) =
- A superconducting magnet produces a constant magnetic field. The measuring coil
detects miniscule fluctuations in the electric field.
- All hydrogen protons align in the same direction due to an external magnetic field. B1
tilts the magnetic field (like squeezing a spring). The way it recovers after release of
the magnetic field differs depending on the molecule and tissue. This creates the
contrasts in the image.
- Many different contrasts are possible by combinations and sequences of different
magnetic fields.
When the hydrogen molecules move back to the original place after release, it creates a
current in the measuring coil. B0 means there is no movement of the protons because there
is netto no magnetic field.
fMRI (functional Magnetic Resonance Imaging) =
- Functional MRI is made possible by the fact that M0 (M0: magnetic field of proton)
recovers more slowly in oxygenated blood than in deoxygenated blood.
- By correlating the measured signal with this model response, it is possible to
determine when and how strongly the tissue was activated.
- Compare the activity when the stimulus is present with when no stimulus is present.
BOLD signal = Blood Oxygen Level Dependent. BOLD is not an absolute measure of
activity; it measures relative activity (to baseline). Yellow blobs in the image of the brain
indicate spots with statistical differences between conditions.
- Haemodynamic response = blood releases oxygen to active neurons at a greater
rate than to inactive neurons. This causes a change of the relative levels of
oxyhemoglobin and deoxyhemoglobin (oxygenated or deoxygenated blood) that can
be detected on the basis of their differential magnetic susceptibility.
Advantage Disadvantages
You can measure a whole, active human You don’t measure the neuronal activity, but
brain oxygen consumption (fMRI)
It can be combined with many kinds of Do all forms of neural activity consume the
cognitive task same amount of oxygen?
• Action potentials vs. synaptic potentials?
, • Excitation vs. Inhibition?
Non-invasive Only correlational; you don’t know the effect
of the measured ‘activity’
Limited temporal and spatial resolution
Behavioral task is limited by the scanner
Expensive and time consuming
Blocked design: The stimulus is given at a very precise and contant pattern.
- Stimuli are often presented in quick succession in blocks between baseline periods
- Signal increases to plateau
- Multiple trials needed for good SNR (signal-to-noise ratio)
- No information about duration or time course of activation
- Only possible for simple tasks (‘yes or no stimulus response?’)
- CONS = costly, takes time, needs a very precise setup.
- PRO = every second is known.
Event related design: The stimulus is given at random times to study event related
response. The person in the MRI scanner does not know when the stimulus is coming, so it
is unpredicted.
Between stimuli the signal goes back to the baseline.
- Information about duration and time course of activation is available
- Complex tasks are possible
- Signal-to-noise ratio can be worse because:
- There are netto smaller signals
- Less trials in the same time / the same budget
- More complex tasks have more conditions; fewer trials per condition.
Electrical recordings:
Electrical recordings =
- Electrodes in the extracellular medium can pick up two types of signals:
1. Action potentials / Spikes
2. Local Field Potentials (LFP):
- A combination of transmembrane currents from many neurons near
the electrode; a summed transmembrane currents at one specific site
in the brain.
, - LFPs are a linear superposition of the electric potentials that are
generated by separated sinks and sources. The excitatory synaptic
currents on the apical dendrites (current sink) and resulting return
currents on the basal dendrites (current source) of cortical pyramidal
neurons are separated in space. Sinks and sources occur
simultaneously, at different locations of a neuron, such that the net
transmembrane current of the entire neuron is (virtually) zero.
- The largest and most clearly observable fluctuations in LFP arise from
correlated (simultaneous) inputs into brain structures where bipolar
neurons are aligned in cortical layers. Cortical LFPs can be recorded
from outside the skull (EEG).
- LFPs are used to measure oscillations. Alfa, beta, gamma → different
frequency bands.
- Information is encoded in spikes by variations in the number of spikes (spike rate),
the timing and sequences of spikes.
EEG (electroencephalogram) =
- Advantages = non-invasive, high temporal resolution
- Disadvantages = signal distortion and attenuation → difficult to interpret the signals,
skin dampens the signal and you measure a summation of signals.
No BMI (Brain Machine Interface) with EEG, because the signal is not precise enough.
ECoG (electrocorticography) =
- Disadvantage = invasive, also summated activity measured
- Advantage = better signal compared to EEG
Needed to measure spikes and LFPs:
- Electrode array into the brain
- Other electrodes
- Amplifiers, converters and recording PC
- Behavioral setup
- Laboratory animals
Tetrodes = four entangled electrodes (distance measure, like binocular view)
Silicon probes = used to record LFPs in different cortical layers. The fixed distance
between recording electrodes enables studying the relationships between cortical layers.
Tetrodes can measure spike data of better quality. Silicon probes offer a variety of options for
the number of electrodes, spacing between electrodes etc.
- Recording location can be estimated by LFP profile and histology (after recording)
(“now i’m in hippocampus”).
Intracellular recording technique = allows the recording of the membrane potential of a
single neuron (or even the current through a single ion channel) using a patch pipette.
Advantage Disadvantage
direct measure of neuronal activity invasiveness (there are invasive and
non-invasive techniques)
, high temporal resolution limited number of neurons can be studied
limited applicability to humans
Optogenetics:
Optogenetics = a method to control the activity of a neuron using light and genetic
engineering.
- A powerful technique to explore causal links in neural systems
- (Relatively) easy to use
- It can be integrated within most experimental setups: in vitro, slices, in vivo, within
behavioral paradigms, imaging and electrophysiology…
- CONS: Invasive, limited applicability to humans, dependent on light.
Correlation does not necessarily explain causality. Researchers are usually interested in
finding causal effects, and one possible solution is to manipulate neuronal activity and verify
the effects of such manipulations.
Characteristics of optogenetics: reversible, graded (not all-or-none), cell-type specific, both
positive and negative, high temporal and spatial specificity.
Main components of a setup for optogenetics:
1. Opsins (= light sensitive ion channels)
- controlling neural activity with light
2. Viral vectors and/or transgenic animals
- limiting viral expression to specific neuronal subpopulations by using:
- cell-type specific promoters
- cre-lox recombination system
3. Light sources and light manipulation
4. Integrate optogenetics with a pre-existing experimental setup (electrophysiology,
behavior, imaging,etc.)
You can silence a single brain area by:
- blocking sodium/potassium channels
- promoting chloride
- inhibit interneurons
DREADDs:
DREADDs = Designer Receptors Exclusively Activated by Designer Drugs.
Pharmacogenetic approach: pharmacological on/off switch affecting only
genetically modified cells. Unique modifier receptors responding to a unique drug.
3 steps of DREADDs:
1. Make your desired receptor – activator or inhibitor
- Engineered G-protein coupled receptors
- Responding only to a specific drug
- Responding only with a specific action
HC1: Neurobiological techniques
MRI and fMRI:
Electrical induction = a moving magnetic field induces an electric field (and vice versa)
which causes measurable electric current to flow through e.g., a wire.
MRI (Magnetic Resonance Imaging) =
- A superconducting magnet produces a constant magnetic field. The measuring coil
detects miniscule fluctuations in the electric field.
- All hydrogen protons align in the same direction due to an external magnetic field. B1
tilts the magnetic field (like squeezing a spring). The way it recovers after release of
the magnetic field differs depending on the molecule and tissue. This creates the
contrasts in the image.
- Many different contrasts are possible by combinations and sequences of different
magnetic fields.
When the hydrogen molecules move back to the original place after release, it creates a
current in the measuring coil. B0 means there is no movement of the protons because there
is netto no magnetic field.
fMRI (functional Magnetic Resonance Imaging) =
- Functional MRI is made possible by the fact that M0 (M0: magnetic field of proton)
recovers more slowly in oxygenated blood than in deoxygenated blood.
- By correlating the measured signal with this model response, it is possible to
determine when and how strongly the tissue was activated.
- Compare the activity when the stimulus is present with when no stimulus is present.
BOLD signal = Blood Oxygen Level Dependent. BOLD is not an absolute measure of
activity; it measures relative activity (to baseline). Yellow blobs in the image of the brain
indicate spots with statistical differences between conditions.
- Haemodynamic response = blood releases oxygen to active neurons at a greater
rate than to inactive neurons. This causes a change of the relative levels of
oxyhemoglobin and deoxyhemoglobin (oxygenated or deoxygenated blood) that can
be detected on the basis of their differential magnetic susceptibility.
Advantage Disadvantages
You can measure a whole, active human You don’t measure the neuronal activity, but
brain oxygen consumption (fMRI)
It can be combined with many kinds of Do all forms of neural activity consume the
cognitive task same amount of oxygen?
• Action potentials vs. synaptic potentials?
, • Excitation vs. Inhibition?
Non-invasive Only correlational; you don’t know the effect
of the measured ‘activity’
Limited temporal and spatial resolution
Behavioral task is limited by the scanner
Expensive and time consuming
Blocked design: The stimulus is given at a very precise and contant pattern.
- Stimuli are often presented in quick succession in blocks between baseline periods
- Signal increases to plateau
- Multiple trials needed for good SNR (signal-to-noise ratio)
- No information about duration or time course of activation
- Only possible for simple tasks (‘yes or no stimulus response?’)
- CONS = costly, takes time, needs a very precise setup.
- PRO = every second is known.
Event related design: The stimulus is given at random times to study event related
response. The person in the MRI scanner does not know when the stimulus is coming, so it
is unpredicted.
Between stimuli the signal goes back to the baseline.
- Information about duration and time course of activation is available
- Complex tasks are possible
- Signal-to-noise ratio can be worse because:
- There are netto smaller signals
- Less trials in the same time / the same budget
- More complex tasks have more conditions; fewer trials per condition.
Electrical recordings:
Electrical recordings =
- Electrodes in the extracellular medium can pick up two types of signals:
1. Action potentials / Spikes
2. Local Field Potentials (LFP):
- A combination of transmembrane currents from many neurons near
the electrode; a summed transmembrane currents at one specific site
in the brain.
, - LFPs are a linear superposition of the electric potentials that are
generated by separated sinks and sources. The excitatory synaptic
currents on the apical dendrites (current sink) and resulting return
currents on the basal dendrites (current source) of cortical pyramidal
neurons are separated in space. Sinks and sources occur
simultaneously, at different locations of a neuron, such that the net
transmembrane current of the entire neuron is (virtually) zero.
- The largest and most clearly observable fluctuations in LFP arise from
correlated (simultaneous) inputs into brain structures where bipolar
neurons are aligned in cortical layers. Cortical LFPs can be recorded
from outside the skull (EEG).
- LFPs are used to measure oscillations. Alfa, beta, gamma → different
frequency bands.
- Information is encoded in spikes by variations in the number of spikes (spike rate),
the timing and sequences of spikes.
EEG (electroencephalogram) =
- Advantages = non-invasive, high temporal resolution
- Disadvantages = signal distortion and attenuation → difficult to interpret the signals,
skin dampens the signal and you measure a summation of signals.
No BMI (Brain Machine Interface) with EEG, because the signal is not precise enough.
ECoG (electrocorticography) =
- Disadvantage = invasive, also summated activity measured
- Advantage = better signal compared to EEG
Needed to measure spikes and LFPs:
- Electrode array into the brain
- Other electrodes
- Amplifiers, converters and recording PC
- Behavioral setup
- Laboratory animals
Tetrodes = four entangled electrodes (distance measure, like binocular view)
Silicon probes = used to record LFPs in different cortical layers. The fixed distance
between recording electrodes enables studying the relationships between cortical layers.
Tetrodes can measure spike data of better quality. Silicon probes offer a variety of options for
the number of electrodes, spacing between electrodes etc.
- Recording location can be estimated by LFP profile and histology (after recording)
(“now i’m in hippocampus”).
Intracellular recording technique = allows the recording of the membrane potential of a
single neuron (or even the current through a single ion channel) using a patch pipette.
Advantage Disadvantage
direct measure of neuronal activity invasiveness (there are invasive and
non-invasive techniques)
, high temporal resolution limited number of neurons can be studied
limited applicability to humans
Optogenetics:
Optogenetics = a method to control the activity of a neuron using light and genetic
engineering.
- A powerful technique to explore causal links in neural systems
- (Relatively) easy to use
- It can be integrated within most experimental setups: in vitro, slices, in vivo, within
behavioral paradigms, imaging and electrophysiology…
- CONS: Invasive, limited applicability to humans, dependent on light.
Correlation does not necessarily explain causality. Researchers are usually interested in
finding causal effects, and one possible solution is to manipulate neuronal activity and verify
the effects of such manipulations.
Characteristics of optogenetics: reversible, graded (not all-or-none), cell-type specific, both
positive and negative, high temporal and spatial specificity.
Main components of a setup for optogenetics:
1. Opsins (= light sensitive ion channels)
- controlling neural activity with light
2. Viral vectors and/or transgenic animals
- limiting viral expression to specific neuronal subpopulations by using:
- cell-type specific promoters
- cre-lox recombination system
3. Light sources and light manipulation
4. Integrate optogenetics with a pre-existing experimental setup (electrophysiology,
behavior, imaging,etc.)
You can silence a single brain area by:
- blocking sodium/potassium channels
- promoting chloride
- inhibit interneurons
DREADDs:
DREADDs = Designer Receptors Exclusively Activated by Designer Drugs.
Pharmacogenetic approach: pharmacological on/off switch affecting only
genetically modified cells. Unique modifier receptors responding to a unique drug.
3 steps of DREADDs:
1. Make your desired receptor – activator or inhibitor
- Engineered G-protein coupled receptors
- Responding only to a specific drug
- Responding only with a specific action
