Download 4. Neurotransmitter imaging

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STROKE
WHAT? Cerebrovascular disorder, brain dysfunction due to abnormal blood supply
CLINICAL SIGNS? * sudden onset
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Focal neurological deficit (associated with specific vascular territory)
Associated symptoms:
o (thunderclap) headache (sudden-onset, takes sec/min to reach max
intensity)
o Nausea/vomiting
o Reduced consciousness/coma
CELEBRAL BLOOD SUPPLY:
- Anterior cerebral artery
-> sensorimotor deficit in contralateral leg
- Middle cerebral artery
-> sensorimotor deficit in contralateral face & arm
-> aphasia (language disorder, dominant hemisphere)
/anosognosia (deficit of self-awareness, non- dominant
hemisphere)
- Posterior cerebral artery
-> homonymous hemianopsia (contralateral): visual field loss
on the same side of both eyes
ETIOLOGICAL CLASSIFICATION:
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Hemorrhagic (accumulation of blood in cranial vault) (due to:)
o Hypertensive (high blood pressure)
o Cerebral amyloid angiopathy (disease of blood vessels in which toxic protein
(amyloid) deposits form in the walls of the blood vessels of the CNS)
o Vascular malformation
Subarachnoid hemorrhage (bleeding into the subarachnoid space)
o Ruptured aneurysm (weakness of the wall of a celebral artery or vein causes a
localized dilation or ballooning of the blood vessel)
Cerebral venous sinus thrombosis (presence of acute thrombosis (bloot blot) in the dural
venous sinuses, which drain blood from the brain)
o Female
o Smoker
o Oral contraceptives
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Ischemic (insufficient blood flow to the brain, causing a shortage of oxygen supply and thus
to the death of brain tissue)
o Atherothrombotic: stenosis (abnormal narrowing in blood vessel or other tubular
organ or structure) of major artery, large infarcts
o Small vessel disease: small perforating arteries, typically “lacunar” infarcts (stroke
that results from occlusion of one of the penetrating arteries that provides blood to
the brain’s deep structures), hypertension/diabetes, angiography looks normal
o (cardio-) emboligenic: clot originates from outside the brain, eg arterial fibrillation,
endocarditis, paradoxal embolus
Ischemic <> TIA (transient ischemic attack):
 Resolves within 24h
 No infarct zone (on MRI)
 Warning sign! => search for origin and start prevention
Infarct core = dead tissue <> penumbra = salvageable tissue/tissue at risk, reduced perfusion
Ischemic stroke, TREATMENT:
1. IV thrombolysis: recombinant tissue plasminogen activator (=r-TPA): protein that is involved
in the breakdown of blood clots. It catalyzes the conversion as an enzym of plasminogen to
plasmin (the major enzyme responsible for clot breakdown). Within 3 (-4.5)h, 30-40%
success. Elegibility criteria -> contra-indications!
2. Mechanical thrombectomy, generally <6h, but depends on imaging
A stroke is considered an emergency because early recognition of a stroke is deemed important as
this can expedite diagnostic tests and treatment.
Acute phase (=immediate post-injury healing processes) -> Goal: reperfusion
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Subacute/chronic phase = prevention: investigate (“stroke workup”), treat (risk factors, direct
causes), revalidation, support system
EPILEPSY
= recurrent, spontaneous seizures (at least 2 unprovoked).
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Positive or negative symptoms
Depend on location of seizure activity within the brain
CLASSIFICATION:
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According to seizure type:
o Primary generalized
o Partial (possibly wit secondary generalization)
 Simple: no change in consciousness
 Complex: change in consciousness (<> unconscious)
According to etiology:
o Genetic
o Structural/metabolic
o Unknown
TREATMENT ALGORITHM
refractory epilepsy = not
curable with medication!
Anti-epileptic
drugs
(AEDs): efficacy = 2/3,
side-effects!
Resective
surgery:
presurgical evaluation
° patient motivation (not
okay if they just want to
live without meds)
° is there a single epileptic
focus? (localization with imaging)
° is the focus resectable “without” functional deficit? (wada-test, fMRI, intracranial
mapping)
functional
° probability of success (temporal lobe = 60%, extratemporal = 35%)
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Neuromodulation: ZIE LATER
Impact: precautions: no driving! Avoid specific activities/jobs!
PNES = psychogenic non-epileptic seizures: seizure-like symptoms with no abnormal brain activity.
Can be difficult to diagnose. Higher prevalence in epilepsy patients. Treatment: psychotherapy.
PARKINSON’S DISEASE
= hypokinetic movement disorder
CLINICAL FEATURES:
Main features: - Tremor
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Rigidity
Akinesia (*) = absence, poverty, or loss of control of voluntary muscle movements
Postural instability
(*)bradykinesia = reduced armswing while walking, short shuffling steps, hypomimia (=”Parkinson
mask”, reduced degree of facial expression), dysdiadochokinesis (impaired ability to perform rapid,
alternating movements), micrographia (abnormally small, cramped handwriting)
Non-motor symptoms: - cognitive impairment, bradyphrenia (slowness of thought)
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Autonomic disorders: orthostatic hypotension (head rush, due to low blood pressure),
urinary and sexual dysfunction
Sleep disorders: restless legs, vivid dreams
PATHOPHYSIOLOGY:
Degeneration of dopaminergic neurons in SNc (substantia nigra pars compacta) -> reduced
dopaminergi input to striatum -> overactivity of indirect pathway (activates GPi), reduced activity
direct pathway -> inhibition of thalamo-cortical connections, inhibition of movement.
TREATMENT:
1. Drug therapy -> side effects! (therapeutic window between akinesia <-> dyskinesia, rigidity <->
psychosis)
Problems: - reduced response to L-dopa
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ON/OFF phenomenon (on-time consistently associated with dyskinesis)
Disease progression: therapeutic need increases
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2. Deep brain stimulation (ZIE LATER)
3. Duodenal (12vingerige darm) administration of levodopa: expensive, technical problems, good
response
4. Additional treatment (!): physical therapy, ergotherapy,…
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CT
3D view of a section of the body. Scans are made by rotating an X-ray beam around the patient. At
each position projections of the transmitted X-rays through the object are obtained. Typically, a
logarithmic transformation of the ratio of a blank scan and a transmission scan is performed first.
After this step, one can transform these transmission images into projections of linear attenuation
coefficients. From these projections, image reconstruction techniques (like filtered backprojection or
iterative methods) determine the linear attenuation coefficients per voxel. The output of a CT image
is a map of voxels containing the density relative to water. Hounsfield units (HU) are used, which
rescale the density to a scale where air is equal to -1000 HU and water is equal to 0 HU.
First select region of interest on a planar view, then perform tomographic CT
+ Extremely fast technique with high throughput
BRIGHT/DARK?
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More dense tissue, brighter on CT
Any calcified structure (like the skull) appears bright
New hemorrhage in the brain is also bright
Water (or CSF) looks dark on CT
USED FOR?
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Assessment of acute stroke
Head injury
Detect aneurysms, blood clots, skull injuries, brain tumors
Iodine based contrast agent is often used for increasing contrast in blood
SCANNING TECHNIQUES:
1. Non-contrast enhanced CT: imaging modality used to identify potential skull fractures
Bone has the highest density on the CT scan -> skull fractures can be easily seen on the CT scan
CT scan is almost always the first imaging modality used to assess patients with suspected
intracranial hemorrhage. Acute blood is hyperdense. Hyperdensity due to the high (hemo)globin
content of retracted clot or sedimented blood (when blood becomes older, globin breaks down and
loses his hyperdense appearance, beginning at the periphery).
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2. CT angiography: visualization of arterial and venous vessels with contrast agents.
* local anaesthesia
* catheter inserted into an artery
* catheter guided to an artery in the neck
* a contrast agent is injected through it (iodine: high absorption of x-rays -> use x-rays to see blood
flowing inside the artery)
* the outline of blood flow through the arteries is then seen on the X-ray (angiogram)
Look for aneurysms, vascular tumors, narrowing and blockage of the vessels -> typically ordered for
the evaluation of stroke to detect blockages and narrowing of the arteries.
There are some important technical aspects to enhance the quality of the exam:
1. The system needs to be able to perform fast synchronized scanning. This is mostly required to
capture the moment of contrast agent passing through region of interest.
2. Quite often a larger region of the brain is of interest, in this case large axial FOV multislice CT
systems have an important advantage over systems with a small axial FOV.
3. CT perfusion imaging
Injection of contrast agent, then dynamic CT of brain is performed -> time activity curves: evolution
of HU over time per voxel.
The baseline value is the HU value of blood and the amount of contrast agent fixed to the blood
determines the increase in HU.
rCBF regional cerebral blood flow
rCBV regional cerebral blood volume
TTP (time to peak)
MTT (mean transit time) = describes the time it
requires for the contrast agent to pass through
the voxel. It can be estimated by determining the
width of the curve on top of the baseline HU
value.
CVA cerebrovascular accident
 Slight disturbances lead to extension TTP
and MTT
CT perfusion maps -> normally largely symmetrical perfusion rates, if something is wrong -> not
symmetrical
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4. Interventional CT techniques
Typical procedure done with iCT: Embolization: non-surgical procedure to “plug” selected blood
vessels to prevent blood flow to the Ateriovenous Malformation (AVM). Liquid glue, PVA spheres or
Onyx liquid is used to plug.
New developments: - more detectors
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3D visualization based on multiple views
Lower dose
Efficient user interaction
Limitations: * images of soft tissue are not as vivid as a MRI image
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Not many contrast options like in MRI scans
Not recommended for repeated use (radiation dose)
Recommendation not more than 2 scan/year
Cannot be performed on a pregnant woman
Novel developments in CT:
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Iterative reconstruction
Dual energy CT: enables more accurate differentiation between materials, used to identify
and remove bone automatically. Differentiate between contrast agents and hemorrhage.
Dose reduction
MRI
CT
MRI
Fast
Slower
Available at emergency
No ionizing radiation
Less expensive
Motion effects
Less sensitive to motion
More options for contrast
Less claustrophobic
Soft tissue
Dense tissue
Bone is visible
Hemorrhage
Most other cases
Head injury
Acute imaging
An MRI scanner is composed of 3 main components:
1. A strong magnet for creating the B0 field (typically 1.5T, 3T or 7T)
2. The gradient coil for inducing a slope in the axial direction and the other directions
3. RF coils for transmitting and receiving the RF pulses.
Process:
Step 1: put object in strong magnetic field
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Step 2: transmit radio waves of right frequency into subject
Step 3: turn off transmission
Step 4: receive radio waves emitted by subject
Step 5: convert measured RF data to image
Effect of RF pulse: reduction in longitudinal
magnetization along z-axis, phase coherence
in transverse magnetization direction. Two
effects:
T1-relaxation: recovery
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Recovery of longitudinal orientation
of M along z-axis
T1 time for 63% recovery of
longitudinal magnetization
Due to spin-lattice interactions
T2-relaxation: dephasing
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Loss of transverse magnetization Mxy
T2 time for 37% loss of original
transverse magnetization
Caused by spin-spin interactions
BRIGHT/DARK?
Different tissues have different relaxation times and this is used to generate different contrasts.
Bright/dark on T1: fat is bright, white matter is brighter than grey matter, water is dark
Bright/dark on T2: water is bright, blood is bright, white matter is darker than grey matter
In reality T2 is replaced by T2*= due to effects of field inhomogeneities of the main magnetic field,
the dephasing and relaxation will appear faster.
SEQUENCES: used in combination with CT for stroke (for brain imaging, MRI 3T is best choice), a lot of
different sequences for anatomical and functional imaging
MRI gives information about ageing blood
Sequences for anatomical imaging (T1w, T2w, Flair, MR angiography, gradient echo)
Sequences for functional imaging (Diffusion Weighted Imaging (DWI), functional MRI (fMRI) and
Perfusion) which makes it possible to derive the Apparent Diffusion Coefficient (ADC) and perform
Diffusion Tensor Imaging (DTI).
CONTRAST AGENTS:
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Chemicals into blood: will alter MRI signal by affecting magnetic environment of H nuclei
Biologically inert
Increase contrast of some tissue types
Most common used is Gd-DTPA
DCE (= DYNAMIC CONTRAST ENHANCEMENT) MRI
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Inject contrast agents rapidly
Take multiple images of brain to observe its influx
Rapid T1-weighted images
Shows accumulation of contrast agent in different regions of the brain
It allows to determine the wash-in and wash-out contrast kinetics within tumors
DISEASES:
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Alzheimer: athropy (grey matter loss visible on MRI). Imaging is used to rule our other
conditions that cause symptoms similar to AD but require different treatment
Multiple sclerosis: typical distribution of lesions in white matter. Role of MRI: show multiple
lesions in space, differentiate from vascular, show new lesions on follow up scan
EMISSION TOMOGRAPHY
SPECT & PET: application fields in functional neuroimaging:
SPECT perfusion scan:
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Tracer used is Tc-99m HMPAO or Tc-ECD
Advantage of this tracer is trapping in brain: tracer is ‘fixed' and representative of perfusion
during injection
Scan can be performed after injection
Activation can be done in normal environment (outside scanner)
1. Epilepsy
Epileptic seizures: patients are monitored during a couple of days with simultaneous video and EEG
recordings. Perfusion SPECT can be used to identify the zone with higher perfusion during a seizure.
This zone is likely to cause the epilepsy.
First, the patient will get a baseline perfusion SPECT (so called interictal scan). Then, the patient is
injected during a seizure by an onsite injection system for the radiotracer. When the seizure is over,
the patient is scanned again to have an ictal (seizure) image, which will show a hyperperfused area
with respect to the baseline scan. This technique is still challenging because of the need for an onsite
injection system and an available SPECT system. A pump is connected to the patient's forearm and is
filled via a pressure extension line. Technician supervises video EEG of patient and can push remotecontrolled injection when seizure is detected. In the final step the intricate and octal data is analyzed
jointly with the anatomical MRI.
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2. Neuro oncology
Brain tumors: glucose is the main source of energy in brain tumors. FDG (F-2-fluoro-2-deoxyglucose)
has high uptake in grey matter. Uptake can be used to differentiate low grade from high grade
tumors. It is also used for the evaluation of tumor recurrence. For most studies, the scans will be
combined with MRI. FDG contrast improves with time (longer time PET, better contrast) ->
disadvantage: long acquisition time. Other tracers, which can give a higher contrast and additional
information than FDG, are also used.
3. Dementia
Historically SPECT in combination with Tc-99m HMPAO or Tc-99m ECD was used, but due to larger
availability of PET systems (and better image quality) shift to FDG-PET.
When PET scans are processed in a uniform manner by Gaussian filtering and spatial normalization,
they allow for a discrimination between AD and controls with 93 percent sensitivity and 93 percent
specificity.
No treatment for AD, but any drug should be administered in early phase of disease -> early
detection, selecting patients for certain drug therapies, test disease-modifying drugs
4. Neurotransmitter imaging
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Exploit the competition between an endogenous (present in body) neurotransmitter and a
radiolabeled ligand
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These bind to the target and can be measured using PET or SPECT
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Gives information on active receptors
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Visualize effect of medication/drugs influencing neurotransmitters
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Relationship between psychiatric and neurological disorders and neurotransmitters
DYNAMIC PET IMAGING AND KINETIC ANALYSIS
Extract from data the “functional or physiological” behaviour of the organ/tumor, e.g. glucose,
oxygen consumption, neuroreceptor density,…
Typical compartment modeling.
Shape and amplitude of time activity curve depends on
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Tracer used
Input function: supply of tracer in arterial blood
“physiology” of tumor/organ
Using model different parametric PET images can be derived
fMRI
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principle: identify regions involved in task by energy consumption (glucose!) in active regions.
Detect changes in blood oxygentation and flow that occur in response to neural activity. When a
brain area is more active it consumes more oxygen and to meet this increased demand, blood flow
increases to the active area.
As a brain imaging technique FMRI has several significant advantages:
1. It is non-invasive and does not involve radiation, making it safe for the subject.
2. It has excellent spatial and good temporal resolution.
3. It is easy for the experimenter to use.
The magnetic field inside the MRI scanner affects the magnetic nuclei of atoms. Normally atomic
nuclei are randomly oriented but under the influence of a magnetic field the nuclei become aligned
with the direction of the field. The stronger the field, the greater the degree of alignment. When
pointing in the same direction, the tiny magnetic signals from individual nuclei add up coherently
resulting in a signal that is large enough to measure. In fMRI, it is the magnetic signal from hydrogen
nuclei in water (H2O) that is detected.
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The brain does not store glucose, the primary source of its energy
When neurons go active, getting them back to their original (polarized) state requires
actively pumping ions back and forth across the neuronal cell membranes.
The energy for these motor pumps is from glucose.
more blood flows in to transport more glucose, also bringing in more oxygen in the form of
oxygenated hemoglobin molecules in red blood cells
Oxy/deoxy Hb different T2*:
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Oxygenated hemoglobin is diamagnetic, deoxygenated hemoglobin is paramagnetic. This
difference in magnetic properties leads to small differences in the MR signal of blood
depending on the degree of oxygenation.
 Significant concentrations of deoxygenated hemoglobin shorten the T2* relaxation time of
the tissue and result in a decrease in signal compared to tissue with oxygenated hemoglobin
 Deoxyhemoglobin induces a local disturbance of magnetic field => MRI signal loss
 No local disturbance => MRI signal gain
Stimulated tissue undergoes an increase in blood flow with an increased delivery of oxygenated
hemoglobin. The amount of deoxygenated hemoglobin decreases within the tissue, reducing the
concentration of paramagnetic molecules. In the stimulated tissue the amount of susceptibility
reduces and T2* is increased.
 Higher signal in the activated region
= BOLD: blood oxygen(ation) level dependent
One important point to note is the direction of oxygenation change with increased activity. You
might expect blood oxygenation to decrease with activation, but the reality is a little more complex.
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There is a momentary decrease in blood oxygenation immediately after neural activity increases,
known as the initial dip in the hemodynamic response. This is followed by a period where the blood
ow increases, not just to a level where oxygen demand is met, but overcompensating for the
increased demand. This means the blood oxygenation actually increases following neural activation.
The blood flow peaks after around 6 seconds and then falls back to baseline, often accompanied by a
post-stimulus undershoot.
SCANNING METHODOLOGIES: small signal, signal increases during activation, greater signal change
for longer delay. Several scans needed for detecting small change.
Needed: * fast sequences, as one gains in statistical power in collecting multiple images in a short
period. This also leads to the need for activation/control intervals to be short for cognitive reasons.
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echo planar imaging or spiral imaging: EPI requires state-of-the-art gradients; spiral less
demanding on the gradient hardware
data are by single shot acquisitions, which collect entire image from a single excitation
image obtained at each TR (repetition time)
EPI can collect the data for an entire image in 40 milliseconds
Smoothing the data can be done by convolving the stimulus function with a canonical HRF( =
hemodynamic response function).
Limitations: - vascular response to activity is delayed -> limited temporal resolution
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distance between activated neurons and vascular variation in the oxyHb/deoxyHb ratio can
lead to imprecisions in locating the activation zone.
Resting state fMRI (rsfMRI or R-fMRI) is a related method of functional brain imaging. It is used to
evaluate regional interactions that occur when a subject is not performing an explicit task. The
resting state approach is useful to explore the brain's functional organization and to examine if it is
altered in neurological or psychiatric diseases.
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NIRS
= based on molecular overtone and combination vibrations.
It is used to measure brain activity and this is done by measuring the absorption of the near-infrared
light between 650 and 950 nm through the intact skull. It is based on the fact that the absorption
spectra of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) are very different in this range of
wavelength and therefore it is possible to determine the concentration changes of HbO2 and HbR
from diffusely scattered light measurements.
A molecular vibration occurs when atoms in a molecule are in periodic motion. A molecular vibration
is excited when the molecule absorbs a quantum of energy E (E=hv). A fundamental vibration is
excited when one such quantum of energy is absorbed by the molecule in its ground state. When
two quanta are absorbed the first overtone is excited, and so on to higher overtones.
Used in-vivo for blood: NON-INVASIVE!
Measure changes in infrared light absorption and scattering (oxy/deoxy Hb).
fNIRS acquisition modes: continous wave, frequency domain, time domain
BIOELECTRICITY
Neurons use electro-chemical interactions to send signals from one neuron to another neuron or to a
muscle by means of action potentials. Function: control organs and muscles.
Action potential not measurable by EEG/MEG, EPSP is measurable! The extracellular spatial spread of
action potentials is limited to sub-millimeters. It prevents the extracellular fields caused by an action
potential to be potentially measurable in the EEG, since the scalp surface is at least 2 cm away from
the brain tissue. Moreover, because of the short duration of individual action potentials (<1ms)
summation in time of several action potentials is unlikely.
Extracellular field potentials reflect the summation of the extracellular post-synaptic potentials in a
large group of neurons in both space and time. They can be measured in the brain when neurons are
both arranged in parallel over some distance, and receive synchronized synaptic input. The
extracellular post-synaptic currents caused by synchronized synaptic input are matched by reverse
intracellular currents resulting in arrangements of sinks and sources in the different cortical layers.
The electrical fields caused by the sinks and sources propagate trough the skull to the scalp and
evoke measurable potential fields on the scalp surface in the range of ≈100 µV.
Recording EEG (Electroencephalography) signals
4 main hardware components are required: (i) a system of electrodes that are placed on top of the
scalp, (ii) an amplifier to amplify the measured signals, (iii) an analog to digital convertor and (iv) a
recording device.
To acquire high quality data, the proper functioning of the EEG recording electrodes is most critical.
To reduce the scalp-electrode impedance, a conductivity gel is used. This gel serves as a conductive
medium between the electrode and the scalp surface.
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Electrodes applied in standard positions. The EEG shows the time course of the potential between an
amount of chosen electrode pairs.
What do we measure? +- 100000 simultaneously active neurons are needed to generate a
measurable EEG signal. Pyramidal cells are the main direct neuronal sources of EEG signals. Synaptic
currents but no AP generate EEG signals.
Rhytmic activity is a consequence of the rhythmic patterns of actions potentials or rhythmic
oscillations in the membrane potentials of pre-synaptic neurons that give rise to oscillating extracellular currents in the post-synaptic dendrites. The rhythmic patterns arise from feedback
connections between the neurons and can be classified according to the observed frequency
content: - delta rhythms (frequencies < 4 Hz, deeply asleep and not dreaming)
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theta rhythms (frequencies between 4 and 7 Hz, drowsy and drifting down into sleep and
dreams)
alpha rhythms (frequencies between 8 and 13 Hz, very relaxed, deepening into meditation)
beta rhythms (frequencies between 14 and 30 Hz, here we are busily engaged in activities
and conversation)
gamma rhythms (frequencies > 30 Hz, hyper brain activity, which is great for learning)
EEG contains many artifacts = waveform in the EEG which are not related to disorder, eg muscle
artifact due to chewing, 50Hz power line artefacts -> remove! Decompositions into topographies
through EEG source analysis & Blind Source Separation
Clinical applications:
Standard EEG examinations: routine clinical EEG recording. Used to distinguish epileptic seizures
from other or for sleep monitoring. Can be used to monitor the depth of anesthesia and to confirm
diagnose brain death.
Epilepsy is a neurological disorder characterized by abnormal electrical discharges. A seizure is the
clinical manifestation of epilepsy: partial and generalized seizures.
Typical EEG patterns can be observed:
-during a seizure: ictal EEG (rhythmic, high amplitude)
- between seizures: interictal EEG (spikes, slow waves)
Video EEG monitoring:
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Multi-channel long term EEG recording with video recording
EEG and video data are stored that can be reviewed later
Supervision by experienced nurses
Review by neurologist or epileptologist
Information on seizure: video and synchronized EEG
Forward modeling and inverse problem:
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Any EEG source imaging approach is characterized by a forward model of the EEG data and an
inverse technique to find a solution (the estimation of the activity and location of these sources
based on the observations). Depending on the application, there may not be enough information to
find a unique solution, i.e. to clear the unknowns, making the problem ill-posed.
Components forward model in EEG:
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Model for source: The major generators of scalp EEG signals are the synchronized
extracellular post-synaptic currents which flow between the layers of parallel pyramidal
neurons in the cerebral cortex. These currents can be represented using a current dipole. It
represents the postsynaptic currents at the apical dendrites and has 6 parameters: the
position r = [x; y; z], the orientation (ϕ and θ) and the intensity (I). the brain compartment is
divided into a number of elementary volumes and to each volume a fixed dipole is assigned.
(Inverse problem highly underdetermined: ~10000 dipoles, ~100 scalp electrodes)
Head model: Due to computational limitations, early EEG source imaging techniques used
(multi-layer) spherical models to approximate the human head. extra anatomical information
about the human head can be incorporated based on structural images of the head. (MRI &
CT used to made model). No detailed conductivity of all tissues => Therefore, the head is
usually modeled simplified as a set of homogeneous volume conductors with isotropic
conductivity values that are reported in literature based on in-vivo measurements.
Electrode positions, eg default positions
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Inverse problem:
An inverse technique allows to find a unique solution by minimizing the difference between the
generated EEG data and the measured EEG data, i.e. the residuals. Each inverse technique will differ
depending on the nature of the forward model and the cost-function that is optimized in order to
find the optimal dipole parameters, i.e the locations and the intensities of the dipoles.
Evolutions in EEG:
 Mobile/wireless EEG
o Subject can move freely
o Useful for brain computer interface, motor tasks
 High density recording
o 3 channel, 64 channel and 128 channel
o Setup time can become a challenge
Integration of EEG and fMRI: - combines high temporal resolution of EEG with high spatial resolution
of fMRI. Applications: even related potentials, EEG-triggered fMRI of epilepsy
- In cognitive experiment, unique chance to record the brain activity originated by a
stimulation under the SAME experimental conditions
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Challenges: static magnetic field, gradients, rf pulses
 Gradient artefact, ballistocardiegraphic artefact, faraday’s induced noise (motion of the EEG
electrodes, machine motion (helium pump, vibration of the table), physiological motion
(heartbeat, breathing))
MEG
MEG is based on the fact that currents in neurons create very tiny magnetic fields. Liquid helium to
cool, shielding necessary, SQUIDs (Superconducting Quantum Interference Devices) to “translate"
the magnetic field into an electrical current which is proportional to this field.
Very accurate, requires complete stillness, expensive, tiny signal (difficult to detect).
FUNCTIONAL BRAIN CONNECTIVITY
Structural <> functional brain connectivity
 White matter tracts <> intercommunication between grey matter regions
FUNCTIONAL SEGGREGATION: functions are carried out by specific areas/cells in the cortex that can
be anatomically separated: Brodmann areas.
FUNCTIONAL INTEGRATION: Networks of interactions among specialized areas. Functional
interaction of the functionally segregated brain regions.
Functional connectivity = study of temporal correlations between spatially distinct neurophysiological
events.
Effective connectivity = influence one neural system exerts over another and is based on different
hidden neuronal states generating the measurements.
FUNCTIONAL CONNECTIVITY MEASURES:
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Describe the interdependence between the considered functional neuroimaging signals
Most commonly used techniques: EEG & fMRI
Used to assess connectivity patterns during behavioral and cognitive tasks or specific for a
pathology
Properties:
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Undirected vs directed
Bivariated vs multivariate
Time vs frequency
Linear vs non-linear
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Pearson correlation: calculates the instantaneous linear relation between two signals based on the
amplitudes of the signals.
Cross-correlation: investigates the correlation between two time series that are shifted in time with
respect to each other. This allows to assess the directionality of the correlation.
The counterpart of the cross-correlation in the frequency domain is the coherency. The absolute
value of the coherency is the coherence, which detects the linear relation between two signals at a
certain frequency. The phase of the coherency can be used to infer the directionality of the
connection.
Granger causality measures: One time series is said to Granger cause a second one, if inclusion of the
past values of the first into the modeling of the second significantly reduces the variance of the
modeling error. Most of the Granger causality measures are constructed based on an autoregressive
(AR) model, in which the present samples of the signals are predicted using a linear combination of
the past samples. From the coefficients of the AR model many measures can be derived: the
Granger-causality index, the directed transfer function (The DTF is a measure that displays the
indirect and direct information transfer between multiple signals at each frequency) and the partial
directed coherence.
Information based measures: model-free nonlinear techniques to estimate the information between
signals, provide complementary info. E.g. mutual information & transfer entropy.
Difference between DTF and PDC: PDC shows direct flows, while DTF is capable of displaying the
cascade flow (origin of information)
Simulations
= to see how we can obtain the functional connectivity pattern from signals.
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Direct transmission
On the diagonal, the PSD of the different signals is plotted and the
connectivity measures are shown in the off-diagonal boxes. The PSD
shows that there is a peak in power at the simulated seizure frequency
(from 8 Hz to 12 Hz). The COH is symmetric, meaning that the connection
from xi to xj is equal to the one from xj to xi. We find high COH values
between all pairs of signals, with highest values at the seizure frequencies.
The DTF and PDC correctly show the connections from x1 to the others at
the seizure frequency. The values of the PDC are lower due to the
normalization. The PDC is normalized in a way that the outgoing ow of
each channel is 1. The DTF on the other hand is normalized with respect to the incoming ow resulting
in high connectivity peaks around 10 Hz from x1 to the other channels.
Indirect transmission
The COH again has high values for all pair of signals especially around
10 Hz. The DTF shows that the information around the seizure
frequency peak originates from signal x1. High connectivity is seen at
that frequency from x1 to all other channels. High values for the DTF
are also seen at higher frequencies from x2 to x3 and x4 and from x3 to
x4. The PDC only shows the direct connections. From x1 to x2 a high
information flow is observed around 10 Hz. This peak is not found in
the other connections.
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Hidden source
We notice high coherence values between all signals especially
around 10 Hz. There is time delay between the considered signals
because the signal of source A is delayed with different number of
samples to construct x1, x2, x3 and x4. The DTF shows the origin of
information flow, resulting in connections from x1 to the other
signals. With the PDC the same connections as with the DTF are
found, although the amplitude is smaller due to the normalization.
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Unconnected signal
High values of coherence are found between all channels, even between
x1, x2, x3 and the unconnected channel x4. Although stronger connections
are observed between x1, x2 and x3 than between x4 and the other signals.
The DTF shows the connections from x1 to x2 and x3. The PDC shows the
same connections as the DTF, but due to the normalization the peak at the
connection from x1 to x2 and for connection x2 to x3 is not at the same
frequency. The DTF shows peaks for both connections at the same frequency, around 10 Hz.
Functional connectivity from (intracranial) EEG
Intracranial: used for localization epileptic focus. Used to access structures deep within the brain and
to reveal brain activity which is not displayed in scalp EEG recordings.
Seizure onset zone (SOZ): identified by a visual strategy. Problem:




Subjective
Requires advanced expertise
Overestimation?
What if the result is inconclusive?
AIM: replace this visual identification strategy by an objective identification strategy based on brain
connectivity analysis.
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-
-
-
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Directed transfer function connectivity analysis: localization of the seizure onset zone
corresponded in all patients with the visual analysis of the epileptologist and the surgical
resected brain region. Furthermore, the found connectivity pattern was consistent over
multiple seizures in the same patient.
Mutual information analysis of the EEG in patients with AD: information transmission was
found to be lower between interhemispheric electrodes in AD patient compared to controls.
Functional connectivity in single and multislice echoplanar imaging using resting-state
fluctuations: resting state fluctuations from single slice fMRI time series acquisitions are
correlated between the left and right regions of the motor cortex. Procedure: (1) low-pass
filtering (2) selection of region of interest (3) correlation analysis. Correlations to left
hemisphere motor cortex, visual cortex and amygdala are measured in long resting state
scans.
Studying callosal agenesis as it relates to functional connectivity is problematic because: (1) it
is a rare condition, this making it difficult to find subjects (2) since it is a developmental
abnormality, compensatory pathways can be developed.
Detection of functional connectivity using temporal correlations in MR images: the existence
of a functional connection between Broca’s area and Wernicke’s area was confirmed in
healthy subjects at rest. An increase in this functional connectivity when the language system
was actively engaged (when subjects were continuously listening to narrative text) was also
confirmed.
A default mode of brain function: regions of the brain regularly observed to decrease their
activity during attention demanding cognitive tasks -> default mode network
Consistent resting-state networks across healthy subjects: the analysis found 10 patterns
with potential functional relevance, consisting of regions known to be involved in motor
function, visual processing, executive functioning, auditory processing, memory and the so
called default mode network.
Neuromodulation
Neuromodulation methods
Deep Brain Stimulation





Electrodes in deep nuclei
Pulse generator extracranially
Surgery: stereotactic implantation
Workflow: stereotactic frame placement -> MR imaging -> coordinate calculation ->
neurosurgery
Parameter adaption:
- Mono/bipolar/…
- Voltage driven
- Frequency
- Pulse width
 Mostly trial and error
Applications:
- Parkinson’s disease. Target: bilateral stimulation of the subthalamic nucleus
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-
epilepsy (resective epilepsy surgery better results, but people who are not candidates
DBS can be an option). Target: thalamus (anterior nucleus), hippocampus
depression. Treatment with psychotherapy, antidepressants. Refractory depression:
Target: subgenual cingulated cortex (bilateral), identified by H2O-PET, FDG-PET, resting
state fMRI.
Cortical electrical stimulation


-

direct electrical stimulation of cerebral cortex
- electrodes placed over cerebral surface
- current injection
Implantation:
Subdural:
- grid and strip electrodes
generally short-term
Extradural:
- more common for long term implantation
applications:
- functional mapping: presurgical evaluation, localization of eloquent cortex (= cortex with
significant function). Nowadays used for resective surgery, in part replaced by fMRI.
Functional mapping helped discovering the homunculus!
- refractory pain: extradural stimulation, target = motor cortex
CES + DBS: application: epilepsy
-
responsive neurostimulation at seizure focus
o determined by presurgical evaluation
o possibility of 2 foci
o each electrode can measure and stimulate
o stimulation only applied if abnormal activity
Transcranial magnetic stimulation


Magnetic field perpendicular to cortical surface
induction of cortical electric field
Method: During a TMS procedure, a magnetic field generator, or "coil" is placed near the head of the
person receiving the treatment. The coil produces small electrical currents in the region of the brain
just under the coil via electromagnetic induction. The coil is connected to a pulse generator, or
stimulator, that delivers electrical current to the coil.
TMS uses electromagnetic induction to generate an electric current across the scalp and skull
without physical contact. A plastic-enclosed coil of wire is held next to the skull and when activated,
produces a magnetic field oriented orthogonal to the plane of the coil. The magnetic field passes
unimpeded through the skin and skull, inducing an oppositely directed current in the brain that
activates nearby nerve cells in much the same way as currents applied directly to the cortical surface.
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The path of this current is difficult to model because the brain is irregularly shaped and electricity
and magnetism are not conducted uniformly throughout its tissues.
From the Biot–Savart law
it has been shown that a current through a wire generates a magnetic field around that wire.
Transcranial magnetic stimulation is achieved by quickly discharging current from a large capacitor
into a coil to produce pulsed magnetic fields of 1-10 mT. By directing the magnetic field pulse at a
targeted area of the brain, one can either depolarize or hyperpolarize neurons in the brain. The
magnetic flux density pulse generated by the current pulse through the coil causes an electric field as
explained by the Maxwell-Faraday equation,
This electric field causes a change in the transmembrane current of the neuron, which leads to the
depolarization or hyperpolarization of the neuron and the firing of an action potential.
Applications:
Motor evoked potentials (MEP):
-
most frequent use of TMS
diagnostic test of descending tract
used it: multiple sclerosis, peripheral neuropathy
single TMS pulse over vertex -> primary motor cortex
measurement of muscle activity in leg or arm
repetitive TMS (rTMS):
-
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consecutive TMS pulses
low frequency = inhibition; high frequency = stimulation
- neuromodulatory effect
- applications:
depression: target = dorsolateral prefrontal cortex, connected to limbic system. Hypothesis:
imbalance between left and right DLPFC
left DLPFC: hypo-activity -> HF-rTMS
right DLPFC: hyper-activity -> LF-rTMS
right versus left rTMS equally potent?
Epilepsy: refractory, focal, neocortical epilepsy
Low frequency rTMS over epileptogenic focus
What with epileptogenic foci located deeper, eg hippocampus
Vagus Nerve Stimulation
Vagus nerve = 10th cranial nerve (parasympathic system)
Surgically accessible in the neck
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Electrode around left vagus nerve
Stimulator in subclavicular pocket
Applications:
epilepsy: - indications: * medically refractory
* multifocal or non-resectable focus
* inadequate surgery candidate (eg low IQ)
- goal: seizure reduction, seizure freedom = seldom!
- results: <5% of patients seizure free, mean seizure reduction rate 30-40%
Depression: based on effects on mood in epilepsy w/ VNS. Responder rate (= 50% seizure reduction)
is lower (<30%)
Mechanism of action (?)
Activation of afferent fibers. Connect to N tractus solitaries => locus coeruleus. Increase in
noradrenaline release.
Rat model: increase in noradrenaline under VNS distinguishes responders from non-responders
Mechanism of action (MoA)
Electrical stimulation largely unclear. Parameters derived by trial and error. Better understanding->
more therapeutic success?
Questions: excitatory or inhibitory? Conflicting results e.g. functional mapping, DBS
Affected structures? Different structures in stimulated medium. Electroresponsive structures:
neuronal cell body, dendrites, axons, astrocytes (?)
 Generation of AP is needed.
Threshold voltage. Depends on position relative to electrode, orientation relative to
electrode, voltage response to current injection.
Electrical stimulation uses current injection: each pulse is defined by current amplitude
and pulse duration. Relationship between current and pulse duration that initiates AP.
Responsive structures: local cells (activated at axon, cell body/dendrites: much higher
threshold), local afferents & fibers of passage (activation orthodromically/antidromically)
Complexity: intrinsic brain organization.
Novel methods
Optogenics: modulate neuronal activity using light, using rhodopsins = ion channels sensitive to light,
from bacterial origin.
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Advantage: selectivity.
Applications: nematodes, zebrafish, fly, mice, ….
Diffusion MRI
MRI measures relaxation properties of induced tissue magnetization.
Diffusion = describes the spread of particles through random motion from regions of higher
concentration to regions of lower concentration.
The underlying physical process of diffusion (by Brownian motion) causes a group of water molecules to
move out from a central point, and gradually reach the surface of an ellipsoid if the medium is anisotropic
(it would be the surface of a sphere for an isotropic medium). In an
isotropic medium such as cerebro-spinal fluid, water molecules are
moving due to diffusion and they move at equal rates in all
directions. The Apparent Diffusion Coefficient in anisotropic tissue
varies depending on the direction in which it is measured.
Hindered <> restricted diffusion
<r²> = 6Dt
r = displacement, t = time, D = diffusion coefficient
From diffusion properties, derived with MRI, we
can find the (unknown) tissue properties.
Diffusion MRI pipeline
1. Acquisition
Diffusion weighted (DW) imaging sequence
S = S0 e-bD
S = DW signal, S0= non-DW signal,
b = diffusion weighting factor, D = apparent
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diffusion coefficient
2. Data quality assessment
Look at your raw data! Make a movie loop.
Standard deviation across the DWI: no (little) motion <> a lot of motion
Standard deviation across the non-DWIs: no motion, but pulsation artifacts!
Different views: axial, sagittal, coronal.
Gibbs ringing: artifacts that appear as spurious signals near sharp transitions in a signal
3. Preprocessing
- correction for subject motion and eddy current induced distortions: The B-matrix must be rotated!
- correction for EPI (echo planar imaging) deformations
4. Modeling & feature extraction
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D -> eigenvalue decomposition: D = E.Λ.E-1
𝑒1𝑥
E = 𝑒1𝑦
𝑒1𝑧
𝑒2𝑥
𝑒2𝑦
𝑒2𝑧
𝑒3𝑥
𝜆1
𝑒3𝑦 ; Λ = 0
𝑒3𝑧
0
0
𝜆2
0
0
0
𝜆3
The diffusion of each voxel leads to an ellipsoid
The shape tells us more about the anisotropy:
the colour information reflects
dominant diffusion orientation
OTHER OPTION: make simplified models of reality! Brain complexity: “crossing fibers” -> at voxel
scale! Spot “crossing fibers” regions with DTI.
What can we do about crossing fibers? Constrained spherical
deconvolution. The measured DWI signal profile ≠ DWI signal
profile from DTI. Use spherical harmonics (set of basic
functions on the sphere). The idealized fiber orientation
distribution function leads to a response function of a single
fiber population. By summing all
these response functions, the
ideal DWI signal can be derived.
So now do the inverse,
assuming we know the response
function (can be estimated from
the data!).
5. Data analysis
Fiber tractography: connecting neighboring ellipsoids. Multiple starting points in the entire brain. Can
be CSD based or DTI based.
Applications
Cohort-based research (99%) <-> single-subject in routine clinical practice (*)
In vivo dissection of WM pathways -> development of healthy WM fiber bundles.
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(*) -> facilitate interpretation of fiber architecture, facilitate neurosurgical planning (tumors,
epilepsy) (identification of eleoquent fiber pathways)
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