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11: Methods
• Chris Rorden• What is neuropsychology?• Tools• Methods• Pathology
• www.mricro.com
2What is neuropsychology?
Patient WW– History of hypertension– Massive Right Hemisphere Stroke– Poor emotional control and judgment.– Anosognosia: unaware of illness.– Partially paralyzed on left side.
3Stroke
Stroke ruined WW’s life and career.Stroke is the leading cause of disability.3rd leading cause of death
– In USA alone500,000 people suffer stroke per year150,000 people die of stroke per year4 million living with stroke$30 billion in health care costs
– True cost to society greater still– What was the cost of WW’s stroke?
4President Woodrow Wilson
28th US President Stroke on October 1919: remained
in office until 1921.– Cabinet, Vice President, public
unaware– Unable to continue supporting League
of Nations Senate rejected the League’s Treaty of
Versailles– Wanted to run for president for another
4 years despite handicap.– Edith Wilson controlled access to
president. No new policy Major defeat for Wilson’s party in 1920
elections.
5What is neuropsychology?
Examine consequences of brain injury.– Identify problems experienced by patient,
e.g. movement, vision, memory, etc.– Identify brain regions injured.– Infer that impaired functions require
damaged brain regions.– Allows us to understand brain function.
6Neuropsychology: Defined
Psychology attempts to understand behavior
1860-1980’s: Neuropsychology = science relating anatomy to behavior.
Today: ‘cognitive neuroscience’ = science relating anatomy to behavior.
Today: ‘neuropsychology’ = branch of cognitive neuroscience that examines neurological patients.
7Neuropsychology: Branches
Clinical: Assessment and RehabilitationExperimental: Gain theoretical
understanding of the brain and developing new treatments.
8Basic method
Explore patients with brain damage.– Infer impaired behaviour dealt with by damaged regions.– Infer that damaged regions are not required by skills that are
preserved. Common logical tools
– Association: similar symptoms– Dissociations: specific deficits– Double dissociations: two anatomically and behaviourally distinct
groups. Group vs. Single subject designs
– Lesions tremendously variable: makes group designs difficult as patients have hetergenous pathology.
– Group designs better for making generalizations regarding anatomy.
9Behavioural testing
Goal: relate brain anatomy to behaviourRequires
– technique for assessing anatomy (e.g. CT)– behavioural tasks.
Tasks should tell us about the patient’s deficits:– What functions are compromised?– What functions are spared?
10Behavioural testing
Common test batteries allow us to compare different studies, e.g.– General intelligence (WISC/WAIS) with subtests
revealing verbal or reasoning deficits.– Common tests for vision, memory, motor control,
language, etc
To test specific hypotheses, we also often employ custom designed experiments– Designed to get a pure measure of deficit than
general test batteries.
11Associations
Damage to one region of the brain often leads to a series of deficits.
Example: Balint’s syndrome: – Simultanagnosia (only perceive one item at a time)– Optic ataxia (failure to make eye movements)– Optic apraxia (inability to reach to seen target)
Damage to region X leads to deficits in A,B,C Inference: Tasks A,B,C require same neural
circuit. Alternative: A,B,C may be processed by separate
functional regions that are anatomical neighbors.
12Dissociations
Patient is impaired in one task but fine in a different task.
Example: Blindsight– Loss of perception: patient reports being blind– Motion detection fine
Dissociations suggest that tasks rely on separate networks.
Problem: perhaps impaired task is simply more difficult. Performance on the ‘unimpaired’ task is at ceiling.
13Double dissociation
Two patient groups with complementary dissociations: – Group 1: good at task A, impaired on task B– Group 2: impaired on task A, good at task B
Suggests distinct processing for the two tasks. Patient groups have distinct behaviour and
anatomy.p
erf
orm
an
ce
TaskA TaskB
14Double Dissociation (Goodale et al. [1994] Curr Biol. 4:604-610)
When shown two shapes (left), DF was poor at saying if the shapes were same or different, RV was good at this task.
DF RV
chance
100%
0%
DFControl RVF
req
uen
cy
25%
0%
Distance from centre (mm)0 15 0 15 0 15 30
When asked to grasp an object, DF grasped near the centre (like healthy people), RV was poor at this task.
15Strokes
Strokes– Ischemic: Blood supply occluded 80%
Embolic Thrombotic
– Haemorrhagic: Blood bleeding 20% Some ischemic strokes are temporary: transitory
ischemic attacks (TIA). ‘Infarct’: Dead tissue following stroke. Stroke-buster drugs (Thrombolytic agents) can dissolve
clots, saving the brain if given early after onset. – Contraindicated if haemorrhagic.
16Ischemic Strokes
– Thrombosis: growth in artery prevents bloodflow If narrowing (stenosis) is detected early, operation can
prevent stroke.
– Embolism: particle in blood flow lodged in artery
Major Arteries Carotid Anterior Cerebral Middle CerebralPosterior Cerebral
17Middle cerebral artery (MCA)
MCA occlusion– Most common: embolism travels
up carotid artery – MCA supplies lateral bank of
cortex (image from strokecenter.org)
– Damages regions near superior temporal sulcus (sylvian fissure).
Lower figure shows regions damaged in 24 MCA patients, Mort et al. 2003.
18Haemorrhages
20% of strokes are bleeds Typically, due to ruptured aneurysm
– An aneurysm is a sac-like protrusion of an artery caused by a weakened area within the vessel wall.
– Introspectively, the worst headache of your life.– http://www.microvent.com/ – Surgery to clip aneurysm can save patients life.
CT o
f re
cent
haem
orr
hage
19Impact injuries (RTA)
Regardless of direction of impact, frontal and temporal poles vulnerable– Coup injury– Contre coup
White matter damage common
Swelling of brain or bleeding can be fatal
20Visualising brain injury
Neuropsychology – correlate brain injury with brain function
Requires accurate measures of brain injury.
Historically: autopsy. Today: brain imaging. Warning: symmetry makes mirror-
mistakes easy.– Radiological convention: left shown
on right side.– Neurological convention: left shown
on left.
L
21Visualising brain injury
Anatomical methods: show appearance of brain– X-rays – CT/CAT scans – MRI/MRA (magnetic resonance)
Measures of brain function– Blood flow (PET/SPECT/fMRI). – Neuron’s electrical responses (EEG/EEG)– Neuron’s magnetic responses (MEG)
22
X-ray tube projects through head Detector plate measures transmission of X-rays
– Bone relatively opaque to X-rays– Soft tissue relatively transparent
Useful for Angiography, looking for broken bones Poor for questions about grey vs white matter
Plain Film X-rays
23CT scans (aka CAT scans)
A series of X-rays are taken at different angles– X-ray tube and detector spin around axis,
hence ‘computerized axial tomography’ (CAT scan)
– Computer reconstructs 2D slices
24CT scans
Neurological uses– Stroke - Cerebrovascular Accident
blockage or bleed Haemorrhagic CVA from Ischemic CVA
– Brain tumors (larger than 2-4 mm)– Enhanced with contrast material– Hydrocephalus– Subdural Hematoma – Evaluation of traumatic Head Injury
25
Plain film vs computerized tomography (CT) Plain film CT Rendered CT
No
Con
tras
tC
ontr
ast
XRays
26MRI
Magnetic resonance imaging Does not expose individual to X-rays
27MRI
Powerful magnetic field (often 1.5Tesla, e.g. 30,000 times Earth’s magnetic field).
Atoms align with field.Radio pulses ‘flip’ hydrogen atoms.Different tissues
have different times to realign.
28MRI compass analogy
Compass needle points NorthBriefly put magnet on right side:
needle points EastAfter magnet is removed, needle
points North again (lower energy state)
Needles in different fluids will take different time to return to North
N
N
N
29MRI compass analogy
Spin of H atoms aligns with static magnetic field
Briefly apply radiofrequency pulse: spin tipped
After RF pulse, H atoms realign to field (‘relaxation’, lower energy state)
Relaxation releases energy in the form of a radio signal.
Atoms in different tissues (fat, muscle, etc) require different time to realign (relax).
30Traditional MRI protocols
Different types of MRI scan– T1 (anatomical): fast to acquire, excellent
structural detail (e.g. white and gray matter).– T2 (pathological): slower to acquire,
therefore usually lower resolution than T1. Excellent for finding lesions.
T1 T2
31MRI scans
3 T1-weighted MRI scans:– Left image: Healthy individual– Right image: MCA infarct: note lesioned tissue and
enlarged ventricles.– Middle: Healthy individual, despite large ventricles and
wide sulci. Large skull: perhaps hydrocephalus early in development.
32MRI clinical uses for neurology
Arteriovenous malformation Hydrocephalus Subacute subtle hemorrhagic CVA Ischemic CVA with 48 hours of symptom onset Cerebral Contusion Shearing injury Dementia Brain tumor Cerebral atrophy Multiple Sclerosis Pituitary disease (Amenorrhea or Galactorrhea) Congenital anomalies
from www.fpnotebook.com
Clinical MRI 68 year old male Right MCA infarction T1-weighted scan Husain & Rorden (2003)
33MRI problems
Problems with MRI– T1/T2/PD images not sensitive to stroke < 24
hours old.– Noisy, confined space– Bone better imaged by CT than most MRI scans– Image intensity relative, not comparable across
patients.– CT and conventional MRI show damaged areas,
but structurally intact areas are not necessarily functioning correctly!
34MRI problems: Metal and MRI
Ferromagnetic materials (e.g. most steel alloys) can cause problems
– Heating or movement
– Many haemorrhagic stroke patients treated with metal ‘aneurysm clips’
Ensure clip is MRI-friendly metal
< welding tank
hoover >
35Different scans
Scan type (CT, MRI) influences lesion appearance. Lesions appear different with time.
For more examples, www.med.harvard.edu/AANLIB/
T2 MRI
CT
acute +3days
Example of stroke: writes, but can’t read, “alexia without agraphia”
Lesion invisible in acute scans
36Imaging Infarcts
MRA (Magnetic Resonance Angiography): sometimes with contrast agent (Gadolinium)
Xray’s with contrast agent in blood
MRI MRA stroke MRA Xray
37Future MRI protocols
Diffusion-weighted imaging– Strokes show up immediately.– Shows permanent white-matter damage.– Some DWI techniques are calibrated values.
Perfusion-weighted imaging– Strokes show up immediately.– Indicates amount of blood supply and latency
Images courtesy Paul Morgan (Nottingham)
38Measuring brain activity
MRI/CT can show us damaged regions Major problem: Are anatomically intact regions
functioning normally?– Impossible to tell with anatomical scans– Our goal: relate behaviour to anatomy
Requires accurate measure of damaged anatomy.
Measures of brain activity– help us determine anatomical consequence of brain
damage.– Identify lesions immediately after onset, when they
are invisible to standard CT/MRI.
39PET/SPECT
Positron Emission Tomography and Single Photon Emission Computerized Tomography (SPET/SPECT) are a type of CT scan.
–Standard CTs: transmission of XraysMeasure Xray transparency of material between xray tube and detector
–PET/SPECT looks at emission of radioactive material.
E.G. Radioactive oxygen isotope injected into blood
Brain regions that use oxygen emit more positrons
40fMRI
Functional MRI offers indirect measure for brain activity.
May help show whether patient will recover. Example: Stroke patient unable to move left hand.
– Forced left hand movement (curling fingers)– Below: statistical map from fMRI (red) on top of T1 MRI
scan (gray).– Note: appropriate regions respond: perhaps spared.
41Diaschisis
Destroyed regions of the brain stop firing. Consequence: connected regions also stop functioning normally. ‘Crossed Cerebellar Diaschisis’: damage to one hemisphere
temporarily stuns other side.
Stroke: Reduced
blood flow
Diaschisis:intact regionis notfunctioningnormally
42Diaschisis
Diaschisis poses a major problem for neuropsychology– Immediately after lesion, many regions will be
disabled.Difficult to assess which regions are really
inoperative.Impossible to see what single region does if many
are knocked out.– If we wait to test patients, their brains may
reorganize.Difficult to infer healthy function of damaged region
if intact regions have changed their function.
43Measuring electrical activity
When neurons fire, they create electical dipoles.
Neurons aligned perpendicular to cortical surface.
+
-
44EEG
With EEG we measure rhythms of the brain:– Alpha 7-13 Hz: mostly posterior. It is brought out by closing the eyes
and by relaxation, and abolished by thinking. It is the major rhythm seen in normal relaxed adults
– Beta >13 Hz: most evident frontally. It is accentuated by sedatives. It is the dominant rhythm in people who are alert or anxious or who have their eyes open
– Theta 3.5-7.5 Hz and is classed as "slow" activity. It is abnormal in awake adults but is perfectly normal in children upto 13 years and in sleep
– Delta <3 Hz. It tends to be the highest in amplitude. It is quite normal and is the dominant rhythm in infants up to one year and in stages 3 and 4 of sleep
Useful for measuring sleep http://www.brown.edu/Departments/Clinical_Neurosciences/louis/eegfreq.html
45Event related potentials
ERPs are a type of EEG– Continuously collect EEGs– Present many trials of stimuli (e.g. brief sound)– Compute average brain response to stimuli
0 100 200 300
+
_
Time (ms)
Spatial resolution poor, (use MRI to localize damage)
Good temporal resolution (when is activity happening).
Sig
na
l V
46Magnetoencephalography [MEG]
MEG is the measurement of the magnetic fields naturally present outside the head due to electrical activity in the brain. Sensors make no contact with scalp
Better spatial resolution than EEG/ERP
Expensive Requires very low noise
environment (e.g. no lorries driving by)
www.aston.ac.uk/psychology/meg/
47Problems with neuropsychology
“George Miller coined the term ‘cognitive neuroscience’…we already knew that neuropsychology was not what we had in mind…the bankruptcy and intellectual impoverishment of that idea seemed self evident.”
-Michael S. Gazzaniga, 2000
48Problems with Neuropsychology
What are weaknesses of this technique?This course examines findings from
neuropsychologyBe critical of science: particularly of
frontierUnderstand the limitations of every
technique
491.) Modularity assumption
Modularity assumption:– We assume that when one region is
damaged, other regions do not adapt their function.
– In reality, brain reorganizes quickly. Intact regions change their behaviour, so difficult to infer function of damaged region.
– aka ‘Locality Assumption’, see Farah’s Behav Brain Sciences article.
502.) Lesions extensive and varied
Small lesions (e.g. lacunar infarts) often have no behavioural consequence.– Brain redundant, robust to partial damage of system
Most work done with patients who have large lesions.– Lesions often damage several functional centers, so
few ‘pure’ patients– Lesion size and location variable, so hard to find
group of similar patients. Inferences from single patients weak.
513.) Lesion anatomy inaccurate
Anatomical scans show us regions that are destroyed.
But anatomically intact regions may not be functioning (e.g. perhaps disconnected, or diaschisis).
Poor anatomy will weaken our level of inference.
524.) Variability of functional anatomy
We assume that an anatomical region of the brain does the same function in all individuals.– Clearly not always correct: e.g. Wada test
indicates left hemisphere required for language in MOST but not all individuals.
– Variability of function across individuals reduces power of group studies.
535.) Poor temporal resolution
Even if neuropsychology establishes which regions are required for task, it is hard to infer the stages of processing.
For example, V1 damage causes visual deficits. But how long after the onset of a visual stimuli does V1 become active?
Other cognitive neuroscience techniques offer converging evidence.
54Do we despair?
Neuropsychology has major limitationsEvery tool used in cognitive neuroscience
has major limitations.Convergent evidence required:
– Do different techniques give the same answer?
– This is why cog neuro is exciting! We have to think critically about the implications of each result.
55Reflection, questions
New tools offer new insight into brain function
Golden age for neuroscience: like explorers in age of Columbus
Q: What are weaknesses for other techniques used by cognitive neuroscience?
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