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

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cent

haem

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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?