1: Methods

1. 1: Methods • Chris Rorden • What is neuropsychology? • Tools • Methods • Pathology • www.mricro.com

2. What 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.

3. Stroke • Stroke ruined WW’s life and career. • Stroke is the leading cause of disability. • 3rd leading cause of death • In USA alone • 500,000 people suffer stroke per year • 150,000 people die of stroke per year • 4 million living with stroke • $30 billion in health care costs • True cost to society greater still • What was the cost of WW’s stroke?

4. President 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.

5. What 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.

6. Neuropsychology: 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.

7. Neuropsychology: Branches • Clinical: Assessment and Rehabilitation • Experimental: Gain theoretical understanding of the brain and developing new treatments.

8. Basic 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.

9. Behavioural testing • Goal: relate brain anatomy to behaviour • Requires • 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?

10. Behavioural 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.

11. Associations • 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.

12. Dissociations • 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.

13. Double 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. performance TaskA TaskB

14. Double 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. 100% chance 0% DF RV When asked to grasp an object, DF grasped near the centre (like healthy people), RV was poor at this task. DF RV Control 25% Frequency 0% 0 15 0 15 0 15 30 Distance from centre (mm)

15. Strokes • 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.

16. Ischemic 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 Cerebral Posterior Cerebral

17. Middle 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.

18. Haemorrhages • 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 of recent haemorrhage

19. Impact 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

20. Visualising 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

21. Visualising 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. Plain Film X-rays • 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

23. CT 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

24. CT 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. XRays • Plain film vs computerized tomography (CT) • Plain film • CT • Rendered CT No Contrast Contrast

26. MRI • Magnetic resonance imaging • Does not expose individual to X-rays

27. MRI • 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.

28. MRI compass analogy N • Compass needle points North • Briefly put magnet on right side: needle points East • After magnet is removed, needle points North again (lower energy state) • Needles in different fluids will take different time to return to North N N

29. MRI 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).

30. Traditional 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. T2 T1

31. MRI 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.

32. MRI 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)

33. MRI 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!

34. MRI 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 hoover > < welding tank

35. Different scans • Scan type (CT, MRI) influences lesion appearance. • Lesions appear different with time. acute +3days • Example of stroke: • writes, but can’t read, “alexia without agraphia” • Lesion invisible in acute scans CT T2 MRI For more examples, www.med.harvard.edu/AANLIB/

36. Imaging Infarcts • MRA (Magnetic Resonance Angiography): sometimes with contrast agent (Gadolinium) • Xray’s with contrast agent in blood Xray MRI MRA stroke MRA

37. Future 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)

38. Measuring 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.

39. PET/SPECT • Positron Emission Tomography and Single Photon Emission Computerized Tomography (SPET/SPECT) are a type of CT scan. • Standard CTs: transmission of Xrays • Measure 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

40. fMRI • 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.

41. Diaschisis • 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 region is not functioning normally

42. Diaschisis • 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.

43. Measuring electrical activity • When neurons fire, they create electical dipoles. • Neurons aligned perpendicular to cortical surface. - +

44. EEG • 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

45. Event 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 • Spatial resolution poor, (use MRI to localize damage) • Good temporal resolution (when is activity happening). + Signal V _ 0 100 200 300 Time (ms)

46. Magnetoencephalography [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/

47. Problems 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

48. Problems with Neuropsychology • What are weaknesses of this technique? • This course examines findings from neuropsychology • Be critical of science: particularly of frontier • Understand the limitations of every technique

49. 1.) 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.

50. 2.) 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.