How Clinical Neuropsychological assessment can inform research. Professor Lisa Cipolotti

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1 How Clinical Neuropsychological assessment can inform research Professor Lisa Cipolotti

2 Neuropsychological Diagnosis 1. Assess impairments arising from brain damage 2. Identify neuropsychological syndromes 3. Further our understanding of the brain

3 Contribution of Neuropsychological Assessment 1. Diagnosis Short historical review on how the methods of assessing cognitive functions have developed Discuss some of the principal methods of assessing cognitive functions 2. Research Clinical research-fad, MOCA Theoretically driven research-dynamic aphasia, amnesia, inhibition

4 ..His vocabulary is copious, but he does not talk much, and speaks in a drawling manner. From time to time he misses a word or construction...he repeats correctly whole sentences, if not too long... (Lichtheim, 1885, p.p ; derived from Shallice, 1988)

5 ...the methods in general use were too crude to provide satisfactory records... (Head, 1926; derived from Shallice, 1988)

6 ...it would appear that the clinical psychologists contribution to the problems of the neurosurgeon and the psychiatrist is of little value owing to the lack of proper diagnostic tools... (Meyer, 1957)

7 ...The assessment of organic impairment of intellect is a task which might be expected to be within the competence of a clinical psychologist. Nevertheless, recent literature on the subject contains statements by psychologists disclaiming their ability to do so with an adequate degree of validity... (Piercy, 1959)

8 Halstead-Reitan Battery

9 ...little, if anything, could be gained by translating neuropsychological deficits into quantitative values... Letter from Luria to Reitan (1967; translated)

10 Early sixties: Clinical tests usually adopted fell into two categories: 1. Psychometric tests, originally developed for the measurement of either scholastic attainment or occupational guidance 2. Qualitative tests often improvised by the various clinicians. These tests were developed in order to explore specific cognitive skills

11 Clock, bicycle and daisy drawing (Zangwill) Lawson, 2006 e.g. Lezak, 1983; McFie & Zangwill, 1960

12 Incomplete Letters

13 Phonemic fluency

14 Cognitive neuropsychology three principles 1. The cerebral cortex has a high degree of functional specialisation 2. Complex cognitive skills are organised in a broadly modular fashion 3. Brain damage can selectively disrupt these cognitive skills

15 Brain damage can selectively disrupt cognitive skills (Cipolotti, 2000; Incisa della Rocchetta et al, 2004 ) Patients BF TM AD SMcD TF STM Non Verbal LTM Verbal LTM

16 Patients with selective preservation of country names (Cipolotti, 2000; Incisa della Rocchetta et al, 2004 ) Maps BF TM AD SMcD TF (%) Correct Colours (%) Correct Objects (%) Correct Animals (%) Correct Body Parts (%) Correct

17 The development of cognitive neuropsychology and its three principles resulted in series of important research studies. This led to a far better understanding of the functioning of complex cognitive skills. They stimulated the development of a large number of measurement tools designed to investigate cognitive functions in neurological patients.

18 Identification of acquired cognitive impairments 1. Whether the individual is functioning at his premorbid optimal level or whether there has been deterioration 2. Whether the individual is suffering from an organic or a functional condition

19 Assessment of premorbid intellectual functioning Reading skill 1. Highly correlated with general intelligence in a normal population 2. Highly resistant to brain damage National Adult Reading Test (NART)

20 NART

21 Assessment of current intellectual functioning Intelligence tests 1. Raven tests 2. Wechsler Adult Intelligence Scales (WAIS; WAIS-R; WAIS-III; WAIS-IV)

22 Similarities WAIS-III Verbal subtest Piano-Drum Orange- Banana Eye-Ear Work-Play Steam-Fog Poem-Statue Praise-Punishment Fly-Tree Hibernation-Migration Enemy-Friend

23 WAIS-III Performance subtest Picture Completion

24 Differential diagnosis: Organic and functional memory impairments Can be distinguished by: a) Highlighting discrepancies between subjective complaints and objective performance b) Identifying improbabilities in the patient s apparent pattern of impairment

25 Implicit learning task Degraded words

26 Implicit learning task Degraded words

27 Implicit learning task Degraded words

28 Assessing the extent of the cognitive impairment I NEUROPSYCHOLOGICAL ASSESSMENT 1. Premorbid ability 2. General intelligence 3. Memory 4. Language 5. Calculation 6. Executive function 7. Alertness and attention 8. Visual and space perception

29 Assessing the extent of the cognitive impairment II (1) RELIABLE in the same circumstances they produce the same results (2) VALID they measure what they are designed to measure i.e. they probe an established module of cognition. (3) OF COMPARABLE DIFFICULTY so the results can be compared across tasks (4) SENSITIVE TO CHANGE graded difficulty tests for which normally distributed scores are available allow the rate of disease progression to be monitored and avoid uninformative ceiling and floor effects

30 Recognition Memory Test Words and Faces

31 Contribution of Neuropsychological Assessment 1. Diagnosis Short historical review on how the methods of assessing cognitive functions have developed Discuss some of the principal methods of assessing cognitive functions. 2. Research Clinical research: Theoretically driven neuropsychological research

32 Contribution of Neuropsychological Assessment 1. Diagnosis Short historical review on how the methods of assessing cognitive functions have developed Discuss some of the principal methods of assessing cognitive functions. 2. Research Clinical research: Familial Dementia; cognitive screening tests Theoretically driven neuropsychological research

33 FAD Performance on The RMT (Godbolt et al,. 2006) Words (max. 50) Faces (max. 50) Session Session ± * 28 ± ± * 27 ± ± 25 ± 13 ± 33 ± 35 ± 11 Discrepancy score: * <25%; <5%; ± <1%. Maximum 25

34 Clinical research: Cognitive screening tests Cognitive screening tests 1. Identify major cognitive deficits 2. Overcome resource limitations

35 The UK national guidelines recommends that, within 6 weeks from stroke, patients should be assessed for cognitive impairment (e.g. NCGS, 2012; Nice, 2013). The assessment should entail a validated tool such as the MoCA (e.g. Nasreddine et al, 2011).

36 Determining the presence of cognitive impairment Stroke Screening Normal 25 Impaired < 25

37 Domain Specific cognitive impairment are good predictors of post-stroke outcomes For example, memory and executive functioning are good predictors for: length of hospital stay long-term impairment burden on community services (e.g. Barker- Collo, Feigin, 2006;Galski, et al., 1993; Tatemichi et al, 1994; Van Zandvoort et al., 2005).

38 Determining the nature of cognitive impairment Intellectual functioning Speed of information processing Non-verbal memory

39 174 acute stroke patients with MoCA and neuropsychology 1. Are MoCA intact patients also intact on the neuropsychological assessment? 2. How do patients with MoCA intact cognitive domains perform on the corresponding neuropsychological domain? 3. Does lesion side impact on the sensitivity of the MoCA? (Chan et al., 2014 and Chan et al., submitted)

40 1. Are MoCA intact patients also intact on the neuropsychological assessment? NO! 40 MoCA intact patients all neuropsychologically impaired MoCA Intact % of patients with neuropsychological impairment 2 Cognitive Domain 70% 1 Cognitive Domain only 30%

41 2. How do patients with MoCA intact cognitive domains perform on the corresponding neuropsychological domain? MoCA-specified domain % of patient scoring full marks on the MoCA % of patients impaired in neuropsychological corresponding domains Attention 30% 59% Memory 14% 35% Visuospatial/executive 18% 30% Naming 68% 21% Abstraction 42% 12% Language 26% 9%

42 3. Does the lesion laterality impact on sensitivity of the MoCA? YES! Laterality MoCA Intact (n = 40, 23.6%) Right Side lesion 32 (80%) Left Sided lesion 3 (7.5%) Bilateral Lesion 5 (12.5%)

43 The neuropsychological assessment allows us to evaluate cognitive screening tests. In acute stroke it demonstrated that MoCA underestimates cognitive impairment, particularly in right brain damaged patients.

44 Contributions of Neuropsychological Assessment to Clinical Research Powerful methodology! 1. Diagnose cognitive impairment at an early presymptomatic stage - FAD 2. Evaluate popular cognitive screening tests - MoCA

45 Contribution of Neuropsychological Assessment 1. Diagnosis Short historical review on how the methods of assessing cognitive functions have developed Discuss some of the principal methods of assessing cognitive functions. 2. Research Clinical research: Familial Dementia; cognitive screening tests Theoretically driven neuropsychological research

46 Theoretically driven research has proven of fundamental importance in the study of the organisation of cognitive functions. Dynamic Aphasia Amnesia Executive Function - Inhibition

47 Dynamic Aphasia Marked impairment of propositional language Absence of impaired nominal and phonological skills

48 Dynamic Aphasia patient CH Tell me about the stage show Miss Saigon. Miss Saigon was... {60 s}... Miss Saigon was... {90 s} a poor unfortunate... poor unfortunate... poor unfortunate lady {120 s})... Robinson et al, 2005

49 Sentence Generation Tasks (Robinson et al., 1998; 2005; 2006) No. Correct ANG CH Generation of a sentence from a single word 2/15 11/20 or picture (e.g. phone) 0/6 nt Generation of a sentence from a scene (e.g. Describe the scene. ) 34/34 20/20

50 Hypothesis The patients impairment was due to an inability to select a verbal response in situations where the stimulus activated many competing response options. In a situation where a stimulus activates a single prepotent response option, they should overcome their impairment.

51 Predictions 1. The patients ability to generate sentences from proper nouns should be superior to their ability to generate sentences from common nouns. 2. Sentence generation from sentences with high response predictability should be superior to sentence generation from sentences with low predictability.

52 Verbal Generation: Experimental Tests Number Correct ANG CH Controls (n=5) Proper Nouns Tell me a sentence which includes the word Hitler Common Nouns Tell me a sentence which includes the word sea 26/28 22/28 28/28 11/28* 10/28* 28/28 Sentences (high predictability) The man sat in the dentist s chair Sentences (low predictability) The man sat in his chair 9/12 19/24 12/12 3/12* 12/24* 12/12

53 Summary Both patients were impaired in the generation of sentences when the target stimulus activated many competing verbal response options. In sharp contrast, they were unimpaired when the target stimulus activated a prepotent response option.

54 Language generation involves a mechanism of conceptual preparation requiring the ability to select verbal response options among competitors. A failure at this stage results in a conflict condition and an inability to select between competing verbal responses. However, if a stimulus activates prepotent responses, less stress is placed on the damaged verbal selection mechanism.

55 ANG had a frontal meningioma impinging on the left IFG (BA 45, and 44 to a lesser extent). CH had focal atrophy in the left IFG (BA 44, and BA 45 to a lesser extent). Some atrophy in the left superior temporal gyrus.

56 Sentence Generation Task: Group Study (Robinson, Shallice, Bozzali & Cipolotti 2012) Frontal Patient Sub-Groups LIFG (n=11) Non-LIFG (n=36) Mean No. Correct (/15) (SD) Proper Nouns 14.7 (0.6) 14.4 (1.8) Common Nouns 12.9 (3.3)***~ 14.1 (3.2) LIFG = Left Inferior Frontal Gyrus ***~ = p<0.001

57 Conclusions 1.The LIFG plays a crucial role in one of the mechanisms involved in conceptual preparation. 2.This mechanism is responsible for the selection of verbal response option among competitors.

58 Theoretically driven research has proven of fundamental importance in the study of the organisation of cognitive functions. Dynamic Aphasia Amnesia Executive Function - Inhibition

59 Amnesia - Patient HM Dr Brenda Milner Amnesia: The profound loss of memory in the presence of relatively preserved cognitive abilities

60 The Hippocampus Plays a Crucial Role in Amnesia

61 Impaired Functions: Episodic Memory (EM) Episodic refers to memory for episodes with a spatial temporal context involving a detailed reexperience of the initial event, such as, for example, autobiographical memories (Tulving, 1972).

62 memory Impaired Functions Impaired Episodic Memory i) Retrograde Amnesia ii) Anterograde Amnesia retrograde anterograde lesion time

63 Squire s Standard Consolidation Model Hippocampus Neocortex Neocortex Larry Squire Neocortex Hippocampus allows the learning of new declarative memories which are stored in the permanent neocortical memory store.

64 Squire s Standard Consolidation Model Hippocampus Hippocampus Neocortex Neocortex Neocortex Neocortex Neocortex Neocortex Time Consolidation allows declarative memory traces to become gradually independent from the hippocampus and dependent on neocortical storage sites

66 Assessment of Retrograde Memory Tests for non-personal events - famous public events/personalities Tests for autobiographical events

HM: Performance on Non Personal Retrograde Memory Tests More distant memories relatively preserved taken as support for consolidation. BUT are test items equally salient across decades?

67 HM: Performance on Non Personal Retrograde Memory Tests More distant memories relatively preserved taken as support for consolidation. BUT are test items equally salient across decades? HM s remote memories are highly semantic in nature (Steinvorth et al, Neuropsychologia 2005) See Cipolotti & Moscovitch Lancet Neurol (4):792-3 versus Squire & Bayley Lancet Neurol (5):112-3

68 Retrograde Amnesia - Non Personal Events (Reed and Squire, 1998)

69 Famous Public Events Questionnaire Test 120 Questions Examples of Questions Recall condition: Who is Paula Jones? Recognition condition: Widow of Kurt Cobain the rock singer who died of an overdose Woman who accused President Clinton of sexual harassment Famous tennis player Recall condition: How was the Queen Elizabeth liner destroyed in Hong Kong? Recognition condition: Fire..Bombed..Crashed into by another boat.

70 Coronal sections through temporal lobe at the level of the body of the hippocampus. High signal return seen in each hippocampus.

71 Midsaggital section of the hippocampus Control Patient VC

72 VC s neuroimaging investigations Volumetry Voxel-Based Morphometry Magnetic Resonance Spectroscopy Functional MRI All reporting selective bilateral hippocampal damage (Cipolotti et al, 2001; 2006; Maguire et al, 2005; Bird et al, 2007)

74 Hippocampal patient VC Percentage Correct for each 5 year period on Famous Public Events Questionnaire (Cipolotti et al., 2001)

neurons representing that experience into a memory

75 Multiple Trace Theory Hippocampal complex encodes learned information and binds the neocortical neurons representing that experience into a memory trace. Morris Moscovitch Lynn Nadel Nadel and Moscovitch, 1997

76 Critical Distinction between SMC and MTT Hippocampal Lesion SMC s prediction MTT s prediction Remote Memories Remote Memories

77 Evidence against a temporal gradient in R.A. Autobiographical memory tests Viskontas et al, 2000: P s with MTL resections Rosenbaum, Gilboa, Levine, Winocur, Moscovitch, 2009: internal and external details given by KC

78 Hippocampal patient VC Kopelman s Autobiographical Memory test Autobiographical Memory Interview No. Correct Comment Autobiographical 3/27 Definitely abnormal Childhood 1/9 Definitely abnormal Early Adult Life 2/9 Definitely abnormal Recent Life 0/9 Definitely abnormal

79 Neuropsychological assessment of amnesic patients The hippocampus serves a critical role for memory Remote memories rely on the hippocampus

80 Theoretically driven research has proven of fundamental importance in the study of the organisation of cognitive functions. Dynamic Aphasia Amnesia Executive Function - Inhibition

81 Executive Functions Variety of general purpose control mechanisms thought to modulate and organize more basic cognitive subprocesses to achieve effective behaviour (e.g. Stuss and Levine, 2002)

83 Inhibition: The ability to suppress a pre-potent response Patients with PFC lesions are impaired in tasks requiring inhibitory control Inappropriate and/or perseverative behaviour 3 different inhibitory tasks: Stop-signal, Stroop, Hayling

84 Inhibition: Stop-Signal Aron and colleagues (2003) reported a significant correlation between right inferior frontal gyrus (RIFG) lesions and stop-signal reaction time (RT). They suggested that the RIFG is critical for inhibitory control in general.

85 Inhibition: Stroop Colour-Word Test

86 Inhibition: Stroop Colour-Word Test - Lesions Left dorsolateral PFC (e.g. Perret, 1974; Stuss et al., 2001) Right lateral PFC (Vendrell et al., 1995) Anterior cingulate cortex (ACC) (e.g. Swick and Turken, 2002; but see for opposite results Fellows and Farah, 2005; Baird et al., 2006). Recent Voxel-based Lesion Symptom Mapping (VLSM) Left lateral PFC (Tsuchida and Fellows, 2013) Left ventral lateral PFC (Geddes et al., 2014) Left dorsolateral frontal cortex (Glascher et al., 2012)

87 Inhibition: The Hayling Sentence Completion Test The patient is asked to complete sentences by providing words that are unrelated to the sentence frame. London is a very busy..., could be completed by saying... banana Frontal patients may: Produce Suppression errors (SS) London is a very busy... may be completed with...city... and/or Require longer reaction times (RT2 SS)

88 Inhibition: The Hayling Sentence Completion Test - Lesions Right PFC (Roca et al., 2010) Right lateral PFC (Robinson et al., 2015; Cipolotti et al., 2015)

89 Part 2 of the Hayling and Stroop Colour- Word Tests (Cipolotti et al., submitted) Left Frontal Patients Right Frontal Patients Healthy Comparison Suppression Error * 6.05 SS (SD) (2.64) (2.47) (1.80) Suppression RT ** 6.00 SS (SD) (1.71) (1.80) (0.63) Stroop (No. of colours named in 2 minutes) 90.21* (SD) (27.96) (35.23) (20.30) Legend. Scores with significant p-values are in red; *p <0.05; **p< 0.01, compared with Healthy Comparison; SS: Scaled Score; (SD): Standard Deviation; RT: reaction time

90 A deficit in fluid intelligence can explain most the reported executive impairments in frontal patients (e.g. Duncan et al., 1995; Roca et al., 2010)

91 Three separate 2x2 mixed-method ANOVAs with: Type of measure - Hayling measure/stroop (z-scores) - as the within-groups factor Site of damage - left/right - as the between-groups factor Fluid intelligence - RAPM - as covariate For: 1. Suppression errors and Stroop 2. Suppression RT2 and Stroop 3. Suppression errors and Suppression RT2

92 Significant interactions: Type of measure Site of damage 1. Suppression errors and Stroop (p=.008) 2. Suppression RT2 and Stroop (p=.028) 3. Suppression errors and Suppression RT2 (p=.468)

93 Results of voxel lesion-symptom mapping analyses (VLSM): Hayling Voxels in red show the area found to be significant (p<0.05 FWEcorrected at cluster level) (A) Hayling Suppression errors (B) Hayling Suppression RT 2

94 Results of voxel lesion-symptom mapping analyses (VLSM): Stroop Voxels in red show the area found to be significant (p<0.05 FWE-corrected at cluster level)

95 Inhibition: Conclusion I 1. Lesion location, right or left PFC, is a critical factor in producing impairments on two inhibitory tasks loading similarly on verbal control 2. Hayling and Stroop assess dissociable components of executive functions, related to separate and lateralized PFC circuits 3. Inhibition may actually comprise qualitatively different forms with different neuronal substrates

96 Inhibition: Conclusion II The assessment of inhibition in frontal patients need: to use a variety of tests to develop different types of treatments

97 The clinical neuropsychological assessment can inform research by: 1. Developing a powerful neuropsychological methodology Pre-symptomatic changes in FAD; cognitive screening tests - MoCA 2. Refining the diagnosis of neuropsychological syndromes Dynamic aphasia, amnesia and impairments in inhibition 3. Furthering our understanding of the functioning of the brain The role of the LIFG in propositional speech The role of the hippocampus in remote memory The lateralized PFC contributions to inhibition

Right lateral prefrontal cortex Specificity for inhibition or strategy use?

Right lateral prefrontal cortex Specificity for inhibition or strategy use? M. Hornberger 1 & M. Bertoux 1 1 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK The specific functions