How Clinical Neuropsychological

assessment can inform research

Professor Lisa Cipolotti

Neuropsychological Diagnosis

1. Assess impairments arising from brain damage

2. Identify neuropsychological syndromes

3. Further our understanding of the brain

Contribution of

Neuropsychological Assessment

1. Diagnosis

• Short historical review on how the methods of assessing cognitivefunctions have developed

• Discuss some of the principal methods of assessing cognitivefunctions

2. Research

• Clinical research-FAD, MOCA

• Theoretically driven research-Dynamic aphasia, amnesia, inhibition

“..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. 448-449; derived from

Shallice, 1988)

“...the methods in general use were too

crude to provide satisfactory records...”

(Head, 1926; derived from Shallice, 1988)

“...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)

“...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)

Halstead-Reitan Battery

“...little, if anything, could be gained by

translating neuropsychological deficits into

quantitative values...”

Letter from Luria to Reitan (1967; translated)

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 developedin order to explore specific cognitive skills

Clock, bicycle and daisy drawing

(Zangwill)

Lawson, 2006

e.g. Lezak, 1983; McFie & Zangwill, 1960

Incomplete Letters

Phonemic fluency

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

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

Patients with selective preservation

of country names (Cipolotti, 2000; Incisa della

Rocchetta et al, 2004 )

BF TM AD SMcD TF

Maps

(%) Correct 100 100 90 100 90

Colours

(%) Correct 50 40 60 70 70

Objects

(%) Correct 30 10 60 30 10

Animals

(%) Correct 60 10 40 40 20

Body Parts

(%) Correct 20 50 90 50 10

The development of cognitive neuropsychologyand its three principles resulted in series ofimportant research studies.

This led to a far better understanding of thefunctioning of complex cognitive skills.

They stimulated the development of a largenumber of measurement tools designed toinvestigate cognitive functions in neurologicalpatients.

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

Assessment of premorbid

intellectual functioningReading skill

1. Highly correlated with general intelligencein a normal population

2. Highly resistant to brain damage

National Adult Reading Test (NART)

NART

Assessment of current intellectual

functioning

Intelligence tests

1. Raven tests

2. Wechsler Adult Intelligence Scales

(WAIS; WAIS-R; WAIS-III; WAIS-IV)

WAIS-III Verbal subtest

Similarities

• Piano-Drum

• Orange- Banana

• Eye-Ear

• Work-Play

• Steam-Fog

• Poem-Statue

• Praise-Punishment

• Fly-Tree

• Hibernation-Migration

• Enemy-Friend

WAIS-III Performance subtest

Picture Completion

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

Implicit learning task – Degraded words

Implicit learning task – Degraded words

Implicit learning task – Degraded words

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

(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

Assessing the extent of the cognitive

impairment II

Recognition Memory Test –

Words and Faces

Contribution of

Neuropsychological Assessment

1. Diagnosis

• Short historical review on how the methods of assessing cognitivefunctions have developed

• Discuss some of the principal methods of assessing cognitivefunctions.

2. Research

• Clinical research:

• Theoretically driven neuropsychological research

Contribution of

Neuropsychological Assessment

1. Diagnosis

• Short historical review on how the methods of assessing cognitivefunctions have developed

• Discuss some of the principal methods of assessing cognitivefunctions.

2. Research

• Clinical research:

Familial Dementia; cognitive screening tests

• Theoretically driven neuropsychological research

FAD Performance on The RMT (Godbolt et al,. 2006)

Words (max. 50) Faces (max. 50)

Session Session

1 2 3

4.3 49 48 45 48 46 48

4.13 46 45 46 45

4.5 49 49 47 45 47 45

4.9 37± 48 47 47 46 44

4.1 40* 28± 38 49 31± 36†

4.12 40* 27± 42 37

4.10 33± 25± 13±§ 33± 35± 11†§

Discrepancy score: * <25%; † <5%; ± <1%. § Maximum 25

1 2 3

Cognitive screening tests

1. Identify major cognitive deficits

2. Overcome resource limitations

Clinical research: Cognitive screening

tests

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).

Determining the presence of cognitive impairment

Stroke Screening

Normal ≥ 25

Impaired < 25

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).

Domain Specific cognitive impairment are

good predictors of post-stroke outcomes

Intellectual functioning

Speed of information

processing

Non-verbal memory

Determining the nature of cognitive

impairment

174 acute stroke patients with MoCA and

neuropsychology

(Chan et al., 2014 and Chan et al., submitted)

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?

1. Are MoCA intact patients also intact on the

neuropsychological assessment? NO!

MoCA Intact% of patients with neuropsychological

impairment

≥2 Cognitive Domain 70%

1 Cognitive Domain only 30%

40 MoCA intact patients – all neuropsychologically

impaired

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%

3. Does the lesion laterality impact on

sensitivity of the MoCA? YES!

LateralityMoCA Intact

(n = 40, 23.6%)

Right Side lesion 32 (80%)

Left Sided lesion 3 (7.5%)

Bilateral Lesion 5 (12.5%)

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.

Contributions of Neuropsychological

Assessment to Clinical Research

Powerful methodology!

1. Diagnose cognitive impairment at an early pre-

symptomatic stage - FAD

2. Evaluate popular cognitive screening tests -

MoCA

Contribution of

Neuropsychological Assessment

1. Diagnosis

• Short historical review on how the methods of assessing cognitivefunctions have developed

• Discuss some of the principal methods of assessing cognitivefunctions.

2. Research

• Clinical research:

Familial Dementia; cognitive screening tests

• Theoretically driven neuropsychological research

Theoretically driven research has proven of fundamental

importance in the study of the organisation of cognitive

functions.

• Dynamic Aphasia

• Amnesia

• Executive Function - Inhibition

Dynamic Aphasia

• Marked impairment of propositional language

• Absence of impaired nominal and phonologicalskills

Dynamic Aphasia patient CH

‘Tell me about the stage show Miss Saigon.’

‘…Miss Saigon was . . . {60 s} . . . MissSaigon was . . . {90 s} a poor unfortunate. . .poor unfortunate . . . poor unfortunate lady{120 s})...’

Robinson et al, 2005

Sentence Generation Tasks

(Robinson et al., 1998; 2005; 2006)

No. Correct

ANG CH

Generation of a sentence from a single

word2/15 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

Hypothesis

• The patients’ impairment was due to aninability to select a verbal response insituations where the stimulus activated manycompeting response options.

• In a situation where a stimulus activates asingle ‘prepotent’ response option, theyshould overcome their impairment.

Predictions

1. The patients’ ability to generate sentences fromproper nouns should be superior to their ability togenerate sentences from common nouns.

2. Sentence generation from sentences with highresponse predictability should be superior tosentence generation from sentences with lowpredictability.

Verbal Generation: Experimental TestsNumber Correct

ANG CH Controls (n=5)

Proper Nouns

Tell me a sentence which includes

the word Hitler

26/28 22/28 28/28

Common Nouns

Tell me a sentence which includes

the word sea

11/28* 10/28* 28/28

Sentences (high predictability)

“The man sat in the dentist’s

chair…”

9/12 19/24 12/12

Sentences (low predictability)

“The man sat in his chair…”

3/12* 12/24* 12/12

* = impaired (p<0.05)

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.

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.

• 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.

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

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.

Theoretically driven research has proven of fundamental

importance in the study of the organisation of cognitive

functions.

• Dynamic Aphasia

• Amnesia

• Executive Function - Inhibition

Dr Brenda Milner

Amnesia: The

profound loss of

memory in the

presence of

relatively preserved

cognitive abilities

Amnesia - Patient HM

The Hippocampus Plays a Crucial Role in

Amnesia

Impaired Functions: Episodic Memory

(EM)

• Episodic refers to memory for episodes with a

spatial temporal context involving a detailed re-

experience of the initial event, such as, for

example, autobiographical memories (Tulving,

1972).

Impaired Episodic Memory

Impaired Functions

timelesion

mem

ory retrograde anterograde

i) Retrograde Amnesia

ii) Anterograde Amnesia

Hippocampus

Squire’s Standard Consolidation Model

Neocortex

Neocortex

Neocortex

Hippocampus allows the learning of new declarative

memories which are stored in the permanent neocortical

memory store.

Larry Squire

Hippocampus

Squire’s Standard Consolidation Model

Neocortex

Neocortex

Neocortex

Time

Hippocampus

Neocortex

Neocortex

Neocortex

Consolidation allows declarative memory traces to

become gradually independent from the hippocampus

and dependent on neocortical storage sites

Assessment of Retrograde Memory

• Tests for non-personal events - famous

public events/personalities

• Tests for autobiographical events

HM’s remote memories are highly “semantic” in nature (Steinvorth et al,

Neuropsychologia 2005)

See Cipolotti & Moscovitch Lancet Neurol. 2005 (4):792-3

versus Squire & Bayley Lancet Neurol. 2006 (5):112-3

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?

Retrograde Amnesia - Non Personal

Events (Reed and Squire, 1998)

Famous Public Events Questionnaire Test

120 Questions

1960-1964 15

1965-1969 15

1970-1974 15

1975-1979 15

1980-1984 15

1985-1989 15

1990-1994 15

1994-1998 15

Examples of Questions

1994-1998

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.

1970-1974

Recall condition: How was the Queen

Elizabeth liner destroyed in Hong Kong?

Recognition condition:

Fire…..Bombed…..Crashed into by another

boat.

Coronal sections through temporal lobe at the level of

the body of the hippocampus. High signal return seen in

each hippocampus.

Control Patient VC

Midsaggital section of the

hippocampus

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)

Hippocampal patient VC

Percentage Correct for each 5 year period on Famous Public

Events Questionnaire

(Cipolotti et al., 2001)

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

Critical Distinction between SMC

and MTT

Hippocampal Lesion

SMC’s

prediction

MTT’s

prediction

Remote Memories Remote Memories

Rosenbaum, Gilboa, Levine, Winocur, Moscovitch,

2009: internal and external details given by KC

Evidence against a temporal gradient

in R.A. Autobiographical memory tests

Viskontas et al, 2000:

P’s with MTL resections

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

Hippocampal patient VC

• The hippocampus serves a critical role for

memory

• Remote memories rely on the hippocampus

Neuropsychological

assessment of amnesic

patients

Theoretically driven research has proven of fundamental

importance in the study of the organisation of cognitive

functions.

• Dynamic Aphasia

• Amnesia

• Executive Function - Inhibition

Executive Functions

Variety of general purpose control

mechanisms thought to modulate and

organize more basic cognitive sub-

processes to achieve effective

behaviour (e.g. Stuss and Levine, 2002)

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

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.

Inhibition: Stroop Colour-Word

Test

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)

Inhibition: The Hayling Sentence

Completion Test

The patient is asked to complete sentences by providingwords that are unrelated to the sentence frame.

‘London is a very busy. . .’, could be completed bysaying. . .‘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)

Inhibition:

The Hayling Sentence

Completion Test - Lesions

• Right PFC (Roca et al., 2010)

• Right lateral PFC (Robinson et al., 2015; Cipolotti

et al., 2015)

Part 2 of the Hayling and Stroop Colour-

Word Tests (Cipolotti et al., submitted)

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

Left Frontal

Patients

Right Frontal

Patients

Healthy

Comparison

Suppression Error

SS

5.47 4.13* 6.05

(SD) (2.64) (2.47) (1.80)

Suppression RT2

SS

5.07 4.40** 6.00

(SD) (1.71) (1.80) (0.63)

Stroop (No. of

colours named in

2 minutes)

90.21* 99.31 114.49

(SD) (27.96) (35.23) (20.30)

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)

Three separate 2x2 mixed-method ANOVAs with:

• Type of measure - Hayling measure/Stroop (z-scores) - as thewithin-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

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)

Results of voxel lesion-symptom mapping

analyses (VLSM): Hayling

Voxels in red show the

area found to be

significant (p<0.05 FWE-

corrected at cluster level)

(A) Hayling Suppression

errors

(B) Hayling Suppression RT 2

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)

Inhibition: Conclusion I

1. Lesion location, right or left PFC, is a criticalfactor in producing impairments on twoinhibitory tasks loading similarly on verbalcontrol

2. Hayling and Stroop assess dissociablecomponents of executive functions, relatedto separate and lateralized PFC circuits

3. Inhibition may actually comprise qualitativelydifferent forms with different neuronalsubstrates

Inhibition: Conclusion II

The assessment of inhibition in frontal

patients need:

• to use a variety of tests

• to develop different types of treatments

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