executive function and executive function the cerebellum · the cerebellum executive function •...

Executive Function and The Cerebellum

Executive Function

• In theory, a system that controls and manages other cognitive processes

• Encompasses a number of higher-order cognitive functions

Outline: Neuroimaging &Patient Studies

• Executive variant of verbal working memory task, requiring information manipulation

• Verbal Fluency• Cognitive Flexibility: Wisconsin Card Sorting Task• Reasoning• Dual Task/Divided Attention• Inhibition of prepotent response: Stroop Test• Planning• Theory of Mind

X J F Q V C f

ReadLetters

Remember (Rehearse) Letters

Decide if ProbeMatches a Letter

Encoding Phase Maintenance Phase Retrieval Phase

Sensory AcquisitionArticulatory Preparation

Articulatory Motor ControlError Correction

Refreshment of Phonological Store

Executive Search,Comparison,

Response Selection

Sternberg Verbal Working Memory Task

Executive Variant of Working Memory Task

HighLoad

(X J F)+

(Q V C)

1.5 s 5.0 sec 1.0 s

f h

Read6 Letters

Remember6 Letters

Respond ifprobe is a match

R P W+

L (K) X

1.5 s 5.0 sec 1.0 s

r t

Read1 Letter

Remember1 Letter

Respond ifprobe is a match

LowLoad

0.5 s

0.5 s

Encoding Retrieval

BA 4/6BA 46

R

Executive – Match: Healthy Subjects

Marvel, C.L. and Desmond, J.E. (2010) Cortex 46, 880-95

Strick et al. (2009) Annu Rev Neurosci 32:413-434.

Concordance WithAnimal Tracing Literature

Cerebellar Dentate Nucleus

The N-Back Task

Cohen JD, et al. Nature 386: 604 (1997)

Verbal Fluency

• Thought to be sensitive to frontal lobe function

• Typical test: Give subject a letter and ask him/her to generate as many words as possible that start with that letter

Lurito et al (2000)

• Subjects received fMRI scan while alternately performing 2 tasks– Generate words to single letter (32 s)

– Fixate on a symbol (32 s)

• 4 cycles of generate/fixate

Generatestimulus Fixate

stimulus

Results

Group Average

Lurito et al (2000) Hum Brain Mapp 10, 99-106

Two Individual Subjects

R L

Verbal Fluency: Cerebellar Patients (Molinari et al, 1997)

• Generation of words often involves clustering according to phonemic or semantic criteria

• Phonemic clusters: Successive words have word sound similarities– E.g., rhyming: bite, bright, blight– E.g., same initial sound: frog, fruit, frown

• Semantic clusters: Successive words have meaning similarities – E.g., same category: salmon, sailfish, shark,

stingray

Tasks

• Patients and controls asked to perform two tasks– Phonemic task: Generate words that

begin with F, A, and S (no proper names)– Semantic task: Generate as many words

possible belonging to categories of birds and furniture

• Each of these tasks can exhibit clusters that are either phonemic or semantic

Cluster Definitions

• Phonemic task:– Phonemic clusters: Successive words have same first 2

letters (e.g., fruit, friend) or rhyme (e.g., fake, flake)– Semantic clusters: Successive words belong to same

semantic category (e.g., apple, apricot), or are two forms of a word (e.g., sing, sang)

• Semantic task:– Phonemic clusters: Successive words beginning with same

phoneme (e.g., raven, robin) or which rhymed (e.g., wren, hen)

– Semantic clusters: Successive words belong to same subcategory (e.g., birds of prey: hawk, eagle)

Total Word Generation

*

*

Focal tumor orstroke

CBL atrophyControls

Leggio et al (2000) J Neurol Neurosurg Psychiatry 69, 102-6

Cluster Results

* *

*

* *

Ratio =Num clusters ÷Num gen words

Leggio et al (2000) J Neurol Neurosurg Psychiatry 69, 102-6

Cerebellar damage affects phonologically basedword retrieval strategy

Word RetrievalPeterburs et al (2010)

• Cerebellar patients and controls were tested on– Verbal fluency

• Semantic: Generate names of countries• Phonematic: Nouns starting with “b”• Switch: Alternate between categories “vegetables” and

“male first names”

– Verbal working memory: 2 back task– Verbal long-term memory: Recall as many

details as possible from a prose passage they hear (immediate and 30-min delayed recall tested)

Patient MRIs

Lesions from strokesinvolving either superiorcerebellar artery or posteriorinferior cerebellar artery

Peterburs et al (2010) Cerebellum 9, 375-83

No Effects on VerbalLong-Term Memory


Significant Decrement in Verbal Working Memory


Significant Impairment onPhonematic & Switch Tasks

Consistent with Leggioet al (2000) results This task has both

word generationand working memoryrequirements


Wisconsin Card Sorting Test(WCST)

• Lie et al 2006 – fMRI study

• Sensitive to executive dysfunction and right frontal damage

WCST WCST

WCST

• A number of cognitive functions are involved in the task

• Patients with executive dysfunction tend to perseverate on obsolete category rather than shift set– High rate of perseverative errors is

associated with dorsolateral prefrontal damage (especially right side)

WCST fMRI Design

Lie et al (2006) Neuroimage 30, 1038-49.

Contrast Results

Lie et al (2006) Neuroimage 30, 1038-49.

Comments• A-B and A-C contrasts

attempted to isolate error-correction, higher level working memory, set shifting, and concept formation components of the task, while controlling for motor, sensory, and response selection aspects

• Cerebellar activations were prominent (and bilateral, more medial on right)

• Frontal, esp. right, more promininent on A-C than A-B– Perseveration is more often

observed in right frontal damage

WCST – Patient Studies

• Karatekin et al (2000)

• Tested full scale IQ and WCST in 4 children with cerebellar astrocytoma (2L, 2R) and 6 children with temporal lobe tumor (4L, 2R) after surgery

• No chemotherapy or radiation

Example

Patient Performance

0

10

20

30

40

50

60

70

80

WCST IQ

Percentile

CerebellarTemporal

WCST results indicate perseverative errors. Cerebellar patientsshowed higher IQ scores, but performed more poorly on WCST (i.e., more perseveration errors).

LowerPercentile =More Perseveration

WCST: Adult CBL Patients

• Mak et al (2016)

• 30 patients who had undergone tumor removal and 30 matched controls

Conceptual ReasoningRao et al (1997)

T X

X T

T X

X T

Relevant Dimensions:Size: Large or SmallLetter: X or TColor: Red or BluePosition: Left or Right

6 sec

6 sec

6 sec

6 sec

(Arrow next to letter indicates subject’s choice)

“correct”could be:RedTLeftLarge

“wrong”could be:RedLeft

“wrong”must be:Red “correct”

Time

Control TaskRao et al (1997)

T X

X T

T X

X T

Subject is cued at the beginningof each series to respond to a single stimulus feature, e.g., large

6 sec

6 sec

6 sec

6 sec

“correct”

Time

“correct”

“correct”

“correct”

(Arrow next to letter indicates subject’s choice)

Controls for visualinput from stimuliand motor responses

Imaging Results

Conceptual Reasoningminus

Control Task

L R

Rao et al. (1997) Neuroreport 8, 1987-1993.

Syllogistic ReasoningGoel et al

(2000)

Results

• Content Reasoning – Preparation and No Content Reasoning – Preparation produced somewhat different maps– Content reasoning: Left neocortical and

right cerebellum

– No Content reasoning: Bilateral neocortical and bilateral cerebellum

Neuroimaging Results

Goel et al (2000) Neuroimage 12, 504-14.

Reasoning: Neuropsychological Study (MacLullich et al 2004)

• Studied 50 healthy men, age 65-70• Quantified volume of vermis, divided

into 4 regions• Computed correlation of volume and

neuropsychological test scores• Among the tests was Raven’s

progressive matrices, a test of reasoning

Example 1

Example 1

QuantitativeProgression

Example 2

Example 2

Addition

Example 3

Example 3

Each row has 3 shapesEach row has 3 types of barsThe orientation of the baris the same within each row

MacLullich (2004) Measurements

MacLullich et al (2004) Brain and Cognition 56, 344-348.

MacLullich (2004) Results

(Raven’s) *

Significant correlation of vermis volume with Raven’s test performance.Effect seen especially in Regions 2 and 3 (neocerebellar vermis)

Divided Attention/Dual Task: PET Study

• Klingberg et al. (1998) looked at brain activation during concurrent auditory and visual working memory tasks

Tasks

Klingberg, T. (1998) Cereb Cortex 8, 593-601.

Single auditory and visual WM tasks.Subject compares each tone withpreviously heard tone. Press button ifnew tone is lower than previous.Same idea for visual task (consistingof disks), but now press button if newdisk has lower luminance than previousone.

For dual task condition, the auditory and visual tasks were performedconcurrently.

Results

Klingberg, T. (1998) Cereb Cortex 8, 593-601.

Left cerebellum among thebrain regions showing increasedactivation for dual task

Dual Task Patient StudyAttend to Auditory and Visual Modalities

• Gottwald et al (2003)

• 16 patients with focal cerebellar lesions of different types (e.g., strokes, tumors)– 6 left, 10 right side

• 16 controls matched for age, gender, education

Gottwald et al (2003) task

• Task 1: Listen to 2 notes and press key if they hear the same note twice

• Task 2: Look at visual display of X’s and press key if 4 X’s form a square

Gottwald et al. (2003) Neuropsychologia 41, 1452-60.

Gottwald et al (2003) task

• Task 1: Listen to 2 notes and press key if they hear the same note twice

• Task 2: Look at visual display of X’s and press key if 4 X’s form a square

For Example


Results

On average, patients andcontrols had similar RT’sbut patients were morevariable. However, patientsmissed significantly moretargets than controls indual task test.Note lower percentile=Worse performance


Dual Task (motor/cognitive) fMRI: Wu et al (2013)

• Task 1 (motor): Tap index and middle fingers alternately at 1 Hz frequency

• Task 2 (working memory): Series of letters presented on screen and subjects asked to identify the number of times they saw a target letter

Dual TaskBehavioral Performance

Very accurate performance for all conditions. Movement rateis nearly identical for all tapping conditions

Results

Tapping Counting

Dual

Wu et al. (2013) Neuroimage 65, 466-75.

Dual Task > Single Task


Focus on Cerebellum

Tapping Counting

Dual Task

Dual > Single


Single Tasks


Dual Task (motor/cognitive)Patient Study

• Lang & Bastian (2002)• Examined the effects of a working

memory task (sequence of letters, remember how many occurrences of target letter) on a practiced movement (making figure of eights)

• 10 patients with cerebellar atrophy and 10 controls

Motor Task

Lang & Bastian (2002) J Neurophysiol 87, 1336-47.

Motor Task Performance


Group Results

Interpretation:Cerebellum involved inShifting movement performance to a more skilled and automatic state


Stroop Test

• For the words that will appear, say aloud the color of the word

DOG CHAIR

APPLE GREEN

HORSE BLUE

Stroop Effect

• Involves a relevant response (color naming)

• …and an automatically activated, irrelevant response (word reading)

• Most investigators characterize this as a response selection

Stroop Neuroimaging StudyTaylor et al (1997)

* * *

Taylor et al. (1997) Neuroimage 6, 81-92.

Neuroimaging Results

Taylor et al. (1997) Neuroimage 6, 81-92.

Authors emphasize frontal involvement, but also note consistent cerebellar activation

Stroop Test: Patient StudyNeau et al (2004)

• Examined 15 patients with cerebellar infarcts (SCA, AICA, PICA), confirmed by MRI

• 15 controls matched for age, gender, and education

Results

Cerebellar patients impaired on Stroop interference even after 1 yearSCA infarction produces poorer performance than PICA infarcts

Planning: Neuroimaging

• Kim et al (1994) – Strick is co-author

• Scanned dentate nucleus under 2 conditions– Manipulating pegs under visual guidance

– Manipulating pegs to solve a puzzle

Two Tasks

Kim et al (1994) Science 265, 949-951.

Rules for Insanity Task:“(i) Only one peg may bemoved at a time. (ii) A peg may be moved to an adjacent open space or may jump an adjacent peg (of a different color).(iii) A peg may be movedforward, never backward.”

Visually Guided Task

Insanity Task

D=dorsal, V=ventralC=contralateral (to moving hand)I=ipsilateral

Kim et al (1994) Science 265, 949-951.

Conclusions

• Ventral dentate activation is consistent with transneuronal tracing studies demonstrating connectivity between ventral dentate and prefrontal regions

Strick et al. (2009) Annu Rev Neurosci 32:413-434.

Concordance WithAnimal Tracing Literature

Cerebellar Dentate Nucleus

Planning: Patient Study

• Grafman et al (1992)

• 12 patients with cerebellar atrophy

• 12 matched controls

• Compared performance on Tower of Hanoi Task

Tower of Hanoi

Grafman et al. (1992) Neurology 42, 1493-6.

Tower of Hanoi

• Results: Cerebellar patients solved significantly fewer puzzles than controls

• They also made significantly more illegal moves than controls

• No correlations were found between TOH performance and motor impairment

Grafman et al. (1992) Neurology 42, 1493-6.

Theory of Mind (TOM)

• The ability to attribute mental states, intentions, or beliefs to others

• Empathy: Ability to infer and share the emotional experiences of others

TOM/Empathy: Neuroimaging

• Vollm et al (2006)

• Showed subjects short cartoon strips and asked them to choose the most appropriate ending scene

TOM: Example

Vollm et al (2006) Neuroimage 29, 90-8.

What will the main character do next?

TOM Control(Physical Causality: 1 character)

What is most likely to happen next?


Empathy ExampleWhat will make the main character feel better?


Empathy Control(Physical Causality:2 Characters)

What is most likely to happen next?


Results

Areas common to TOM and Empathy, ie. conjunction ofTOM-Control1 and Empathy-Control2Note bilateral cerebellar activation


TOM and EmpathyActivations were Similar but not Identical

TOM > Empathy

(TOM-Contro1) – (Empathy-Control2)Orbitofrontal Cortex


Empathy > TOM

(Empathy-Control2) – (TOM-Control1)Amygdala


TOM/Empathy: Patient Studies

• Roldan Gershcovich et al (2011)• A case study: Patient with extensive and

bilateral cerebellar stroke (52 year old male)• Test 1: “Reading the Mind in the Eyes and

Faces Test”– Evaluates the recognition of emotions from the

patient’s choice of the word that best describes an emotion in pictures of faces and eyes

• Test 2: “Faux Pas” test– Evaluates capacity to recognize an inappropriate

situation in stories

Reading the Mind in the Eyes

Reflective or Unreflective?


Sympathetic or Unsympathetic?


Playful Message or Serious Message?


Concerned or Unconcerned?

Reading the Mind in Faces

Happy or Sad? Angry or Afraid?

Faux Pas Test

Jeanette bought her friend Anne a crystal bowl for awedding gift. Anne had a big wedding and therewere a lot of presents to keep track of. About a yearlater, Jeanette was over one night at Anne’s for dinner.Jeanette dropped a wine bottle by accident onthe crystal bowl, and the bowl shattered. “I’m reallysorry, I’ve broken the bowl,” said Jeanette. “Don’tworry, ” said Anne, “I never liked it anyway. Someonegave it to me for my wedding.”

Stone et al (1998) J Cogn Neurosci 10, 640-56.

Faux Pas Test: Questions

1. Did someone say something they shouldn’t havesaid? (Tests for detection of faux pas.)

Stone et al (1998) J Cogn Neurosci 10, 640-56.

If Yes:

2. Who said something they shouldn’t have said?(Tests for understanding of faux pas.)

3. Why shouldn’t they have said it? (Requires understandingmental state of listener.)

4. Why did they say it? (Requires understanding mentalstate of speaker.)

If No:

What had Jeanette given Anne for her wedding? (Control questionthat asks about some detail of the story.)

Cerebellar Damage in Case Study

Roldan Gerschcovich (2011) Neurocase 17, 270-5.

Impaired TOM/Empathy Performance

Roldan Gerschcovich (2011) Neurocase 17, 270-5.

TOM: Patient Group Study

• A group study of 10 patients with cerebellar degeneration showing TOM deficit relative to 10 controls– Faux Pas Test (p < .01)

– Reading the Mind in the Eyes test (p<.014)

• Abel et al (2007) Arq Neuropsiquiatr 65, 304-12

ToM: Patient Group StudyClausi et al, 2018

• 27 patients with cerebellar atrophy, 27 matched controls

• Deficits found in Reading Mind in Eyes (RME), Theory of Mind (ToM) stories, Faux Pas stories

• Emotion attribution test (EA) was not sig., attributed to low level of prediction required

Clausi et al Conclusions

• “Cerebellum seems to be involved in the construction of internal models of mental processes during social interactions in which the prediction of sequential events plays a role, allowing us to anticipate the other person’s behavior.”

executive function and executive function the cerebellum · the cerebellum executive function •...

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