verbal working memory q x v t w r - johns hopkins university · schmahmann et al. (2000) mri atlas...

Verbal Working Memory

Q X V T W R

b

X J F Q V C f

ReadLetters

Remember (Rehearse) Letters

Decide if ProbeMatches a Letter

Encoding Phase Maintenance Phase Retrieval Phase

Sternberg Verbal Working Memory Task

High Load: 6 lettersLow Load: 1-3 letters

Advantages of Task

• Can examine activation during different phases of the task

• Parametric modulation is possible, ie., we can vary the working memory load, e.g.,– High Load = 6 letters– Low Load = 2 letters– Can then do a High - Low contrast

• The subject is doing the same task in High and Low conditions, which is better controlled than using Rest or other task for the control condition

# J Z # # #

j

Working Memory in Action

Verbal Working Memory in Action

FrontalTemporal-

Parietal

articulatory control system

phonologicalstore

phonologicalloop


Baddeley Model of Verbal Working Memory

FrontalTemporal-

Parietal


phonologicalstore

phonologicalloop

Cerebellar Contribution toThis System?

Cortico-Ponto-Cerebellar circuitry

Kandel, E.R. et al, eds. Principles of Neural Science, 3rd Ed. New York: Elsevier, 1991

A

B

Cortico-ponto-cerebellar Anatomy

Schmahmann, 1996

Brodal, 1979

FrontalTemporal-

Parietal

MedialPN

LateralPN

Superior

Inferior

Cortico-Ponto-Cerebellar Circuitry: Summary

Neocortex

PontineNuclei

CerebellarCortex

Stimulus Timing: Working Memory

HighLoad

(X J F)+

(Q V C)

1.5 s 5.0 sec 1.0 s

f

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

Read1 Letter

Remember1 Letter


LowLoad

0.5 s

0.5 s

FrontalTemporal-

Parietal

MedialPN

LateralPN

Superior

Inferior

Predicted Activations: Working Memory Task

Neocortex

PontineNuclei

CerebellarCortex

phonologicalloop

Articulatory Control System Phonological Store

FrontalTemporal-

Parietal

MedialPN

LateralPN

Superior

Inferior

Predicted Activations: Working Memory Task

Neocortex

PontineNuclei

CerebellarCortex

phonologicalloop


Stimulus Timing: Motoric Rehearsal

0.5 s1.0 s

(M K S) +(H Z Q)

(M K S) +(H Z Q)

(M K S) +(H Z Q)

(M K S) +(H Z Q)

press

Read6 Letters

Read6 Letters

1.35 s

Read6 Letters

Read6 Letters

Follow instructions

0.275 s

HighLoad

0.275 s 0.275 s 0.275 s1.35 s 1.35 s 1.35 s

1.0 s

(B) R L + N G D

(B) R L + N G D

(B) R L + N G D

(B) R L + N G D

press

Read1 Letter

Read1 Letter

1.35 s

Read1 Letter

Read1 Letter

Follow instructions

0.275 s

LowLoad

0.275 s 0.275 s 0.275 s1.35 s 1.35 s 1.35 s

0.5 s

MedialPN

FrontalTemporal-

Parietal

LateralPN

Superior

Inferior

Predicted Activations: Motoric Rehearsal Task

Neocortex

PontineNuclei

CerebellarCortex

phonologicalloop


FrontalTemporal-

Parietal

MedialPN

LateralPN

Superior

Inferior

Predicted Activations: Motoric Rehearsal Task

Neocortex

PontineNuclei

CerebellarCortex

phonologicalloop


(X J F)+

(Q V C)

1.5 s 5.0 sec 1.0 s

f

Read6 Letters

Remember6 Letters


0.5 s

0.5 s1.0 s

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)

(M K S)+

(H Z Q)press

Read6 Letters

Read6 Letters

Read6 Letters

Read6 Letters

1.35 s

Read6 Letters

Read6 Letters

Read6 Letters

Read6 Letters

Follow instructions

Follow instructions

0.275 s 0.275 s 0.275 s 0.275 s1.35 s 1.35 s 1.35 s

Cerebro-Cerebellar Activations: With vs Without Phonological Storage

Chen & Desmond, Neuroimage, 24: 332-338 (2005)

During Which Phase(s) of the Trial Does Cerebellar Activation Occur

X J F Q V C f

ReadLetters




Sensory AcquisitionArticulatory Preparation

Articulatory Motor ControlError Correction

Refreshment of Phonological Store

Executive Search,Comparison,

Response Selection

Sternberg Verbal Working Memory TaskDistinguishing

Trial Events

Encoding

Maintenance

Retrieval

2s

4s

3s

SimulationResponses toSingle Events

SimulationResponses to

CombinedEvents

Analysis of Phase-Dependent Activations

Encode

Maintain

Retrieve

+

+

+

Temporal Specificity +LoadEffect = Response to Phase

= Encoding Response

= Maintenance Response

Retrieval Response=

(2 vs. 6 letters)X J F

+Q V C

f +

Match?

4 or 6 seconds2 seconds 3 seconds

RetrievalEncoding Maintenance

Left Frontal / Right Superior Cerebellar Concordance

Chen & Desmond, Neuropsychologia, 43: 1227-1237 (2005)

X J F +

Q V C

f +

Match?

4 or 6 seconds2 seconds 3 seconds


Left Temporal-Parietal / Right Inferior Cerebellar Concordance

Chen & Desmond, Neuropsychologia, 43: 1227-1237 (2005)

Summary

• Neuroanatomical connections and patterns of functional neuroimaging suggest two cerebro-cerebellar circuits participating in two subsystems of verbal working memory– Left frontal/right superior cerebellum linked to


– Left inferior parietal/right inferior cerebellum linked to phonological storage

X J F Q V C f

ReadLetters








Response Selection


fMRI ExperimentAuditory vs Visual Encoding

Y S R F MH K+

Time (s)

Encoding Next TrialMaintenance Retrieval

hyes noh

yes no

2 13 15 18

+

8

Y S R F MHY S R F MH+ hyes noh

yes noM+

Time (s)2 13 15 188

Visual

Auditory

3024 8

-1 -41

-64 -64

-41 -18

2430

30 24 8

-1 -41 -64

L R

Auditory/VisualActivations

Auditory

Visual

Both

Kirschen, Chen & Desmond (2010)Behav Neurol 23:51-63.

Belin et al, Neuropsychologia, 40 (2002) 1956-64.

Cerebro-Cerebellar Activation During Auditory DiscriminationPediatric Cerebellar Tumor Patients

Kirschen et al. (2008) Behavioural Neurology.

Cerebellar Patients

• 12 Children who had undergone surgical resection for a cerebellar pilocytic astrocytoma– No radiotherapy or chemotherapy– Mean age 12.5 (range 6-19)– Tested 5.5 +/- 3.1 (SD) years post-surgery

• 12 controls matched on gender, age, and education level

Cerebellar Patients Have Decreased Digit SpanWith Auditory Presentation of Items

*


Silveri et al. (1998). Brain, 121, 2175-2187.

Verbal Working Memory Deficit from a Cerebellar Lesion

RL

Ravizza SM, et al. Brain 129: 306 (2006)

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

Ziemus et al (2007)

• Found digit span deficits in cerebellar stroke patients

• Also performed 2-back verbal working memory in these patients during fMRI

Ziemus et al (2007)• Increased activation in patients during

verbal working memory was found in bilateral parietal cortex, suggesting compensation for the loss of cerebellum

Activation shows 2-back vs 0-back in patients > 2-back vs 0-back in controls

Quantifying Lobular Damage

3.5

4

4.5

5

5.5

6

6.5

7

7.5

Dig

it S

pan

(Aud

)

3.5 4 4.5 5 5.5 6 6.5 7Fitted Digit Span (Aud)

Dependent vs. Fitted

Left Left Superior Left Inferior Right Superior Right Inferior RightSubj DN Crus I IV & V VI Crus II VIIb VIII IX I & II III IV & V VI VII VIII IX X IX Crus I IV & V VI Crus II VIIb VIII DN

1 + - - - - + + - - - - - - - - - - - - - - - - -2 - + + + + + + - - - + ++ ++ ++ + - + + + + + + + ++3 - - - - - - - - - - - + + - - - - + - + + + - -4 - - - - - - - + - - - - - + + - - - - - - - - -5 - + - - + + - - - - - - + - - - - - - - - - - -6 - - - - + + + + ++ + + ++ ++ ++ ++ ++ + - - + + + + -7 - - - - - + - + + - - + + ++ ++ ++ ++ - - - + + + +8 ++ - + + + + + + ++ + + ++ ++ ++ ++ ++ + + + + + + + ++9 - - - - + + + + ++ + - + ++ ++ ++ ++ ++ - - - + + + +

10 - - + + + - - + + - ++ ++ ++ ++ ++ ++ + - + + + + + +11 + + + + ++ ++ + + ++ + + + ++ ++ ++ ++ + + - - + + + +12 - - + - - - - - - - ++ ++ ++ ++ + - - - - - - - - -

- less than 5% of lobule resected; + 5-50% of lobule resected; ++ more than 50 % of lobule resected

Vermis

Lobule VIII

Schmahmann et al. (2000) MRI Atlas of the Human Cerebellum

Left HVIII Damage Correlated with Auditory Digit Span

-64

R

Case Study: Left Lobule VIII / Right Lobule V DamageAuditory Verbal Working Memory Deficits

Chiricozzi et al. (2008) Neuropsychologia 46, 1940-1953

X J F Q V C k b r f +

Identify presented letter

4 seconds1.5 seconds 0.8 seconds


Post-encoding TMS Administration

Tragus

Inion

TMS

LR

Tragus

Inion

TMS

LR

Targeting Cerebellar Activation

TMS Coil PositioningSurface Landmarks

TMS Targeting: Subject-Specific Localization ofRight Superior Cerebellar Activation

Obtained from Verbal Working Memory Task

Superior

Inferior

RightLeft

Posterior View of Cerebellum for 5 subjectsDesmond, Chen, & Shieh, Annals of Neurology, 58: 553-560 (2005)

Identify presented letter

X J F Q V C k b r f

1.5 s 4.0 s 0.8 s 2.5 s

TMS Stim (50% of trials)

Tasks


# # # # # # j v x t

1.5 s 4.0 s 0.8 s 2.5 s

Motor Control

Identify the “x”

TMS Stim (50% of trials)

1

2

3

X J F Q V C k b r f

1.5 s 4.0 s 0.8 s 2.5 s

Verbal Working Memory (Sham Coil)

Sham Stim (50% of trials)Identify presented letter

Desmond, Chen, & Shieh, Annals of Neurology, 58: 553-560 (2005)

TMS Effects on Reaction Time

600

700

800

900

1000

1100

1200

1300

1400

M otor Control Verbal WorkingMemory

Verbal WorkingM emory (Sham Coil)

Rea

ctio

n T

ime

(mse

c)

Stim

No Stim

p < .03

p < .02N.S.

Trial Type

Condition


Motor vs Cognitive RT Effects from Cerebellar TMS

0

20

40

60

80

100

120

140

160

Motor Control Verbal Working Memory

TM

S -

NO

TM

S R

eact

ion

Tim

e d

iff

(mse

c)

p < .03

Condition


Interpretation and a Question

• Superior cerebellar TMS disrupts normal encoding function of cerebellum, thereby making it more difficult to subsequently utilize the information (increased RT)

• If disease compromises cerebro-cerebellar circuitry thereby making the task more difficult, how will brain activation respond?

Effects of Chronic Alcohol Consumptionon Verbal Working Memory

• Why? Alcohol is known to affect cerebellum as well as neocortical regions

Cortical Gray and WhiteMatter Volumes

Alcoholic Control

57 yr old men

Lifetime consumption of alcohol1866 kg 60 kg

Prefrontal Frontal Ant PostParietalTemporal

-2

-1

0

1

controls

Z-s

core

Ant Post

Younger Alcoholics (N=33)

Older Alcoholics (N=29)

Temporal Parietal

-2-2

-1-1

00

11

Z-s

core

Prefrontal Frontal Ant Post Ant Post

controls

Gray Matter

White Matter

Pfefferbaum et al. (1997)

Left Hemisphere Tests: Men

-1.5

-1

-0.5

0

0.5

Sel

f O

rder

ed P

oint

ing

Vis

ual S

earc

h

WC

ST

Cat

egor

ies

WC

ST

% P

erse

vera

tions

Lette

r F

luen

cy ST

M

WM

S S

tory

Rec

all

Wor

d R

ecog

nitio

n

Wor

d R

ecal

l

Dep

th o

f P

roce

ssin

g

Gri

p S

tren

gth

Fin

ger

Mov

emen

t

ControlsAlcoholics

Executive FunctionsSTM &

ProductionMotorAbilityDeclarative Memory

Sullivan et al., ACER 2000

Age

-Cor

rect

ed Z

Sco

re

alcohol

control

Accuracy Reaction Time

Behavioral Results

0

20

40

60

80

100

HighLoad

LowLoad

n.s.n.s.

0

200

400

600

800

1000

1200

HighLoad

LowLoad

n.s.

n.s.

Alcoholic > Non-Alcoholic: Verbal Working Memory

Left Prefrontal

Right Cerebellum

Desmond, Chen, DeRosa, Pryor, Pfefferbaum, & Sullivan (2003), Neuroimage, 19, 1510-1520

Interpretation

• This fronto-cerebellar system is working harder in alcohol-dependent individuals to maintain performance comparable to controls

Encoding Activation: Sensory Acquisition?

• Does the cerebellar load activation found during encoding reflect greater sensory acquisition demands for High Load relative to Low Load?

Manipulating Sensory Acquisition Demands

Luminence corrected

Varying Sensory and Articulatory Demands

Articulatory DemandHigh (4 Letters) Low (2 letters)

Sen

sory

Dem

and

High(Degr)

Low(Non-Degr)

Strategy (Liang et al, 2018)

• Step One: First define cerebellar regions of interest (ROIs) based on High Load – Low Load Contrast

• Step Two: Test those regions to see if the Degraded – NonDegraded contrast is significant

Step One Results Step Two Results

Discussion

• Sensory acquisition demands were increased by degrading the stimuli, as seen by the increased visual cortical activation

• Eye movements were recorded during the scan, and did not differ for high load vs low load, or for degraded vs non-degraded stimuli

• The vermis, but not the hemisphere ROIs exhibited Degraded > NonDegraded activation

Conclusions

• To explain these findings, an overall function of forward model prediction may underlie general cerebellar function, with perceptual prediction of stimuli from partial representations occurring in the vermis, and prediction of impending articulatory rehearsal occurring in the hemispheres.

X J F Q V C f

ReadLetters








Response Selection


Phonological Similarity Effect

B D P T VG+

Time (s)


cyes no

2 13 15 18

+

8

F Q X W RZ+

Time (s)


kyes no

2 13 15 18

+

8

Phonologically Similar

Phonologically Dissimilar

Phonological Similarity Effect

• Phonologically similar words or letters are more difficult to remember than phonologically dissimilar words/letters

• Patients with left temporal/parietal lesions have equally poor verbal working memory for phonologically similar and dissimilar words/letters, ie., there is no phonological similarity effect

DissimilarHigh-LowLoad

SimilarHigh-LowLoad

MaintenanceEncoding

Neural Substrates of Increasing Phonological Storage Demand

Peterburs et al., 2019

fMRI Verbal Working Memory Task

Not AwareLinear Decr in RT

Maintenance Phase: High Load Trials

Peterburs et al., 2019

Inferior cerebellumSensitive to phonologicalStorage demand

Cerebellum sensitive to regularities of sequences in verbal working memory

Investigation of PhonologicalSimilarity Effect: Cerebellar Patients

• Lesion patterns were examined for cerebellar subjects whose PSE was deviant from controls by > 3 SD– 3 subjects with abnormal PSE to aurally-

presented stimuli– 3 different subjects with abnormal PSE to

visually-presented stimuli– In both groups conjunctions of lesions was

performed to determine if there was a region common to affected subjects

Lesions Disrupting Phonological Similarity Effect

Auditory

Visual

L R


Red regions representconjunction of lesions for subjects exhibiting abnormal PSE.

Converging Evidence

Chiricozzi et al. (2008) Neuropsychologia 46, 1940-1953

• Chiricozzi et al. cerebellar case study: Patient exhibited phonological storage deficits:– Abnormal recency effect*

– Absence of phonological similarity effect to aurally-presented stimuli

*Recency effect: Normal healthy subjects tend to have better memory for the mostrecently presented item. This effect does not occur in patients with damage to thephonological storage system (left temporal/parietal lesioned patients).

Phonologically Similar and Dissimilar Word Lists

Justus et al (2005) Brain Lang 95, 304-18.

Results

Phonological similarity effect is strong in controls, and nearly absentin bilaterally damaged cerebellar patients.

Justus et al (2005) Brain Lang 95, 304-18.

Disrupting Cerebellar Predictionin Verbal Working Memory

• Insipired by Miall et al., 2007 study

• In that study, TMS was used to disrupt state estimation in the forward model of a hand trajectory

• An analogous design was used to disrupt the forward model of the “articulatory trajectory” of verbal working memory

Miall et al., 2007

Miall et al., 2007 Miall et al., 2007


Sheu et al. submitted


Sheu et al. submitted

Occipital

Conclusions

• Cerebellar TMS caused more errors on early and correct probes, but not late probes, relative to occipital (control) TMS– Seemed to be using out of date information to

predict the next letter in the sequence.

• This pattern of errors is consistent with TMS causing a temporary disruption of state estimation and cerebellar forward model function, leading to prediction errors in the phonological loop.

X J F Q V C f

ReadLetters








Response Selection


To be discussed in executive function lecture

Summary• Encoding

– Left posterior frontal / right superior cerebellum

– Modality independent (but note L inf cerebellum)

– Load dependent cerebellar activation cannot be universally explained by increased sensory acquisition demands

– Disruption impairs performance; compensatory activation

Chanraud-Guillermo et al. (2009) Alcohol Clin Exp Res 33:977-984.

Converging Evidence: Cerebro-Cerebellar Hyperactivation

alcohol

control

Accuracy Reaction Time

0

20

40

60

80

100

Per

cen

t co

rre

ct

HighLoad

LowLoad

n.s.n.s.

0

20

40

60

80

100

Per

cen

t co

rre

ct

HighLoad

LowLoad

n.s.n.s.

0

200

400

600

800

1000

1200

HighLoad

LowLoad

mil

lisec

on

ds

n.s.

n.s.

0

200

400

600

800

1000

1200

HighLoad

LowLoad

mil

lisec

on

ds

n.s.

n.s.

Auditory Language Task: Alcohol > Control

Summary• Encoding

– Left posterior frontal / right superior cerebellum– Modality independent (but note L inf cerebellum)– Load dependent cerebellar activation cannot be universally explained

by increased sensory acquisition demands– Disruption impairs performance; compensatory activation

• Maintenance– Left inferior parietal / right inferior cerebellum

• Activation depends on phonological storage requirement

– Activations enhanced by phonological similarity• But this activation decreases if there are sequence regularities

• Inferior cerebellar damage impairs phonological similarity effect

– Prediction used during rehearsal can be disrupted by cerebellar TMS

• Retrieval - To be discussed

The Role of the Cerebellum inVerbal Working Memory

• For rapid limb movements, the cerebellar forward model is hypothesized to compute a prediction of the limb trajectory

• When a sequence of letters must be held in mind, an “articulatory trajectory” must be computed– Analogous to a limb trajectory

Hypothesized Functions

• Forward model: Rapid prediction of articulatory trajectory needed for phonological loop

Articulatory structures include: lips,cheeks, tongue, jaw, hard palate (roofof mouth), and soft palate (which hasthe velum, the soft tissue in back of throat, plus uvula, the small cone that hangs down)

Cerebro-Cerebellar Loops in Verbal Working Memory

FrontalTemporal-

Parietal

Lat. PN

phonologicalloop


Med. PN

Sup. CBL

Inf. CBL

Deep Nucl

amusThal

Hypothesized Functions

• Sensory prediction of the letter sequence that the phonological store will contain

Possible Forward Models in Verbal Working Memory

Encoding Phase Maintenance PhaseFrontal/Superior CBL Parietal/Inferior CBL

“QXVTWR”Articulatory trajectory

Refresh phonological store

Prediction of mouth,tongue, lipmovements and sensory consequences

Prediction of thephonological stream

Facial/trigeminalsystems

Frontal

Cerebellar Contribution

• Net result of motor and sensory predictions: Increased efficiency and greater probability of success of the phonological loop

verbal working memory q x v t w r - johns hopkins university · schmahmann et al. (2000) mri atlas...

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