the cerebellum in clinical disorders · 2019. 12. 3. · cerebellum: developmental disorders autism...

December 3, 2019

Cherie Marvel, PhDAssociate Professor

Depts. of Neurology & Psychiatry

The Cerebellum in Clinical Disorders

Overview

Cerebellum anatomy & function

Description of cerebellar clinical disorders

Feedforward motor control

Feedforward cognitive control

Studies of cognition in cerebellar ataxia

The Cerebellum

The Cerebellum

The cerebellum contains more neurons than the rest of the brain put together.(3.6x more than the neocortex)

Cerebellum cut from field of view

Fiez et al., J Neuroscience, 1996

Here’s the activation the authors made a fuss about

Volkow et al., J Neuroscience, 2003 We’ll just pretend it

doesn’t exist…

Van Essen Lab, brain mapping

Cerebellar Anatomy

MRI Atlas of the Cerebellum, 2000

Cerebellar Anatomy

The anatomy of the cerebellum is simple, consistent throughout, and relatively preserved across species.

https://bellspalsycranialnerves.files.wordpress.com/2013/01/cerebellar-connections.jpg

Mossy fibers = transmit the state of the system to Purkinje cells via parallel fibers (e.g., determines the desired motor output)

Climbing fibers = convey error signal (e.g., reports a motor error). This excites discrete Purkinje cells, whose activity can modulate parallel fiber activity.Thus, cerebellum modifies output (e.g., learns) in order to correct the next movement.

Purkinje Cells

View from the front – dendrites fan out View from the side – flat

http://neuroscience.uth.tmc.edu/s3/chapter05.html

Historical Perspective:Henrietta Leiner

1. Had a background in computers prior to studying neuroanatomy (1940s!)

2. Suggested that the homogeneous, parallel circuitry of the cerebellum allows rapid information processing (like a computer)1. Phylogenetically older parts = controlled

motor function2. Newer parts = controlled cognition

Neuropsychology Review, 2010

How does the Cerebellum Work?

Uniform circuitry = whatever the cerebellum is doing, it does it the same way for every computation

Difference in outcome-- depends upon the connections: where is information coming from and where is it going to?

Outcome may also depend upon when the disruption occurred (pre-natal, developmental, sudden injury– as a child or as an adult)

Cerebellum: Neurological Damage

Stroke

Left superior cerebellumStroke Research and Treatment, 2011


Tumor or tumor resection

a) Cerebellar tumor

b) Tumor resectionSurgical Neurology International (2012)


Degeneration due to endogenous factors (e.g., inherited disease of spinocerebellar ataxia, SCA)

Marked cerebellar atrophy in the SCA patientsAmerican Journal of Neuroradiology (2011)


Degeneration due to exogenous factors (e.g., alcoholism)

Marked cerebellar atrophy in the alcoholic patientAlcohol Research and Health, Sullivan et al., 2010

Healthy Control Alcoholic

Cerebellum: Developmental Disorders

Autism Purkinje cell loss, mainly in the posterior cortex

Schizophrenia Smaller total cerebellar volumes Cerebellar signs (e.g., unsteady tandem gait, intention tremor) Poor premorbid social outcome

Dyslexia Anterior cerebellum may be involved but anatomical data are

mixed

Children born very pre-term (< 33 weeks) Smaller lateral lobes

Cerebellum, 2012; Biol Psych, 2004; Cortex 2011; Brain, 2001

Feedforward Motor Control

• The cerebellum utilizes a feedforward motor system that processes signals in one direction (forward) in a sequential manner from input to output.

Pisotta & Molinari, 2014


• Makes a prediction of the motor/sensory outcome -- > compares actual vs. predicted and adjusts accordingly.



• Makes a prediction of the motor/sensory outcome -- > compares actual vs. predicted and adjusts accordingly.

• This feature enables the cerebellum to send quick and clear action-related commands to other brain regions. (no feedback, which takes too long)



• Makes a prediction of the motor/sensory outcome -- >compares actual vs. predicted and adjusts accordingly.

• This feature enables the cerebellum to send quick and clear action-related commands to other brain regions. (no feedback, which takes too long)

• Such commands from the cerebellum are related to fine tuning the timing and sequence of the actions.


Cerebellar Damage -> Disruption of Feedforward Motor Control -> Motor Signs

Unsteady gait, poor balance, incoordination

Dysarthric speech: reduced fluency, slurring

Oculomotor problems: nystagmus, abnormal saccades (over or undershoot to target), jerky saccadic pursuit

Associated with damage to anterior lobe (I – V) but not usually seen when damage is confined to inferior lobes (VII – X)

Neuroscience (2009), Neuroimage (2006)

Cerebellar Ataxia

Feedforward Cognitive Control

• Similar to feedforward motor control, the cerebellum may use a feedforward mechanism of cognitive control.

• Underlying rationale:• Motor/sensory sequences are used covertly in

cognition, enabling the cerebellum to generate internal models and make predictions about the outcome (and make adjustments).

e.g., inner speech to rehearse sounds or search for specific words

e.g., planning out sequential steps to solve a puzzle (i.e., form a strategy)

Neuroscience & Biobehavioral Reviews, 2019

Motor regions are activated during working memory: meta-analysis across several fMRI studies(generation of internal motor sequences)

The Cerebellum’s Role in Cognition

Shows activation during: Executive functions Spatial skills Working memory Language Emotions

Cognitive deficits can occur in each of these domains as a function of cerebellar injury. Effects may be subtle, in the

low-normal range, but significantly lower than well-matched controls.

(Stoodley, 2009)

• For people with ataxia, cognitive processes may be impaired when the cerebellar feedforward system is disrupted by cerebellar degeneration.

Cognitive Studies in Cerebellar Ataxia

1. Timing

2. Implicit sequence learning

3. Organized strategy formation

4. Using covert motor sequences for verbal memory

Motor-cognitive

Cognitive

Timing

The blue cross will begin to flash. Press the button in time with the flashing.

The bar shows your accuracy. If it moves to the left, you are tapping too slowly.

The bar shows your accuracy. If it moves to the right, you are tapping too quickly.

If you are tapping in time, it will

look something like this:

Inter-Tap Interval by Frequency


Ataxia patients slower


Ataxia patients faster



Ataxia patients faster


No group differences in accuracy. However, worse symptoms correlated with lower accuracy.

Implicit sequence learning

Stimuli were presented in one quadrant at a time and remained on the screen until the subject pressed a key that corresponded to the quadrant number (even if incorrect). Stimulus locations were determined by a set of rules: every horizontal “line” was followed by a vertical “line”, which was followed by a diagonal “line”. Every 4th stimulus was determined randomly.

Random location Random location Random location(but pattern consistent)

Every trial is labeled as “pattern” or “random” and analyzed separately.Implicit sequence learning = faster response times to pattern > random trials.

Pattern vs. Random Trials: Response Times

Organized Strategy Formation

Rey Osterrieth Complex Figure (developed in 1941)

(Rey, 1941)

Slapik et. al., 2018

Example: Control Example: Ataxia

Figure drawing strategies range from organized (1) to disorganized (5), following Osterrieth, 1944.


Using covert motor sequences for verbal memory

Verbal Encoding Task

Three tasks (all yes/no button press responses):

1. Is the word shown in uppercase? (perceptual; light encoding)

tourist

JOURNAL




tourist

JOURNAL

2. Do both words rhyme? (phonological; moderate encoding)

mutton/button

perform/cricket




tourist

JOURNAL

2. Do both words rhyme? (phonological; moderate encoding)

mutton/button

perform/cricket

3. Does the word answer the question? (semantic; strong encoding)

Is this a tall building? (tower)

Is this a kind of storm? (feather)


Also given as auditory task:

1. Is the word given in a high-pitched (or female) voice?

2. Do both words rhyme? (goes straight into phonological store without a need for translation of visual to phonological; no internal generation of motor sequences)

3. Does the word answer the question?


3 tasks: perceptual, phonological, semantic

2 modalities: visual vs. auditory

Also tested yes/no recognition at the end of the task

n = 17 ataxia, 7 controls

Required internally generated motor sequences

Cognitive Studies in Cerebellar Ataxia

• Patients are impaired on a variety of tests.

• Common denominator across tests: • ability to predict or formulate sequences

(feedforward mechanism)

• Parsimonious explanation:• disruption of feedforward mechanisms affect

cognition in patients with cerebellar damage

Overall Summary

Cerebellum structure (and function) is uniform throughout

Follows a feedforward model of motor control

Results from studies of cerebellar ataxia support a feedforward model of cognition

Acknowledgements

Lab Members– Current Mitchell Slapik Owen Morgan Jason Creighton Katherine Iannuzzelli

Lab Members—Past Sharif Kronemer Jessica Pietrowski Jessica Rilee Seth Lieberman

Collaborators: Liana Rosenthal Chiadi Onyike

Funding:

Margaret Q. Landenberger Research Foundation, Gordon and Marilyn Macklin Foundation

Study Recruitment:

Ataxia Center of Johns Hopkins, National Ataxia Foundation

Special thanks to the patients and spouses and caregivers for their participation and support.

the cerebellum in clinical disorders · 2019. 12. 3. · cerebellum: developmental disorders autism...

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