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
Cerebellum: Neurological Damage
Tumor or tumor resection
a) Cerebellar tumor
b) Tumor resectionSurgical Neurology International (2012)
Cerebellum: Neurological Damage
Degeneration due to endogenous factors (e.g., inherited disease of spinocerebellar ataxia, SCA)
Marked cerebellar atrophy in the SCA patientsAmerican Journal of Neuroradiology (2011)
Cerebellum: Neurological Damage
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
• The cerebellum utilizes a feedforward motor system that processes signals in one direction (forward) in a sequential manner from input to output.
• Makes a prediction of the motor/sensory outcome -- > compares actual vs. predicted and adjusts accordingly.
Pisotta & Molinari, 2014
• The cerebellum utilizes a feedforward motor system that processes signals in one direction (forward) in a sequential manner from input to output.
• 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)
Pisotta & Molinari, 2014
• The cerebellum utilizes a feedforward motor system that processes signals in one direction (forward) in a sequential manner from input to output.
• 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.
Pisotta & Molinari, 2014
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
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
Inter-Tap Interval by Frequency
Ataxia patients slower
Inter-Tap Interval by Frequency
Ataxia patients faster
Ataxia patients slower
Inter-Tap Interval by Frequency
Ataxia patients faster
Ataxia patients slower
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.
Slapik et. al., 2018
Slapik et. al., 2018
Slapik et. al., 2018
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
Verbal Encoding Task
Three tasks (all yes/no button press responses):
1. Is the word shown in uppercase? (perceptual; light encoding)
tourist
JOURNAL
2. Do both words rhyme? (phonological; moderate encoding)
mutton/button
perform/cricket
Verbal Encoding Task
Three tasks (all yes/no button press responses):
1. Is the word shown in uppercase? (perceptual; light encoding)
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)
Verbal Encoding Task
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?
Verbal Encoding Task
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.