Cerebellum, Psychiatry

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Cerebellum, Psychiatry Routine Disorders

• Dr Khalid Mansour
• Locum Consultant Psychiatrist
• Northgate Hospital

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Cerebellum and Psychiatric Disorders Introduction

• Traditionally cerebellum gt posture, balance,
  motor control (Flourens, 1824).
• Recently cerebellum gt perceptions, emotions,
  cognition, speech personality (Chung et al,
  2010 Konarski et al, 2005 Roskies et al, 2001
  Schmahmann, 1991 schmahmann and Sherman, 1989
  Papez, 1937)
• Cerebellar abnormalities have been found of most
  of the major psychiatric disorders
  (Hoppenbrouwers et al, 2008)
• Cerebellum gt automation of brain performances
  like a computer (Eccles, 1973) software
  programmer of the brain.
• Some clinical implications

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Contents

1. Cerebellar Anatomy, Histology Physiology
2. Cerebellar Abnormalities in Psychiatric
   Disorders.
3. Psychiatric Aspects of Cerebellar Disorders.
4. Clinical applications gt Routines Disorders

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Cerebellar Anatomy, histology Physiology

• Cerebellar Anatomy
• Structural Anatomy
• Functional Anatomy
• Deep Cerebellar Nuclei
• Cerebellar Histology and Physiology
• Cerebellar Cortex
• Mossy Fibers Granule Cells
• Climbing Fibers Purkinje Cells
• Compartmentalization

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Cerebellum Anatomy
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Cerebellar Anatomy

• Structural anatomy Cortex and White matter
• Cortex (Gross Anatomy)
• Anterior lobe (3 lobules),
• Posterior lobe (6 lobules)
• Flocculonodular lobe (2 lobules).
• White matter
• Nerve fibre tracts
• Deep nuclei
• Dentate,
• Interposed (Globose Emboliform)
• Fastigial nuclei.

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Cerebellar Anatomy

• Functional Anatomy
• Vestibulocerebellum (flocculonodular lobe).
• Spinocerebellum (vermis paravermis).
• Cerebrocerebellum (lateral cerebellar
  hemispheres).

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Deep Cerebellar Nuclei

• They receive inhibitory final output from the
  cerebellar cortex (Purkinje calls).
• They also receive afferent projections from
  excitatory inputs from
• Mossy fibers
• Climbing fibers
• provide feedback control of the cerebellar cortex.

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Deep Nuclei
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Cerebellum Anatomy
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Cerebellar Cortex

• Three layers
• Bottom thick granular layer, densely packed with
  Granule cells and Golgi cells.
• Middle Purkinje layer
• Top molecular layer,
• Dendrite trees of Purkinje cells,
• Parallel Fibers
• Stellate cells and Basket cells

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Micrograph of the cerebellar cortex showing its
three layers (molecular layer, Purkinje cells
layer and granule cell layer) and its meningeal
coverings (pia mater and arachnoid mater). HE
stain.
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Mossy Fibers Granule Cells

• Mossy Fibers arise from brainstem spinal cord and
  cerebrum (about 200 million in humans) gt
• A single mossy fiber makes contact with an
  estimated 400600 granule cells.
• Granule cellsgt Parallel Fiber.
• A Parallel fiber gt 80100 synaptic connections
  with Purkinje cell dendritic spines.

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Climbing Fibers

• Spinal cord, brainstem, and cerebral cortex gt
  Inferior Olivary nucleus gt Climbing fibers gt deep
  cerebellar nuclei and Purkinje cell.
• A single climbing fibre gt 3000 contacts with 10
  different Purkinje cell gt Axons travel into deep
  cerebellar nuclei (1000 contacts each).

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Purkinje Cells (Plasticity)(Mial et al, 1998
Ohtsuki et al, 2009 )

• Purkinje cells normally emit action potentials at
  a high rate even in the absence of synaptic
  input
• Simple spike gt single action potential followed
  by a refractory period of about 10 msec
• Complex spike gt stereotyped sequence of action
  potentials with very short inter-spike intervals
  and declining amplitudes
• Parallel fiber-Purkinje cell synapse can undergo
  long-term depression (LTD) in response to the
  coincident firing of both parallel and climbing
  fibers1.
• Repetitive firing of parallel fibers alone can
  induce long-term potentiation (LTP) at the same
  synapses. in controlling this balance.

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Compartmentalization

• Each body part maps to specific points in the
  cerebellum.
• Cerebellar cortex is compartmentalized into zones
  and microzones.
• A Microzones were found to contain on the order
  of 1000 Purkinje cells.
• Cellular interactions within a microzone are much
  stronger than interactions between different
  microzones.

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Schematic Illustration of The Structure of Zones
and Microzones in The Cerebellar Cortex (Apps
Garwicz, 2005).
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• Cerebellar Learning
• Marr Albus model
• Modern Views

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Cerebellar Functional Organisation

• Cerebellum functional structures are largely
  suitable for regulating brain processes (Katz
  Steinmetz, 2002 Ito, 2008)
• 10 of the weight of the brain
• 4 times number of neurones in the cerebral
  cortex.
• 50 of brain neurones
• Fewer types of neurones
• Different systems of interconnections

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Marr Albus Model for Cerebellar learning

• Most theories that assign learning to the
  circuitry of the cerebellum are derived from
  early ideas of David Marr (1969) and James Albus
  (1971).
• Albus (1971) formulated his model as a software
  algorithm he called a CMAC (Cerebellar Model
  Articulation Controller), which has been tested
  in a number of applications.

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Marr Albus model for Cerebellar learning

• Eccles, Ito Szentagothai (1967)
• Feedforward processing signals move
  unidirectionally through the system from input to
  output, with very little recurrent internal
  transmission gt a quick and clear response.
• Divergence and convergence In the human
  cerebellum, information from 200 million Mossy
  fibers inputs is expanded to 40 billion granule
  cells, whose parallel fibers outputs then
  converge onto 15 million Purkinji cells.
• Modularity The cerebellar system is functionally
  divided into more or less independent modules.
• Plasticity The synapses between parallel fibers
  and Purkinje cells, and the synapses between
  mossy fibers and deep nuclear cells, are both
  susceptible to modification of strength LTP and
  LTD.

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Model of Cerebellar Perceptron, James Albus 1971
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Model of Cerebellar functioning James Albus, 1971
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Cerebellar Learning ? Software programmer

• Cerebellar dysfunction gt continue to be able to
  generate motor activity, but uncoordinated.
• Boydon (2004) Cerebellum is involved in motor
  learning to make fine adjustments to the way an
  action is performed.
• Kenji Doya (2000) function of the cerebellum is
  best understood as neural computation.
• Ito (2005) A modulator role of motor and
  non-motor functions matches intentions with
  actual performance.

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(3) Cerebellar Abnormalities in Psychiatric
Disorders (Hoppenbrouwers et al, 2008)

• A- Psychological Studies of Normal Individuals
  with Reduced Cerebellar Volume
• B- Cerebellar Abnormalities in Schizophrenia
• C- Cerebellar Abnormalities in Autism
• D- Cerebellar Abnormalities in other psychiatric
  disorders

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Cerebellar Studies in Psychiatric Disorders
General Observations

• The most common studies but not the most evident.
• Significant number of studies have positive
  findings.
• Findings are not always consistent and
  conclusions are debatable.
• Cerebellar abnormalities can also be secondary /
  compensatory pathology e.g. increased dopamine in
  schizophrenia cause both psychosis and cerebellar
  pathology.
• Best studied autism and schizophrenia.

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A - Psychological Studies of Normal Individuals
with Reduced Cerebellar Volume

• Normal individuals with reduced cerebellar volume
  gt higher scores on scales of anxiety, type A
  personality, phobia, tenderness and hostility
  (Chung et al, 2010)

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B- Cerebellar Abnormalities in Schizophrenia
General

• Large part of imaging studies (Varnas et al,
  2007) support cerebellar malformation in schiz.
• Smaller cerebellar volume (Bottmer et al, 2005)
• Reduced blood flow on PET scan (Andreasen et al,
  1996).
• Reduced level of N-acetylaspartate (marker of
  neurone density and viability) in vermis and
  cerebellar cortex in Magnetic Resonance
  Spectroscopy Imaging (MRSI) studies (Ende et al,
  2005).
• Volume reduction in the cerebello-thalamic-cortica
  l network (Rusch et al, 2007).
• Neuronal disorganisation in the superior peduncle
  on Diffusion Tensor Imaging (DTI) studies
  (Okugawa et al, 2006).

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B- Cerebellar Abnormalities in Schizophrenia
Specific Symptoms (Picard et al, 2008)

• Hallucinations
• Shergill et al, 2003 Neckelman et al, 2006
• Formal Thought Disorder
• Kircher et al, 2001 Levitt et al, 1999
• Affect disorder in schiz
• Stip et al, 2005 Paradiso et al, 2003 Abel et
  al, 2003
• Cognitive function in schiz
• Szesko et al 2003 Toulopoulou et al 2004
• Attention
• Eyler et al, 2004 Honey et al, 2005 Aasen et
  al, 2005
• Language
• Shergill et al, 2003 Boksman et al 2005 Kircher
  et al 2005
• Memory (all types)
• Mendrek et al, 2005 Whyte et al 2006

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B- Cerebellar Abnormalities in Schizophrenia
Clinical Studies

• Increased prevalence of motor impairment in
  schizophrenic patients even drug naïve ones,
  could suggest possible cerebellar abnormalities
  (Hoppenbrouwers et al, 2008 Varambally et al,
  2006).
• However, these motor abnormalities could be
  secondary to schizophrenia e.g. increased
  dopaminergic activities affect the cerebellar
  functioning or morphology (Mittleman et al, 2008).

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B- Cerebellar Abnormalities in Schizophrenia
Cognitive Dysmetria Theory (Andreasen et al,
1998)

• A dysfunctional Cortico-cerebellar-thalamo-cortica
  l circuit gt poor mental coordination (cognitive
  dysmetria) gt Schizophrenia.
• Some disagreed e.g. Kaprinis et al, 2002 split
  between positive negative symptoms gt different
  psychopathologies.
• Others support the theory e.g. Schmahman, 2004
  Honey et al, 2005 Dysmetria also affect
  affective and motivational aspects of brain
  functioning.

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C- Cerebellar Abnormalities in Autism

• One of the most consistent abnormalities found in
  ASD are cerebellar degenerative changes,
  especially Reduced Purkinji cells, especially in
  vermal lobules I II (DiCicco-Bloom et al,
  2006).
• Theory cerebellar malfunction gt loss of
  modulatory control of frontal cortex gt ASD,
  (catani et al, 2008).

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D- Cerebellar Abnormalities in Psychiatric
Disorders Others

• Bipolar Affective Disorder e.g. reduced
  Cerebellar / Vermis volume (Glaser et al, 2006)
• Anxiety e.g. cerebellar-vestibular dysfunction
  (Levinson, 1989)
• Depression e.g. reduced posterior cerebellar
  activities (Fitzgerald et al, 2009)
• ADHD e.g. reduced Cerebellar volume (Glaser et
  al, 2006)
• Post Traumatic Stress Disorder e.g. altered
  function of the vermis (Anderson et al, 2002)
• Alcohol abuse e.g. induced reduction in
  Cerebellar / Vermis volume (Glaser et al, 2006)
• Gender differences (Dean McCarthy, 2008)
• Antisocial Personality Disorder e.g. reduced
  Cerebellar volume (Barkataki et al, 2006).
• Alzheimer Dementia e.g. cerebellar atrophy
  (Wegiel et al, 1999)

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• (4) Psychiatric Aspects of Cerebellar Disorders
• Cerebellar Cognitive Affective Syndrome
• Anatomically Specific Psychiatric Aspects of
  Cerebellar Disorders
• Other Psychiatric Aspects of Cerebellar Disorders

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(1) Cerebellar Cognitive Affective Syndrome
(Schmahman Shermen, 1998).

• Cerebellar lesions in general e.g. acquired
  lesions, congenital cerebellar malformations,
  cerebellar tumour resection, etc can cause motor
  impairments plus the following (Schmahman et al,
  2007 Tavano et al, 2007 Levisohn et al, 2000)
• Cognitive impairments
• Executive dysfunctions e.g. in working memory and
  planning
• Visuo-spatial abnormalities e.g. in visual memory
  and visuo-spatial organisation
• Linguistic dysfunction e.g. dysprosodia,
  agrammatism and anomia
• Affective impairments
• anxiety, lethargy, depression, lack of empathy,
  ruminativeness, perseveration, anhedonia and
  aggression

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(2) Anatomically Specific Psychiatric Aspects of
Cerebellar Disorders

• Vermal Agenesis gt severe LD, Autism abnormal
  motor development (Tavano et al, 2007).
• Vermal lesions gt affective and relational
  disorders (Schmahman et al, 2007).
• Spinocerebellar Ataxia gt impairment in attention,
  memory, executive functions and theory of mind
  (Garard et al, 2008).

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(3) Other Psychiatric Aspects of Cerebellar
Disorders(Wolf et al, 2007)
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• Clinical Implications

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Clinical Implications

• Assessment
• (1) Motor disorders in psychiatric disorders as
  signs of cerebellar dysfunctioning
• (2) Non-motor symptoms equivalent to motor
  symptoms related to cerebellum
• Treatments
• (3) Cerebellar exercises
• (4) Transcranial Magnetic Stimulation (TMS)
• (5) Routine disorders

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(1) Motor disorders in psychiatric patients
signs of cerebellar dysfunctioning

• E.g. Poor saccadic eye movement, Motor
  clumsiness, Gait abnormalities, Stuttering,
  cluttering, stammering, etc
• Used mainly in research as markers and/or
  associations
• Not highly specific to cerebellum but to the
  motor brain circuits which include the cerebellum
• ? Clinical significance

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(2) Non-motor symptoms equivalent to motor
symptoms related to cerebellum

• Usage of Non-motor Dysmetria (Andreasen et al,
  1998) as clinical concepts in assessment and
  treatment of psychiatric disorders (Schmahmann,
  2010) e.g.
• Cognitive dysmetria,
• Emotional dysmetria,
• Social dysmetria,
• Speech/Communication dysmetria,
• ? No available publications

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(3) Cerebellar Training (Schmahmann, 2010)

• Physical exercises that combine movement and
  balance, designed to improve the slow information
  processing with dyslexia and ADHD claimed to
  speed up information processing and improve
  cerebellar functioning gt 
• Controversial treatments for which there is no
  known published scientific literature.

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Cerebellar Trancranial Magnetic Stimulation (TMS)
(Schmahmann, 2010)

• Demirtas-Tatlidede et al (2010) stimulation of
  the vermis in 8 schizophrenic patients gt
  improvements in mood, alertness, memory,
  attention, visual-spatial skills and energy.
• Very early stages
• No RCT

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Routine Disorders

• Follow the established neurological models for
  Motor Behavioural Routines
• Function of brain circuits involving cerebrum,
  striatum, cerebellum and thalamus.
• The cortico-cereller-thalamo-cortical circuit
• The cortico-striato-thalamo-cortical circuit

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Motor Learning Models (Doya, 2000)

• The cerebellum, is best understood as a device
  for supervised learning (also Imamizu et al,
  2000)
• in contrast to the basal ganglia, which perform
  reinforcement learning
• and the cerebral cortex, which performs
  unsupervised learning

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Differences Between Routines, Habits and
Compulsions

• When brain wants to learn a behaviour for a
  frequent use gt Cerebellum then provides the
  software programme gt
• Gradually learn the most efficient way to do the
  task with least effort gt a successful Routine
  (functional Routine)
• if the process fails gt Routine Disorder

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Differences between Routines, Habits and
Compulsions

• When brain wants to learn a behaviour for a
  frequent use gt Basal Ganglia gt Checking /
  Feedback System
• Checks that the learnt behaviour is consistent
  with the data from the Reward System (via
  Nucleus Accumbens Dopamine) (thermostat) gt if
  reward System is dysfunctional gt Habits Disorder
  e.g. addiction, gambling gt (dysfunctional
  routines)
• Avoid anxiety provoking errors (via lateral
  amygdala serotonin) (alarm) gt if gives faulty
  checking gt OCD and/or compulsive disorder gt
  (functional routine unnecessarily repeated)

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Routine Disorders

• Problems with clinical uses
• Multiple systems involved striatum, frontal
  lobe, limbic system as well as environmental
  factors
• Complex system of assessment
• Advantages
• Following a system which is a product of a brain
  circuit is more neurologically meaningful that
  monitoring symptoms related to a
  single-brain-centre.
• More clinically relevant

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Examples of Routine, Habit and Compulsion
Disorders

• Want to learn how to drive the car from home to
  work
• Cerebellum gt software for smooth and quick drive,
  if still struggling to drive smoothly or
  efficiently gt Routine disorder
• Basal ganglia checks your routine if achieving
  the target gt if you develop the habit of drive
  fast to attract attention gt Habit Disorder
• Basal ganglia checks your routine if no errors
  committed gt if it keeps giving you unjustified
  signal that tyres and you have to stop to check
  time after time gt Compulsion.

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Seven Stages of a successful Behavioural Routines

1. Identifying the data relevant to the routine
2. Process (analyse) these data
3. Developing a partial routine
4. Learn from ones mistakes as well as from others
5. Develop an efficient routine
6. Routine works well even in unfamiliar
   circumstances
7. Routine works well even under pressure

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Routine Disorders

• Can not detect the relevant data to the routine
• Can not understand them properly
• Can not formulate a routine
• Can not learn from others how to improve or
  develop the routine
• Can only formulate partially functional
  (mechanical) routines
• Can not use the routine under pressure
• Can not use the routine in unfamiliar situations

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Applying the Seven Stages of Social Routines in
Autism

• Can not detect the relevant social data severe
  Autism
• Can do the above but can not understand them
  well severe Autism
• Can do the above but can not formulate a even
  partially functional routines e.g. High
  Functioning Autism
• Can do the above but can not imitate routines of
  other people High Functioning Autism.
• Can do the above but can not use the routine in
  an unfamiliar situations Asperger Syndrome
• Can do the above but can not use the routine
  under pressure Asperger Syndrome

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