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Cerebellum, Cerebellum, Psychiatric Aspects Psychiatric Aspects & Routine Disorders& Routine Disorders

Dr Khalid MansourConsultant Psychiatrist

Priory Hospital Cefn Carnau

Introduction•10% of the weight of the brain (Llinas et al, 2004).

•80% of brain neurones (Herculano-Houzel, 2010)

•Traditionally: cerebellum only > posture, balance & motor control.

•Not involved in initiating motor activity, but coordinating them (Flourens, 1824).

Introduction •Abundant connections > non-motor brain regions.

•Involved in coordinating all non-motor functions e.g. perceptions, emotions, cognition, speech, personality, etc.

•Cerebellar abnormalities exist in most mental illnesses.

•Mental illnesses exist in most cerebellar disorders.

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1.Anatomy2.Models of Cerebellar

Functioning3.Psychiatric Aspects of

Cerebellar Disorders4.Cerebellar Abnormalities in

Psychiatric Disorders: 5.Cerebellar Mental Therapies.6.Clinical Reflections:

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Anatomy

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Gross anatomy: •Anterior lobe. •Posterior lobe.•Flocculonodular lobe.

Cross sectional:•Gray matter:•White matter:

•Nerve fibre tracts•Deep nuclei

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Functional Anatomy:

•Vestibulocerebellum (flocculonodular lobe).

•Spinocerebellum (vermis & paravermis).

•Cerebrocerebellum (lateral cerebellar hemispheres).

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Deep Cerebellar

Nuclei

•Dentate, •Interposed (Globose & Emboliform)

•Fastigial Nuclei.

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Cerebellar Cortex

•Three layers:•Granular Layer, Granule cells and Golgi cells.

•Purkinje Layer•Molecular Layer,

•Dendrite of Purkinje cells,

•Parallel Fibers •Stellate cells and Basket cells 9

Cerebellar Connections:• Afferent:

• Brainstem, spinal cord and cerebrum > Mossy Fibers > Granule cells> Parallel Fibers > Purkinje cell >

• Inferior Olivary nucleus > Climbing Fibers > Purkinje cells• Efferent:

• Purkinje cell > Deep Cerebellar Nuclei > climbing and/or Mossy fibers > Brainstem, spinal cord and cerebrum

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Models of Cerebellar Functioning

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Marr & Albus Model for Cerebellar Learning (Eccles, Ito & Szentagothai,1967)

•Several theories about cerebellum and learning.

•Most theories about Cerebellar functioning / learning are derived from early models of David Marr (1969) and James Albus (1971).

•Albus (1971) formulated his model as a software algorithm: Cerebellar Model Articulation Controller, which has been tested in a number of computer applications.

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David Marr

James Albus

Marr & Albus Model for Cerebellar Learning (Eccles, Ito & Szentágothai,1967)

1. Feedforward processing.2. Divergence and Convergence.3. Modularity / Compartmentalization4. Plasticity.

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Cerebellar Perceptron, James Albus

(1) Feed-forward Processing:(Eccles, Ito & Szentágothai,1967)

•Signals move uni-directionally from input to output, with very little recurrent internal transmission > a quick and clear response with no reverberation.

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(2) Modularity / Compartmentalization(Oscarsson, 1979; Apps & Garwicz, 2005)

•Cerebellar cortex > zones and micr-ozones (1000 Purkinje cells).

•Interactions within a micro-zone much stronger than interactions between different micro-zones. 15

(3) Plasticity(Mial et al, 1998; Ohtsuki et al, 2009)

• Purkinje cells normally > high rate action potentials : • Simple spike • Complex spike

• Parallel fibre-Purkinje cell synapse > long-term depression (LTD).

• Repetitive firing of parallel fibres alone > long-term potentiation (LTP).

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(4) Divergence & Convergence:(Llinas et al, 2004; Apps & Garwicz, 2005)

•200 million MF > 50 billion GC (1:500).

•Granule Cells > PF > spines > 15 million PC

•PCs < 100000 PF (over 200000 spines) + 1 CF.

•Each micro-zone (1000 PCs) > 50 DNCs.

•100 MF > 10 billion spines > 1 DNC

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Adaptive Filtering (Fujita 1982; Dean & Porell, 2008; Dean et al, 2010)

• Elimination of noise• Fine tuning • Optimality / Coordination

• Execution not creativity

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1. Feedforward processing.2. Divergence and

Convergence.3. Modularity /

Compartmentalization4. Plasticity.

•Kenji Doya (2000): •“Neural computation”. •Katz & Steinmetz (2002): •“Regulates brain processes”.•Boydon (2004): •“Makes fine adjustments to the way an action is performed”.

•Masao Ito (2005): •“Matches intentions with actual performance”.

•Reeber et al (2013): “computational task … recognizing neural patterns … predict optimal movements”. 19Masao Ito

Kenji Doya

Cerebellar Learning: “Software Programmer”

Cerebellar Learning:

(Burguiere et al, 2010, Kalmbach et al, 2011)

•Cerebellum > develops learnt behaviour with >

1.Minimum Errors2.Minimum Time 3.Minimum Effort 4.Minimum Attention /

awareness5.Maximum stability

20Chase Britton

Psychiatric Aspects of Cerebellar Disorders

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1 - Psychological Studies of Normal Individuals with Reduced Cerebellar

Volume•Individuals with reduced cerebellar volume > higher scores on scales of anxiety, type A personality, phobia, tenderness and hostility (Chung et al, 2010).

22Chase Britton

2 - Other Psychiatric Aspects of Cerebellar Disorders: (Wolf et al, 2007)

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3 - Psychiatric Aspects of Anatomically Specific Cerebellar Abnormalities

•Vermal Agenesis > severe LD & Autism (Tavano

et al, 2007).•Vermal lesions > affective and relational disorders (Schmahman et al, 2007).

•Spinocerebellar Ataxia > impairment in attention, memory, executive functions and theory of mind (Garard et al, 2008).

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4 - Cerebellar Cognitive Affective Syndrome (Schmahman et al, 2007; Tavano et al, 2007; Levisohn et al, 2000):

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Cerebellar Syndromes > motor impairments +Cognitive impairments: Executive dysfunctions, visuo-spatial abnormalities, linguistic dysfunction.Affective impairments: Anxiety, lethargy, depression, lack of empathy, ruminativeness, perseveration, anhedonia and aggression.

Jeremy Schmahmann

Cerebellar Abnormalities in Psychiatric Disorders:

General

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Cerebellar Abnormalities in Psychiatric Disorders

•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)

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ADHD:

•Smaller cerebellar volume (Berquin et al 1998; Giedd et al, 2001). 

•Abnormalities in post-inferior cerebellar hemispheres and vermis (Casey et al, 2007; Steinlin, 2007).

•Reduction in the activity of cerebellum and vermis (Mackie et al, 2007).

Cerebellar Abnormalities in Psychiatric Disorders:

•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) 28

•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)

Cerebellar Abnormalities in Psychiatric Disorders:

Dyslexia, Schizophrenia & Autism

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(1) Cerebellum & Dyslexia:•Developmental Dyslexia:

(Stoodley & Stein, 2011; Nicolson et al, 2001; Pernet et al, 2009)

•Dyslexia > cerebellar structural and functional abnormalities in 80% of cases.

•Dyslexia > impairment in the ability to perform skills automatically.

•Cerebellar syndromes > impairments in reading and writing characteristic of dyslexia.

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The Cerebellar Deficit Hypothesis of Dyslexia: (Nicolson & Fawcett, 1990; Nicolson et al,

2001): dyslexia is an impaired automatization of high-order sensory-motor procedures in reading.

(2) Cerebellum & Schizophrenia: General Studies

• ↑ Imaging studies > cerebellar abnormalities in schizophrenia (Vernas et al,

2007): • ↑ Cerebellar-Motor

Dysfunction in Schizophrenia and Psychosis-Risk (Bernard & Mittal, 2014).

• ↓ Cerebellar volume (Bottmer et al, 2005)

• ↓ Blood flow on PET scan (Andreasen et al, 1996).

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• ↓ Level of N-acetylaspartate in Magnetic Resonance Spectroscopy Imaging (MRSI) studies (marker of neurone density and viability) in vermis and cerebellar cortex (Ende et al, 2005).

• ↓ Volume in the cerebello-thalamic-cortical network (Rusch et al, 2007).

• Neuronal disorganisation in the superior peduncle on Diffusion Tensor Imaging (DTI) studies (Okugawa et al, 2006).

(2) Cerebellum & 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 symptoms (Stip et al, 2005; Paradiso et al, 2003; Abel et al, 2003)

•Cognition (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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(2) Cerebellum & Schizophrenia: Cerebellar Glutamate

Theory

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•Hypo-functioning of the Glutamate NMDA receptors in cerebellum > cognitive dysmetria > schizophrenia.

• Yeganeh-Doost et al, 2011):

(2) Cerebellum & Schizophrenia: Cognitive Dysmetria Theory

(Andreasen et al, 1998) •The Cortico-Cerebellar-Thalamo-Cortical circuit is dysfunctional > poor mental coordination > (Cognitive Dysmetria) > Schizophrenia.

•The theory has been criticised by other researchers (e.g. Kaprinis et al, 2002, Kaprinis et al, 2002; Shanagher et al, 2006) Nancy

Andreasen

(2) Cerebellum & Schizophrenia: Secondary Cerebellar Abnormalitites

•Schizophrenia > increased dopaminergic activities > cerebellar disorder > motor disorders in schizophrenia (even neuroleptics naïve) (Mittleman et al, 2008; Hoppenbrouwers et al, 2008; Varambally et al, 2006; Picard et al, 2007).

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(3) Cerebellar & Autism:General Studies

•One of the most consistent abnormalities found in ASD (DiCicco-Bloom

et al, 2006). • 95% of post mortem examinations of autistic individuals (Delong, 2005)

•Consensus related to cerebellar involvement in autism (Fatemi et al, 2012):

• Abnormal cerebellar anatomy, • Abnormal neurotransmitter systems, • Oxidative stress, • Cerebellar motor and cognitive deficits, • Neuro-inflammation

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S. Hossein Fatemi

(3) Cerebellum & Autism:Cerebral Involvement

•Associated with mal-development of the frontal lobe and any other brain regions > ASD (Carper & Courchesne, 2000; Kuemerle et al, 2006; Reeber et al, 2013).

•Loss of modulatory control of Frontal Cortex > ASD, (Catani et al, 2008).

• Cerebellum malfunction hinders neural development (Wang et al, 2014).

Sam Wang

Cerebellar Mental Therapies

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Cerebellar Exercises / Training (Schmahmann, 2010)

• Some claims (e.g. DORE) > Physical exercises (movement + balance) > speed up information processing and improve cerebellar functioning > improve dyslexia, ADHD and Asperger’s syndrome:

• ? Could improve some mental illnesses like schizophrenia . • No known scientific studies. • Controversial treatments (Reynolds & Nicolson, 2007; Bishop,

2007; Rack, 2007)

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Dance & Movement Therapy(Levi, 1988; Jeong et al, 2005)

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

•Demirtas-Tatlidede et al (2010): stimulation of the vermis in 8 schizophrenic patients > improvements in mood, alertness, memory, attention, visual-spatial skills and energy.

•Very early stages (Minks et al, 2010)

•No RCT

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Cerebellum: Clinical Reflections

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Cerebellum: Clinical ReflectionsIntroduction

•Best way to make clinical judgment > follow the model of motor cerebellar functioning:

• Well studied• Must be linked physiologically to non-

motor functioning.

•Two main fields: • Cerebellar connections to mental

disorders specially dyslexia, schizophrenia and Autism > very promising and interesting but slow and small impact .

• Mental equivalent to praxis and dyspraxia > clearer and more promising

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(1) Motor Learning vs Non-motor / Mental Learning

Cerebellum > “motor” and “non-motor / mental” coordination.

a) Motor coordination > “Motor Learning / Praxis”.

b) Mental coordination > Non-motor coordination / Mental Coordination”

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•Cerebellum failing in motor coordination > • (Motor) dyspraxia, • Developmental Coordination Disorder (DCD),

• Clumsy Child Syndrome, etc.

•Cerebellum failing in non-motor / mental coordination > • ? Mental Dyspraxia, • ? Developmental Mental Coordination Disorder (DMCD),

• ? Mentally Clumsy Child Syndrome, or

• ? Mental Routine Disorder (MRD)45

(2) Motor Dyspraxia vs Non-motor Dyspraxia

(3) Mental Routine Disorders (MRD): A new chapter in psychopathology?!1. Better understanding of a

major part of human behaviour.

2. Widespread problem > marked suffering > needs attention.

3. Good room for effective interventions

4. Enhance therapies for major mental disorders e.g. ASD.

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(4) Prevalence of MRDs• Motor Dyspraxia : 6-10 % in school children (Gibbs et al, 2007).

• Dyscalculia: 5-7% (Butterworth et al, 2011)

• Developmental Coordination Disorder (DCD): 5–6% (Blank et al, 2012; Zwicker et al, 2012).

• Dyslexia: 5% - 17% of school-age children (USA) (Shaywitz & Shaywitz, 2003).

• Symptom: 40% reading below grade level (Shaywitz & Shaywitz, 2003).• Special groups: 80% of individuals with LD (Shaywitz & Shaywitz,

2003).• Complications: lower self-esteem and more emotional and behavioural

difficulties than those without dyslexia (Terras et al, 2009).• comorbidity : 95% (Pauc 2005).

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3- Assessment of MRDs:(A) Doya’s Model of Motor Learning (Doya, 2000)

(also Imamizu et al, 2000; Hikosaka et al, 2002, Bosch-Bouju et al, 2013)•Brain circuits:

• The cortico-cerebeller-thalamo-cortical circuit

• The cortico-striato-thalamo-cortical circuit

•Learning paradigms•Cerebral cortex > unsupervised learning

•Basal ganglia > reinforcement learning

•Cerebellum > supervised learning

Kenji Doya

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Ferreira et al, 2008

(B) The Four Primary Components

1. Failure to learn (problem solving, adapting, planning, etc.) e.g. LD.

2. Failure to eliminate anxiety (threat) > marked disturbance of functioning e.g. OCD.

3. Failure to reach satisfaction without causing marked disturbance of functioning e.g. habit disorder

4. Failure to have smooth functioning without errors e.g. dyspraxia

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(C)The Four Components Mixed

•Complex routine abnormalities.•1, 3 & 4 okay but 2 faulty > OCD with inner resistance.

•3 & 4 okay but 1 & 2 faulty > rigid obsessional routines without inner resistance. 52

Functional Routines

Dysfunctional Routines

Meaningful > Serves a purpose

Bizarre (counting lamp posts / eating flies).

Resilient (to stress): stress > little disruption

Unstable: stress > marked disruption

Adaptive (with novelty): new data > little disruption

Rigid: new data > significant disruption

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(4) Classification of MRDs: a- Dysfunctional Routines

(4) Classification of MRDs: b- Simple vs. Complex MRD

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Simple Complex

− Single faulty component (e.g. OCD or drug addiction)

− Highly functional individuals

‒ Multiple faulty components e.g. routine problems in Autism.  

‒ Less functional individuals

(4) Classification of MRDs: c- Primary vs. Secondary MRD

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e.g. primary clumsiness

Secondary clumsiness

− Clumsiness due to faulty cerebellar component (Performance clumsiness)

‒ Clumsiness due to faulty cerebral (cognitive) component. 

(Mentation Clumsiness)

(5) Treatment of MRDs: The Methods

• General Lines:1. Medications.2. Educational.3. CBT.4. Behavioural.5. Others: e.g.

• GORE or Movement Therapies

• Process-oriented approach• Task-oriented approach• Transcranial Magnetic

Stimulation (TMS)• Specific:

• Depends on specific conditions 56

“3 Dimensions” is not the same as “2 Dimensions”: •Integrating the psychiatric dimension into the neuropsychological and OT therapies for dyspraxia > extra depth and sophistications but needs resources and time.

(5) Treatment of MRDs : The Strategy

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Thank you

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