Cerebellum and Psychiatric Disorders 22

7/29/2019 Cerebellum and Psychiatric Disorders 22

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Cerebellum, Psychiatry& Routine Disorders

Dr Khalid Mansour

Locum Consultant PsychiatristNorthgate Hospital


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Cerebellum and Psychiatric

Disorders: Introduction

Traditionally: cerebellum > posture, balance,motor control (Flourens, 1824).

Recently: cerebellum > 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 ofmost of the major psychiatric disorders(Hoppenbrouwers et al, 2008)

Cerebellum > automation of brainperformances 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 > RoutinesDisorders


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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 cerebellarhemispheres).


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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 cerebellarcortex.


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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 materand arachnoid mater). H&E stain.
http://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/Pia_materhttp://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/Arachnoid_materhttp://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/H&E_stainhttp://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/H&E_stainhttp://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/Arachnoid_materhttp://localhost/var/www/apps/conversion/tmp/scratch_5//lhfs03/wiki/Pia_mater


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Mossy Fibers & Granule Cells

Mossy Fibers arise from brainstemspinal cord and cerebrum (about 200million in humans) >

A single mossy fiber makes contact withan estimated 400600 granule cells.

Granule cells> Parallel Fiber.

A Parallel fiber > 80100 synapticconnections with Purkinje cell dendriticspines.


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Climbing Fibers

Spinal cord, brainstem, and cerebral cortex >Inferior Olivary nucleus > Climbing fibers >

deep cerebellar nuclei and Purkinje cell.

A single climbing fibre > 3000 contacts with 10different Purkinje cell > 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 ahigh rate even in the absence of synaptic input:

Simple spike > single action potential followed by arefractory period of about 10 msec

Complex spike > stereotyped sequence of actionpotentials with very short inter-spike intervals anddeclining 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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http://www.pnas.org/content/105/38/14680/F4.large.jpg


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http://www.pnas.org/content/105/38/14680/F4.large.jpghttp://www.pnas.org/content/105/38/14680/F4.large.jpg


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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 of1000 Purkinje cells.

Cellular interactions within a microzone aremuch stronger than interactions between

different microzones.

S h ti Ill t ti f Th St t f Z d Mi i Th


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Schematic Illustration of The Structure of Zones and Microzones in The

Cerebellar Cortex(Apps & Garwicz, 2005).
http://upload.wikimedia.org/wikipedia/commons/f/f9/Microzone.svg


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Cerebellar Learning

1. Marr & Albus model

2. 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 ofDavid 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 ofapplications.


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Marr & Albus model for Cerebellar learning

Eccles, Ito & Szentagothai (1967);

Feedforward processing: signals moveunidirectionally through the system from input tooutput, with very little recurrent internal transmission> a quick and clear response.

Divergence and convergence: In the humancerebellum, information from 200 million Mossy fibersinputs is expanded to 40 billion granule cells, whoseparallel fibers outputs then converge onto 15 millionPurkinji cells.

Modularity: The cerebellar system is functionallydivided into more or less independent modules.

Plasticity: The synapses between parallel fibers andPurkinje cells, and the synapses between mossyfibers 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

M d l f C b ll f ti i J Alb 1971


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Model of Cerebellar functioning; James Albus, 1971


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Cerebellar Learning:

? Software programmer Cerebellar dysfunction > continue to be able

to generate motor activity, but uncoordinated.

Boydon (2004): Cerebellum is involved inmotor learning to make fine adjustments tothe way an action is performed.

Kenji Doya (2000): function of thecerebellum is best understood as neural

computation. Ito (2005):A modulator role of motor and

non-motor functions: matches intentions withactual performance.


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(3) Cerebellar Abnormalities in

Psychiatric Disorders(Hoppenbrouwers et al, 2008)

A- Psychological Studies of Normal Individuals

with Reduced Cerebellar VolumeB- 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 mostevident.

Significant number of studies have positivefindings.

Findings are not always consistent andconclusions are debatable.

Cerebellar abnormalities can also be

secondary / compensatory pathology e.g.increased dopamine in schizophrenia causeboth 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 > 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-corticalnetwork (Rusch et al, 2007).

Neuronal disorganisation in the superior peduncle on

Diffusion Tensor Imaging (DTI) studies (Okugawa et al,2006).

B Cerebellar Abnormalities in


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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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Schizophrenia: Clinical Studies

Increased prevalence of motor impairment in

schizophrenic patients even drug nave 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 cerebellarfunctioning 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-

cortical circuit > poor mental coordination

(cognitive dysmetria) > Schizophrenia.

Some disagreed e.g. Kaprinis et al, 2002:split between positive & negative symptoms >

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-Bloomet al, 2006).

Theory: cerebellar malfunction > loss of

modulatory control of frontal cortex >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 functionof 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. reducedCerebellar 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

(1) Cerebellar Cognitive Affective Syndrome

(2) Anatomically Specific Psychiatric Aspects of

Cerebellar Disorders

(3) 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 etal, 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 > severe LD, Autism &

abnormal motor development (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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(3) Other Psychiatric Aspects of Cerebellar Disorders:(Wolfet 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 motorsymptoms 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/orassociations

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 andtreatment 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 informationprocessing and improve cerebellar

functioning >

Controversial treatments for which there is no

known published scientific literature.

C b ll T i l M ti


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Cerebellar Trancranial 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

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

M t L i M d l


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Motor Learning Models:

(Doya, 2000)

The cerebellum, is best understood as a

device forsupervised learning (also

Imamizu et al, 2000)

in contrast to the basal ganglia, whichperform 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: > Cerebellum then provides the software

programme >

Gradually learn the most efficient way to do the task

with least effort > a successful Routine (functionalRoutine)

if the process fails > Routine Disorder

Diff b R i H bi


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Differences between Routines, Habits

and Compulsions

When brain wants to learn a behaviour for a

frequent use: > Basal Ganglia > Checking /

Feedback System:

Checks that the learnt behaviour is consistent with

the data from the Reward System (via NucleusAccumbens+ Dopamine) (thermostat)> if rewardSystem is dysfunctional > Habits Disordere.g.

addiction, gambling > (dysfunctional routines)

Avoid anxiety provoking errors (via lateralamygdala + serotonin) (alarm) > if gives faulty

checking > OCD and/orcompulsive disorder >

(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 environmentalfactors

Complex system of assessment

Advantages:

Following a system which is a product of abrain circuit is more neurologically meaningfulthat monitoring symptoms related to a single-brain-centre.

More clinically relevant

Examples of Routine Habit and


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Examples of Routine, Habit and

Compulsion Disorders

Want to learn how to drive the car from home to

work:

Cerebellum > software for smooth and quick drive, if

still struggling to drive smoothly or efficiently > Routine

disorder Basal ganglia: checks your routine if achieving the

target > if you develop the habit of drive fast to attract

attention > Habit Disorder

Basal ganglia: checks your routine if no errors

committed > if it keeps giving you unjustified signal that

tyres and you have to stop to check time after time >

Compulsion.

Seven Stages of a successful


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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 fromothers

5. Develop an efficient routine

6. Routine works well even in unfamiliarcircumstances

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

Applying the Seven Stages of


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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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Cerebellum and Psychiatric Disorders 22