Cerebellum, Psychiatry & Routine Disorders

1. Cerebellum, Psychiatry & Routine Disorders Dr Khalid Mansour Locum Consultant Psychiatrist Northgate Hospital

2. 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 of most of the major psychiatric disorders (Hoppenbrouwers et al, 2008) • Cerebellum > automation of brain performances like a computer (Eccles, 1973): “software programmer of the brain”. • Some clinical implications

3. Contents: • Cerebellar Anatomy, Histology & Physiology • Cerebellar Abnormalities in Psychiatric Disorders. • Psychiatric Aspects of Cerebellar Disorders. • Clinical applications > Routines Disorders

4. 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

5. Cerebellum Anatomy

6. 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.

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

11. 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.

12. Deep Nuclei

13. Cerebellum Anatomy

14. 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

15. 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). H&E stain.

17. Mossy Fibers & Granule Cells • Mossy Fibers arise from brainstem spinal cord and cerebrum (about 200 million in humans) > • A single mossy fiber makes contact with an estimated 400–600 granule cells. • Granule cells> Parallel Fiber. • A Parallel fiber > 80–100 synaptic connections with Purkinje cell dendritic spines.

18. 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 10 different Purkinje cell > Axons travel into deep cerebellar nuclei (1000 contacts each).

20. 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 > single action potential followed by a refractory period of about 10 msec • Complex spike > 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.

24. 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.

25. Schematic Illustration of The Structure of Zones and Microzones in The Cerebellar Cortex(Apps & Garwicz, 2005).

26. Cerebellar Learning • Marr & Albus model • Modern Views

27. 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

28. 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.

29. 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 > 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.

30. Model of Cerebellar Perceptron, James Albus 1971

31. Model of Cerebellar functioning; James Albus, 1971

32. Cerebellar Learning:? Software programmer • Cerebellar dysfunction > 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.

33. (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:

34. 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.

35. 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):

36. 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-cortical network (Rusch et al, 2007). • Neuronal disorganisation in the superior peduncle on Diffusion Tensor Imaging (DTI) studies (Okugawa et al, 2006).

37. 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

38. 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).

39. 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.

40. 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 > loss of modulatory control of frontal cortex > ASD, (catani et al, 2008).

41. 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)

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

43. (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

44. (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).

45. (3) Other Psychiatric Aspects of Cerebellar Disorders:(Wolf et al, 2007)

46. Clinical Implications

47. 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

48. (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

49. (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

50. (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 >  • Controversial treatments for which there is no known published scientific literature.