Cerebellum, motor and cognitive functions: What are the common grounds? Eyal Cohen, PhD (Engineering, BIU)

Size: px

Start display at page:

Download "Cerebellum, motor and cognitive functions: What are the common grounds? Eyal Cohen, PhD (Engineering, BIU)"

Cuthbert Stewart
5 years ago
Views:

1 Cerebellum, motor and cognitive functions: What are the common grounds? 1 Eyal Cohen, PhD (Engineering, BIU)

2 Cerebellum The Little Brain 2 The Cerebellum takes ~10% of the Brain in Volume

3 Small but Hefty 3 Over 50% of the Brain s Neurons are in the Cerebellum!! The Convoluted Cerebellar Cortex consists of most Cerebellar Volume

Postural instability, drunken sailor gait, sway, wide standing base 2.

4 Classical symptoms of Cerebellar dysfunction 4 Hypotonia = loss of muscle tone Tremor: limbs, jaw, neck, larynx Ataxia = loss of motor coordination: 1. Postural instability, drunken sailor gait, sway, wide standing base 2. Walking: uncertain, asymmetric, irregular 3. Failure in execution of planned movements i.e. intentional tremor, dysmetria (lack of precision) and dysarthria (speech slurring) 4. Deficits in eye movement control

5 5 Cerebellar is Central in Adaptation

6 Classical Role in Muscle Timing and Coordination Position Velocity Biceps Triceps Cooling => Reducing Neuronal Firing Biceps Triceps 6 Villis and Hore 1977

7 Non-Classical symptoms of Cerebellar dysfunction Lower Intelligence (Verbal) Lower visuospatial abilities Memory problems (i.e. working, procedural) and Dementia Emotional control problems, impulsiveness, aggression Reduced ability of strategy formation Psychosis, Schizophrenia (co-morbid with reduced volume) 7

8 General Structure of the Cerebellar Cortex Ventral/Anterior View Dorsal/Posterior View Flocculus 8 Tonsil Vermis Hemispheres

9 Posterior/Dorsal view of the Cerebellum Anterior Lobe Posterior Lobe Primary Fissure 9 Vermis

10 Anterior/Ventral view of the Cerebellum Vermis 4 th Ventricle Flocculus Cerebellar Peduncles Anterior Lobe Posterior Lobe Tonsil Nodulus 10 Nodules + Flocculi = Flocculu-Nodular Lobe

11 Medio-lateral gross partition of the Cerebellum Spino-Cerebellum Cerebro-Cerebellum Vestibulo-Cerebellum 11

12 12 The 3D Folding of the Cerebellar Lobes

13 Lobes and Lobules of the Cerebellar Cortex Cerebellar Lobule Cerebellar Folia Cerebellar Folium

14 The Cerebellum is not Only Cortex 14 Deep Cerebellar Nuclei (DCN)

15 The Deep Cerebellar Nuclei (DCN) are the Output Relays of the Cerebellum 15 Dentate Interposed (Emboliform+ Globose) Fastigial

16 Functional mapping of the Cerebellar nuclei 16 The Vestibular Nucleus in the Brainstem is Functionally Homologous to cerebellar nuclei.

17 Two Major Input Pathways Serve the Cerebellum Pontine Nuclei (PN) Inferior Olive (IO) 17 MF = Mossy Fibers (~90% via the PN) CF = Climbing Fibers (All via the IO) Inferior Olive Pontine Nuclei

The IO receive low level motor and sensory inputs Visual Inputs: SC = Superior Coliculus NOT = Nucleus of Optic Tract Vestibular Inputs: VN = Vestibular Nucleus Motor Command: RN

18 The IO receive low level motor and sensory inputs Visual Inputs: SC = Superior Coliculus NOT = Nucleus of Optic Tract Vestibular Inputs: VN = Vestibular Nucleus Motor Command: RN = Red Nucleus Somatosensory & Proprioceptive: DCN = Dorsal Column Nucleus Trigeminal & Spinal Chord Inferior Olive (IO) 18 Additionally: Auditory Inputs Sugihara & Shinoda JNS 2004

19 Pontine Nuclei Relay Cerebro-Coritcal Information Non-Cortical Inputs: 1. Mamilary Body 2. Amygdala 3. Midbrain Nuclei 4. Spinal Inputs (Brodal 1978) 19 Forebrain Areas That project to the Pontine Nuclei

Thalamus/Midbrain Inputs/Outputs Medial: Pontine Inputs

20 Cerebellar Peduncles: Input / Output Highways Superior Peduncle Medial Peduncle Inferior Peduncle 20 Superior: Thalamus/Midbrain Inputs/Outputs Medial: Pontine Inputs and Commissure Inferior: Spinal/Medullary Inputs/Outputs

21 Cerebellar Major Output Pathways CTX = Cortex PM = Premotor PAR = Parietal PM CTX Motor CTX PAR CTX PF = Prefrontal RN = Red Nucleus PF CTX VL = Ventrolateral Thalamus DCN = Deep Cerebellar Nuclei VL RN RF = Reticular Formation DCN Other Outputs: Inferior Olive Hippocampus Amygdala Septum RF 21

22 22 Mapping of Cerebellar Cortex Classic View

23 Cerebellar Cortex Mapping is Fragmented 23 Voogd and Glickstein 1998

24 24 Cerebellar Cortex: The Beauty of Network Architecture

25 25 Purkinje Cells: The most Elaborate Neurons of the CNS

26 The 3 Layers of the Cerebellar Cortex Molecular Layer Purkinje cell Layer Granule cell Layer 26

27 Cerebellar Cortex Consists of 5 types of Neurons Inhibitory cells: Purkinje Golgi Basket Stelate Excitatory Cells: Granule cells 27 Apps & Garwicz NatRevNeu 2005

28 PC: The Principal Cell of Cerebellar Cortex Parallel Fibers ~200,000 Synapses Cerebellar Cortex Climbing Fiber ~2000 Synapses Deep Cerebellar Nuclei (DCN) Excitation Inhibition 28 Purkinje Cells are the only neurons projecting from the Cerebellar Cortex!! Modified from Apps & Garwicz 2005

29 The Spatial Organization of Cerebellar Circuitry Notice the perpendicular relationship between Mossy Fiber and Climbing Fiber enervations!! 29

30 Parasaggital Microzones of Cerebellar Cortex 30 Some Molecular Markers (i.e. Zebrin II) divide Purkinje Cells Populations into parasaggital stripes.

31 Parallel fibers are not a delay line: local inhibition prevents signal propagation Stimulation of granular layer Stimulation of parallel fibers 31 Yarom and Cohen AnnNYAc 2003

32 Closing the Loop: The Cerebellar Module Cerebellar Cortex Feedback Dysinhibition Feedback Inhibition Deep Cerebellar Nuclei (DCN) Inferior Olive (IO) Excitation Inhibition 32 Modified from Apps & Garwicz NatRevNeu 2005

33 The simplified Olivocerebellar Module Cerebellar Cortex Parallel Fibers Pontine Nuclei (PN) Mossy Fibers Granular Layer Purkinje Cell Climbing Fibers Inferior Olive (IO) Sensorimotor Context (forebrain) Deep Cerebellar Nuclei (DCN) Sensory Feedback + Efferent Copy of Motor Command Cerebellar Outputs Thalamus, Red Nucleus, Brainstem

34 Cerebellar Physiology Infra Red Fluorescent Dye Double Recording of Purkinje Cell in Slice Hausser M. 34

35 Purkinje Cells exhibit Two distinct Spike Types Simple Spike Complex Spike Mossy Fiber Stimulation Inferior Olive Stimulation Eccles,

36 Cerebellar Learning Theories Eccles,

37 Simple Spikes are Modulated by Inputs Simple spikes of 2 Purkinje cells in awake monkey during hand movements 37 Roitman 2005

38 Olivary Spikes are fired in Unexpected Events 38 Horn, Pong & Gibson 2002

39 Distinct Firing Regimes of Purkinje Cells Complex Spikes & Simple Spikes (Up-State) Complex Spikes Only (Down-State) 10mV 100ms Simple Spikes: 0 - ~80Hz (Mostly 0Hz or 4-8Hz or 20-80Hz, with possible phasic >100Hz) Complex Spikes : 1-3Hz (Phasic 10-15Hz) 39 Cohen and Lamp (unpublished)

40 Complex Spikes as Purkinje Cell Switches 40 Loewenstein et al. NatNS 2005

41 Synchronous Population Coding by Purkinje Cells 41 Welsh 1995

42 Saccade attributes are encoded by a population of ~100 Purkinje cells 42 Tier-Barash 2000

43 Vestibulo - Ocular Adaptation (VOR) VG = Vestibular Ganglion VN =Vestibular Nucleus PA = Pontine Area AOS = Accessory Optic System OM = Oculomotor Neurons Synaptic Changes Synaptic Changes Motor Correction Complex Spike Climbing Fiber Activation Reduced Retinal Slip Retinal Slip Visual Error 43 Ito 1984, Schonville et al. 2010

44 Plasticity in the Cerebellar Cortex 44 Coesmans et al. Neuron 2004

45 Eyelid Reflex Conditioning 45 Bracha and Bloedel 2009

46 Eyelid Reflex Conditioning 46 Medina et al. Nature 2002

47 Eyelid Reflex Conditioning 47 Rasmussen et al 2008

48 IO is crucial for but not 700ms 48 Welsh 2002

49 The Learning Transfer Hypothesis Motor CTX After 12 Hrs VL After 6 Hrs DCN Inferior Olive Cerebellar CTX Fastest Learning~ Sec-Min VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei CTX = 49 Cortex CF = Climbing Fibers

50 What about the Non-Classical symptoms? All physiological results so far: in animals related to motor function or coordination or timing Can timing be also related to higher cognitive functions? Is there evidence from human real-time physiology? Are there specific areas in the cerebellum which relate to cognitive functions? 50

51 Specific cerebellar regions with cognitive dysfunction following focal damage Cognitive effects of focal damage were found when: 1. The damage involved the vermis 2. The damage was in an areas which get blood supply from the posterior inferior cerebellar artery 3. Children with Vermal damage show autistic-like features: Irritability impulsivity Disinhibition Emotional lability 4. Complex verbal dysfunction associated with right cerebellar damage 5. Dysprosodia (pronunciation fault): associated with left cerebellar damage 51

52 FMRI Mapping pf Cerebellar Involvement in Various Processes Somatosensory Processing 52 Stoodley and Schmahmann 2009

53 FMRI Mapping pf Cerebellar Involvement in Various Processes Motor Processing 53 Stoodley and Schmahmann 2009

54 FMRI Mapping pf Cerebellar Involvement in Various Processes Language Processing 54 Stoodley and Schmahmann 2009

55 FMRI Mapping pf Cerebellar Involvement in Various Processes Working Memory 55 Stoodley and Schmahmann 2009

56 FMRI Mapping pf Cerebellar Involvement in Various Processes Spatial Processing 56 Stoodley and Schmahmann 2009

57 FMRI Mapping pf Cerebellar Involvement in Various Processes Executive Processing 57 Stoodley and Schmahmann 2009

58 FMRI Mapping pf Cerebellar Involvement in Various Processes Emotional Processing 58 Stoodley and Schmahmann 2009

59 Cerebellar Involvement in Autism Control Subject Autistic Subject 59 Levitt J. 1999

60 Cerebellar Involvement in Dyslexia Control Subject Dyslexic Subject 60

61 Autism candidate genes affects the Cerebellum Autistic Control Control CASP2 -/- Lose of Purkinje Cells in Autistic Developmental Problems in KO mice Saskia 2004 Sadakata

62 Olivocerebellar Information flow : Mossy Fibers Inputs VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei RN = Red Nucleus (+ mid brain nuclei) CTX = Cortex PF CTX PM CTX Motor CTX Afferent Copy Of Motor Command PAR CTX MF = Mossy Fibers CF = Climbing Fibers VL RN DCN Pontine Nuclei Inferior Olive MF Cerebellar CTX RF 62 Motor Command To Spinal MNs Sensory & Vestibular Information

63 Olivocerebellar Information flow : Climbing Fibers Inputs VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei RN = Red Nucleus (+ mid brain nuclei) CTX = Cortex PF CTX PM CTX Motor CTX PAR CTX Afferent Copy Of Motor Command MF = Mossy Fibers CF = Climbing Fibers VL RN DCN Pontine Nuclei Inferior Olive Cerebellar CTX RF 63 Motor Command To Spinal MNs Sensory & Vestibular Information

Hypothesized information flow during Cerebellar function VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei RN = Red Nucleus (+ mid brain nuclei) CTX = Cortex PF

64 Hypothesized information flow during Cerebellar function VL = Ventro-Lateral Nucleus DCN = Deep Cerebellar Nuclei RN = Red Nucleus (+ mid brain nuclei) CTX = Cortex PF CTX PM CTX Motor CTX Motor Learning PAR CTX MF = Mossy Fibers CF = Climbing Fibers VL RN Pontine Nuclei DCN Inferior Olive Cerebellar CTX RF 64 Motor Real-Time Correction

65 65 The General Role of the Cerebellum

66 The Inferior Olive as the Great Comparator Feedback Inhibition from Deep Cerebellar Nuclei Motor Intention Inferior Olive 66 Sensory feedback

67 IO Neurons are Coupled by Gap Junction Placantonakis et al. PNAS

68 The Inferior Olive as the Great Comparator Feedback Inhibition From the DCN Motor Intention Inferior Olive 68 Sensory feedback

69 IO Neurons are Natural Oscillators 69 Llinas and Yarom JPhysiol 1986

70 IO neurons are not Harmonious Oscillators in-vivo Chorev, Yarom and Lampl JNS

71 71 There are Various Oscillation Patterns

72 Oscillation as a Blocking Device for expected Inputs Expected Inputs How will The IO Differentiate Early vs. Late Inputs? 72

73 Conditioning Memory Retention depends on Nucleo-Olivary Inhibition 73 Medina et al. Nature 2002

74 ISI vs. Oscillation phase encoding 74 Mathy, et al. 2009

75 CF activation Pattern sets the direction of plasticity 75 Mathy, et al. 2009

The Cerebellum. Outline. Lu Chen, Ph.D. MCB, UC Berkeley. Overview Structure Micro-circuitry of the cerebellum The cerebellum and motor learning

The Cerebellum. Outline. Lu Chen, Ph.D. MCB, UC Berkeley. Overview Structure Micro-circuitry of the cerebellum The cerebellum and motor learning The Cerebellum Lu Chen, Ph.D. MCB, UC Berkeley 1 Outline Overview Structure Micro-circuitry of the cerebellum The cerebellum and motor learning 2 Overview Little brain 10% of the total volume of the brain,