1. Supervisor: Dr Towhidkhah Designed by Yashar Sarbaz
Amirkabir University of Technology
BASAL GANGLIA
Supervisor: Dr Towhidkhah
Designed by Yashar Sarbaz

2. Systems-Level Neural Modelling: What and Why?
We know a lot about the brain!
Need to integrate data: molecular/ cellular/ systems levels.
Complexity: Need to abstract away higher order principles
Models are tools to develop explicit theories, constrained by multiple levels (neural and behavioural).
Key: Models (should) make novel testable predictions on both neural & behavioural levels
Models are useful tools for guiding experiments

3. Movement Levels Highest Level (Need & Plan): Limbic System
Associative Cortex
Middle Level (Motor Program):
Cerebellum
Motor Cortex
Basal Ganglia
Lowest Level (Movement):
Spinal Cord
Muscular-Skeletal System

4. Movement Block Diagram

5. Brain

6. Learning Strategies Supervised Learning (Cerebellum)
Reinforcement Learning (Basal Ganglia)
Unsupervised Learning (Cerebral Cortex)
Symbolic Learning (Hippocampal System)

7. Learning Strategies

8. Learning Strategies Cerebral Cortex：Unsupervised Learning
target
error + -
output
input
Cerebellum: Supervised Learning
reward
Basal Ganglia: Reinforcement Learning
Cerebral Cortex：Unsupervised Learning
Cortex
Basal
thalamus
Ganglia SN
Cerebellum IO

9. Basal Ganglia Collection of Subcortical Nuclui
We Know a little about BG
It has main role in movement
Many movement disorders related to this area
Involved in motor coordination, timing and control

10. Basal Ganglia Directly Receive No Direct Sensory Inputs
Send Little Direct to Spinal Cord
Damage in BG has no loss of Specific Motor Function
Damage in BG Cause mainly Deficit in General Control and Initiation of Movement

11. Basal Ganglia It is one of the Old Area of Brain
BG with Thalamus act like a Little Brain
It is Like Funnel

12. BG Functions 1. Inhibition of muscle tone
2. Coordination of slow, sustained movements
3. Suppression of useless patterns of movements

13. Duty of the BG 1.Motor control 2.Reinforcement learning
3.Sensorymotor associative learning
4.Adaptive timing
5.Temporal order learning
6.Initiation of voluntary movement

14. BG is involved in a wide spectrum of functions ranging from simple sensory motor learning to planning, it does not tell to us how this might occur.

15. BG Blocks Striatum: Putamen and Caudate
Globus Pallidus: External and Internal
Subthalamic Nucleus
Subtantia Nigra: Pars Compacta and Pars Reticulata

16. Basal Ganglia Anatomy

17. Basal Ganglia Anatomy

18. Basal Ganglia Anatomy

19. Basal Ganglia Anatomy

20. Blocks of BG

21. Converging Pathways PF: Prefrontal SMA: Supplementary Motor Area
M1: Primary Motor Cortex
PMv: Ventral pre-motor Area
C/P: Caudate Nucleus

22. Disorders of the BG
Hyperkinesia: an excess or spontaneous involuntary movements
Chorea abrupt movements of the limbs and facial muscles
Ballism violent, flailing movements
Athetosis slow writhing movements of the fingers and hands and sometimes toes
Hypokinesia: a lack of or resistance to voluntary movement
Akinesia lack of of slowness of spontaneous and associative movements
Rigidity increased tone on passive manipulation of joints
Irregularities:
Tremor rhythmic, involuntary, oscillatory movements around 4-6 Hz

23. BG Diseases
Parkinson: loss of Dopamine, with hypokinesia (akinesia & rigidity) and irregulaities
Huntington: death in striatum, with hyperkinesia (chorea, ballism, athrtosis)
Hemiballism: lesion in STN with ballism
Tardive Dyskinesia: Using Antipsychotic

24. BG Blocks in Diseases

25. BG and Action Selection
BG selectively facilitates one command while suppressing others

26. Micro Circuitry of the BG
Striosomes: input from limbic system and output to dopaminergic neuron of SNc (reinforcement signal)
Matriosomes: Input from cortical (sensation and movement) and output to SNr and GP

27. Micro Circuitry of the BG

28. Conceptual Models
Such diversity of function embodied in such an intricately organized structure, has inspired numerous models of basal ganglia function ranging from sensory-motor associative to the formation of motor plans

29. Conceptual Models
BG as link between limbic system and motor output (eye movement)

30. Conceptual Models
BG and learning to cortex to select a sequence

31. Reinforcement Learning

32. Physiological Basis of Reinforcement Learning

33. Physiological Basis of Reinforcement Learning

34. Reinforcement Learning
A general idea of “goodness” is used to adjust how the system learns
Temporal Difference (TD) error:

35. Reinforcement Learning
Framework for learning state-action mapping (policy) by exploration and reward feedback
Critic
reward prediction
Actor
action selection
Learning
external reward r
internal reward d: difference from prediction
environment
reward r
action a
state s
agent

36. Dopamine and Learning
There is significant evidence that dopamine acts as a reinforcement signal to neuron in striatum and training them to recognize patterns in their cerebral cortical input.
Dopamine modulates Go and No-Go reinforcement learning in the basal ganglia separately via D1 and D2 receptors

37. Reinforcement Learning and BG
Data from neuronal recording and lesion studies indicate that the basal ganglia are involved in learning and execution of goal-directed, sequential behaviour
Dopamine neuron activity encoding the reward prediction error

38. Reinforcement Learning and BG
It is suggested that the Striosome compartment works as the value prediction mechanism while the Matriosomes compartment works as the action selection mechanism

39. Reinforcement Learning and BG
Striatum
striosome & matrix
dopamine-dependent plasticity
Dopamine neurons
reward-predictive response
TD learning

40. Reinforcement Learning and BG

41. Striatum Learning Mechanism

42. Comparison of the Basal Ganglia and the Cerebellum
The basal ganglia receive input from the entire cortex, whereas the cerebellum is innervated only by parts of cortex directly related to sensorimotor function
Cerebellar output is directed back to the premotor and motor cortex, while the basal ganglia project to these as well as the prefrontal association cortex;
The cerebellum receives somatosensory information directly from the spinal cord and has major afferents and efferents with many brain stem nuclei which are directly connected with the spinal cord, while the basal ganglia have very few connections with the brainstem and no known direct connections with the spinal cord

43. One might also consider that the basal ganglia are the deep nuclei of the cortex, while the cerebellum itself consists of a cerebellar cortex and deep nuclei.

44. History of Parkinson’s disease
Ancient Indian Text: Kampavata
Galen 175 A.D.: Shaking Palsy
James Parkinson 1817: “An Essay on the
Shaking Palsy” (6 patients)
Charcot 1860: Parkinson’s Disease
1960: Role of Dopamine
1981: Levo Dopa
1990s: DBS Treatments

45. Parkinson’s Disease An Ancient Progressive Disease
Second Wide-Spread Brain Disease (After Alzheimer)
Main Symptoms are Movement Disorders
Vast Range of Symptoms
Mean Age of onset is 60
Degeneration of Basal Ganglia
Not Epidemic

46. Famous Parkinsonian People

47. Etiology Not clear Exactly Main Hypothesis:
Free Radicals: Antioxidant Molecules
Genetic Factors
Environmental Toxins: MPTP, Retenone, 6Hydroxy Dopamin
SNc Cells Age Faster than Normal

48. Symptoms of PD
Movement Symptoms
Cognition Symptoms

49. Cognition Symptoms Dementia Depression Anxiety and Panic
Sleep Disorders
Cognitive impairment
Psychosis
Behavioural disturbances
Bradyphrenia: off Thinking

50. Cognition Symptoms Different Movement and Cognition History Lewy Body
Another Degeneration of Brain Area involve in Cognition (For Example in Dementia: Dorsal tier neuron and medial neuronal Groups)
Aging

51. Movement Disorders
Hypokinesia: a lack of or resistance to voluntary movement
Akinesia: lack or slowness of spontaneous and associative movements
Rigidity: increased tone on passive manipulation of joints
Irregularities
Tremor: rhythmic, involuntary, oscillatory movements around 4-6 Hz
Gait Disturbance: shuffling gait, Freezing

52. Problems in Diagnosis Autopsy Show 24% Error in PD Diagnosis
There is no Laboratory Test for Diagnosis
1. Patient History
2. Clinical tests
3. Using Levo dopa

53. Problems in Diagnosis
Starting Tremor, Slowness and Stiffness approximately 12 month Before Diagnosis
lesion of at least 50% of SNc Neuron
Approximately Degeneration Start 5 year before Symptoms (10 years in some texts)
Prognosis is important

54. Diagnosis of PD
At Least Two of these Four Features (Cardinal Features):
Tremor
Rigidity
Akinesia
Gait disturbance
Presence of rest tremor, and a clear cut response to treatment with levodopa

55. Physiological Information about PD
Origin of PD (Basal ganglia)
Parts of Basal ganglia (BG)
Comparing Normal and Patient

56. Reason of PD Loss of nerve cells in substantia nigra pars compacta
Low level of Dopamine in patient’s brain
Changing activity of other blocks

57. Theory of PD Inhibition of GPi Theory BG Selective Theory
Oscillatory Theory
Complex Dynamic System Theory

58. BG Changes in PD
[Kandel, 2000]
Normal
Person
Parkinsonian
Person

59. States of disease After unfolding movement Symptoms
Before unfolding movement Symptoms

60. Treatments for PD Nonpharmacologic treatment Pharmacologic treatment
Surgical treatment

61. Nonpharmacologic treatment
EDUCATION (
SUPPORT
EXERCISE
NUTRITION

62. Pharmacologic treatment
NEUROPROTECTIVE THERAPY
SYMPTOMATIC THERAPY

63. NEUROPROTECTIVE THERAPY
All of the available treatments are symptomatic and do not appear to slow or reverse the natural course of the disease.
Neuroprotective therapy of PD is still theoretical.
Neuroprotective drug could be used in patients with early clinical signs of disease or potentially even prior to the appearance of disease in those shown to be at genetic risk.
Selegiline and rasagiline (both monoamine oxidase inhibitors), dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10 have been evaluated in clinical trials and are receiving the most attention as possible neuroprotective agents

64. SYMPTOMATIC THERAPY Levodopa MAO B inhibitors Dopamine agonists
COMT inhibitors
Anticholinergic agents
Amantadine

65. Drug Treatments of PD

66. Surgical treatment DEEP BRAIN STIMULATION
THALAMOTOMY (With conventional thalamotomy, stereotactic surgical techniques are employed to create a lesion in the ventral intermediate (VIM) nucleus of the thalamus under electrophysiologic guidance. Gamma knife thalamotomy uses radiation delivered to the intracranial target, but electrophysiologic guidance is not possible)
PALLIDOTOMY
IMPLANTATIONS AND INFUSIONS:
1. Tissue transplantation
2. GDNF infusion
3. Duodenal levodopa infusion

67. MainTreatment
Levodopa is the most effective drug in the treatment of PD.
Most patients develop abnormal involuntary movements (dyskinesias) and unpredictable fluctuations in motor functioning within three years of treatment.
Patients with onset before age 20 years are most likely to be affected. As a result, therapy is initiated with other drugs that will control the symptoms and delay the need for levodopa.
They include anticholinergic drugs (eg, trihexyphenidyl, amantadine) and dopamine agonists (eg, pramipexole, ropinirole, and pergolide)

68. THE END