Amirkabir University of Technology BASAL GANGLIA Supervisor Dr

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

Systems-Level Neural Modelling: What and Why? n n n 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 2

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

Movement Block Diagram 4

Brain 5

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

Learning Strategies 7

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

Basal Ganglia n n n 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 9

Basal Ganglia n n 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 10

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

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

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 13

n 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. 14

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

Basal Ganglia Anatomy 16

Basal Ganglia Anatomy 17

Basal Ganglia Anatomy 18

Basal Ganglia Anatomy 19

Blocks of BG 20

Converging Pathways n n n PF: Prefrontal SMA: Supplementary Motor Area M 1: Primary Motor Cortex PMv: Ventral pre-motor Area C/P: Caudate Nucleus 21

Disorders of the BG n n n n n 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 22

BG Diseases n n 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 23

BG Blocks in Diseases 24

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

Micro Circuitry of the BG n n 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 26

Micro Circuitry of the BG 27

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

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

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

Reinforcement Learning 31

Physiological Basis of Reinforcement Learning 32

Physiological Basis of Reinforcement Learning 33

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

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

Dopamine and Learning n n 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 D 1 and D 2 receptors 36

Reinforcement Learning and BG n n 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 37

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

Reinforcement Learning and BG n Striatum n n n Dopamine neurons n n striosome & matrix dopaminedependent plasticity reward-predictive response TD learning 39

Reinforcement Learning and BG 40

Striatum Learning Mechanism 41

Comparison of the Basal Ganglia and the Cerebellum n n n 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 42

n 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. 43

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

Parkinson’s Disease n n n n 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 45

Famous Parkinsonian People 46

Etiology n n 1. 2. 3. 4. Not clear Exactly Main Hypothesis: Free Radicals: Antioxidant Molecules Genetic Factors Environmental Toxins: MPTP, Retenone, 6 Hydroxy Dopamin SNc Cells Age Faster than Normal 47

Symptoms of PD n Movement Symptoms n Cognition Symptoms 48

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

Cognition Symptoms n n 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 50

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 n Irregularities Tremor: rhythmic, involuntary, oscillatory movements around 4 -6 Hz n Gait Disturbance: shuffling gait, Freezing n 51

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

Problems in Diagnosis n n 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 53

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

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

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 56

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

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

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

Treatments for PD n Nonpharmacologic treatment n Pharmacologic treatment n Surgical treatment 60

Nonpharmacologic treatment n n EDUCATION (www. wemove. org) SUPPORT EXERCISE NUTRITION 61

Pharmacologic treatment n NEUROPROTECTIVE THERAPY n SYMPTOMATIC THERAPY 62

NEUROPROTECTIVE THERAPY n n 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 Q 10 have been evaluated in clinical trials and are receiving the most attention as possible neuroprotective agents 63

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

Drug Treatments of PD 65

Surgical treatment n n 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) n n PALLIDOTOMY IMPLANTATIONS AND INFUSIONS: 1. Tissue transplantation 2. GDNF infusion 3. Duodenal levodopa infusion 66

Main. Treatment 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) 67

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