Motor Modulation BG and Cerebellum - Part 1 BG Student PDF

Motor Modulation: the Basal Ganglia and Cerebellum Part 1 – Basal Ganglia Neuroanatomy Dr. Kathleen Keefe [email protected] Disclosure I currently have no relationships of any kind with any company whose products or services in any way relate to the practice of medicine, medical education...

Motor Modulation: the Basal Ganglia and Cerebellum Part 1 – Basal Ganglia Neuroanatomy Dr. Kathleen Keefe [email protected] Disclosure I currently have no relationships of any kind with any company whose products or services in any way relate to the practice of medicine, medical education or research Two main systems modulate motor output The Basal Ganglia and Cerebellum modulate motor output by influencing upper motor neurons to: ○ Improve movement efficiency Performing only ‘wanted’ movements, and no ‘unwanted’ movements Motor ‘learning’ – improving movements with practice ○ Coordinating timing between muscle groups to produce fluid movements ○ Making movements adaptable in real time The Basal Ganglia Learning Objectives (Basal Ganglia) Describe the general function of the basal ganglia Recognize input, output and modulatory nuclei and describe their projection patterns Explain the function of the body motor loop, specifically: ○ Describe the direct motor pathway and pinpoint key projections whose abnormalities cause dysfunction ○ Describe the indirect motor pathway and its associated pathologies Analyze the motor deficits in a case study and propose a diagnosis The Basal Ganglia (BG) A group of nuclei which function to: ○ Select and initiate a collection of relevant movements for a given task (“motor programs”) ○ Inhibit competing movements for that task ○ Control saccadic eye movements ○ Process social cues Nuclei of the Basal Ganglia System What is a motor program? Movement theory states that simple movement sequences are “stored” in our brains ○ I.e. stimulation of a subset of UMNs sets off a chain reaction of LMN stimulations that contract groups of muscles associated with common movements BG accesses these programs and ensures that only one is active (e.g. use hand to bring food to mouth) at a given time and competing programs BG neurons are inactive (e.g., use hand to shield face from dangerous object) BG Receive Input from Most Cortical Areas Purple shading below represents areas that project to the BG Neurons of the basal ganglia influence upper motor neurons BG as a Funnel and Filter BG aren’t initiators of movement – they are more of a funnel and a filter: ○ Funnel – receive information from many cortical areas, process it and output it to a few select structures ○ Filter – only movements appropriate to the task at hand are ‘selected’ Movement Phases and Involved Structures Remember movement can be broken into discrete phases, and certain neurons fire during specific phases BG neurons fire before a movement Thalamus happens (planning) ○ Lesions of the BG cause disturbances in initiation of a movement BG acts on the motor cortex via the thalamus What other structures fire during the ‘planning’ phase?  Thalamic Nuclei Stimulate the Motor Cortices Certain thalamic nuclei are key primary motor cortex stimulators of motor cortices At rest, BG neurons tonically inhibit the thalamus ○ When movement is needed inhibition is transiently relieved Vocab Tonic – a state of continuous activity – either stimulatory or inhibitory Can you remember a sensory system where cells were tonically active? BG act as a gate on thalamic nuclei When the neurons of BG are stimulated, the following pathways are activated: ○ Direct pathway → ‘Go’ signal Disinhibits (releases inhibition) – thalamic neurons that could stimulate wanted motor programs can now fire ○ Indirect pathway → ‘Stop’ signal Reinforces inhibition so the thalamic neurons that could stimulate unwanted motor programs will not fire These pathways work together to ensure intended movements are made Overview of BG Anatomy BG nuclei are located in the brain and brainstem: ○ Brain nuclei: Caudate Putamen Globus pallidus (GP) 3d model of BG structures (ventricles in light blue) Subthalamic nucleus coronal ○ Brainstem nuclei: Substantia nigra caudate putamen GP Input Nuclei of the BG – the ‘Striatum’ Certain nuclei of the BG receive the initial stimulus from the cerebral cortex (input nuclei) Caudate (head) Input nuclei include the caudate and Internal capsule Putamen putamen, which can be referred to collectively as the striatum ○ Caudate and putamen are heavily interconnected with axons, making them look ‘striped’ in certain sections lateral fissure coronal Caudate – An Input Nucleus ‘C’ shaped nucleus that curves into multiple cerebral lobes caudate putamen LV Caudate in peach Putamen – An Input Nucleus Main input nucleus for motor Caudate (head) movement Internal capsule Most lateral structure of the Putamen BG – adjacent to the lateral fissure and insula lateral fissure coronal Output - the Globus Pallidus (GP) Output nuclei deliver the final signal to Caudate the thalamus. BG output is provided via (head) Internal a segment of the globus pallidus Putamen capsule GP is medial to the putamen with two distinct segments: ○ Internal segment (GPi) – most medial segment, outputs motor info (direct and indirect pathways) lateral fissure ○ External segment (GPe) – lateral segment, modulatory projections to the subthalamic nucleus (indirect pathway only) Globus The GPi has high levels of tonic Pallidus inhibitory activity, acting to inhibit the thalamus in a resting state coronal Close up of red box in a coronal section of the brain. The separation of the internal and external globus pallidus can be seen here. Modulatory nuclei Certain nuclei communicate only with other nuclei in the BG – either reinforcing or inhibiting their signals (modulatory) ○ Globus pallidus external (GPe) – medial to the putamen and lateral to the GPi ○ Subthalamic nucleus – inferior to thalamus Thalamus ○ Substantia nigra – midbrain nucleus with characteristic black appearance adjacent to crus cerebri Subthalamic nucleus Substantia nigra coronal Direct Pathway Flowchart At rest, the ability of the thalamus to excite the cortex At rest, inhibition from Cerebral the GPi represses (and therefore initiate a motor excitatory signals from cortex program) is inhibited due to the the thalamus to the cerebral cortex tonic action of the GPi Thalamus Excitatory Globus pallidus (internal) Inhibitory Direct Pathway Flowchart For a motor program to be activated, activity of the GPi Cerebral must be transiently inhibited cortex The thalamus is now able to stimulate the Stimulation of the cerebral cortex and encourage cortex from other sources movement causes the cortex to stimulate the striatum Thalamus Stratum then inhibits the Gpi, Striatum Transient inhibition from freeing the thalamus the striatum represses the inhibitory influence of the GPi on the thalamus Direct Disinhibits Globus pallidus (internal) Excitatory Inhibitory Direct Pathway Flowchart Once the thalamus is freed from inhibition, transient stimulation from Cerebral cortex other sources allows it to stimulate The thalamus is now able to stimulate the the cortex, activating the motor cortex and encourage program movement Thalamus Transient inhibition from the striatum represses the inhibitory influence of the GPi on the thalamus Movement! Globus pallidus Excitatory (internal) Inhibitory Direct Pathway Modulation from the SN Substantia nigra is another important source of stimulation for the striatum Cerebral At rest, striatal neurons are cortex hyperpolarized, and need multiple excitatory inputs to reach firing threshold ○ Loss of stimulatory drive from the substantia nigra can result in hypokinetic syndromes such as Parkinson’s disease Substantia Striatum nigra Excitatory Inhibitory Parkinson’s disease Neurodegenerative disease whose main symptom is slowness or absence of movement Associated with degeneration of dopaminergic neurons in the SN Neurodegeneration preferentially affects neurons of the direct pathway, causing loss of stimulation to the striatum, thus loss of the ‘go’ signal Cardinal Motor Features of Parkinsonism (TRAP) Tremor ○ Resting tremor may be described as “pill A black background with white text rolling” Description automatically generated Rigidity ○ Mask-like facial expression ○ Resistance to stretch Akinesia/Bradykinesia ○ Akinesia – lack of movement/trouble initiating movements ○ Bradykinesia – slower, smaller movements ○ Shuffling gate with reduced arm swing Postural changes ○ Imbalance/falls ○ Flexed posture Summary Slide - Direct Pathway Cortical neurons excite the striatum Striatum inhibits Globus Pallidus internal segment Thalamus (now released from GPi inhibition) can fire and excite the motor cortex excitation! If considered in the form of a multiplication equation, where excitatory synapses are +1 and inhibitory are -1, it is evident that two inhibitory synapses in the direct pathway can cause net excitation Check-in Question 1 Which nuclei of the Basal Ganglia receive direct cortical input? A. Globus pallidus internal and external segments B. Caudate and putamen C. Substantia nigra and subthalamic nucleus Check-in Question 2 Within the direct pathway, the globus pallidus internal segment provides ______ input to the ________ A. Excitatory; thalamus B. Inhibitory; thalamus C. Excitatory; striatum D. Inhibitory; striatum Indirect Pathway Indirect pathway reinforces inhibitory drive to the thalamus, repressing movement – especially targeted at unwanted movement (e.g. competing motor programs) Indirect Inhibits Accurate movement relies on a balance between the activation of these two pathways Indirect Pathway Flowchart Thalamic neurons controlling unwanted movements are inhibited One way to increase inhibitory drive to the thalamus is to provide greater Cerebral stimulus to the GPi, strengthening its cortex signal The subthalamic nucleus (STN) has excitatory synapses with the GPi Thalamus This enhances the inhibitory drive of the GPi, causing enhanced inhibition of the Globus pallidus thalamus (internal) Excitatory Inhibitory Subthalamic nucleus (STN) Indirect Pathway Flowchart Thalamic neurons controlling unwanted movements are inhibited However, the circuitry is set up such that the globus pallidus external segment Cerebral (GPe) is tonically inhibiting the STN cortex Neurons of the striatum can inhibit the GPe to release the STN and allow it to fire Striatum Thalamus Inhibition of the GPe by the striatum represses the inhibitory drive on the subthalamic nucleus, allowing it to excite the GPi Globus pallidus (external) Globus pallidus (internal) Excitatory Inhibitory Subthalamic nucleus (STN) Summary of Indirect Pathway Cortical neurons excite the striatum Striatum inhibits Globus Pallidus external (which now cannot inhibit subthalamic nucleus) Subthalamic nucleus excites Globus Pallidus internal Globus Pallidus internal inhibits the thalamus Thalamus is inhibited, no unwanted movement occurs Back to the multiplication analogy: inhibition! There are 3 negative numbers in the equation, thus the net effect is negative. Huntington’s Disease Huntington’s Disease causes degeneration of neurons in the striatum (preferentially indirect pathway neurons) This results in unwanted movements such as: ○ Chorea – writhing and twisting movements of the limbs, face or trunk ○ Rigidity (hypertonia) +1 Huntington’s Disease Genetic disorder – ‘Huntington’ gene on chromosome 4 mutates such that an A black background with white text abnormally large number of repeats of the Description automatically generated nucleotide sequence CAG occurs – this causes dysfunction ○ Mnemonic: CAGE Dominant mutation – offspring have a 50% chance of inheritance Huntington’s disease is progressive with a usual onset in 30s-40s  This reduces the Modulation of the Indirect Pathway inhibition on the thalamus, making it easier to tip the balance Indirect pathway can be in favor of movement Cerebral modulated by neurons of the cortex substantia nigra, which provide an inhibitory signal Substantia Thalamus Striatum nigra Globus pallidus Inhibition of the striatum by the SN frees the GPe (external) Globus pallidus from inhibition, allowing (internal) it to inhibit the Excitatory subthalamic nucleus Inhibitory Subthalamic nucleus (STN) Nigrostriatal pathway Neurons of the substantia nigra use dopamine as a neurotransmitter Striatal neurons associated with direct pathway have D1 dopamine receptors, which depolarize a cell in response to dopamine Striatal neurons associated with indirect pathway have D2 dopamine receptors, which hyperpolarize a cell in response to dopamine Thus, SN can both excite the direct pathway and inhibit the indirect pathway Case study Resources Worksheets – next three slides are worksheets you can fill out, including direct and indirect pathways Basic Clinical Neuroscience, Chapter 8 3d models: ○ Model used here: https://www.neuroanatomy.ca/3Dreconstructions.html ○ Brainfacts model: https://www.brainfacts.org/3d- brain#intro=false&focus=Brain-basal_ganglia Patient with Parkinson’s disease: https://www.youtube.com/watch?v=kXMydlXQYpY&t=50s Patient with Huntington’s disease: https://www.youtube.com/watch?v=KleHA0fv0Eg&t=146s Ninja nerd video on the Basal Ganglia: https://www.youtube.com/watch?v=hxvep2Y8ShI Label the anatomical structures: These are ___________ sections (plane) Fill in the names of the nuclei and color in the arrows Fill in the names of the nuclei and color in the arrows