Neuroscience: Motor Systems PDF

MOTOR SYSTEMS - Be able to describe the mechanisms of muscle and tendon receptors and the role and organization of spinal reflexes - Be able to describe the main principles of postural control - Be able to describe and explain basic motor functions at the spinal level, and the concept of the central...

MOTOR SYSTEMS - Be able to describe the mechanisms of muscle and tendon receptors and the role and organization of spinal reflexes - Be able to describe the main principles of postural control - Be able to describe and explain basic motor functions at the spinal level, and the concept of the central motor programme - Be able to describe the nervous system’s control of locomotion - Be able to describe the different descending motor pathways and relate their organisation to the control of different movements - Be able to describe the functional principles behind the balance control system - Be able to describe the location and main function of different cortical motor areas and describe and analyze the areas’ respective roles with different types of cortical controlled movements -Be able to describe the basal ganglia´s structure and internal connections as well as their connections to other parts of the CNS - Be able to relate this knowledge to and describe the role of the basal ganglia in motor control - Be able to describe the different types of eye movement and their general functions - Be able to describe the cerebellum’s macroscopic and microscopic structure and its connections to other parts of the CNS and general role in motor control - Be able to explain synaptic connections in the cerebellum cortex and relate these to the function of the cerebellum -Be able to describe motor defects caused by damage to or degeneration of different parts of the CNS, including stroke and Parkinson´s disease Overview of motor systems Classification of movements: - Voluntary movements: they are purposeful, initiated by stimulus or will, with a goal in mind, and they improve with practice and become more automatic - Reflex responses: they are rapid, stereotyped and involuntary. - Rhythmic movements: like locomotion or chewing. Voluntary or involuntary initiation or termination. Stereotypes cycles repeated automatically. Components of motor system - Muscles and joints  - Agonist muscles: the ones that generate the primary movement - Antagonist movement : oppose the action of agonist allowing smooth and controlled movement. A motor unit is constituted by an alpha motor neuron and the muscle fibers it innervates. These neurons are in the spinal cord and in the motor nuclei of cranial nerves in brainstem. Each type of movement (swallowing, locomotor, scratching…) has it own motor pattern. Each of the numerous motor patterns is generated by a group of neurons, the neuronal network. For example, both the flexor muscles and extensor muscles of both legs end up forming a neuronal network. There is a feedback mechanism from muscle receptors to motoneurons - Muscle spindles: detect changes in muscle length providing feedback that leads to the activation of motoneurons to contract the muscle (stretch reflex). - Golgi Tendon Organs (GTOs): they are receptors located in the tendons that sense changes in muscle tension. If too high they inhibit motoneuron activity - Alpha motoneurons mediate the stretch reflex. They are inhibited by GTOs. - Gamma motoneurons modulate the sensitivity of muscles spindles. Network generating scratching does not require rhythmic sensory input from the limb Scratching behavior is controlled by a central pattern generator (CPG), which is a neural network that produces the rhythmic movements required for scratching. This CPG can generate the scratching pattern on its own, without needing continuous rhythmic sensory input from the limb. Sensory input (such as an itch or irritation) triggers the start of scratching, but once the behavior begins, the CPG controls the rhythm of the movement. The rhythmic movement of scratching can continue even without further sensory feedback. The sensory input mainly initiates the behavior, but the CPG ensures the rhythmic motor pattern persists once started. It is not only scratching but also respiration, chewing and locomotion controlled by the CPG  Role of sensory information in movement control Movements are modified in relation to external world through: - Feedback mechanism: after a perturbation of movement has occurred - Feed-forward mechanism: anticipation of expected disturbances of movement. Specific sensory signals can trigger behaviorally meaningful motor acts such as withdrawal, coughing or swallowing reflexes Sensory information is also necessary to plan voluntary movements. Conclusions. 1. Motor behavior involves a coordinated contraction of many muscles and is controlled by motor control systems. CNS contains neuronal networks mediating different types of motor coordination. A typical network consists of a group of interneurons that activate a specific group of motoneurons in a certain sequence and inhibit other motoneurons that may counteract the intended movement. There are preformed networks that allow performance of a basic movement repertoire (e.g. locomotion, posture, breathing, eye movements, etc.), as well as basic networks that underlie reaching hand and finger movements, and sound production as in speech. This constitutes the motor infrastructure that is available to a given individual, after maturation of the nervous system has occurred. In addition, we are able to learn new motor coordinations through plastic changes taken place in genetically expressed motor infrastructure. 2. In CNS one can distinguish three levels of motor control: spinal cord, brainstem and cortical motor areas. They are organized hierarchically and in parallel. Spinal cord contains networks that mediate spinal reflexes (e.g. flexion reflex, crossed extension reflex) and some rhythmical motor patterns (e.g. locomotion, scratching). Brainstem contains networks that mediate bulbar reflexes (e.g. swallowing, coughing) and such rhythmical motor patterns as breathing, chewing, etc. It also contains neuronal systems whose axons project to the spinal networks. Through these descending systems brainstem controls movements generated by the spinal cord. Cortical motor areas are responsible for voluntary movements, as well as for corrections of motor patterns generated by the spinal cord and brainstem. Cerebellum, basal ganglia and motor coordination. Cerebellum thalamus do not participate directly in generation of movements, but are involved in improves a "quality" of movements by coordinating activity of motor cortex, brainstem and spinal cord on the basis of peripheral and central feedback signals. Basal ganglia are responsible for selection and initiation of proper type of motor behavior. Thalamus is a "relay station" transmitting different type of signals to the cortex. 3. Sensory information influences motor output in many ways and at all levels of the motor control. Sensory input to the spinal cord and brainstem directly triggers reflex responses. It is also essential for determining the parameters of voluntary movements. Sensory input may influence a transition from one phase of rhythmical motor pattern to another. Finally, sensory information is used to correct actual as well as expected errors in the performing movement through feedback 4. Each level of motor control affects its subordinate level via descending and feed-forward mechanisms, respectively. pathways. The spinal cord receives commands via five descending tracts. The vestibulo-, reticulo-, rubro- and tectospinal tracts originate from vestibular, reticular, and red nuclei of the brainstem and from tectum, respectively. The corticospinal tracts originate from the primary motor cortex, and to a lesser extent from the premotor and supplementary motor areas. Descending tracts have different basic functions. The reticulospinal for initiation of locomotion and control of upright body posture. The vestibulospinal tract is responsible tract is involved in generation of tonic activity in the antigravity muscles during standing and walking, as well as in different postural reflexes. Tectospinal tract is important in coordinating head and eye movements. The rubro- and corticospinal tracts play two major roles: (1) Transmission of commands for non-stereotypic (voluntary) movements, and (2) Correction of the motor patterns generated by the spinal cord. Parallel descending pathways, with partly overlapping functions, offer the advantage that, if one pathway is lesioned, the remaining ones can to some extent take over its functions. Motor Units Muscles contract slowly and the force generated by a train of impulses summates. Muscles are innervated by a pool of motor neurons. Three basics types of mammalian muscle fibers: - Type 1: or red, these fibers are specialized for slow, sustained, aerobic exercises. - Type 2: or white, fibers that are specialized for rapid contractions. - Type 2a: capable of rapid contractions that can be sustained for a relatively long time without fatigue. - Type 2b: capable of rapid contractions, duration of which is limited by fatigue. Henneman’s principle: states that motor units are recruited in a fixed order during muscle contraction following size: type 1 first, then type 2a and then 2b. The nervous system grades the force of muscle contraction by increasing the firing rate of motor units and by recruitment of new motor units. 1. Individual muscle fibers are classified into three types (1, 2a and 2b) according to their contractile and metabolic properties. The properties of a whole muscle depend on the proportion of muscle fiber types it contains. 2. The motor unit is defined as a single motor neuron and the group of muscle fibers it innervates. All muscle fibers in a single motor unit consist of the same muscle fiber type. The amount of the force produced by the muscle fibers of a motor unit is governed by the frequency of action potentials produced by the motor neuron. Three types of motor units– slow, fast fatigue-resistant, and fast fatigable– can be categorized on the basis of their twitch speed, produced force and fatigability. 3. Each muscle is innervated by a pool of motor neurons, which typically contains a mixture of motor unit types, although in different proportions depending on the typical use of that muscle. An orderly sequence of motor neuron activation within a pool leads to activation of units producing the smallest amount of force before those producing larger amounts of force. This sequence, known as a size principle, results from a difference in passive electrical properties of motor neurons forming three types of motor units. 4. The nervous system grades the force of the muscle contraction by increasing the firing rate of already active motor units and by recruiting (according to the size principle) of new motor units in activity Muscle receptors Muscle spindles and GTOs. - Muscle spindles respond to stretch of specialized muscle fibers. Muscle fibers have two types of intrafusal fibers within each spindle and different sensory endings interact with these fibers. - Primary endings (Group Ia fibers): fire at high rate during dynamic changes in muscle length. Highly sensitive to the velocity of the strech - Secondary endings (Group II fibers): they respond to the static length of the muscle, meaning that they are less sensitive to changes in length over time. Functional differences between spindles and GTOs derive from their different anatomical arrangements within the muscle. When the muscle is passively stretched the muscle spindles’ activity is higher than the GTOs, and the reverse happens when the muscle is actively contracted. The CNS can control sensitivity of muscle spindles through the gamma motor neurons. Gamma activation maintains the stretch on the sensory region of the spindle. 1. Specialized sensory receptors (spindles and tendon organs) in the muscle provide feedback to the CNS regarding the amount the muscle stretch and tension. 2. Muscle spindles are located within the muscle and provide signals on the muscle length. The length of the muscle and changes in length are coded by the pattern and frequency of action potentials in the primary or Ia afferents and secondary or Group II afferents. Gamma motor neurons innervate the spindle fibers and can adjust the sensitivity of the spindle. 3. Golgi tendon organs lie within the musculotendinous junctions. A single 1b afferent innervating a Golgi tendon organ is activated when tension is produced by nearly active motor units. 4. Muscle spindles and tendon organs provide the CNS with continuous information (proprioceptive information) about the mechanical state of the muscle. Sensory signals from muscle receptors are transmitted to the spinal cord as well as to the higher levels of the central nervous system. In the spinal cord, they activate networks of spinal reflexes. At the higher levels of CNS, proprioceptive information is used for generation of voluntary movements. Spinal reflexes The discharge of muscle spindles triggers the stretch reflex, a key mechanism for maintaining muscle tone and posture. The reflex quickly counteracts any unintentional lengthening of the muscle, preserving its optimal length. 1. Muscle Spindle Activation When a muscle is stretched, the intrafusal fibers of the muscle spindle are elongated. This deformation activates Ia afferent neurons, which are sensory neurons that send signals to the spinal cord about the stretch. 2. Stretch Reflex Arc The Ia afferent neurons synapse directly onto alpha motor neurons in the spinal cord. The alpha motor neurons then stimulate the extrafusal fibers of the same muscle, causing it to contract and resist the stretch. 3. Purpose of the Stretch Reflex Maintain Muscle Length: The reflex quickly counteracts any unintentional lengthening of the muscle, preserving its optimal length. Postural Control: Helps maintain stability by adjusting muscle tension in response to changes in position or external forces. Reciprocal coordination of muscles: mechanism where one set of muscles contracts while the opposing set relaxes to produce smooth and efficient movement. Here's how it works: 1. Muscle Spindle Activation o When a muscle is stretched, the Ia afferent neurons of the spindle are activated and send signals to the spinal cord. 2. Alpha Motor Neuron Activation  o The Ia afferents synapse with alpha motor neurons of the same muscle (agonist), causing it to contract. 3. Inhibition of the Antagonist o The Ia afferents also synapse with inhibitory interneurons in the spinal cord. o These interneurons inhibit the alpha motor neurons of the antagonist muscle, preventing it from contracting. The stretch reflex is like a self-adjusting system that helps muscles resist being stretched too far. Here’s how it works, step by step: 1. What Triggers the Reflex? When a muscle gets stretched (e.g., if you're holding something heavy and it pulls your arm down), the muscle spindle (a stretch sensor inside the muscle) detects this change. 2. What Happens Next? The muscle spindle sends a signal to the spinal cord through a nerve called the Ia afferent. The spinal cord processes this signal and tells the muscle to contract (via alpha motor neurons) to counteract the stretch and restore its original length. 3. Why Gamma Neurons Are Important? Without gamma motor neurons, the muscle spindle would go slack when the muscle contracts. This would stop the spindle from detecting further stretch. Gamma motor neurons keep the spindle tight so it can keep sensing even when the muscle is already contracted. 4. How Does the CNS (Brain and Spinal Cord) Control This Reflex? The CNS adjusts the reflex using: 1. Gamma motor neurons: To fine-tune spindle sensitivity. 2. Inhibitory pathways: To make sure the reflex doesn’t overreact. 3. Descending brain signals: To increase or decrease the reflex depending on the situation (e.g., suppressing the reflex during precise movements). Key Point: The stretch reflex is a feedback system—when the muscle stretches too much, the reflex pulls it back. This keeps your movements steady and prevents injury from overstretching.  Reciprocal coordination of muscles GTOs are innervated by Ib afferent fibers, which send information to the spinal cord when the muscle generates tension, and provide feedback on muscle force, these signals help regulate muscle contraction. In the spinal cord, Ib afferents synapse onto Ib inhibitory interneurons. These interneurons inhibit the activity of alpha motor neurons that innervate the same muscle. The inhibition reduces muscle contraction, protecting the muscle and tendon from damage caused by excessive force. 1. Spinal reflexes are initiated by stimuli that activate receptors in muscles and skin. Signals from specific receptors activate a specific spinal neuronal network that generates a particular motor pattern. 2. Discharge of muscle spindle afferents caused by the muscle stretch evokes stretch reflex that is a muscle contraction caused by its stretch. It is a monosynaptic spinal reflex, which allows muscle tone to be regulated quickly and efficiently without direct intervention by higher centers. Effectiveness of stretch reflex is regulated by CNS, adapting it to the requirements of specific motor acts. 3. Discharge of Golgi tendon organ Ib afferents caused by muscle contraction, disynaptically inhibits the discharge of alpha motor neurons innervating the contracting muscle, thus providing a negative feedback mechanism for regulation of muscle tension. 4. Spinal reflex networks perform three main functions: (1) control of individual muscles, (2) coordination of muscle action around a joint, (3) coordination of muscles at different joints.  5. Interneurons are important elements of spinal networks. They (i) mediate influences of sensory input upon motoneurons and (ii) constitute the networks generating complicated patterns. Two groups of inhibitory interneurons (1a, 1b inhibitory interneurons) contribute to reciprocal coordination of muscle action around a joint. 6. The spinal cord contains networks underlying generation of a set of elementary patterns of coordination, from relatively simple combinations, like reciprocal innervation at a single joint, to more complex spatial patterns of movement, such as flexion reflex and cross extension reflex. When a specific spinal network is activated by sensory signals from receptors, the corresponding coordination is executed in context of a spinal reflex. However, the same spinal network can be activated by signals from higher levels of CNS. In this case, the corresponding coordination is executed in context of a voluntary movement. Locomotion  Stepping movements - Stance phase: the period when the food is in contact with the ground - Swing phase: the period when the foot is not in contact with the ground and is moving forward. Changes is locomotor speed are accompanied by changes in interlimb coordination, and the shortening of the cycle duration with increasing of locomotor speed is mainly due to he shortening of the stance phase.  Locomotor central pattern generator (CPG) This system is able to generate the basic locomotor pattern without sensory feedback from the limb. It is located in the spinal cord and divided into: left forelimb CPG, right forelimb CPG, left hind limb CPG, right hind limb CPG. This system can be activated by glutamate. Spinal locomotor CPG is subjected to sensory influences. Afferent input from the limb assists in switching from one phase of the locomotor cycle to another. This is essential for adaptation of locomotor pattern to environment. For example, Stretch of hip flexor causes earlier initiation of the swing phase. Switch from stance to swing: (i) Appearance of signal from hip flexor afferents (muscle spindels) (ii) Disappearance of signal from extensor group 1 afferents (muscle spidels and Golgi tendon organs)  Initiation of locomotion Spinal locomotor mechanism is activated from the brainstream. The mesencephalic locomotor region is composed of glutamatergic neurons in the cuneiform (CnF) and the caudal pedunculopontine (PPN) nuclei. Reticulospinal neurons transmit the command from MLR that activates spinal CPGs. MLR and subthalamic locomotor region are used for eliciting locomotion in different behavioral contexts. MLR is controlled by basal ganglia.  Role of cerebellum in control of locomotion Function of cerebellum in locomotor coordination is optimization of the motor pattern.  Role of motor cortex in control of locomotion Commands for visually induced modifications of the locomotor pattern come to the spinal locomotor CPG from the motor cortex 1. Locomotion is an active propulsive movement of the animal in space. Movements of locomotor organs (limbs, wings, etc.) are cyclic. In terrestrial animals, each cycle of the limb movement consists of the stance and swing phases. 2. The basic locomotor pattern of each limb can be generated without sensory feedback from the limb, by a spinal network termed the central pattern generator, CPG. It provides the basic features of the movement– the rhythm, the duration of the stance and swing phases, and the level of muscle activity. In intact animals, however, afferent influences from the moving limb can be strongly modify this centrally generated pattern thus adapting it to the environmental conditions. Coordination of movements of the limbs is achieved due to interactions of individual CPGs. 3. Activation of spinal locomotor CPGs is produced by a population of reticulospinal neurons. They can be activated via two inputs– from the mesencephalic locomotor region (MLR) and from the subthalamic locomotor region (SLR). Activity of MLR neurons is controlled by a specific population of neurons forming out of basal ganglia. Via the MLR, basal ganglia may initiate and terminate locomotion. 4. During locomotion, the cerebellum receives information about intended locomotor movements (from CPGs) and about ongoing locomotor movements (sensory information from limbs). It processes this information and through the descending pathways of the brainstem optimizes the locomotor pattern. 5. The motor cortex does not play any significant role in the control of steady locomotion in a regular environment. Its role becomes decisive, however, when visually induced modifications of the locomotor pattern are necessary Control of posture 1. Stabilization of upright posture. Postural control system is keeping the projection of the center of mass within the limits of the supporting area. Postural stability in the frontal plane and in the sagittal plane is maintained by two different system: - Operation of the sagittal plane system; by correcting motor responses (The tibialis anterior (TA) and gastrocnemius (calf muscle) work in opposition to maintain balance; the TA activated when the body leans forward; the G activates when the body leans backward). - Stabilizing different position: at different angles, it shifts the set-point, by adjusting the activation of TA and G. If the projection of the CM occurs outside the supporting area, the only way to prevent falling down is to perform a step. 2. Postural support of voluntary movements: aim of anticipatory adjustment, to counteract the destabilizing consequences of a voluntary movement (Before a voluntary action (e.g., raising an arm), the body predicts the destabilizing forces that the movement will cause. Specific postural muscles activate in advance to counteract the shift in the center of mass or balance). Postural control can be adapted to suit specific behaviors (anticipatory adjustment adapts to the behavioral context). 3. Stabilization of head and limb orientation in relation to the body and the gravity vector. This is thanks to the reflexes found in neck-neck (cervicocollic) that stabilize the head position in relation to trunk and vestibular-neck (vestibulocollic) that stabilize the head position in relation to gravity vector. These two have opposing actions on limbs so they cancel each out or sum. These reflexes are mediated by several neurons. 4. Role of different parts of CNS in the postural control. Integrity of the brainstem is necessary for postural control (DFT, dorsal tegmental field and VFT, ventral tegmental field). Adaptive postural control requires an intact cerebellum. 5. Development of postural control. 1. Posture is an actively stabilized definite orientation of the body and its segments in space and in relation to each other. 2. Postural control systems minimize deflections of the body from desirable orientation. Postural control systems are able to stabilize different postures. 3. Multimodal sensory inputs– somatosensory, visual, vestibular are used for postural control. 4. To maintain a desirable posture, a family of adjustments is needed. Postural adjustments are necessary also for all motor tasks and need to be integrated with voluntary movements. 5. Postural adjustments are achieved by means of two major mechanisms: (i) The compensatory or feedback mechanisms are activated by sensory events following loss of desirable posture. (Compensatory postural adjustments). (ii) The anticipatory or feed-forward mechanisms predict disturbances and produce preprogrammed responses that maintain stability. (Anticipatory postural adjustments). 6. Postural control is adaptive. The shape of postural adjustment depends on behavioral context. 8. All levels of CNS are involved in postural control. Integrity of brainstem centers is necessary for generation of compensatory postural adjustments. Integrity of highest levels of the CNS including the motor areas of the cerebral cortex is necessary for anticipatory postural adjustments. Adaptive postural control requires an intact cerebellum Eye movement Why do we move our eyes? - To acquire objects for central viewing: saccadic eye movements - To maintain objects in foveal view: smooth pursuit eye movements - To fast fix a focus point: vergence eye movements - To stabilize the world on the retina: vestibulocular reflex (VOR), which stabilizes images during head movements and optokinetic reflex (OKR), that tracks moving objects across the visual field. The paramedian pontine reticular formation (PPRF) as the "center" for horizontal eye movements. The PPRF, located in the brainstem, controls horizontal gaze by coordinating signals to the abducens nucleus and contralateral oculomotor nucleus. This system enables smooth, coordinated lateral movements of both eyes, essential for tasks like reading and tracking moving objects. Movements Conjugate Movements: Synchronized movement of both eyes in the same direction (e.g., saccades, smooth pursuit). Smooth pursuit: Vital for maintaining a stable gaze while observing moving targets. Saccades: new target, rapid change in eye position Disconjugate Movements (Vergence): Eyes move in opposite directions (e.g., convergence for near objects, divergence for far objects). Supports depth perception. Reflexes: VOR stabilizes vision during head rotation. When head moves but eyes are still fixed OKR ensures image stability when the entire visual field shifts (e.g., while in a moving car) Areas involved in eye movement: MT (Middle temporary) and MST (medial superior temporal) Areas: Located in the visual cortex, these regions process motion information. o MT specializes in detecting speed and direction of motion. o MST handles more complex tasks like optic flow (movement of the visual field during self-motion). Frontal eye field: Responsible for voluntary eye movements, including saccades (rapid, jerky movements of the eye) and smooth pursuit. Parietal eye field: Plays a role in spatial attention and coordinating eye movements in response to visual stimuli in the environment. Context-dependent information: mood and intensions, beauty, attraction, food, predators and dangers Motor system overview: Motor Neurons: Alpha and gamma motor neurons control muscle contraction and adjust muscle tone, respectively. Size Principle: Motor units are recruited from smaller (low force) to larger (high force) for efficiency. Central Pattern Generators (CPGs): Neural circuits in the spinal cord generate rhythmic movements like walking or swimming. Descending Control: Motor commands from the cortex, basal ganglia, and cerebellum modulate CPGs for precise execution of movements. Basal Ganglia and Cerebellum: These systems ensure smooth transitions between movements and prevent unwanted motions, integrating with cortical planning centers. Basal ganglia The basal ganglia is a subcortical brain system that through the cortex control selects, plans and executes motor programs, is involved in motor programs, in motor learning, habit formation and motivation and reward systems. 1. Cortex: initiates and plans voluntary movements 2. Basal ganglia: selects appropriate movements and suppresses unwanted or competing movements. 3. Thalamus: send processed motor commands back to the cortex for execution - Striatum (inhibitory), uses GABA to send inhibitory signals to other basal ganglia components. - Globus pallidus (inhibitory) - Externa: GABAergic signals to subthalamic nucleus - Interna: GABAergic signals to thalamus to prevents unwanted movement. - Subthalamic nucleus (excitatory):excitatory signals to globus pallidus and substantia nigra reticulata to reinforce inhibition of the thalamus. - Substantia nigra - Compacta: provide dopaminergic input to the striatum which has excitatory and inhibitory effects. - Reticulata: sends GABAergic signals to the thalamus. - Input structures = striatum. Major inputs from cortex, thalamus and nigra.  Motor loops ▪ Body movement loop: primary motor, premotor, supplementary motor cortex ▪ Oculomotor loop: frontal eye field, supplementary eye field.  Non-motor loop ▪ Prefrontal loop: dorsolateral prefrontal cortex ▪ Limbic loop: anterior cingulate, orbital frontal cortex. - Output structures = globus pallidus interna, substantia nigra reticulata  Medium spiny neurons (MSNs): found in the putamen and caudate going to the globus pallidus and substantia nigra reticulata. These are predominantly GABAergic inhibitory neurons that have high-pass filtering (respond only to strong cortical inputs) and are hyperpolarized resting potentials ( Hyperpolarization makes it less likely for the neuron to fire an action potential, as the membrane potential is further from the threshold required for depolarization.) and voltage rectification (refers to the phenomenon where the current- voltage relationship (I-V curve) of a membrane or ion channel is non-linear, meaning the current passing through the membrane does not increase proportionally with the voltage applied). They also have spiny dendrites.  Diagram showing convergent inputs onto a medium spiny neuron from cortical neurons, dopaminergic cells of the substantia nigra, and local circuit neurons within the striatum. The arrangement of these synapses indicates that the response of the medium spiny neurons to their principal input, derived from the cerebral cortex, can be modulated by dopamine and the inputs of local circuit neurons. The primary output of the medium spiny cells is to neurons in the globus pallidus and substantia nigra pars reticulata. Microcircuitry of the Basal Ganglia o Medium Spiny Neurons (MSNs): ▪ Found in the striatum; they are inhibitory (GABAergic). ▪ Integrate inputs and send signals to GPi/GPe. ▪ Key feature: High-pass filtering (respond only to strong inputs). o Cholinergic Interneurons: ▪ Regulate local striatal circuits. o Other Interneurons: ▪ GABAergic subtypes (e.g., parvalbumin-positive fast-spiking neurons). Dopaminergic Modulation: o D1 Receptors (Direct pathway): excited by dopamine, Inhibits output structures substantia nigra reticulata and globus pallidus interna. o D2 Receptors (Indirect pathway): inhibited by dopamine. Indirectly excites output structures substantia nigra reticulata and globus pallidus interna. Direct Pathway (Facilitates Movement) 1. Cortex sends excitatory inputs to striatal MSNs. 2. Striatal MSNs inhibit GPi/SNr. 3. Reduced GPi/SNr activity disinhibits the thalamus.  4. Thalamus excites the motor cortex, facilitating movement initiation. Indirect Pathway (Suppresses Movement) 1. Cortex excites a different set of striatal MSNs. 2. These MSNs inhibit the GPe. 3. Reduced GPe activity excites the STN (via disinhibition). 4. STN excites GPi/SNr. Experimental support for the functional role of the direct an indirect pathways in motor control: - Electrical stimulation: to activate specific regions in the basal ganglia to observe changes in motor activity. This found that stimulating the direct pathway promotes movement by reducing inhibitory output from the GPi and SNr. Stimulating the indirect pathway suppresses movement by increasing inhibitory output from the GPi/SNr, further inhibiting the thalamus. - Optogenetic excitation: Optogenetics allows precise activation of specific neuronal populations using light-sensitive ion channels, this drives activity in basal ganglia circuitry.. Exciting D1 receptor-expressing MSNs (direct pathway neurons) increases motor activity, confirming its facilitatory role. Exciting D2 receptor-expressing MSNs (indirect pathway neurons) reduces motor activity, supporting its inhibitory role. - Optogenetic inhibition: Using optogenetics to inhibit specific pathways demonstrates their necessity in motor function. Inhibiting the direct pathway impairs movement initiation, as the thalamus remains excessively inhibited. Inhibiting the indirect pathway causes hyperactivity, leading to uncontrolled or exaggerated movements, as inhibition of the thalamus is insufficient. Experimental evidence shows that both pathways are concurrently activated during action initiation, contributing complementary roles to motor control. Here’s a detailed explanation: During action initiation, experiments using electrophysiology and optogenetics revealed that neurons in both the direct and indirect pathways show increased activity. Direct pathway MSNs (D1 receptor-expressing): Facilitate the selection and execution of the desired movement.  Indirect pathway MSNs (D2 receptor- expressing): Suppress competing motor actions to ensure the selected movement is refined and precise. Direct Pathway: Reduces GPi/SNr output. Disinhibits the thalamus to promote the desired motor command. Indirect Pathway: Temporarily suppresses the GPe, activating the STN, which increases inhibitory control of the GPi/SNr on competing motor signals. Prevents "noisy" or conflicting motor outputs. Integration of cortical input by the striatum leads to the activation of the direct and indirect pathways. With activation of the indirect pathway, neurons in a “surround” region of the internal segment of the globus pallidus are driven by excitatory inputs from the sub thalamic nucleus; this reinforces the suppression of a broad set of competing motor programs. Simultaneously, activation of the direct pathway leads to the focal inhibition of a more re stricted “center” cluster of neurons in the internal segment; this in turn results in the disinhibition (bottom arrow) of the VA/VL complex and the expression of the intended motor program. Movement disorders related to basal ganglia dysfunctions - Parkinson’s disease: loss of dopaminergic SNc neurons. Dopaminergic loss disrupts this balance: Underactive direct pathway → Reduced facilitation of movement. Overactive indirect pathway → Excessive suppression of movement. Symptoms: Bradykinesia: Slowness of movement due to reduced thalamic output. Rigidity: Increased muscle tone caused by overactive indirect pathway. Tremors: Resting tremors due to imbalances in oscillatory activity within basal ganglia- thalamocortical circuits. Postural Instability: Difficulty maintaining balance. - Huntington’s Disease: autosomal dominant disease that causes protein misfolding and neurodegeneration of indirect pathway MSNs. Chorea: Involuntary, irregular, and rapid movements due to thalamic hyperactivity. Dystonia: Sustained, abnormal muscle postures as basal ganglia degeneration progresses. Cortical control of movement Brodmann divided the cortex based of the microanatomy of cell types and their organization. Primary motor cortex and premotor areas in the human cerebral cortex: - Primary motor cortex (M1): anterior wall of central sulcus. In charged of voluntary movements, skill learning, in particular skilled hand / finger movements. - Supplementary motor area (SMA): medial surface of precentral gyrus. Internally generated movements, learning and performance of movement sequences. Bimanual coordination. - Dorsal premotor cortex (PMD): dorsolateral Surface of precentral gyrus. Visuo-motor integration, selection of movements based on sensory cues. Visuo-motor integration: reaching, targeting of movements in space and spatial structure of sequences. - Ventral premotor cortex (PMV): ventrolateral precentral gyrus. Involved in speech (Broca’s area). Mirror neurons, they fire during performance of an act and during observation of someone else performing the same act (function?). Descending pathways: - Corticobulbar tract: motor and sensory nuclei in the brainstream. Cranial nerves. Muscles face and nerve. - Ventral corticospinal tract: postural control, trunk movements. Uncrossed in medulla but bilateral terminations in spinal cord. Ventral white matter of upper spinal cord. - Lateral corticospinal tract: skilled, fine movements. Crosses in the medulla. Lateral white matter of entire spinal cord. M1 Extensive direct connections with motor neurons and interneurons in the spinal cord and the brainstem (low current stimulation evokes movements). The influence of single cortical upper neurons on muscle activity 1. Spike-Triggered Averaging: The method is used to correlate the activity of individual cortical motor neurons with muscle activation. It records the spikes of a single cortical motor neuron and observes their influence on muscle activation via an electromyograph (EMG). 2. Postspike Facilitation: The spikes from cortical neurons induce a consistent and time-locked increase in muscle activity. This facilitation occurs with a short, fixed latency and reflects the neuron’s direct influence on a specific muscle. 3. Importance of Upper Motor Neurons: These neurons in the primary motor cortex (M1) have extensive direct connections to spinal motor neurons and interneurons. The precise timing of their spikes enables them to encode fine motor control. M1 also has a topographic representation of the body. There is a coordinated movement of trunk and extremities (population coding of movement direction). It slso participates in learning a wide range of motor tasks. Premotor and supplementary motor areas. No detailed motor map. Indirect influence of motor through reciprocal connects to M1. Weak connections with motor neurons (need higher current to evoke motor behavior). Microsimulation evokes complex behaviors. Select movements appropriate to the context and goal of action. The cerebellum From the CNS, the cerebellum has 50% of the neurons. t plays a crucial role in several motor functions, including coordination, precision, and timing of movements. Beyond motor control, it contributes to cognitive functions, such as attention and language, as well as emotional regulation. The cerebellum excels in fast, precise processing, which is crucial for maintaining balance, posture, and coordinated movement. Its high density of neurons supports rapid signal transmission and feedback. It has 5 types of neurons (Purkinje cells, granule cells, basket cells, Golgi cells and stellate cells), a laminar organization (molecular, Purkinje cell and granular cell) and it is experimentally accessible. - Motor functions: voluntary movements, gait control, posture, speech. - Diseases: ataxia, dystonia, MS, tremor - Non-motor functions: cognition, emotions, sleep, visceral responses - Diseases: autism, dyslexia, schizophrenia, OCD, vertigo Purkinje cells are a type of neuron found in the cerebellar cortex, playing a critical role in motor coordination. They are distinguished by their large, flask-shaped cell bodies and an extensively branched dendritic tree, which allows them to receive a vast amount of synaptic input, primarily from parallel fibers and climbing fibers. Act as the sole output of the cerebellar cortex, sending inhibitory signals to the deep cerebellar nuclei via GABAergic neurotransmission. Each of this neurons receives 200k inputs primarily from parallel fibers and climbing fibers. This extensive connectivity allows the cerebellum to integrate vast amounts of sensory and motor information, ensuring precise modulation of motor commands. We also have - Granule cells: excitatory neurons creating parallel fibers - Basket and stellate cells: modulate Purkinje cell activity - Golgi cells: regulate granule cells via inhibitory feedback- - Vestibulocerebellum: Controls balance and eye movements. - Spinocerebellum: Regulates posture and gait by processing spinal inputs. - Cerebrocerebellum: Involved in planning and timing of complex movements, as well as cognitive functions. Somatotopy: The cerebellum contains an organized representation of the body, akin to a "map," where specific regions correspond to different body parts. Cerebellar output: The cerebellum communicates with the rest of the brain through three cerebellar peduncles. The cerebellar peduncles are bundles of nerve fibers that connect the cerebellum to the rest of the brain and spinal cord. They are the primary pathways for input and output to/from the cerebellum: 1. Superior Peduncle: Sends output to motor and cognitive areas. 2. Middle Peduncle: Receives input from the cortex via the pons. 3. Inferior Peduncle: Integrates sensory information and sends feedback to the spinal cord. - Spinocerebellum:  Fastigial nucleus: via inferior peduncle to the medial descending systems to motor execution. Vermis  Interposed: via superior peduncle to lateral descending systems for motor execution. In the medial part of cerebellar hemisphere. - Cerebrocerebellum   Dentate. In cerebrocerebellum, to motor planning. It communicates with the thalamus and motor/premotor cortex. - Vestibulocerebellum  Vestibular Nuclei: Function as part of the vestibulocerebellum’s output, regulating eye movements and maintaining equilibrium. Functions of cerebellum:  Balance and Posture Control: The cerebellum integrates input from the vestibular system to maintain equilibrium.  Voluntary Movements: By fine-tuning motor commands, the cerebellum ensures movements are smooth and purposeful.  Motor Learning: The cerebellum adjusts motor patterns through feedback, such as adapting to new environments or tools. Can cause LTD.  Cognition and Emotions: Its connections to prefrontal and limbic areas allow participation in tasks like decision-making and emotional regulation. Principles of cerebellum 1. Feedforward processing mechanism. The cerebellum predicts motor commands’ effects, allowing quick adjustments. 2. Extensive divergence and convergence. Signals are extensively processed through granule cells and Purkinje cells to generate accurate outputs. Few mossy fibers (~1 million) provide input to billions of granule cells. Granule cells (via parallel fibers) interact with Purkinje cells, condensing vast information streams into fewer outputs. 3. Modular organization. The cerebellum is divided into functional units or modules, each specialized for specific tasks. 4. Plasticity. The cerebellum adapts through structural and synaptic plasticity, crucial for learning new skills. Synaptic Plasticity: Long-term depression (LTD) occurs at Purkinje synapses, refining motor output by reducing the strength of certain connections.Structural Plasticity: The cerebellum can form new connections in response to learning or injury, showcasing its adaptability.