Motor behaviour is the manifestation of collaborative actions between the central and peripheral nervous systems, communicating with the striated and unstriated muscles via nerves to generate voluntary and involuntary motor outputs. In order to understand the pathophysiological changes after stroke, it is necessary to consider the inter/intra-cellular mechanisms involved in purposeful, or automatic generation of movements. Here, a brief overview of the action potentials, motor neurons, neural communication, constituents of muscle fibres, and the implication of external electrical stimulation of the peripheral nervous system in order to generate motor outputs, primes the reader for a better understanding of changes in motor behaviour due to pathological causes, and the differences between physiological and pathological motor behaviour.
Table of Contents
- Action Potentials Vs. Graded Potentials: electrical signals and ion movements
- Neurotransmitters and synaptic behaviour
- Motor neuron “the final common pathway”
- Electrical Stimulation of a Nerve and the Mechanism of Muscle Contraction : Going beyond the final common pathway
- Action Potentials Vs. Graded Potentials: electrical signals and ion movements
In basic cell physiology, the cell membrane regulates the movement of ions in or out of a cell. Whether via passive diffusion, leaky channels, or ATP-dependent sodium/potassium channels, these ions ( sodium, potassium, chloride, etc.) create a net electrical charge at the membrane level, making the intracellular (inside the cell or the cytoplasm) space more negative or polarized compare to the intercellular (outside the cell or between two individual cells) space at rest ¹. While most sources, report the measured membrane resting potential to be around -70mV, the movement of ions change the polarization of the membrane potential, and as a result, triggering and event 2 .
Although there are multiple specialized channels, responding to different local changes ( e.g. mechanically and thermally gated channels), it is the electrical and chemical gradients of these ions, that at a larger scheme, will lead to changes in membrane potentials, causing excitatory or inhibitory outcomes due to the initial triggering events 3.
Figure 1: Membrane potential determines the net charges in intracellular space (cytoplasm) and the extracellular space. Positive and negative ions maintain the balance between charges (picture credit: wikipedia).
These changes in cellular polarity require a system that delivers these signals to other cells and parts of the body. Therefore, in order to provide a means for communication between neighbouring cells, graded and action potentials have evolved as the two main mechanisms controlling signal transduction and propagation between the central nervous system (CNS), peripheral nervous system (PNS) and the effector cells and organs.
In each neural cell, graded potentials (GPs), are the changes in membrane potentials, mainly due to triggering events with varying magnitudes and durations. GPs rely heavily on chemically and mechanically gated channels (voltage gated channels are not usually involved), and generate stronger responses, when encountering stronger (higher amplitude) triggering events 4. Decremental conduction is a hallmark of GPs, meaning that the magnitude of signals decrease as the distance from the initial active site increases 5. Individual GPs could be summed together, generate a higher stimulation, and as a result depolarize or polarize membranes.
Action potentials (ACs) on the other hand, are all-or-none membrane responses, coded mainly in frequency rather than amplitude. The duration of ACs are constant (as opposed to GPs with varying durations), and unlike GPs, ACs are self-perpetuating and have a refractory period. Refractory period or one way propagation of signals is an important feature of neural communication, that ensures an action potential can only be propagated in the forward direction along the axon, preventing the second stimulus to trigger an action potential before the membrane returns to its resting potential 6. This mechanism avoids interference in signal transduction and helps with an orderly transduction of neural signals. ACs are always propagated in an undiminishing fashion and can only depolarize when the threshold potential (about -50 mV) through the spread of GPs is reached. ACs occur almost exclusively in the regions of the membrane with abundance of voltage-gated sodium (Na+) channels 7.
In stroke, due to lack of oxygen, apoptosis or sometimes inflammation, neural cells that once were programmed to generate these signals die, or the the disturbances in connections between them (dendrites and axons) leaving the affected neurons dysfunctional, causing paresis or paralysis in the effector organs.
Figure 2: Graded potentials (Picture credit: BC open textbooks, 12.4 The Action Potential – Anatomy and Physiology).
Figure 3: Action potentials (Picture credit: BC open textbooks, 12.4 The Action Potential – Anatomy and Physiology).
2. Neurotransmitters and synaptic behaviour
In the late 19th century, it was Santiago Ramón y Cajal who proposed that neurons are not continuous, and in fact are barely touching each other via synapses 8 (Figure 4). The synaptic cleft, is the space between two neurons, where presynaptic neurons release their neurotransmitters and the post synaptic neurons receive these endogenous chemical messengers via specific receptors and a response is made accordingly. Although, synapses have both excitatory and inhibitory characteristics, neurotransmitters and their availability in the synaptic cleft play an important role in the outcome of signal transduction, and the generated response.
Figure 4: Activation of neighbouring neurons via neurotransmitter exchange in synaptic cleft (Photo credit: Khan Academy).
There are over 60 different types of neurotransmitters discovered so far, but the major neurotransmitters and their simplified functions are listed in figure 5. These neurotransmitters, coming from a presynaptic neuron, determine the generated response in the postsynaptic neurons. For instance ethanol (drinking alcohol) has been shown to activate the gamma-aminobutyric acid (GABA) receptors, a primary inhibitory neurotransmitter in the mammalian CNS, depressing excitation in certain regions of the CNS 9. Beer goggles, poor reaction time, and blackouts are usually awarded to the intoxicated individuals for the very same reason.
One of the most important neurotransmitter involved in both cognitive and motor processes is acetylecholine (ACh). In the CNS, ACh plays an important role in cognition (decreased ACh receptors in the CNS is observed in Alzheimer’s disease) 10. In the PNS, and in neuromuscular junctions, a chemical synapse formed between a motor neuron and a muscle fibre, ACh excites muscle fibres and promotes muscle contractions. for example Botulinum toxin, a neurotoxin protein produced by the bacterium Clostridium botulinum found in contaminated soil or canned food, blocks the release of ACh from the motor neurons (terminal buttons to be exact) in the neuromuscular junction (figure 6), blocking muscle contractions 11. This is one of the most lethal neurotoxins and even 0.0001 mg of it could be lethal. Interestingly, using the same principle, BOTOX (contains way less than the lethal dose) can generate focal paralysis or relaxation of muscle fibres. That is the main reason BOTOX is used for cosmetic purposes or to treat focal limb plasticity in stroke or other traumatic brain injury cases.
Figure 6: Actions potentials in the CNS activate the release of ACh in the neuromuscular junction contracting muscle fibres (photo credit: BC Open Textbook).
It is important to note that neurotransmitters are not the only messengers in the synaptic junction. Neuropeptides, are another type of neuromodulators that do not cause instant inhibitory, or excitatory changes in the post synaptic neurons, but rather bring about long-term changes, and thus fine-tune the synaptic response. This mechanism is involved in the process of learning and carry over after repetitive exposure or training. Although these neuromodulators play an important role in post-stroke rehabilitation and the carry over effects of neurorehabilitation, their role will be discussed in future posts.
3. Motor neuron “the final common pathway”
Nerves and muscles are considered excitable tissues because, when excited, they change their resting potential in order to produce electrical signals. The excitation required to activate the resting potential in nerves and to mobilize muscle groups originates from the motor cortices ( and the premotor and supplementary motor areas), from the neuronal cell bodies called the pyramidal cells to be precise, coordinated via the basal ganglia, cerebellum, and the thalamus (using the received sensory input from the periphery as feedback via interneurons), sending their fibres uninterrupted (continuous axons) to the motor neurons located in the brain stem and the spinal cord 12. Note that cross-wiring occurs at the level of medulla in the brainstem region, meaning the pyramidal or corticospinal fibres of one hemisphere cross-wires to the opposite side at the level of medulla oblongata, hence the contralateral hemispheric control of the body 13.
The motor neurons in the spinal cord are considered “the final common pathway” because the motor neurons by which nerve impulses from many central sources such as the motor areas pass to a muscle or gland ends at this level. In other words, a purposeful and conscious generation of movement or activation of a gland could only be achieved if sufficient stimulation brings about action potentials in the CNS, which in turn activates the effector cells or glands.
In stroke, all the fibres in the brainstem, spinal cord, and the periphery remain intact (in the absence of other injuries and pathologies) , but the initial burst of actions potentials that were once generated in the cortical and subcortical motor areas are impaired.
4. Electrical Stimulation of a Nerve and the Physiology of contraction : Going beyond the final common pathway
Galvani in 1780 discovered that the muscles of a dead frog’s legs twitched when struck by an electrical spark. This was the first experimental evidence that movement and muscle contractions could be achieved well beyond the properties of motor neurons as the final common pathway 14. Before moving on to the electrical stimulation of muscle groups, it is important to understand the concept of a motor unit. As shown in figure 7, a motor unit comprises a motor neuron and a number of muscle fibres it innervates, it is known that the greater the number of fibres recruited to contract, the greater the total muscle tension. Therefore, larger muscles have a tendency to generate a larger force and muscle tension in comparison to the smaller muscles with fewer fibres 15.
Figure 7: Motor Unit (photo credit: unknown, google images).
Figure 8: Constituents of muscle and the contractile units: Note that the sarcomere is the functional unit of skeletal muscles located in the myofibril consists of an A-band plus half an I-band. An I-bnad consists of the area between thick filaments (myosin) where only thin filaments (actin) exist. And an A-band is the area where myosin (thick filaments) are and may include regions with overlapping actin (thin filaments). (photo credit: Copyright© 2009 Pearson Education INC.).
As explained above, stimulation of a muscle fibre does not itself lead to movement, it is the stimulation of a specific nerve innervating a specific group of muscle fibres that signals contraction. Using a neuromuscular electrical stimulator (NMES) device, electrical currents can trigger the flow of ions against their gradients, depolarizing the nerve. Just like an action potential reaching from the motor neuron to the effector organ, at the level of motor endplate, this excitation activates the sarcoplasmic reticulum, and as a result calcium ions (Ca 2+ ) yield the cross-bridge between the actin and myosin filaments (the contractile units) as seen in figure 6 16. As a side note, and as shown in figure 9, it is important to note that there is a latent period of ~1-2 msec between the propagation of action potentials, and the muscle stimulation, and it takes about 50 msec by the time a contractile response is at its peak. This is one of the principles used in functional MRI and motor imagery studies in neuroscience laboratories.
Figure 9: Action potentials and muscle contraction (photo credit: Copyright© 2009 Pearson Education INC.)
In neurorehabilitation settings, this mechanism allows clinicians to induce movement in paretic limbs, optimizing muscle re-learning, reduce spasticity and delay or reverse muscle atrophy. Although NMES has proven to be a valuable tool most clinicians hesitate to incorporate it in the treatment plan, mainly due to its complexity.
Other limitations and contraindications of NMES also complicates its utilization. For example stroke patients often have other cardiovascular morbidities such as cardiac arrhythmia, and pacemaker/defibrillator implants (especially in patients with a history of cardioembolic strokes) . Also, the cognitive status of the patient plays an important role in movement re-education, because patient need to develop a basic understanding of sequencing and synchrony involved in movements and underlying muscles while NMES acts as a feedback mechanism (But in both cases the right candidate could be chosen after a thorough history and physical).
You can watch some of the NMES demonstration videos on StrokeSciences channel on YouTube: https://www.youtube.com/channel/UC_nTclnzJN0CV2pXXiBTX7g?view_as=subscriber