Imaging of neural contributions to voluntary hand movement
Skilled motor behavior requires the precise exchange of information between the muscles of the body and various levels of the central nervous system (CNS). Motor behavior, limb mechanics and neural control must be precisely coordinated in order to achieve the required movement1.
Despite the array of complex interactions involved, movements are typically smooth and flowing. For example, when the hand reaches out for an object, the hand follows a fairly straight path and hand velocity follows a smooth, bell-shaped profile.
Although the nerves serving the arm and hand are well defined and well studied, the split between sensory neural input and motor neural input in volitional upper limb movement has not been determined.
It is known that a complex interplay of sensory and motor information is involved in the achievement of smooth and precise hand movements. This has been highlighted in patients with a range of CNS injuries. For example, patients with damaged sensory pathways but intact motor neural pathways present with a complete inability to move without simultaneous visual feedback2.
Skilled motor behavior is controlled by widely distributed control circuits with the CNS. Motor control involves the spinal cord, brainstem and cerebral cortex. These are connected to other organs of the body and the limbs by the peripheral nervous system.
Nerves of the peripheral nervous system extend from CNS so that the brain and spinal cord can send information to and receive signals from other areas of the body, enabling reaction to stimuli. The peripheral motor system converts signals from the peripheral nervous system into specific muscle activity that leads to movement.
The nerves that make up the peripheral nervous system are actually the axons or bundles of axons from neuron cells. The principal components of peripheral nerves are afferent and efferent somatic axons3.
The afferent axons convey sensory feedback from the skin and proprioceptive feedback from muscles and joints, whereas efferent axons transmit the signals for muscle activation. Although afferent and efferent somatic axons are anatomically separate within the spinal cord, they merge on forming the spinal nerve.
The peripheral nerves that enable dexterous control of the arm and hand are contained within the brachial plexus. The majority are a mixture of sensory and motor neurons. Information travels along the axons of the brachial plexus in both directions to ensure precision of movement.
Quantification of nerve activation
Although the anatomical course of the axons comprising the brachial plexus is well defined, little is known about the actual quantity and distribution of sensory axons and motor axons4. In particular, it is unclear how many motor neurons are involved in the control of muscle activity and whether this is reflected in the accuracy of muscle control that can be achieved.
This gap in knowledge has arisen largely as a result of the availability of techniques enabling quantification of motor and sensory contributions to peripheral nerves. Such evaluations have been hindered by the fact that alpha motor neurons and type I afferent fibers are not distinguishable by histomorphometric analysis alone.
Although this was overcome by selective denervation in animal models, human data remained elusive. Efferent and afferent axons can be differentiated by differences in the levels of acetylcholinesterase activity, but this does not distinguish between motor and sensory neurons5.
The enzyme choline acetyltransferase (ChAT), however, is exclusively expressed in efferent neurons so motor neurons can be visualized using a monoclonal anti-ChAT antibody6. Most recently, a polyclonal anti-ChAT antibody has been developed that selectively labels motor axons at peripheral nerve level7. This enables motor neurons to be visualized even when only a low concentration of ChAT is being expressed.
Study of neurons involved in human arm movement
A quantitative analysis of the axonal components of the human upper limb nerves was conducted using ChAT and neurofilament (NF) immunofluorescence7. The labeled polyclonal anti-ChAT antibody bound to highly specific molecular features from spinal cord level to the terminal nerves at wrist level.
Transverse sections of whole nerve taken from nine human heart-beating organ donors were imaged using the TissueGnostics TissueFAXS™ fully integrated imaging system. The total number of NF-positive and double-positive axons (NF and ChAT) were automatically quantified using StrataQuest™ and TissueQuest™ software, incorporating seamless processing of whole-slide images in an optimized way.
Using a custom adjusted profile, the software marked the axons and calculated the statistical results using predefined criteria. The NF label was used as a reference, and only ChAT-positive axons with an overlap with the reference were considered positive.
To ensure a high reliability of the study, all automatically found positive results were visualized as an encircled event. Manual correction was available to allow for finetuning, and yield to software accuracy was independently checked and verified, with a minimal <1% deviation.
The findings revealed that only around 10% of the axons emerging from the spinal cord to innervate the human upper limb are motor neurons7. In all the samples studied, sensory axons outnumbered motor axons by a ratio of at least 9:1. The contribution of sensory axons increased towards the hand, whereas only 1,700 motor axons were found to innervate the intrinsic musculature of the hand.
This is the first time that the quantity and proportion of sensory and motor axons has been described along the entire brachial plexus and its branches. The latest study has revealed that an unexpectedly low number of motor neurons are involved in upper limb motor execution and the dexterous coordination of hand movement. In contrast, there is a large convergence of afferent input from the hand for feedback control.
It thus appears that greater movement complexity, such as fine motor control, does not require an elevated number of efferent axons. In contrast, the findings indicate that more complex control problems require a relatively greater input from sensory axons.
The authors postulate that the most likely central motor strategy for coping with complex control challenges, such as hand dexterity, is the grouping of motor neurons to achieve synchronous activity in several independent groups rather than increasing the number of efferent axons.
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2. Cole JD, Sedgwick EM. J Physiol 1992;449:503–515.
3. Brushart TM. Nerve repair. New York, NY: Oxford University Press, 2011.
4. Farina D, et al. J Physiol 2014;592:3427–3441.
5. Gruber H, Zenker W. Brain Res 1973;51:207–214.
6. Zimmermann L, et al. J Neurosci 2013;33:2784–2793.
7. Gesslbauer B, et al. Ann Neurol 2017;82:396–408.