Our Wired Nerves: The Human Nerve Connectome

By Douglas W Zochodne

The nervous system is a complex, sophisticated system that regulates and coordinates body activities. It is made up of two major divisions: the central nervous system consisting of the brain and spinal cord and the peripheral nervous system. This consists of all other neural elements, including the peripheral nerves and the autonomic nerves. Peripheral nerves are the essential connections between the brain and spinal cord and the body. Without nerves there is no movement or sensation. Our Wired Nerves: The Human Nerve Connectome, reviews the essential anatomy and physiology of the peripheral nerve. It introduces the reader to what neuropathies are, how pain arises from damaged nerves and how nerves might be regenerated, including new and exciting ideas over how to coax their regrowth. Written by Dr. Douglas Zochodne leading expert in the field, and first book to focus on the Peripheral nerves it will surely be an essential reference for researchers and clinicians alike.

• Discusses the barriers to nerve regrowth and new strategies to reverse them
• Reviews of disorders of the peripheral nerves
• Exams reasons for nerve injuries
• Reviews recent discoveries in nerve research

• Language: English
• Publisher: Academic Press
• Release date: Jul 25, 2020
• ISBN: 9780128214886

Douglas W Zochodne

Dr. Douglas Zochodne is a Neurologist and Neuroscientist, Director of the Neuroscience and Mental Health Institute, and Past Divisional Director of Neurology at the University of Alberta (UofA). Dr. Zochodne’s career has included faculty positions at Queen’s University, Canada, the University of Calgary and more recently the University of Alberta. Dr. Zochodne’s roles have included Editor-in-Chief of the Canadian Journal of Neurological Sciences, and President of the Peripheral Nerve Society. He is a Fellow of the Canadian Academy of Health Sciences and his book “Our Wired Nerves: The Human Nerve Connectome” was published in 2020. He has devoted his career toward understanding the biology and diseases of the peripheral nervous system.

Book preview

Introduction

It is possible you have never heard of the peripheral nervous system. Although it is also called the PNS for short, that does not help much. When thinking of the nervous system, there of course is the brain and with it there is thought, control and action. The brain is often described as the central player, the director and master of all human activity. The brain is connected to the spinal cord, allowing commands and inputs to travel outward from the control center. Beyond the spinal cord and the CNS, however, how the house is wired is often not considered. This is the forgotten part of the nervous system and the topic of this book.

Here we describe the story around nerves, the neglected but critical links between the brain and the body. The proper scientific terminology for nerves is the peripheral nervous system (PNS). The PNS has three main tasks, using three types of nerves. Motor nerves connect to muscles and allow us to move. Sensory nerves are connections to skin and the body that allow us to feel. Dr. Marilène Oliver’s image conveys the extensive outreach offered by our sensory nerves to our surroundings (cover image, Fig. 1). Autonomic nerves automatically keep us functioning without our having to think. The beauty of nerves is how they act as highways of communication. They share similar but very unique and well designed biology that allows them to transmit their messages. Yet when nerves fail, it can be catastrophic. Damage to nerves is called neuropathy, or polyneuropathy if many nerves are involved. However, neuropathies may be the most common problem you have never heard of. For good reason, most of us routinely learn about other kinds of neurological problems like stroke or dementia. How about Guillain-Barré polyneuropathy or amyloid neuropathy? Yet Guillain-Barré polyneuropathy is a dramatic condition involving complete paralysis over just a few days in an otherwise healthy person. Recovery can occur but it might take months. Imagine what this might do to your life. Amyloid neuropathy is a relentlessly progressive problem that causes pain, loss of sensation and enormous disability. The first person I ever met with this problem had lost both large toes and several fingers to the condition. These conditions are most definitely below the radar.

Fig. 1

Fig. 1 Shredded by Marilène Oliver, Faculty of Arts, University of Alberta (Reproduced by permission). Oliver reported that the inspiration of the piece arose from a sense of self that followed her learning of the tragic death of a friend. The image conveys the connection between the physical body and its external environment, conveyed by sensory nerve fibers that transmit it (original is laser cut acrylic, MR scans printed on film, fishing wire and crimps. 175 × 50 × 50cm).

The body brain connection: A fully infiltrated body

Nerves are the essential connections between the CNS (the brain and spinal cord) and the body. They represent the brain body connection and can be thought of as an ome. Like the genome that includes all of our genetic output, the proteonome that includes all of our proteins, the metabolome that constitutes all of our metabolic products, the PNS is a connectome. Connectomes have also been coined to describe connections within the brain, not our meaning here. In our context, the PNS connectome links the CNS with skin, bones and organs like the gastrointestinal tract, liver, heart and lungs. All of our sensations are coded and transmitted to and from the CNS by peripheral nerves, here called nerves. The only exceptions are the optic nerves for vision and they are instead considered part of the CNS; in reality they are extensions of the brain to the eyes. However, peripheral nerves are different. Wiring diagrams that illustrate the major nerves, as in Fig. 2, vastly underestimate their wide distribution. Nerve endings are microscopic connections that permeate virtually every tissue of the body. For perspective, have a look at a magnified image of the external ear of a mouse, with axons labeled by a fluorescent marker (Fig. 3A). The branches are extensive! In the skin, they are only separated by a few microns. A micron is one thousandth of a millimeter in length! For yet greater perspective, examine the fine nerve endings of the epidermis of the skin taken from a human volunteer (Fig. 3B). Finally, the work of Belle, Chédotal and colleagues, that labels individual nerves and branches of the human fetal hand, offers a spectacular appreciation of nerve development using state of the art imaging techniques (Fig. 4).¹

Fig. 2

Fig. 2 A simplified depiction of major nerve trunks in the human body (green). This image does not capture the complexity of fine detailed innervation of the skin or organs innervated by individual axons.

Fig. 3

Fig. 3 (A) Nerve fibers in the pinna (external portion) of the ear of a mouse engineered to express a fluorescent protein (thy1-YFP) in its peripheral nerves. The fine meshwork of branching sensory axons (arrowhead) extends out to the edge of the ear visible through the skin and hairs. The edge of the pinna is to the upper right (Image taken by Virginia Woo, Zochodne laboratory). (B) A section of human skin from the lower limb of a normal subject from a small punch biopsy. The image depicts the layers of the skin with keratinocytes (skin cells) having blue nuclei in the epidermis and fine green fluorescent epidermal axons (arrows) labeled using immunohistochemistry to a nerve protein called PGP9.5. The lower left is the deeper dermis showing a bundle of nerve fibers that supply the branches to the epidermis. (Image take by Dr. Jesi Bautista, Zochodne laboratory.)

Fig. 4

Fig. 4 Images of developing nerves in the human fetal hand from gestation weeks (GW) 7-11. The images were created from solvent cleared (renders the hand transparent) tissues. The images show radial (blue), median (pink) and ulnar (green) labeled nerves, as they grow into future digits (fingers). The arrows point to a small branch (black) of the musculocutaneous nerve, transiently entering the hand (not found in the adult hand). To label the nerves, the authors used immunohistochemistry directed to a nerve protein called peripherin and performed reconstruction of the pathways of the nerve in 3D. For further details including spectacular images and videos please refer to Belle et al. (Cell 169: 161-173, 2017). ¹ (The images were reproduced with the kind permission of the senior, corresponding author Dr. Alain Chédotal.)

Hence, a map of the human body, based solely on where all of our axons and nerves reside, would outline our external contours and organs very well! It would also be surprising. There are some empty areas. For example, large areas in the brain and liver are surrounded by nerves but not penetrated by nerves. Thus we cannot feel ourselves thinking about something. We cannot feel strokes or bleeding developing in the brain, unless the covering of the brain, known as the meninges, is stretched. We might recognize that a stroke is occurring because of a change in speech or paralysis but the only sensation triggered may simply be a headache. Rises in intracranial pressure, or pressure within the skull, cause headache not because of their damage in the brain but because of meningeal stretch. Our nerves do spread or ramify through the meninges and surround its blood vessels. These nerves are peripheral despite their location within the skull and in the meninges but they do not enter the brain. Instead, the brain itself is composed of CNS neurons and their connections oversee our thought processes. Similarly, nerves do not infiltrate the liver but are found in the capsule covering the liver. Thus, when a person has a needle biopsy of their liver, pain arises as the needle passes through and irritates these surrounding capsule nerves. How did organisms decide where or where not to send nerve terminals? This is a good question, but we can only guess at why we want nerves in some places but not others.

Ignoring the spaces that lack nerves, with their degree of infiltration, nerves are among the most common structures in the body. However, despite their abundance, we know less than we might. How do nerves decide exactly where to locate? Is it by chance or is there a system of rewards and punishments that will determine where they grow? Rewards are sometimes called attractant cues by biologists because they encourage nerve fibers to come hither. Punishments, in contrast, are called repulsive cues because they tell the fibers to go away. Think of attractive and repulsive foods or situations and you will understand. Future research about nerves may eventually answer these fascinating questions. Another question is whether nerves are fixed and immobile like concrete highways or constantly growing and remodeling like hiking pathways? You may be surprised to know that they are actually highly plastic and mobile! Perhaps then nerves are more like hiking pathways! This is likely true for the fine endings of nerves. However, large nerve trunks like the sciatic nerve in the leg or median nerve in the arm are more fixed in the body. These large nerves are more like interstate or provincial main thoroughfares. Have you driven on Highway 401 in Ontario, a large freeway that connects Toronto, Montreal and Windsor? Think of the sciatic nerve being its counterpart in the leg connecting the spinal cord to the leg and foot. Of course, my argument is that the nerve is a far more interesting place to travel than this famous but somewhat tedious Ontario freeway.

The nerve-immune system explores how peripheral nerves and immune cells work together. A number of ideas, only some proven, around this relationship abound. For example, nerve endings, or terminals, can release molecules from their endings. These in turn can activate or signal immune cells. The immune cells, in turn, can release further molecules that either worsen or dampen inflammation. Given a pathway from the brain through nerves to the immune system, it’s possible that the immune system could be instructed. The brain might signal immune cells and direct their responses. It is an interesting connection that has had plenty of attention.

Some of the ideas around the brain immune connection are unproven and others remain controversial. For example, it’s thought by some that special signals through nerves from the brain might alter your level of immunity. An example is depression, and the idea is that a change in brain function might lower your immune function. While there is some evidence for this, there are also instances where autoimmune disorders involving an overactive immune system are instead activated by depression. Another example might be the idea that positive thinking, transmitted through your nerves, might prevent or suppress cancer. This idea is without much support. Unfortunately, this popular idea nonetheless can make persons with cancer feel guilty that they have failed to think positively enough. Like all of science, there are good ideas out there. Some ideas center on unexpected relationships within our complex connectome. However, some ideas should be shelved until there is solid science behind them. What we do know is that a fully integrated system of nerves neighbor virtually all other cells of the body. This does imply that nerve and body health are closely related.

What does it take to activate nerves? Under normal conditions, without thinking about your body, nerves are active. How do we know this? A procedure known as neurography allows investigators to record ongoing nerve discharges with fine wires in nerves. What neurography tells us is that resting discharges are common in nerves, but there are fewer discharges in a normal resting nerve than if they are signaling something terrible, like pain from a serious injury. What we also know is that the brain has an important role in filtering this ongoing flood of information from nerves throughout the body. Only the most intense, localized and persistent information reaches awareness. This is obviously very helpful for allowing us to focus on our tasks at hand without annoying and ongoing distractions. Most of the time we are unaware of isolated and transient nerve discharges. They are minor blips in a universe of noise. However, when such discharges arise from a number of adjacent nerves together, suddenly they might be important. The signal rises above the level of ongoing noise. For example, many of us rarely pay attention to how many parts of our body send us discharges at any given time. Our bodies change constantly and these changes are continuously detected and signaled by nerves. These might include simple actions like sitting, standing or walking. Being aware of every nerve discharge that erupts because of our posture or stance would overrun our brain with noise! Filtering is important! This is not simply a matter of attention. Attention requires active engagement of the cortex of the brain and determines what we choose to focus on.

The purpose of this book is to raise much-needed awareness. However, it is also about much more than awareness. There is a beauty in the structure and function in nerves that is worth fully appreciating. After some terminology, some anatomy and some physiology, its splendor unfolds. Not only is the operation of the PNS elegant under normal circumstances, but its behavior during disease is fascinating and how it regenerates is exquisite. It may be that the reader is planning a career in health sciences or has an acquaintance pursuing this goal. Others may have had to deal with neuropathies themselves or in family members. Yet others I hope to convince are simply interested in unique biology, called here peripheral neurobiology.

References

1 Belle M., Godefroy D., Couly G., et al. Tridimensional visualization and analysis of early human development. Cell. 2017;169:161–173.

Chapter 1: Elegant wiring: Structural beauty of the peripheral nervous system

Abstract

Nerve connections, or axons, pervade the body and define its complex folds and structure. Axons of the peripheral nervous system (PNS) are distinct from those of the brain and spinal cord (CNS) and they associate with almost all other cell types. Understanding the structure and beauty of our nerve communication highways requires immersion into a fascinating anatomy. Axons partner with the Schwann cell named after Theodor Schwann, remarkable cells that offer guidance, communication and support. Moreover this partnership involves varying types of nerves: motor, sensory and autonomic axons of varying structure, size and connection. Without nerves there is no movement or sensation and their fine and delicate anatomical features, when disrupted, define very unique disorders.

Keywords

Peripheral nervous system; Nerves; Axons; Schwann cells; Nodes of Ranvier; Neuromuscular junction; Dorsal root ganglia; Motor axons; Sensory axons; Autonomic axons

How are nerves structured?

Nerve fibers mingle among the cells of almost every tissue in the body. They are more widespread than blood vessels. When a tissue has its normal and expected group of axons, it is invested with axons or innervated. Tissues that lose their nerve supply are denervated. There are some surprising exceptions, as seen in the brain and liver. Of course, the scalp and skull are also innervated, explaining why it is uncomfortable to bang or injure your head. Damage to the liver does not usually cause pain unless the innervated liver capsule is stretched or irritated. If you drink significant quantities of alcohol you may not be aware that your liver is undergoing damage because you do not feel it. Perhaps if you could, alcoholism would no longer exist as a public health problem!

The nerve trunks, also just called the nerves, are specialized superhighways for axons that transmit signals. Nerve trunks contain hundreds to thousands of individual axons, our wiring, along with supporting cells, blood vessels, and proteins that add structure and strength. Each nerve contains fascicles, the contents of which are called the endoneurium, compartments that house axons (inside the nerve).² Certain large nerves may have 20 fascicles, others 1–2, and these may identify groups of axons with specific destinations in some nerves, like the large sciatic nerve in the upper thigh. The axons in each fascicle are also diverse, with admixed motor, sensory and autonomic types that sometimes change fascicles as they move toward their target destinations. Some further definitions will help (Fig. 5). The perineurium (around the nerve) is a layer of interwoven cells that surround the all-important endoneurial fascicles. They offer protection of axons from the elements by erecting a blood nerve barrier, preventing free access of blood or other body fluids to the endoneurium. Many nerve disorders involve breakdown of this important barrier, allowing vulnerability of axons to inflammation and other issues. The epineurium (on top of the nerve) links and surrounds all of the fascicles binding them into a cohesive structure or nerve trunk with connective tissue. It includes collagen, an important supporting protein, and arterioles and venules that ultimately supply blood to the endoneurial compartment. These blood vessels are called vasa nervorum, supplying blood to nerves that mingles through the epineurium in complicated arrangements (a vascular plexus), sending feeding vessels into the fascicles. Most of the blood vessels within the endoneurial fascicles are capillaries, also tightly constructed to add to the blood nerve barrier. In some nerve disorders, this vascular supply is targeted by disease. An interesting twist on this story is that nerve trunks, the highways of axons that travel from the spinal cord throughout the body, are self innervated. In other words, they are invested with small axons of their own. This will be described in more detail later. The overall structure of nerve trunks is maintained through much of their travels in the body until they reach target tissues, or connect to the nerve roots and spinal