History of neuroscience: John Hughlings Jackson

In 1860, when John Hughlings Jackson was just beginning his career as a physician, neurology did not yet exist as a medical specialty. In fact, at that time there had been little attention paid to developing a standard approach to treating patients with neurological disease. Such an approach was one of Jackson's greatest contributions to neuroscience. He advocated for examining each patient individually in an attempt to identify the biological underpinnings of neurological disorders. This examination, Jackson asserted, should be guided by the tenets of localization of function, which had been popularized by Franz Joseph Gall in the decades before Jackson was born. Concordant with these tenets, Jackson believed that neurological dysfunction could be traced back to dysfunction in specific foci of the nervous system, and the ability to identify the part of the nervous system that was affected to produce a disease was critical for making an accurate diagnosis.

Jackson's perspective on understanding neurological diseases is exemplified by his efforts to elucidate the neurobiological origins of epilepsy---the work he is probably best known for. Jackson's observations on epilepsy date back to the very beginning of his medical career. At that time, the most popular explanation for epileptic seizures was that they were associated with abnormal function in a region of the brain known as the corpus striatum, a term that refers to a composite structure consisting of the striatum and the globus pallidus. The corpus striatum was known to be involved with motor functions, which caused it to be implicated in epileptic seizures as well.

Jackson, however, began to suspect that the cerebral cortex participated in creating the convulsions that epileptics suffered from during seizures. To support this hypothesis, he cited cases where patients experienced convulsions that primarily struck one side of the body. Very often, Jackson argued, these patients upon autopsy would display damage to the cerebral hemisphere on the opposite side of the body that was affected by seizures.

Watch this 2-Minute Neuroscience video to learn more about epilepsy.

Jackson approached the idea that there were certain areas of the cortex devoted to movement with hesitancy for multiple reasons. First, at the time the prevailing view was still that the cortex was unexcitable, and thus would be unlikely to be affected by what Jackson considered to be a disease of increased excitability. Additionally, it was still common in Jackson's time to consider the cortex to be homogenous. Although the concept of localization of function was challenging this idea, many still held the belief that all gray matter in the cortex was equivalent and there were no areas of functional specialization. According to this view, the entire mass of the cortex had to act together to produce some sort of response. Jackson's idea that seizures could be linked to increased excitability in one half of the cortex did not conform to this perspective.

In addition to his observations about the link between hemispheric damage and seizures on the other side of the body, Jackson also noted a unique feature of some of the seizures he observed. He pointed out that in certain patients convulsions started in one specific area of the body and then proceeded to travel outward from that area in a predictable fashion. For example, convulsions might begin in the hand and then move up the arm to the face, and then down the same leg on the same side of the body. Or they might start in the foot and travel up the leg, then down the arm and into the hand on the same side of the body.

This process, later called the Jacksonian march, would help Jackson to formulate some of his most important ideas about the brain. He hypothesized that there were areas of the cortex that were devoted to controlling the movement of different parts of the body. When excitation spreads throughout the cortex, Jackson posited, it stimulates these different areas one by one, creating the Jacksonian march of convulsions through the patient's body. Furthermore, Jackson suggested that the parts of the body that were capable of the most diverse movements (e.g. hand, face, foot) likely had the most space in the cortex devoted to them.

With his observations on epilepsy Jackson was essentially predicting the existence of the motor cortex as well as anticipating the functional arrangement of the gray matter that the motor cortex is made up of. His hypothesis that there was a distinct region of the cerebral cortex devoted to motor function was confirmed in 1870 when Gustav Fritsch and Eduard Hitzig provided experimental evidence of a motor cortex in dogs. The arrangement Jackson envisioned, where one part of the cortex is devoted to one part of the body, we now call somatotopic arrangement. It has been verified by a series of experiments, capped by Wilder Penfield's electrical stimulation studies of the 1930s. It is now common neuroscience knowledge that there are regions of the motor cortex that seem to be devoted specifically to movement of the hands, other regions devoted to the movement of the face, and so on. As Jackson predicted, areas of the body that are involved in more diverse movements generally have more cortical area devoted to them.

Jackson's clinical observations of epilepsy and his hypotheses about the motor regions in the cortex accurately predicted what would soon be discovered through experimentation, and acted as a guide for researchers like Fritsch and Hitzig. Thus, Jackson's work contributed significantly to a better understanding of the organization of the cortex, a region that we now consider to be functionally diverse and intricately arranged---a far cry from the idea of cortical homogeneity common in Jackson's time. Additionally, Jackson's development of a more formalized methodology of observation in neurology has caused him to be considered one of the founding fathers of the field.

Jackson's contributions to neuroscience, however, were much more extensive than there is room to cover here. He wrote copiously on diverse topics ranging from the evolution of the nervous system to aphasia. At a time when our understanding of the brain was still so lacking in comparison to today, Jackson had a brilliant mind that seemed capable of comprehending brain function in a way that has rarely been replicated in the history of neuroscience.

Finger, S. Origins of Neuroscience. New York, NY: Oxford University Press; 1994.

York GK, Steinberg DA (2007). An Introduction to the Life and Work of John Hughlings Jackson. Med Hist Suppl. (26), 3-34

2-Minute Neuroscience: Long-Term Potentiation (LTP)

Long-term potentiation, or LTP, is a process by which synaptic connections between neurons become stronger with frequent activation. LTP is thought to be a way in which the brain changes in response to experience, and thus may be an mechanism underlying learning and memory. In this video, I discuss one type of LTP: NMDA-receptor dependent LTP. I outline the mechanism underlying NMDA-receptor LTP and describe how it is thought to strengthen synaptic connections where it occurs.

Know your brain: Midbrain

Where is the midbrain?

The midbrain is one of the three subdivisions of the brainstem; it is the most rostral of these subdivisions, or the one that is closest to the top of the brainstem. The midbrain connects the brainstem to the diencephalon at a location sometimes called the midbrain-diencephalon junction.

What is the midbrain and what does it do?

Although it is a relatively small section of neural tissue, the midbrain contains a long list of nuclei, tracts, nerves, and other structures---each with its own diverse catalog of functions. Thus, any attempt to define all of the actions of the midbrain in a just a few sentences, paragraphs, or even pages is inherently inadequate. Rather than attempt to do that, I will simply discuss some of the most prominent anatomical features of the midbrain and some of their putative functions.

One of the most noticeable external features of the midbrain is the presence of four bumps on its posterior surface (the side that faces the back of the brain). Those bumps are indicative of the presence of four large underlying clusters of neurons; the upper pair of those clusters are known as the superior colliculi and the lower pair are known as the inferior colliculi. The superior colliculi are thought to be involved in directing behavioral responses toward stimuli in the environment, while the inferior colliculi are best known for their role in auditory processing.

The anterior surface of the midbrain is marked by the presence of the crura cerebri (plural for crus cerebri), two large bundles of axons that travel along the base of the midbrain as they stretch from the pons to the cerebral hemispheres. They contain fibers that are part of important motor pathways like the corticospinal and corticobulbar tracts. The crura cerebri are sometimes called the cerebral peduncles, although this term is generally used to refer to a larger area that includes the crura cerebri as well as much of the rest of the midbrain.

The midbrain is often divided into three regions. At the level of the midbrain, the fourth ventricle has narrowed to form the cerebral aqueduct, a channel that connects the fourth ventricle with the third ventricle. The region of the midbrain posterior to the cerebral aqueduct is called the tectum, which means "roof" in Latin. The tectum consists primarily of the superior and inferior colliculi.

The area of the midbrain anterior to, or in front of, the cerebral aqueduct is called the tegmentum. The tegmentum contains a variety of ascending and descending tracts that pass through the midbrain, such as the medial lemniscus and the anterolateral tracts. Fibers from the superior cerebellar peduncles, the major efferent pathway from the cerebellum, decussate in the midbrain. Some of these fibers project to a midbrain nucleus called the red nucleus, which is thought to play an important role in motor coordination.

There are several other important nuclei and neuronal clusters in the midbrain tegmentum. For example, the midbrain tegmentum contains nuclei for two cranial nerves: cranial nerve III (oculomotor nerve) and cranial nerve IV (trochlear nerve). It also contains neurons that are part of the raphe nuclei---clusters of serotonin-producing neurons found in the brainstem that send serotonin throughout the central nervous system. Additionally, one of the largest collections of dopamine-producing neurons in the brain, the ventral tegmental area, is located in the midbrain tegmentum.

The third region of the midbrain is made up of two structures called the basis pedunculi. They cover the anterolateral portions (to the front and toward the sides) of the brainstem. The basis pedunculi include the crura cerebri (discussed above) as well as the substantia nigrae, which---like the ventral tegmental area---contain large collections of dopamine-producing neurons.

Finally, the area surrounding the cerebral aqueduct is called the periaqueductal gray, or PAG. The PAG has long been recognized for its role in pain inhibition, although it is also thought to be involved in many other functions ranging from emotional responses to the production of vocalizations.

References:

Haines DE. Fundamental Neuroscience for Basic and Clinical Applications. 4th ed. Philadelphia, PA: Elsevier; 2013.

Vanderah TW, Gould DJ. Nolte's The Human Brain. 7th ed. Philadelphia, PA: Elsevier; 2016.

History of neuroscience: Camillo Golgi

By the second half of the 19th century, scientists were beginning to develop a better understanding of the overall function of the nervous system. Discoveries like Paul Broca's identification of Broca's area and Fritsch and Hitzig's description of the motor cortex, for example, had led researchers to a deeper appreciation of the functional specialization of different parts of the brain. What was still missing by the 1870s, however, was an awareness of some of the most fundamental information about the basic building blocks of the nervous system: neurons.

In fact, the word neuron (along with the terms axon, dendrite, and synapse) would not be introduced until the 1890s, and at the middle of the 19th century there was some debate about whether the brain was even made up of distinct cells like other tissues in the body. This was because when one viewed brain tissue under a microscope, nerve cells appeared to have many extensions that stretched out to other cell bodies, seeming to make contact with them. In this way, the brain looked as if it consisted of a collection of uninterrupted processes that formed an expansive net of cellular entities. This view of the structure of the brain came to be called reticular theory, as the word reticulum is Latin for "net."

The main obstacle that prevented researchers from being able to describe the true structure of neurons was the lack of a stain that allowed for the clear differentiation of neurons under the microscope. Because cells are not distinctly colored like they often are in textbooks, their clear borders are difficult to discern against a similarly colorless fluid background (even under the microscope). Microscopists must rely on dyes or stains, which selectively color cells or individual components of cells so they stand out and are able to clearly be seen.

Before the 1870s, the most widely used stain in brain science was a substance called carmine, a reddish stain that could be obtained from certain insect species (it is still used today as a coloring agent in a variety of products ranging from cosmetics to yogurt). Carmine was recognized as a staining agent in the 1850s. Its discovery was a major breakthrough, as prior to its widespread use staining was not even a regular practice nor was its utility fully appreciated. The carmine stain, however, still did not allow brain scientists to attain a perfectly clear picture of neurons, instead leading to the view that supported reticular theory as discussed above. 

This was the context when Camillo Golgi made his contributions to the field in the 1870s. Golgi was a thirty-year old physician working at a small, little-known hospital in northern Italy. He did not have the benefit of using the laboratory facilities of a large research institution. Instead, he created a makeshift laboratory in a kitchen of the hospital. The laboratory consisted of not much more than his microscope, which he mostly used in the evening by candlelight.

a pyramidal neuron stained with a golgi stain

It was in that hospital kitchen that Golgi developed a new method of staining that would revolutionize the way people looked at the brain. The stain involved soaking cells in a solution of silver nitrate, and although Golgi was not the first to attempt to stain cells with silver, his method was a tremendous improvement over past efforts.

The silver staining method caused neurons to appear dark against a yellow background (for this Golgi initially called the method the "black reaction"), but the essential feature of the stain for making it useful in visualizing neurons was that it only caused about 3% of the neurons in a tissue sample to be darkened. This was important because if all neurons were stained, the abundance of cells in any sample would cause the whole sample to appear black. Due to its selectivity, the silver stain allowed for the visualization of a selection of neurons in such detail as had never been possible before.

Golgi used his new stain to make a number of important observations about the nervous system. He provided more detailed descriptions of neurons, including the first good descriptions of axon collaterals, or branches that extend off of the main processes of axons. He described two types of neurons in the brain, one that has long a long axon that can stretch from the grey matter of the brain to other parts of the brain or nervous system, and another that has a short axon. These neurons have since been named Golgi I and Golgi II cells, respectively. He detailed ways in which glial cells can be differentiated from neurons and described the structure of the cortex, corpus callosum, and spinal cord. He discovered sensory receptors in muscle that detect muscle tension; these are now known as Golgi tendon organs. And of course he was the first to describe in detail the protein- and lipid-packaging cellular organelle now called the Golgi apparatus. 

Despite all of Golgi's achievements, his contribution of the silver stain may have been the most significant, as it allowed later researchers to appreciate the true structure of neurons for the first time. Golgi's stain (with some refinement) would be used by neuroscientists like Santiago Ramon y Cajal to prove that neurons did not fuse together to form a net, and instead were independent of one another (just like other cells in the body); Cajal's observations on the structure and organization of neurons would soon come to be known as neuron doctrine, and it would supplant reticular theory in the minds of most of the scientific community. Golgi and Cajal would share the 1906 Nobel Prize in Physiology or Medicine for their important contributions to neuroscience.

Although Golgi's stain had helped Cajal to disprove reticular theory, Golgi refused to accept the evidence that suggested neurons were independent of one another. In his Nobel Prize acceptance speech, Golgi railed against the neuron doctrine, shocking much of the audience to whom the evidence in support of it was distinctly clear. Even though he was incredibly stubborn on this point, however, Golgi's obstinance does not overshadow the significant contributions he made to neuroscience and biology as a whole.

Finger S. Minds Behind the Brain. New York, NY: Oxford University Press; 2000.

2-Minute Neuroscience: Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder characterized by a progressive loss of motor function. ALS affects upper motor neurons and lower motor neurons. As these motor neurons stop working, muscles also begin to atrophy; this can eventually lead to respiratory failure, which is often the cause of death in ALS patients. The pathophysiology of ALS is not completely understood, but similar to other neurodegenerative diseases like Alzheimer's disease it is characterized by clusters of dysfunctional proteins within neurons. In this video, I discuss ALS symptoms and pathophysiology.