History of neuroscience: The mystery of trepanation

In 1867, an archaeologist and diplomat named Ephraim George Squier sought out the help of Paul Pierre Broca, the esteemed anatomist and surgeon. He was trying to solve a mystery about an ancient Incan skull that had been given to him by a wealthy artifact collector in Peru. In addition to its age, the Neolithic skull had a unique feature: on the top of the cranium a rectangular piece of bone had been removed. The presence of several cross-cuts surrounding the hole suggested that it was not a simple battle wound, but instead the result of a surgical procedure known as trepanation.

This alone would have made the skull an interesting relic, but what really sparked a scientific controversy about the skull was that many who examined it believed the surgery had been performed some time before the individual's death, as the bone seemed to show evidence of healing after the cuts had been made. While it was conceivable that Neolithic Peruvians could have performed such an operation as part of some after-death ritual, it was hard for many in Squier's time to believe these ancient peoples possessed the surgical acumen necessary to excise part of the skull of a living patient without causing death in the process. After all, the survival rate for surgical trepanation in the 1800s seldom reached 10% in the best hospitals of the day. Being unable to elicit a consensus view on the timing of the surgery from the members of the New York Academy of Medicine, Squier sent the skull to France to get an opinion from Broca, who was a distinguished expert in the study of the human skull.

At the time, Broca had already made the key discovery that would cause him to be a household name among psychologists and neuroscientists: that there was a region of the frontal lobe (now known as Broca's area) that seemed to be involved specifically in the production of language. He was still in the midst of vigorously defending this hypothesis (as he would continue to do for years to come), but he immediately developed a great interest in the skull Squier sent to him.

After examining the skull, Broca also was convinced that the opening was evidence of a surgical procedure done while the patient was still alive; Broca believed the patient survived for up to two weeks after trepanation. Doubts among the rest of the scientific community remained, however, until a collection of skulls was unearthed from a Neolithic grave site in central France several years later; a number of the skulls also had holes in them and the healing observable on these skulls made a more convincing argument for the idea that the holes were made well before death. In many cases, in fact, it seemed years may have passed between surgery and death.

Why trepanation?

The discovery of the French skulls helped to convince many of Broca's contemporaries that Neolithic peoples had the ability to perform trepanation on the living in such a way that the patient could often survive, but major questions remained as to how and why they did it. After Broca's interest had been piqued by Squier's skull he pursued answers to these other questions with characteristic determination. In fact, Broca ended up writing more papers on the reasons for prehistoric trepanation than he did on Broca's area and language.

To answer the question about how trepanation was done, Broca tried using simple tools that were available to Stone Age peoples (like flint) to scrape holes in the crania of recently-deceased individuals. He found that, although it took him 50 minutes to scrape through an adult skull (counting time spent taking breaks to rest his tired hand), it could be accomplished with these crude instruments. Now we know that this scraping method was only one of several different primitive approaches to trepanation. Others included making intersecting cuts in the skull and then removing a rectangular portion of the bone (this was what was seen in Squier's skull), or making a circular cut and then removing a disc of skull.

It's unclear if anesthesia was used during the operation when conducted in ancient times. Some have suggested Peruvians may have used coca (the plant cocaine would later be isolated from), as it can act as a local anesthetic. Others have hypothesized ancient peoples used substances like alcohol or opium to reduce pain associated with the procedure. It's also very possible, however, that no anesthesia was used; studies of Oceanic and African cultures that still practiced trepanation in the 20th century found that many of them did so without any type of anesthesia.

But the biggest mystery about trepanation is why the procedure was done. Broca thought and wrote extensively about this subject, eventually coming to favor a hypothesis that the practice was rooted in superstition. According to his view, Stone Age peoples did not understand the physiological basis of disorders like epilepsy, and thus were inclined to believe they were due to mystical events like demonic possession. Trepanation, Broca thought, may have been a way of treating these intractable mental disorders by creating a hole in the head through which demonic spirits could escape.

Although there are some aspects of Broca's original hypothesis that have become discredited (such as his belief---formed due to how long it took him to scrape through an adult skull---that the procedure was conducted only on children), it is still considered by many to be a valid explanation for why trepanation was done in the ancient world. Others, however, like Broca's colleague P. Barthelemy Prunieres, argued that trepanation had a more practical justification. Prunieres reasoned that the procedure grew out of the attempted treatment of cranial fractures, which would likely have involved efforts to remove pieces of fractured bone from the site of the injury. In some cases, head injuries can cause the accumulation of blood within the cranium, which may lead to a potentially life-threatening increase in intracranial pressure; this pressure can sometimes be partially relieved by trepanation. Thus, the primitive surgery may have produced a real benefit for some patients. If trepanation appeared to lead to an improvement in the condition of some patients, this may have caused the procedure to be utilized more frequently even if the true reasons for the improvements were not fully understood.

The perspectives of Broca and Prunieres represent two general views of ancient trepanation that each continue to receive support today: one that contends trepanation was done due to the influences of mysticism, another that argues it was a prehistoric attempt at rational surgery. It is likely, however, that different groups in different geographical areas had different reasons for performing the procedure, as trepanation was not a practice confined to one region or culture. Indeed, studies of 20th-century African tribes who still use the procedure found that reasons for trepanning varied among tribes, with some using it to treat cranial injuries and others using it to expel evil spirits.

Trepanation beyond the Stone Age

Trepanation did not begin and end with ancient Stone Age peoples. It was advocated by the famous Greek physician Hippocrates to allow for the drainage of blood after a cranial injury. Galen, the preeminent surgeon of the Roman Empire, also promoted the use of the procedure for blood drainage, but added to his recommendations a discussion of its beneficial effects on intracranial pressure. In the process, Galen provided an explanation of the potential palliative effects of trepanation that crudely resembles a contemporary understanding of them. The ancient Greeks and Romans also began developing more modern tools to use in trepanation; in the 1600s a three-pronged device for drilling through the skull was invented; it was called a tre fines, from the Latin for three ends. This led to the term trephination becoming a synonym for trepanation.

Trepanation continued to be used up through the 1800s for the treatment of head injuries as well as for epilepsy and other mental illnesses. Gradually, however, the practice fell out of favor in the 19th century. The mortality rates for trepanation at the time were very high, and it came to be recognized that any benefits it might offer were significantly outweighed by the risk of death associated with the surgery. Today similar procedures like craniectomy, which also involves removing part of the skull, are sometimes used to treat instances of increased intracranial pressure caused by major head trauma.

We will likely never be certain of the reasons Neolithic peoples practiced trepanation. Perhaps it was due to primitive beliefs in demonic possession, or maybe it was an attempt to protect the brain from the pressure created by intracranial bleeding. Then again, it may be that both of these explanations are erroneous. We can, however, feel fairly confident that trepanation was one of the first common surgical procedures and likely the first attempt at any intervention that could be considered remotely neurosurgical. And it likely will forever remain one of the longest-standing mysteries of neuroscience, due both to its origins in ancient human prehistory as well as to the improbability of its mystery ever being fully solved.

Clower, W., & Finger, S. (2001). Discovering Trepanation: The Contribution of Paul Broca Neurosurgery, 49 (6), 1417-1426 DOI: 10.1097/00006123-200112000-00021

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

Gross, CG. A Hole in the Head: More Tales in the History of Neuroscience. Cambridge, MA: MIT Press; 2009.

2-Minute Neuroscience: Basal Ganglia

In this video I discuss the group of structures known as the basal ganglia, which includes the caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus. I describe the role of the basal ganglia in facilitating movement, and I briefly discuss the direct and indirect pathways, two circuits in within the basal ganglia that are thought to promote and inhibit movement, respectively.

Know your brain: Vestibular system

Where is the vestibular system?

The vestibular system is comprised of several structures and tracts, but the main components of the system are found in the inner ear in a system of interconnected compartments called the vestibular labyrinth. The vestibular labyrinth is made up of the semicircular canals and the otolith organs (all discussed below), and contains receptors for vestibular sensations. These receptors send vestibular information via the vestibulocochlear nerve to the cerebellum and to nuclei in the brainstem called the vestibular nuclei. The vestibular nuclei then pass the information on to a variety of targets, ranging from the muscles of the eye to the cerebral cortex.

What is the vestibular system and what does it do?

The vestibular system is a sensory system that is responsible for providing our brain with information about motion, head position, and spatial orientation; it also is involved with motor functions that allow us to keep our balance, stabilize our head and body during movement, and maintain posture. Thus, the vestibular system is essential for normal movement and equilibrium.

Vestibular sensations begin in the inner ear in the vestibular labyrinth, a series of interconnected chambers that are continuous with the cochlea. The most recognizable components of the vestibular labyrinth are the semicircular canals. These consist of three tubes, positioned approximately at right angles to one another, that are each situated in a plane in which the head can rotate. This design allows each of the canals to detect one of the following head movements: nodding up and down, shaking side to side, or tilting left and right. These movements of the head around an axis are referred to as rotational acceleration, and can be contrasted with linear acceleration, which involves movement forward or backward.

The semicircular canals are filled with a fluid called endolymph, which is similar in composition to the intracellular fluid found within neurons. When the head is rotated, it causes the movement of endolymph through the canal that corresponds to the plane of the movement. The endolymph in that semicircular canal flows into an expansion of the canal called the ampulla. Within the ampulla is a sensory organ called the crista ampullaris that contains hair cells, the sensory receptors of the vestibular system.

Hair cells get their name because there is a collection of small "hairs" called stereocilia extending from the top of each cell. Hair cell stereocilia have fine fibers, known as tip links, that run between their tips; tip links are also attached to ion channels. When the stereocilia of hair cells are moved, the tip links pull associated ion channels open for a fraction of a millisecond. This is long enough to allow ions to rush through the ion channels to cause depolarization of the hair cells. Depolarization of hair cells leads to a release of neurotransmitters and the stimulation of the vestibulocochlear nerve.

The hair cells associated with the semicircular canals extend out of the crista ampullaris into a gelatinous substance called the cupula, which separates hair cells from the endolymph. When the endolymph flows into the ampulla, however, it causes the distortion of the cupula, which leads to movement of hair cells. This prompts stimulation of the vestibulocochlear nerve, which transmits the information about head movement to the vestibular nuclei in the brainstem as well as to the cerebellum.

The vestibular system uses two other organs, known as the otolith organs, to detect linear acceleration, gravitational forces, and tilting movements. There are two otolith organs in the vestibular labyrinth: the utricle and the saccule. The utricle is specialized to detect movement in the horizontal plane, while the saccule detects movement in the vertical plane.

The process of sensation in the otolith organs bears some similarity to the process in the semicircular canals, but there are also some distinct differences. Like the semicircular canals, the otolith organs also contain a sensory organ where hair cells can be found; in this case, however, it is called the macula. As in the semicircular canals, there is a gelatinous layer above the hair cells; in the otolith organs, however, there is another fibrous structure called the otolithic membrane above the gelatinous layer. The otolithic membrane has small crystals of calcium carbonate called otoconia embedded within it. These crystals make the otolithic membrane heavier than the rest of the structure; when linear acceleration occurs, it causes the otolithic membrane to shift relative to the macula, which leads to the displacement of hair cells and thus the release of neurotransmitters from these cells. The structure of the otolith organs makes them especially sensitive to movements like linear acceleration and head tilts.

The vestibular system uses this information about movement obtained via the semicircular canals and otolith organs to maintain balance, stability, and posture; one way it does this is through its involvement in reflex actions. For example, the vestibulo-ocular reflex (VOR) is a mechanism involving connections between the vestibular system and the muscles of the eyes that allows our gaze to remain fixed on a particular point even when we move our heads. Disruption of the vestibular system, whether due to some inherent pathology or to a transient state like alcohol intoxication, can involve symptoms like vertigo, loss of balance, and nausea and can range in severity from mild to incapacitating.

Khan S, Chang R (2013). Anatomy of the vestibular system: A review NeuroRehabilitation, 32 (3), 437-443

Capgras delusion

Think for a moment about the people in your life whom you are closest to and most familiar with---those whom you see, talk to, and maybe share intimate moments with on a regular basis. Perhaps this would be your spouse, partner, parents, siblings, or friends. Now, try to imagine waking up tomorrow and, upon seeing one of these people, being overcome with an unshakable feeling that it is not really them you are seeing. Even though you know it sounds crazy, you can't stop yourself from thinking that this person you have known for so long has been surreptitiously replaced with an impostor---someone else who looks just like them but is a different person altogether. You know this is irrational and even absurd, but it feels so true to you that you have to believe it's what really is going on.

The sense that people we are familiar with have been replaced with look-alike impostors is the defining symptom of a rare condition known as Capgras delusion. First described in 1923 by psychiatrist Joseph Capgras and his assistant Jean Reboul-Lachaux, Capgras delusion is one of a group of disorders known as delusional misidentification syndromes that involve persistent problems in accurately identifying oneself or others. The original description of Capgras delusion involved a 53-year-old woman who had experienced the death of four of five of her children, leaving her with only a daughter. Several years after the death of her children she began to believe that her daughter and husband had been replaced by identical look-alikes. She eventually felt this was true for everyone she was close to, and she devised elaborate explanations for the duplicity that involved the existence of multiple look-alikes for each person. She believed, for example, that each day she would sometimes see (and communicate with) several different impostors who looked just like her daughter---without ever actually speaking to her "real" daughter.

Patients with Capgras delusion often don't display other major cognitive deficits and can usually appreciate how ludicrous their beliefs may seem to others. They may be able to, for instance, admit that it would be hard for them to believe if someone else described a similar experience with look-alike impersonators. For example, this interaction (from a 1979 paper on the subject) occurred between an experimenter and a Capgras patient who---after a head injury---believed his wife and five children had been replaced with look-alikes:

E. [Experimenter] Isn't that [two families] unusual?                                                                                   S. [Patient] It was unbelievable!                                                                                                                     E. How do you account for it?                                                                                                                       S. I don't know. I try to understand it myself, and it was virtually impossible.                                            E. What if I told you I don't believe it?                                                                                                          S. That's perfectly understandable. In fact, when I tell the story, I feel that I'm concocting a story...It's not quite right. Something is wrong.                                                                                                             E. If someone told you the story, what would you think?                                                                              S. I would find it extremely hard to believe...

Despite a Capgras patient recognizing the irrationality involved, the delusion continues. Even time spent with the "impostor" doesn't dissuade the patient; in fact it only tends to strengthen the conviction that the "look-alike" is not who he or she claims to be.

Explaining the Capgras delusion

Although it is believed to stem from some neurological dysfunction, the Capgras delusion is not fully understood; several hypotheses have been proposed over the years to explain the phenomenon. Most recent hypotheses involve a deficit in the neurobiological mechanisms responsible for the recognition of familiar faces. To understand how this may lead to the development of the Capgras delusion, it can be useful to make a comparison to a disorder called prosopagnosia.

In prosopagnosia, patients have an impaired ability to recognize faces despite otherwise normal visual processing. This impairment often involves a general "face-blindness" that leads to a failure to recognize even the most familiar faces. Even though prosopagnosics are unable to overtly identify faces, however, past experiments have suggested they may experience a type of unconscious recognition when they see a familiar face. One way this has been tested has been to measure the skin conductance response (SCR) of prosopagnosic patients as they look at pictures of recognizable faces. SCR, which can detect slight changes in perspiration levels, is often used an indication of autonomic nervous system arousal and thus considered by some to be representative of a type of emotional response. An increased SCR has been observed in prosopagnosics when they look at images of people they are familiar with---even when they aren't able to identify the faces; this SCR has been interpreted as a physiological expression of unconscious recognition.

Capgras delusion is sometimes described as the "mirror-image" of prosopagnosia because Capgras patients recognize the faces of those closest to them, but their SCR is not increased upon seeing those familiar faces. Thus, it has been hypothesized that their conscious recognition is intact but their unconscious emotional response---that visceral familiarity we are used to sensing when we see those we are close to---is lacking. So, when Capgras patients are in the presence of someone they know they should have an emotional connection with, they are understandably disturbed when they don't feel any familiarity with the person. Instead they experience the same degree of autonomic arousal they would when seeing a stranger on the street.

The neurobiology underlying these unusual disruptions of familiarity is not very clear, and explanations of the mechanism responsible remain somewhat speculative. Because Capgras patients are able to recognize faces but do not display a typical emotional response to familiar faces, it has been hypothesized that there is some interruption in the pathways that connect facial recognition areas in the temporal lobe with areas of the limbic system---like the amygdala---that are involved with generating emotional responses. Although facial recognition is still functional, without the ability to activate the limbic system during facial recognition, the patient experiences a lack of emotion and familiarity.

It is thought that this dearth of familiarity is just one component of the Capgras delusion, however. Another aspect involves the pathological logic that leads to the belief that the suddenly unfamiliar person is actually an impostor. Why Capgras patients come to this specific conclusion instead of deciding that they are experiencing an abnormal neurobiological event is not very clear. It may involve an attempt to deal with the cognitive dissonance Capgras patients experience when they have a complete absence of feeling for someone they know they "should" have some emotional link with. In other words, a man would be perturbed to find he feels devoid of any familiarity towards his wife of 30 years; deciding that she must be an impostor allows him to explain his lack of emotion and perhaps reduce some of the mental strain caused by the alarming situation. The development of such an extreme and persistent delusion, however, also likely involves some neurological disruption of executive functions. For example, damage to the frontal areas of the brain, which are thought to be important in the management of rational thought, is often seen in Capgras patients and may contribute to the delusions that characterize the disorder.

There is a paucity of hard evidence to support the current hypotheses about the neurobiological bases of Capgras delusion, however. Likely due to the rarity of the disorder, many studies of Capgras patients (including the relatively few neuroimaging studies that have been published) have been case studies of just one patient. This approach, although informative, does not provide us with the type of evidence that can be used to make strong conclusions about the underlying neurobiology of the Capgras delusion. It is not surprising that research in this area has progressed relatively slowly, for Capgras delusion is far from a public health crisis; thus, answers are not pursued with the same fervor as they are in a much more prevalent disorder like Alzheimer's disease. To the neuroscientist, however, the Capgras delusion represents a fascinating opportunity to explore functions of the brain that we normally take for granted. The recognition of a spouse, for example, as someone who has been part of your life for years seems so natural and ingrained that it is difficult to believe it is dependent upon the proper functioning of neurobiological mechanisms in the same way that sight or movement might be. Capgras delusion, however, demonstrates that even our most fundamental beliefs can crumble with the dysfunction of certain brain regions.

Young, G. (2008). Capgras delusion: An interactionist model Consciousness and Cognition, 17 (3), 863-876 DOI: 10.1016/j.concog.2008.01.006

2-Minute Neuroscience: Motor Cortex

In this video, I discuss the motor cortex. I describe the location and functions of the primary motor cortex and the nonprimary motor cortex, which is often divided into the supplementary motor cortex and premotor cortex. I also describe the main pathways by which motor information travels away from the motor cortex: the corticospinal tract, which carries motor information to the spinal cord to cause movement of the body, and the corticobulbar tract, which carries motor information to the brainstem to cause movement of the head, neck, and face.

Know your brain: Motor cortex

Where is the motor cortex?

Motor cortex (in red).

Motor cortex (in red).

The motor cortex is found in the frontal lobe, spreading across an area of cortex situated just anterior to a large sulcus known as the central sulcus, which runs down the side of the cerebral hemispheres. The motor cortex is often divided into two major regions: the primary motor cortex, which is found in a gyrus known as the precentral gyrus that is positioned just in front of the central sulcus, and the nonprimary motor cortex, which is anterior to the primary motor cortex and contains two prominent regions known as the premotor cortex and supplementary motor cortex.

What is the motor cortex and what does it do?

In 1870 physicians Gustav Theodor Fritsch and Eduard Hitzig, using awake dogs as their subjects, electrically stimulated the area of the brain we now know as the motor cortex and found that the stimulation caused the dogs to move involuntarily. Additionally, they found that stimulating the motor cortex in different locations caused different muscles to move. This experiment led to the identification of the motor cortex as the primary area of our brain involved with planning and executing voluntary movements.

There are several distinct regions within the motor cortex. The area found to be the most sensitive to electrical stimulation--in that it requires the least amount of stimulation to produce a corresponding muscle movement--is the primary motor cortex. The primary motor cortex is arranged such that different parts of the region are associated with motor control of different parts of the body, a topographic organization that is similar--although less precise--than that seen in the somatosensory cortex.

The primary motor cortex contains large neurons with triangular-shaped cell bodies that are called pyramidal neurons; these are the primary output cells of the motor cortex. The axons of pyramidal cells leave the motor cortex carrying information about a desired movement and enter one of the tracts of the pyramidal system, which includes the corticospinal and corticobulbar tracts. Both tracts carry information about voluntary movement down from the cortex; the corticospinal tract carries such information to the spinal cord to initiate movements of the body, while the corticobulbar tract carries motor information to the brainstem to stimulate cranial nerve nuclei and cause movements of the head, neck, and face. Pyramidal neurons of the motor cortex are also known as upper motor neurons. They form connections with neurons called lower motor neurons, which directly innervate skeletal muscle to cause movement.

Other areas of the motor cortex, known collectively as the nonprimary motor cortex, are found anterior to the primary motor cortex and also appear to play important roles in movement. Despite their name, the nonprimary motor areas shouldn't be viewed as taking a secondary role to the primary motor cortex. Instead, the nonprimary motor areas are just involved in different aspects of movement, such as the planning of movements and the selection of actions based on environmental context.

The nonprimary motor cortex is often divided into two main regions: the supplementary motor cortex and the premotor cortex. The exact functions of these areas are not very well understood. It is thought that the supplementary motor cortex may be important to the execution of sequences of movement, the attainment of motor skills, and the executive control of movement, which can involve things like making decisions to switch to different movements based on incoming sensory information. The premotor cortex makes a large contribution (~30%) to the neurons that will enter the corticospinal tract, but it seems to be more active than the primary motor cortex during the planning of--rather than the execution of--movements. Neurons in the premotor cortex also appear to be involved with incorporating sensory cues (e.g. the location of an object to be grasped) into a movement to ensure it is executed properly, as well as with the selection of actions based on behavioral context (e.g. picking up a cup to move it from the table vs. picking up a cup to take a drink from it). There are also populations of neurons, sometimes called mirror neurons, in the premotor cortex that are activated when observing someone else carry out a movement; these cells may be involved in helping us to understand and/or imitate the actions of others.

Kandel ER, Schwartz JH, Jessell TM 2000. Principles of Neural Science. 5th ed. New York. McGraw-Hill; 2013.
Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia AS, McNamara JO, White LE. Neuroscience. 4th ed. Sunderland, MA. Sinauer Associates; 2008.

2-Minute Neuroscience: Cerebellum

In this video, I discuss the cerebellum. I describe the location of the cerebellum in the nervous system and its role in facilitating movement. I cover the different regions of the cerebellum: the cerebrocerebellum, spinocerebellum, vermis, and vestibulocerebellum. Lastly, I discuss the cerebellar peduncles as the routes by which the cerebellum communicates with the rest of the nervous system and the deep cerebellar nuclei as the primary output cells of the cerebellum.