Know Your Brain: Chronic Traumatic Encephalopathy (CTE)

Background

comparison of a healthy brain and brain afflicted with CTE, from the Boston University Center for the Study of Traumatic Encephalopathy

In 1928, physician and researcher Harrison Martland published a scientific paper titled Punch DrunkIn it, he described 23 cases of boxers who had started to display neurological symptoms after experiencing the repetitive head trauma that goes hand in hand with their sport. They sometimes developed symptoms that resembled Parkinson's disease, like tremors and abnormalities in gait, as well as more general types of cognitive deterioration. About a decade later, another researcher gave a new name to Martland's punch drunk syndrome, calling it dementia pugilistica.

A year before Martland's popularization of the term punch drunk syndrome, physicians Michael Osnato and Vincent Gilberti had published a review of cases of what was known at the time as postconcussion neurosis---a neurological disorder that emerged after a concussion. Osnato and Gilberti concluded that concussions could be associated with subsequent neurodegeneration, or the degeneration and death of neurons. Because the pathology they saw in the cases they studied resembled the effects of a type of brain inflammation known as encephalitis, Osnato and Gilberti decided this disorder should be called traumatic encephalitis, which soon was modified to traumatic encephalopathy.

In 1940, researchers Bowman and Blau coined the term chronic traumatic encephalopathy when describing the case of a 28-year old professional boxer who had been unable to get commisioned to continue boxing because he was suffering from a number of symptoms including paranoia, depression, memory deficits, and impaired cognition. Bowman and Blau added the word chronic to Osnato and Gilberti's original terminology because this patient's case had not improved over the course of 18 months. They thus called the condition chronic traumatic encephalopathy, or CTE.

Although the first reports of CTE described boxers, it wasn't long before similar symptoms were reported in American football players---and players of any sport that involved the potential for multiple head injuries. It wasn't until 2005, however, that widespread attention was focused on American football as a potential cause of CTE. This attention followed the publication of a report by neuropathologist Bennet Omalu and colleagues after the examination of the brain of former NFL player Mike Webster. Webster had died of a heart attack but had suffered from memory problems and depression late in his life. Upon autopsy, it was found that Webster's brain showed signs of degeneration and the researchers concluded that Webster had suffered from CTE. Autopsies of the brains of a number of other football players have resulted in similar observations.

What is CTE?

CTE is a neurological condition thought to be the consequence of repetitive head trauma, although other risk factors must also be at play since not everyone who experiences repetitive head trauma develops CTE. Symptoms associated with CTE generally begin to appear years (sometimes decades) after trauma and may include: problems with cognition like memory and attentional deficits; behavioral abnormalities like paranoia, aggression, and impulsivity; mood disturbances like depression, anxiety, and suicidal thoughts; and movement problems like tremor and other Parkinsonian symptoms. In the majority of cases, the symptoms of CTE are progressive---meaning they get worse over time.

Despite a long list of recognized symptoms, however, there are no widely accepted diagnostic criteria that define what CTE should look like (although at least two sets of diagnostic criteria have been proposed). Sometimes CTE is defined specifically as the pathological changes that occur in the brains of patients, while the presentation of symptoms is called traumatic encephalopathy syndrome.

What causes CTE?

Typically, CTE is associated with repeated concussions and subconcussive blows (i.e. trauma that doesn't result in clinical symptoms). The evidence is not clear at this point as to how many instances of head trauma are required to cause CTE, or if it could be caused by one incident. Also, not everyone who experiences repetitive head trauma will develop CTE, which suggests that other factors must also be involved. But researchers are still working to identify those other risk factors.

Populations who are at risk for frequent head trauma are also most likely to develop CTE, as CTE has been observed in: boxers, American football players, professional hockey players, professional wrestlers, victims of physical abuse, military personnel, and so on. It's important to emphasize that, as mentioned above, head trauma does not have to result in clinical symptoms to increase the risk of CTE. Someone who takes frequent blows to the head may be at greater risk of developing CTE, even if those blows don't result in concussive symptoms.

What happens in the brain in CTE?

The pathological features of CTE in the brain are perhaps better defined than the overt symptoms of CTE. The principal feature is the accumulation of a protein called tau into insoluble clusters, also known as aggregates. This process is thought to begin when tau protein becomes hyperphosphorylated, which means that multiple chemical groups called phosphoryl groups have attached to tau to the point where no more can attach to the molecule. At this point, tau, which normally interacts with and helps to maintain the stability of microtubules in the cell, disassociates from the microtubules. Then, the hyperphosphorylated tau protein forms the aggregates mentioned above in neurons and astrocytes surrounding blood vessels in the brain. The clusters of tau are called neurofibrillary tangles when they appear in neurons and are often called astrocytic tangles when they appear in astrocytes.

The tau aggregates in CTE form in the cerebral cortex, primarily at the depth of the invaginations of the cortical surface known as the cortical sulci. These aggregates may also form in other layers of the cortex, some regions of the hippocampus, and in other subcortical nuclei.

What effect these clusters have exactly is still uncertain, as while their presence is correlated with the severity of neurodegeneration, it has not been clearly demonstrated to cause it. Still, neurofibrillary tangles are thought to be able to disrupt cellular communication, which could lead to detrimental effects on the cell. They also have the ability to pass from one affected neuron to other unaffected neurons, which seems to indicate a potential for the pathology to spread within the brain. 

Aggregates of tau are found in other neurodegenerative diseases like Alzheimer's disease as well, and some hallmarks of other neurodegenerative diseases, like the amyloid plaques commonly seen in Alzheimer's disease, also occur in CTE. But the distribution of tau in CTE, as well as the absence of defining features of another neurodegenerative disease is what allows for the diagnosis of CTE. For example, if tau-associated degeneration occurs in certain regions of the hippocampus alongside the formation of amyloid plaques, it would be indicative of Alzheimer's disease rather than CTE.

While tau deposits are the primary microscopic sign of CTE, there are also more evident signs, like reduced brain weight, atrophy of the cerebral cortex (especially in the frontal and temporal lobes), atrophy of various other regions of the brain like the hippocampus and amygdala, enlargement of the ventricles, and thinning of the corpus callosum

Prevalence of CTE

CTE has received a great deal of media attention over the past several years, and this has led to some misunderstandings about the prevalence of the disorder. For example, in 2017 a story about CTE in National Football League (NFL) players received a lot of media attention, with headlines reporting that CTE was found in 99% of brains of NFL players that had been studied. This study, however, used brains that had been donated to be studied for CTE, regardless of whether or not symptoms had emerged during the players' lives. This introduces a potential source of bias, as relatives of players may have donated the players' brains because of concern about symptoms that had arisen during the players' lives. In other words, many of the brains involved in the study may have been donated because of concerns about CTE, making it less surprising that almost all of the brains showed signs of CTE.

Due in part to the potential biases surrounding brain donation for CTE study, the actual prevalence of CTE is difficult to estimate. One study that included a larger brain bank found CTE in 31.8% of the brains of individuals with a history of repetitive head trauma, and no cases among 198 brains without such a history. Larger studies are underway now to try to get a better sense of how prevalent CTE is in the general population.

Read more about the neuroscience of traumatic brain injury.

References (in addition to linked text above):

Asken BM, Sullan MJ, DeKosky ST, Jaffee MS, Bauer RM. Research Gaps and Controversies in Chronic Traumatic Encephalopathy: A Review. JAMA Neurol. 2017 Oct 1;74(10):1255-1262. doi: 10.1001/jamaneurol.2017.2396.

Montenigro PH, Corp DT, Stein TD, Cantu RC, Stern RA. Chronic traumatic encephalopathy: historical origins and current perspective. Annu Rev Clin Psychol. 2015;11:309-30. doi: 10.1146/annurev-clinpsy-032814-112814. Epub 2015 Jan 12.

2-Minute Neuroscience: Long-Term Depression (LTD)

Long-term depression, or LTD, is a process by which synaptic connections between neurons are weakened. Although the functions of LTD are not completely understood, it may be important to memory formation---perhaps by resetting previous synaptic changes to allow for new memories to be formed via long-term potentiation (LTP). In this video, I discuss the best understood mechanism underlying LTD, which involves AMPA and NMDA glutamate receptors.

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: Mammillary bodies

Where are the mammillary bodies?

The mammillary bodies are part of the diencephalon, which is a collection of structures found between the brainstem and cerebrum. The diencephalon includes the hypothalamus, and the mammillary bodies are found on the inferior surface of the hypothalamus (the side of the hypothalamus that is closer to the brainstem). The mammillary bodies are a paired structure, meaning there are two mammillary bodies---one on either side of the midline of the brain. They get their name because they were thought by early anatomists to have a breast-like shape. The mammillary bodies themselves are sometimes each divided into two nuclei, the lateral and medial mammillary nuclei. The medial mammillary nucleus is the much larger of the two, and is often subdivided into several subregions.  

What are the mammillary bodies and what do they do?

The mammillary bodies are best known for their role in memory, although in the last couple of decades the mammillary bodies have started to be recognized as being involved in other functions like maintaining a sense of direction. The role of the mammillary bodies in memory has been acknowledged since the late 1800s, when mammillary body atrophy was observed in Korsakov's syndrome---a disorder characterized by amnesia and usually linked to a thiamine deficiency. Since then a number of findings---anatomical, clinical, and experimental---have supported and expanded upon a mnemonic role for the mammillary bodies.

The mammillary bodies are directly connected to three other brain regions: the hippocampus via the fornix, thalamus (primarily the anterior thalamic nuclei) via the mammillothalamic tract, and the tegmental nuclei of the midbrain via the mammillary peduncle and mammillotegmental tract. Two of the three connections are thought to primarily carry information in one direction: the hippocampal connections carry information from the hippocampus to the mammillary bodies and the thalamic connections carry information from the mammillary bodies to the thalamus (the tegmental connections are reciprocal). 

These connections earned the mammillary bodies the reputation of being relay nuclei that pass information from the hippocampus on to the anterior thalamic nuclei to aid in memory consolidation. This hypothesis is supported by the fact that damage to pathways that connect the mammillary bodies to the hippocampus or thalamus is associated with deficits in consolidating new memories. Others argue, however, that the mammillary bodies act as more than a simple relay, making independent contributions to memory consolidation. Both perspectives emphasize a role for the mammillary bodies in memory but differ as to the specifics of that role.

Further supporting a role for the mammillary bodies in memory, there is evidence from humans that suggests damage to the mammillary bodies is associated with memory deficits. Several cases of brain damage involving the mammillary bodies as well as cases of tumor-related damage to the area of the mammillary bodies suggests that mammillary body damage is linked to anterograde amnesia. Indeed, mammillary body dysfunction has been identified as a major factor in diencephalic amnesia, a type of amnesia that originates in the diencephalon (Korsakoff's syndrome, an amnesia that is seen primarily in long-term alcoholics, is one type of diencephalic amnesia).

Experimental evidence from animal studies also underscores the importance of the mammillary bodies in memory. Studies with rodents and monkeys have found deficits in spatial memory to occur after damage to the mammillary bodies or the mammillothalamic tract. 

In addition to involvement in memory functions, there are cells in the mammillary bodies that are activated only when an animal's head is facing in a particular direction. These cells are thought to be involved in navigation and may act somewhat like a compass in creating a sense of direction.

Reference (in addition to linked text above):

Vann SD, & Aggleton JP (2004). The mammillary bodies: two memory systems in one? Nature reviews. Neuroscience, 5 (1), 35-44 PMID: 14708002

Know your brain: Fornix

Where is the fornix?

The term fornix comes from Latin and means "arch." It is used to refer to various arch-like structures in the body, but when used in reference to the brain it indicates a bundle of white matter fibers that arches around the thalamus. The fornix originates in the hippocampus, where it emerges from a collection of fibers called the fimbria. It then stretches up and around the thalamus toward the front of the brain. When it reaches a tract called the anterior commissure, it branches downward. Some fibers then split off and terminate mainly in the septal nuclei, preoptic nuclei, and ventral striatum, while others enter the hypothalamus and form connections with the mammillary bodies.

What is the fornix and what does it do?

In 1937 the neuroanatomist James Papez described what came to be known as the Papez circuit. The Papez circuit consisted of a group of structures---including the hippocampus, mammillary bodies, anterior nucleus of the thalamus, cingulate gyrus, and parahippocampal gyrus---that Papez hypothesized were the "anatomic basis of emotions." The fornix was a critical component of the Papez circuit, acting as a primary connection among several structures within the circuit. The Papez circuit would later be expanded upon and termed the limbic system. 

The diverse group of structures known as the limbic system is now thought to be involved in much more than emotion, and the fornix is still considered an important part of the limbic system. The fornix acts as the primary outgoing pathway from the hippocampus, and thus its most recognized function is its involvement in memory. The hippocampal projections that travel in the fornix are thought to be important for memory consolidation, and damage to the fornix has been associated with anterograde amnesia, which involves the inability to create new memories. Fornix damage is primarily linked to deficits in declarative memories, or memories for factual information---and especially episodic memories, which are a type of declarative memory that deals with autobiographical information.

Neurodegeneration in the fornix has also been associated with the cognitive impairment seen in Alzheimer's disease. The integrity of the fornix may be compromised in the early stages of Alzheimer's disease, and thus may be an early indicator of the disease that can predict the progression of Alzheimer's disease from preclinical (i.e. asymptomatic) to clinical (i.e. symptomatic) stages. Degeneration of the fornix in Alzheimer's disease seems to precede degeneration of the hippocampus, an area that is known to be severely affected by the disease.

Although the functions of the fornix are still relatively poorly understood, its role in memory processes seems to be one that is relatively well supported. Due to its diverse connections, the fornix likely is involved in a list of other brain activities, but more research will be needed to further elucidate these roles.