2-Minute Neuroscience: Epilepsy

In this video, I discuss epilepsy. Epilepsy is a chronic condition characterized by recurrent seizures. Seizures are characterized by excessive neural activity, which is caused by both increased action potential firing rates and synchronous firing (i.e. many neurons fire action potentials at the same time). When seizures originate in one area of the brain, they are known as focal seizures. Alternatively, when seizure activity occurs in widespread areas of the brain all at once, it is referred to as a generalized seizure. In this video I discuss these types of seizures and the abnormal brain activity that is associated with them.

What's really the deal with toxoplasma gondii and human behavior?

T. gondii cyst in a mouse brain.

T. gondii cyst in a mouse brain.

For a simple protozoan, Toxoplasma gondii has experienced something of a meteoric rise in popularity over the past several years. Actually, to be fair T. gondii has garnered quite a bit of interest since the 1930s, when it was discovered the parasite could be transmitted from a mother to a fetus in the womb, sometimes resulting in severe congenital disorders. Curiosity about T. gondii grew significantly in the early 2000s, however, when it was found that T. gondii infection in mice and rats might influence the behavior of the rodents so as to make them less afraid of cats.

Recently, interest in T. gondii has been especially focused on the hypothesis that the microorganism might also be able to influence human behavior. Indeed, this idea has become a popular topic of discussion even outside the sphere of research. This notoriety, however, has led to a spectrum of opinions that range from the suggestion T. gondii is responsible for a variety of psychiatric symptoms to the viewpoint that there is no sound evidence at all to indicate such a thing. Is one of these perspectives more accurate than the other?

T. gondii and rodent behavior

Effects of T. gondii infection on rodent behavior have been recognized since the late 1970s when it was observed that infected mice displayed impaired performance on memory tasks. Various other studies over the next couple of decades noted effects on behavior and cognition in rodents, but widespread interest in the behavioral effects of T. gondii infection was triggered by the publication of a study that suggested T. gondii-infected rats exhibit a diminished aversion to cat urine---and that some infected rats may even display an attraction to it. This effect was eventually seen in mice as well.

This finding was compelling when placed in the context of something called the parasite manipulation hypothesis, which states that some parasites have evolved mechanisms to influence their hosts so as to promote the parasite's transmission. This hypothesis was thought to make sense when used to describe T. gondii because T. gondii is only capable of reproducing within the intestines of cats; felines thus play an essential role in the life cycle of the parasite. After reproduction, however, several million oocysts (sort of a protozoan parasite version of an embryo) are expelled from the feline intestines in the feces. Unfortunately for these oocysts, this causes them to be forced out of their preferred feline intestinal environment, seemingly without a clear path of return. That is where rodents come in.

Many animals who are exposed to the feces of an infected cat (e.g. through contaminated food or drinking water) can become infected with T. gondii. Rodent infection, however, might be especially useful to T. gondii due to the role of cats as natural predators of rodents. Some have suggested that the ability of T. gondii to reduce rodent fear of cat urine gives T. gondii a method by which to find its way back to its preferred environment. By making rodents less cautious around cat urine, which previously had acted as a distinct threat-identifying odorant, rodents may put themselves in harm's way and be more likely to be eaten by cats. If they are, T. gondii ends up right where it needs to be to reproduce and continue its life cycle.

Neuronal mechanisms for T. gondii action

In order to manipulate the behavior of rodents it would seem necessary for T. gondii to have a means by which it could influence neurobiology; of course, such a mechanism would also be necessary for the manipulation of human behavior. What exactly this mechanism might be is still under investigation, but one thing that's certain is that T. gondii does have a way of making it to the brain of its host, whether that host be a human or a rodent. Indeed, T. gondii invasion of the central nervous system is associated with the most severe complications of T. gondii infection in humans, and by some estimates T. gondii may cross the blood-brain barrier and enter the brain as quickly as 7 days after infection occurs.

Once T. gondii is in the brain, it can infect neurons directly. What happens as a result is still uncertain, but several hypotheses have been proposed to explain the ways T. gondii infection can disrupt neuronal function. One hypothesis is that T. gondii infection of neurons can alter dopamine metabolism to increase dopamine synthesis and release. Another hypothesis contends that T. gondii infection can influence calcium signaling in such a way as to make neurons either hypo- or hyper-responsive. A complete model of T. gondii's effects on neurons has not yet been elucidated, however, so the true mechanism may involve these processes or something different altogether.

When T. gondii enters the brain, it also infects glial cells like microglia and astrocytes; activation of these cells is associated with the production of a general inflammatory response in the brain. This neuroinflammation may have a variety of effects on neurobiology, including influences on neurotransmitter metabolism, changes in neurotransmitter receptor levels, and effects on synaptic morphology or connectivity. Thus, the repercussions of inflammation caused by T. gondii infection may also be extensive enough to modify the behavior of the host.

While there is much to still be understood about the way or ways in which T. gondii can affect host behavior, there are at least plausible mechanisms identified by which such an effect might occur in mammalian hosts (including humans). And, when we are investigating the potential of an exposure like T. gondii infection to cause an effect on a host, biological plausibility can support the argument that the potential exists. In other words, if there were no plausible biological mechanism by which T. gondii could influence behavior, then we would be less confident it is actually affecting behavior (even when studies like those discussed below find some correlation between infection and behavioral changes). Just because there is a biologically plausible manner by which T. gondii can influence behavior, however, doesn't mean it actually does. To be confident about the relationship between T. gondii and human behavior we also need some strong evidence showing a relationship between infection and behavioral changes in human populations.

T. gondii and human behavior

The relationship between T. gondii infection and human behavior has been a subject of research for many years, and studies of the prevalence of T. gondii infection in psychiatric patients date back to the middle of the 20th century. However, the suggestion that T. gondii may be manipulating rodent behavior led to a resurgence of interest in T. gondii 's potential to affect people. Along with that increase in research-related interest came heightened interest from the popular press, which caused the potential influence of T. gondii on psychiatric symptoms to become a trendy---but often sensationalized---topic.

Regardless, legitimate research into this topic continues to be conducted; by now researchers have explored the potential association between T. gondii infection in humans and a wide range of behavioral and psychiatric outcomes. And, a number of studies have detected correlations between the presence of T. gondiii antibodies and behavioral or psychiatric abnormalities. For example, one study found T. gondii infection to be associated with increased aggression in women and increased impulsivity in younger men. Another study detected a correlation between homicide rates and rates of T. gondii infection in the population. Other findings include links to suicide rates and even traffic accidents (hypothetically due to the effect of the parasite on characteristics like reaction time).

By far, though, it seems the most frequently investigated relationship between T. gondii infection and psychiatric abnormalities is the association between T. gondii and schizophrenia. Over 40 studies examining the relationship between T. gondii infection and schizophrenia or psychotic symptoms have been published since the 1950s. In 2012, a group of researchers synthesized data from 38 of these studies to determine if there was a consistent association between T. gondii infection and schizophrenia. The results of this analysis suggested that, across all of the studies included, individuals who had been diagnosed with schizophrenia were about 2.73 times more likely to also be infected with T. gondii. In terms of how this increase in risk stacks up against other known risk factors for schizophrenia, it is similar in magnitude to the increase in risk of schizophrenia seen in those who grow up in an urban environment or in those who have a father who is age 55 or older at birth, but significantly lower than the increased risk imparted by having another immediate family member with schizophrenia.

Based on this information along with the biological plausibility of T. gondii's mechanism for affecting brain activity, it may sound to you like there is something to the idea that T. gondii infection can lead to psychiatric disorders (or schizophrenia in particular). However, there are some reasons to take all of these T. gondii findings regarding human behavior with a grain of salt. One is that the studies conducted up to this point generally have followed this methodology: get a sample of individuals, test them for antibodies to T. gondii (which would indicate an infection if present), and look for correlations between the presence of antibodies and schizophrenia (or some other psychiatric outcome). 

While a study like this can be informative, it leaves many questions unanswered. For example, even if this type of study finds a link between T. gondii and schizophrenia, because data was only collected at one point in time it is impossible to tell if the T. gondii infection preceded (and thus caused) schizophrenia. This allows for a number of other possible explanations for the relationship between infection and schizophrenia. For example, there is a possibility that the correlation between T. gondii infection and schizophrenia exists because infection becomes more likely after the onset of schizophrenia. What if, for instance, the onset of schizophrenia is associated with behavioral changes (e.g. eating and hygiene changes specifically) that increase exposure to sources of T. gondii contamination?

Alternatively, what if some common variable increases the risk of both T. gondii infection and schizophrenia? For example, what if something about one's neurobiology makes one more likely to own a cat (and thus be exposed to T. gondii through exposure to cat feces) and also predisposes one to schizophrenia? Or, what if T. gondii doesn't increase the risk of schizophrenia, but some other microorganism passed from a cat to a human does? In that case, owning a cat would make someone more likely to be infected with T. gondii and more likely to develop schizophrenia, but not due to a direct link between T. gondii and schizophrenia. Indeed, one study found no significant link between T. gondii infection and schizophrenia, but did find a significant association between having close contact with cats and schizophrenia. In the end, the problem is that observational studies that rely on data collected at only one point in time allow for too many other possibilities to let us have any confidence that there is a causal relationship between the variables we are interested in. Hence these studies can detect correlation, but not causation.

With this in mind, one way to get closer to some answers to these questions about T. gondii and psychiatric symptoms is to conduct more studies using longitudinal designs. A longitudinal study design, for example, would begin with a sample of overtly healthy people---some people who were infected with T. gondii and some who were not; these individuals would then be followed up with over a period of years to see if those with T. gondii infection were more likely to subsequently develop psychiatric disorders. This approach can provide more convincing evidence of a causal relationship, in part because it can provide insight into whether T. gondii infection precedes the onset of the symptoms (since at the start of the study the symptoms were not present).

Because of the paucity of studies that have the ability to detect causal links between T. gondii and human psychiatry, there are researchers who argue that some are inferring a causal relationship when the evidence for that causal relationship doesn't exist. For example, a recent study looked at the association between T. gondii infection and a number of psychiatric measures ranging from IQ to schizophrenia diagnosis. The authors found no link between T. gondii infection and shizophrenia or most other psychiatric measures, and in the concluding paragraphs they suggest that "earlier reports of links between T. gondii infection and behavioral impairments are exaggerated," due in part to the intrigue both researchers and the public have with the idea of T. gondii being able to manipulate human behavior. Interestingly, the study in question did actually detect a link between T. gondii infection and recent suicide attempts, suggesting that perhaps the idea the pathogen is influencing behavior is not entirely unreasonable.

Regardless, although there are some titillating findings concerning T. gondii infection and psychiatric disorders, at this point it is not a relationship we can be very confident in. This is not to say that there is no ground for the hypothesis to stand on, but instead that more research is needed before we can decide if the microorganism is really having some influence on human behavior. Despite the lack of strong evidence, however, there is likely a reason that infectious origins of psychiatric disorders has been such a popular topic in recent years. It's mind-boggling for most of us to imagine that this complex, highly-evolved organ we call the human brain can be manipulated and turned dysfunctional by organisms that have a diameter on the scale of micrometers. It creates for us a strangely wonderful sense of impotence that causes us to step back and reassess the position of superiority we generally give ourselves over other organisms. And that reminder of our own helplessness to control some aspects of the natural world can be both frightening and fascinating at the same time. Thus, the idea is inherently captivating, and it is likely to continue to attract speculation and exaggeration until we come to a more definite conclusion on its accuracy.

Parlog A, Schl├╝ter D, & Dunay IR (2015). Toxoplasma gondii-induced neuronal alterations. Parasite immunology, 37 (3), 159-70 PMID: 25376390

2-Minute Neuroscience: Multiple Sclerosis

In this video, I discuss multiple sclerosis. Multiple sclerosis is a central nervous system disorder that can create a variety of symptoms ranging from visual disturbances to paralysis. It is characterized by damage to myelin, the insulatory material that surrounds neurons. This damage is linked to disruptions in healthy neuronal function, which are thought to lead to the symptoms of the disease. It is widely believed that the myelin damage that occurs in multiple sclerosis is due, at least in part, to the cells of the immune system targeting myelin. Thus, most of the treatments for multiple sclerosis involve drugs that suppress the immune response in some way.

2-Minute Neuroscience: Alzheimer's Disease

a coronal slice of a brain that has atrophied severely due to the effects of alzheimer's disease.

a coronal slice of a brain that has atrophied severely due to the effects of alzheimer's disease.

In this video, I discuss Alzheimer's disease---the most common form of neurodegenerative disease. In addition to the widespread neurodegeneration that occurs in Alzheimer's disease, there are specific neurobiological abnormalities that appear in the brains of Alzheimer's disease patients. For example, clusters of a misfolded form of a protein called amyloid beta develop around neurons; the clusters are called amyloid plaques. Additionally, clusters of misfolded tau protein develop inside neurons; these clusters are called neurofibrillary tangles. The most common treatments for Alzheimer's disease are acetycholinesterase inhibitors, which are drugs that inhibit the breakdown of the neurotransmitter acetylcholine. Acetylcholine is thought to be important to healthy cognition, but acetylcholinesterase inhibitors have relatively modest effects on the symptoms of Alzheimer's disease.

2-Minute Neuroscience: Parkinson's Disease


In this video, I discuss Parkinson's disease---the second most common neurodegenerative disease behind Alzheimer's disease. Parkinson's disease is associated with the degeneration and death of dopamine neurons in the substantia nigra. The substantia nigra is a region of the brain that is part of a collection of structures known as the basal ganglia, which are important to movement. Parkinson's disease patients experience severe movement difficulties that become more problematic as the degeneration of substantia nigra neurons becomes more extensive. The most common treatment for Parkinson's disease involves the administration of L-DOPA, a precursor to dopamine that allows the brain to synthesize more of the neurotransmitter to replenish depleted dopamine levels.

The amygdala: Beyond fear



The amygdala---or, more appropriately, amygdalae, as there is one in each cerebral hemisphere---was not recognized as a distinct brain region until the 1800s, and it wasn't until the middle of the twentieth century that it began to be considered an especially significant area in mediating emotional responses. Specifics about the role of the amygdala in emotion remained somewhat unclear, however, until the 1970s and 1980s when it was studied in fear conditioning experiments in rodents. A typical fear conditioning experiment in rodents involves pairing an aversive stimulus (e.g. an electrical shock to the feet) with a previously neutral stimulus like an audible tone until the rodent begins to display signs of fear at simply hearing the tone. Using this experimental approach, researchers were able to demonstrate that functioning amygdalae are very important for rodents to learn the fear responses typically seen as a result of fear conditioning.

From this time on, research began to accumulate that identified the amygdala as having an integral role in fear in general. And thus was born the conception of the amygdala as a "threat-detector." According to this view, the amygdala helps us to identify threats in our environment and---if threats are present---to initiate a fight-or-flight response. This basic understanding of the function of the amygdala is repeated in many textbooks and classrooms---and has even found its way into popular culture. The problem is, however, that this is an oversimplified view of the amygdala. Yes, the amygdala seems to play a significant role in fear. But it is also likely involved in a slew of other behaviors and emotional responses.

An intricate structure with manifold connections

The name amygdala comes from the Greek word for almond, and the amygdala earned this designation because it is partially composed of an almond-shaped structure found deep within the temporal lobes. The almond-shaped structure, however, is just one nucleus of the amygdala (the basal nucleus)---for although it is often referred to as one entity, the amygdala is actually made up of a collection of nuclei along with some other distinct cell groups. The nuclei of the amygdala include the basal nucleus, accessory basal nucleus, central nucleus, lateral nucleus, medial nucleus, and cortical nucleus. Each of these nuclei can also be partitioned into a collection of subnuclei (e.g. the lateral nucleus can be divided into the dorsal lateral, ventrolateral, and medial lateral nuclei). 

Exactly how the amygdala should be divided anatomically has been the subject of some debate, and no clear consensus has been reached. Many researchers group the lateral, basal, and accessory basal nuclei together into a structure referred to as the basolateral complex, and sometimes the cortical and medial nuclei are aggregated as the cortico-medial region. However, there is even a lack of consistency in the application of these terms. For example, some investigators use the basolateral designation to refer to the complex mentioned above, while others use it to refer to just the basal nucleus or basolateral nucleus specifically. Thus, the anatomy of the amygdala is much more complex than is often implied in simple descriptions of the structure. Indeed, the complexity is significant enough that neuroanatomists still have a hard time agreeing on how the different components of the amygdala should be categorized.

In addition to its anatomical diversity, the amygdala has abundant connections throughout the brain---connections that are widespread and divergent enough to suggest many functions beyond just threat detection. For example, many areas of the prefrontal cortex as well as sensory areas throughout the brain have bidirectional connections with the amygdala. The amygdala also has projections that extend to the hippocampi, basal ganglia, basal forebrain, hypothalamus, and a variety of other structures.

Evidence for diversity of function

It is true there is ample evidence that suggests the amygdala is important in the processing of fearful emotions and the identification of threatening stimuli. However, there is also a significant amount of evidence pointing to functions for the amygdala beyond simple threat detection. For example, studies have found the amygdala to be active not just during fear conditioning, but also when learning to link a previously neutral stimulus with a positive experience. Indeed, these studies suggest the amygdala may be involved in learning to assign a positive or negative value to a neutral stimulus, suggesting it has a role in assigning value in general and in the formation of positive and negative memories.

Due to its role in assigning value to stimuli and then creating memories about such valuations, it may not be surprising that some have implicated the amygdala in addictive behaviors. The amygdala has been shown to interact with reward areas of the brain like the ventral striatum, and it seems to play an important role in forming memories associated with drug use. Studies have found, for example, that disrupting amygdala function can inhibit the ability of rodents to learn positive associations with drugs like cocaine. Thus, disrupting activity in the amygdala can also disrupt the acquisition of drug-taking behavior in rodents.

Therefore, instead of being involved only with aversive memories and the learning of conditioned responses to fearful stimuli, the amygdala has come to be considered an important region for the consolidation of memories that have any strong emotional component---whether positive or negative. And this is still really only scratching the surface of the function of this complicated structure. Some studies have suggested, for example, that the amygdala plays a key role in social interaction, others have linked it to aggressive tendencies, and still others have indicated that amygdala connectivity may help to predict sexual orientation.

It may be involved with all of these things. Because the amygdala is a complex structure made up of multiple nuclei, it is unlikely it would serve only one function like "fear detection." Indeed, it is probably unlikely it would even be involved with only one large category of function like emotions. Simplifying the functions of a structure like the amygdala does help to make the brain easier to understand on a superficial level, but it's important to keep in mind that when we do so we are avoiding a more complicated reality in order to make the details of the organ more comprehensible. Although this can be a useful tactic, if we forget we are using it we can hinder the attainment of a more complete understanding of a structure by focusing too much on the simplified model.

LeDoux, Joseph (2007). The Amygdala Current Biology

2-Minute Neuroscience: Glutamate

In this video, I discuss glutamate---the primary excitatory neurotransmitter of the human nervous system. Glutamate is an amino acid neurotransmitter that interacts with both ionotropic and metabotropic receptors. There are 3 identified ionotropic glutamate receptors: NMDA, AMPA, and kainate receptors, and 3 identified metabotropic glutamate receptors. Glutamate is removed from the synaptic cleft by excitatory amino acid transporters, or EAATs. Glutamate transported into glial cells is converted to glutamine before being sent back to the neuron to be converted back to glutamate, a process referred to as the glutamate-glutamine cycle.