Is depression an infectious disease?

Over the past several decades we have seen the advent of a number of new pharmaceutical drugs to treat depression, but major depressive disorder remains one of the most common mood disorders in the United States; over 15% of the population will suffer from depression at some point in their lives. Despite extensive research into the etiology and treatment of depression, we haven't seen a mitigation of the impact it has on our society. In fact, there have even been a lot of questions raised about the general effectiveness of the medications we most frequently prescribe to treat the disorder.

This perceived lack of progress in reducing the burden of depression and the accompanying doubts about the adequacy of our current treatments for it have led some to rethink our approach to understanding the condition. One hypothesis that has emerged from this attempted paradigmatic restructuring suggests that depression is more than just a mood disorder; it may also be a type of infectious disease. According to this perspective, depression may be caused by an infectious pathogen (e.g. virus, bacterium, etc.) that invades the human brain. Although it may sound far-fetched that a microorganism could be responsible for so drastically influencing behavior, it's not without precedent in nature.

Microorganisms and brain function

Perhaps the best-known example of an infectious microorganism influencing brain activity is the effect the parasite Toxoplasma gondii can have on rodent behavior. A protozoan parasite, T. gondii lives and reproduces in the intestines of cats, and infected cats shed T. gondii embryos in their feces. T. gondii thrives in the feline intestinal tract, making that its desired environment. So, after being forced out of their comfy intestinal home, T. gondii embryos utilize what is known as an intermediate host to get back to into their ideal living environment.

Enter rodents, the intermediate hosts, which have a habit of digging through dog and cat feces to find pieces of undigested food to eat. When rodents ingest feces infected with T. gondii, they themselves become infected with the parasite. Through a mechanism that is still not well understood, T. gondii is then thought to be able to manipulate the neurobiology of rodents to reduce their inherent fear of cats and their associated aversion to the smell of cat urine. While most rodents have an innate fear of cat urine, T. gondii-infected rodents seem to be more nonchalant about the odor. This hypothetically makes them less likely to avoid the places their natural predators frequent, and more likely to end up as a feline snack--a snack that puts T. gondii right back into the feline intestinal tract.

This is only one example of microorganisms influencing brain function; there are many others throughout nature. Because some microorganisms appear to be capable of manipulating mammalian nervous systems for their own purposes, it's conceivable that they could do the same to humans. Indeed, studies in humans have found links between depression and infection with several different pathogens.

One example is a virus known as Borna disease virus (BDV). BDV was initially thought to only infect non-human animals, but has more recently been found to infect humans as well. In other animals, BDV can affect the brain, leading to behavioral and cognitive abnormalities along with complications like meningitis and encephalomyelitis. It is unclear whether BDV infection in humans results in clinically-apparent disease, but some contend that it may manifest as psychiatric problems like depression. A meta-analysis of 15 studies of BDV and depression found that people who are depressed are 3.25 times more likely to also to be infected by BDV. Although the relationship is still unclear and more research is needed, this may represent a possible link between infectious microorganisms and depression.

Other infectious agents, such as herpes simplex virus-1 (responsible for cold sores), varicella zoster virus (chickenpox), and Epstein-Barr virus have been found in multiple studies to be more common in depressed patients. There have even been links detected between T. gondii infection and depressed behavior in humans. For example, one study found depressed patients with a history of suicide attempts to have significantly higher levels of antibodies to T. gondii than patients without such a history.

Additionally, a number of studies have found indications of an inflammatory response in the brains of depressed patients. The inflammatory response represents the efforts of the immune system to eliminate an invading pathogen. Thus, markers of inflammation in the brains of depressed patients may indicate the immune system was responding to an infectious microorganism while the patient was also suffering from depressive symptoms--providing at least a correlative link between infection and depression.

Interestingly, a prolonged inflammatory response can promote "sickness behavior," which involves the display of traditional signs of illness like fatigue, loss of appetite, and difficulty concentrating--which are symptoms of depression as well. It is also believed that a prolonged inflammatory response can lead to sickness behavior that then progresses to depression, even in patients with no history of the disorder. Thus, inflammation could serve as indication of an invasion by an infectious pathogen that is capable of bringing about the onset of depression, or it might represent the cause of depression itself.

At this point, these associations between depression and infection are still hypothetical, and we don't know if there is a causal link between any pathogenic infection and depression. If there were, however, imagine how drastically treatment for depression could change. For, if we were able to identify infections that could lead to depression, then we might be able to assess risk and diagnose depression more objectively through methods like measuring antibody levels; we could treat depression the same way we treat infectious diseases: with vaccines, antibiotics, etc. Thus, this hypothesis seems worth investigating not only for its plausibility but also for the number of new viable treatment options that would be available if it were correct.

Canli, T. (2014). Reconceptualizing major depressive disorder as an infectious disease Biology of Mood & Anxiety Disorders, 4 (1) DOI: 10.1186/2045-5380-4-10

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Know your brain: Substantia nigra

Where is the substantia nigra?

The substantia nigra is a nucleus in the midbrain that is considered part of the basal ganglia. It looks like a darkened streak in unstained brain tissue; this is where it gets its name, which is Latin for "black substance." Although it is often referred to as one structure, the substantia nigra is actually made up of two anatomically and functionally distinct portions: the substantia nigra pars compacta and the substantia nigra pars reticulata. Neurons in the pars compacta are much more densely packed together (or compact) than those in the pars reticulata.

What is the substantia nigra and what does it do?

Most of the dopamine neurons of the brain originate in the midbrain and are found in either the substantia nigra or the ventral tegmental area, which is located adjacent to the substantia nigra. The dopamine neurons in the substantia nigra express high levels of a pigment called neuromelanin, which accounts for their dark color. These dopamine neurons, however, are found predominantly in the substantia nigra pars compacta. The pars reticulata is instead populated largely by GABA neurons.

Many of the dopamine neurons of the substantia nigra project to the striatum, another part of the basal ganglia that is made up of the caudate and putamen. In doing so they form a pathway called the nigrostriatal dopamine pathway that is thought to be crucial in the facilitation of movement.

The influence of the substantia nigra on movement is made apparent by observing the symptoms of Parkinson's disease, which are associated with the death of dopamine neurons in the substantia nigra pars compacta. Although it still isn't clear what exactly causes neurodegeneration in Parkinson's disease, when a significant number of these neurons have died, the individual will likely start to experience movement-related problems like tremors, rigidity, slowness of movement, and postural instability--all hallmark symptoms of Parkinson's disease.

Being one of the major dopamine-producing areas of the brain, however, the substantia nigra has functions that extend beyond just motor control. It is also thought to play important roles in a number of other functions and behaviors, including learning, drug addiction, and emotion.

Further reading:

What are the basal ganglia?

Parkinson's disease and autoimmunity

Our unclear understanding of ADHD

Attention-deficit hyperactivity disorder, or ADHD, has engendered a great deal of debate over the past several decades. ADHD is a psychiatric disorder that involves symptoms of inattention (e.g. being easily distracted, having difficulty focusing) or symptoms of hyperactivity (e.g. being fidgety or restless), or a combination of both types of symptoms. The controversy surrounding ADHD became a bit louder in the 1990s, when the number of children being prescribed stimulant drugs like methylphenidate (Ritalin) and amphetamine (e.g. Adderall) to treat the disorder increased dramatically.

Part of the debate has focused on the long-term safety of prescribing these stimulant medications to children. There has also been a significant amount of discussion, however, about the nature of the disorder itself. For example, some have argued that ADHD is not a true pathology, but instead indicative of normal behavior that is considered less appropriate in certain cultures. According to this "social construct" hypothesis, only in those cultures where things like orderly behavior are emphasized is ADHD regarded as a disorder. Others have suggested that ADHD is overdiagnosed, and that diagnosis accuracy is inherently inconsistent because the physician often is forced to rely on second-hand reports of a child's behavior to make a diagnosis. On the other side of the debate are those who assert that ADHD is a distinct condition characterized by a specific neuropathology.

The controversy surrounding ADHD has only grown more vociferous over time because the number of children and adolescents in the United States diagnosed with ADHD has consistently been rising since the 1970s. By 2011, about 1 in every 10 children ages 4 to 17 in the United States had been diagnosed with ADHD. Of course, as the number of diagnoses increases, so does the number of children and adolescents who take stimulant medication (which is now at about 1 in every 20 to 25).

While these disagreements about medication safety and how to classify ADHD continue, however, another debate has been going on, if perhaps more quietly, among neuroscientists--most of whom subscribe to the perspective that ADHD has a neurobiological etiology. That discussion has centered on the neural bases of ADHD, and on the question of how accurate the hypotheses we've been relying on to understand the disorder really are.

ADHD and the brain

The two most widely-used pharmaceutical treatments for ADHD are methylphenidate and amphetamine. Although their mechanism of action is slightly different, both drugs cause levels of dopamine and norepinephrine to increase in the synapse, allowing increased interaction between those neurotransmitters and the receptors they act upon. Based on the purported effectiveness of amphetamine and amphetamine-like drugs, and because of the high levels of dopamine activity in areas of the brain thought to be important for attention, early hypotheses about the cause of ADHD focused on the potential role of deficits in dopamine functioning. In other words, it was recognized that drugs that increased dopamine levels improved the symptoms of ADHD, and then (with the support of experimental evidence) it was deduced that low levels of dopamine function might be part of what was causing the problem to begin with.

For example, one popular hypotheses, referred to as the low arousal hypothesis, suggests that low baseline levels of dopamine lead to deficiencies in attention and other executive functions. This may cause an individual to have trouble paying attention and be less interested in stimuli that aren't overly exciting (like schoolwork). The person may compensate for this lack of interest (i.e. low arousal) by frequently looking for stimulation from other things in the environment, which may lead to hyperactivity.

However, research has not consistently supported the idea of a deficiency in dopamine signaling in ADHD patients. Early studies did indicate increased levels of the dopamine transporter in the ADHD brain, which would suggest dopamine was being removed from the brain more quickly in ADHD patients. This would theoretically cause dopamine hypoactivity, supporting dopamine deficiency as part of the etiology for ADHD. Later studies, however, didn't find increased dopamine transporter levels in ADHD patients, and some even found levels of the dopamine transporter to be decreased.

Another approach has been to look at levels of dopamine receptors in areas of the brain thought to play a role in attention, like the striatum and prefrontal cortex. Lower levels of receptors in these areas might suggest a reduced level of dopamine signaling there. Again the results of these studies have been mixed, with outcomes varying depending on the imaging method used, the brain region examined, the age of the participants, and even whether the participants had previously taken ADHD medication or not.

Recent findings

A study published in 2013 may help to shed some light on what is really going on in the ADHD brain. In the study, del Campo and colleagues used neuroimaging to assess structural differences in the brains of ADHD patients and healthy controls, and then looked at functional differences in the brains of these two groups before and after taking methylphenidate.

They found that the ADHD patients had less grey matter in several brain areas--including those thought to be involved in attention like the prefrontal cortex. Such structural abnormalities in ADHD patients have been seen before, and may be associated with deficits in attentional processes subserved by those structures.

When it came to dopamine function, however, the ADHD patients and healthy controls were about the same. The groups had similar levels of dopamine receptor availability and both displayed equivalent increases in dopamine levels after taking methylphenidate. The individuals with ADHD did display overall deficits in attention compared to the control group, but the lack of differences in dopamine activity would suggest dopamine functioning was not the primary explanation for these differences. Interestingly, methylphenidate improved performance in a sustained-attention task in a baseline-dependent manner in both groups, regardless of ADHD diagnosis.

When the researchers looked only at the individuals in both groups who performed most poorly on tasks of attention, however, they saw something interesting. Poor performers in both groups had lower levels of dopamine activity in the caudate, an area of the brain that has previously been implicated in attention. Methylphenidate raised caudate dopamine levels in the poor performers from both groups back to normal levels. Thus, methylphenidate acted to change dopamine levels in areas associated with attention, and this improved performance--but it wasn't an effect that was limited to patients with ADHD. Instead, methylphenidate improved performance in everyone, and it seemed to rectify dopamine imbalances that were seen in poor attention performers, whether they had ADHD or not.

What this means for dopamine and ADHD

The study conducted by del Campo and colleagues supports the hypothesis that dopaminergic mechanisms are involved in processes of attention. However, because potential dysregulation of dopaminergic attentional processes was seen in poor performers in both groups, it suggests that dopamine dysregulation may not be the primary cause of ADHD.

It should be noted that del Campo et al. did not examine differences in dopamine activity in all areas of the brain, including some areas important for attention like the frontal cortices. However, the lack of abnormalities in dopamine function in ADHD patients in other areas of the brain involved in attention makes a dopamine-centered hypothesis of ADHD seem a bit tenuous. And that, of course, leaves us with more questions than answers.

If a dopamine deficiency isn't the underlying cause of ADHD, then what is? Perhaps other neurotransmitter systems, like the noradrenergic system, are also heavily involved. But another possibility is that ADHD is a heterogeneous disorder, characterized by a number of different underlying mechanisms. Which mechanisms are most important may depend on the individual case.

With this in mind, maybe a spectrum approach is a better way to look at ADHD. According to this perspective, attention deficits can be found on a continuum that ranges from minor to more severe symptoms, and the presentation and causes may vary from case to case. As we discover that many mental disorders are much more complex than we initially assumed, it seems the appreciation of heterogeneity offered by a spectrum approach is often more in line with what we see in real practice.

Either way, ADHD research seems like it might be providing us with another lesson in avoiding the allure of simplicity. Although dopamine may still very well play an important role in ADHD, the condition probably should not be explained as a disorder of dopamine deficiency, and this seems to be the direction we were headed in. If we've learned anything from our experiences with supposed serotonin deficiency and depression, it's that these one neurotransmitter explanations of mental disorders seldom turn out to be true.

del Campo, N., Fryer, T., Hong, Y., Smith, R., Brichard, L., Acosta-Cabronero, J., Chamberlain, S., Tait, R., Izquierdo, D., Regenthal, R., Dowson, J., Suckling, J., Baron, J., Aigbirhio, F., Robbins, T., Sahakian, B., & Muller, U. (2013). A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment Brain, 136 (11), 3252-3270 DOI: 10.1093/brain/awt263