Methods and Techniques for Studying Parasite-Induced Neurological Changes

Neurocysticercosis
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Networks of tapeworms colonizing in the fluid-filled cavities of the brain.
Taenia solium cysts [Photograph]. (2012). Retrieved March 1, 2013, from:
http://discovermagazine.com/2012/jun/03-hidden-epidemic-tapeworms-in-the-brain.

In the past, the popular theory explaining why parasites alter their host’s behaviour was the manipulation hypothesis. This theory states that parasites altered their host’s behaviour in order to increase their transmission rate and thereby increase their own selective benefit[1]. There is a great multitude of case studies that would support this theory; however, recent studies using brain imaging technologies have revealed a new possibility. Changes made to the brain by parasitic infections may be a result of the host’s physiological response to the infection[2], as in the case of neurocysticercosis, a condition where brain tapeworms create lesions in the human brain[5]. In this section, various popular methods used to study the effects of parasites on the host’s brain will be discussed. The most common method used to study the effects of parasites on host neurological function is magnetic resonance imaging (MRI)[3]. A major limitation with the MRI method is that it fails to confirm whether the image results are illustrative of parasitic alterations for their own adaptive benefit or whether the damage is merely due to the host’s immune responses[3]. Therefore, the existing controversy in this field is ongoing and scientists are searching for methods that will display more definitive findings. They must account for instances in which the manipulation hypothesis does not ring true through correlation studies [4].

MRI and CT Scans

Many parasitic infections cause changes in host behaviour through physical changes to the brain. These changes can include lesions, by-products, breakdown of the blood-brain barrier, and calcifications, which are made visible through diagnostic methods such as magnetic resonance imaging and computed tomography (CT) scans. MRI is currently the most popular method for the detection of parasitic diseases due to its high spatial and contrast resolution[5]. CT scans also share this advantage, although to a slightly lesser degree[3]. MRI and CT scans are complementary methods that are non-invasive. MRI utilizes the nucleus of hydrogen to produce images of a part of the body. Normally, hydrogen atoms spin at random but when subjected to a strong magnetic field, the atoms will align themselves creating a magnetic vector. During an MRI, a radio wave is sent which deflects the magnetic vector until the wave source is turned off. As the magnetic vector returns to its rest state, it emits a radio wave which produces an image because different tissues return to rest at varying rates. T1 relaxation is the amount of time it takes for the magnetic vector to return to rest, whereas T2 relaxation is the time needed for the hydrogen atoms’ axial spin to return to rest[8]. The main difference between MRI and a CT scan is that CT scans use radiation to generate an image. CT scanners pass a series of x-rays through the body and the beams that travel through denser tissue will be weaker than beams that have travelled through less dense tissue. Therefore, lesions will appear as illuminated areas on a CT scan. The scans are taken from cross sections of the body and pieced together to create a two dimensional image[9].

Neurocysticercosis

Video 1: Pork Tapeworms
Tapeworms in the brain show up on MRI as darkened lesions and as illuminated dots on CT scans.

The most common cause for epilepsy in humans is a parasitic condition called neurocysticercosis. This is a good example of a case where the alteration of host behaviour is evidently due to a physiological response from the presence of parasites rather than from an adaptive mechanism to increase the parasite’s transmission. The culprits responsible for neurocysticercosis are brain tapeworms called Taenia solium[5]. These worms exist as larvae in uncooked pork and are transmitted to the human bloodstream upon consumption. The human becomes the intermediate host for the life cycle of the Taenia solium worm. Since the worm generally resides in the muscles of an infected pig, it chooses to stick to the muscles and soft tissues of an infected human as well[7]. They eventually create an elaborate network in the cavities of the brain and thus begin to alter the human’s central nervous system[5]. Brain tapeworms create lesions in the parts of the brain they invade, creating holes that are visible on MRI and CT scans. The types of symptoms that develop can vary depending upon the location of the lesion. The symptoms can range in severity from headaches, dizziness and seizures all the way to sudden death. Clearly, early diagnosis is of the utmost importance and MR imaging has proven invaluable in this process. The progression of the condition can be monitored through MRI and CT scans as the lesions will worsen over time. Perilesional edemas and the deterioration of the blood-brain barrier are detectable through these imaging techniques, which is imperative to determine the degree to which an individual is suffering and to outline an appropriate treatment[5].

Brain tapeworms create lesions in the parts of the brain they invade, creating holes that are visible on MRI and CT scans. The cysts containing the growing larvae appear as dots of light on a CT scan (Video 1). The types of symptoms that develop can vary depending upon the location of the lesion. The symptoms can range in severity from headaches, dizziness and seizures all the way to sudden death. Clearly, early diagnosis is of the utmost importance and MR imaging has proven invaluable in this process. The progression of the condition can be monitored through MRI and CT scans as the lesions will worsen over time. Perilesional edemas and the deterioration of the blood-brain barrier are detectable through these imaging techniques, which is imperative to determine the degree to which an individual is suffering and to outline an appropriate treatment[5].

There are four categorized stages for Taenia solium development that can be viewed through MRI: vesicular, colloid vesicular, granular nodular, and nodular calcified. The presence of vesicular stage larvae will induce an inflammatory physiological response from the host’s surrounding tissue. The knobbed anterior of the worm that acts as a hook to attach to the brain cavity (called the scolex) will also be detectable (Video 1). The visualization of the scolex is the defining characteristic in the diagnosis of neurocysticercosis. Entering into the second stage of development, the worm will induce further inflammatory reactions and the fluid surrounding the worm will become more viscous and a perilesional edema will be visible through MRI. Interestingly, perilesional edemas are common in epileptic individuals with neurocysticercosis; however, individuals with non-cysticercosis epilepsy do not present with such edemas. It is therefore plausible that these edemas form as a result of the host's inflammatory reaction to the parasite, but edemas are not necessarily the cause of epileptic seizures[6]. As the larvae progressed into the granular nodular stage, the worms have died and the lesions will dissolve, so an MRI can reveal the larval stage based upon the number of lesions present. Calcified lesions are better viewed on CT scans[5].

Encephalitic Versus Non-Encephalitic

Figure 1
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MRI of patient with encephalitic neurocysticercosis (adapted from [10]).

Figure 2
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CT scan of patient with non-encephalitic neurocysticercosis (adapted from [10]).

Of the patients with neurocysticercosis that present with lesions in their brain, only some are encephalitic. MRI is used to determine which form a patient has because they have different treatment plans due to the difference in pathological mechanisms. In figure 1, MRI is used to detect encephalitis in the brain and degenerating cysticerci. In figure 2, a CT scan was used to identify many lesions, but the image does not depict any swelling as this patient presented with the non-encephalitic form[10]. Through these images the location of inflammation can be determined. There has been evidence that inflammation is not specific to a particular area of the brain in toxoplasmosis per se but rather, it is the combined effects of the multiple affected areas that plays a role in the onset of the cognitive and behavioural deficits observable in toxoplasmosis[13].

Toxoplasmosis

Figure 3
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MRI of patient with AIDS and toxoplasmosis (adapted from [3]).

Toxoplasmosis is a common behaviour-altering parasitic disease that is caused by the presence of a protozoal parasite called Toxoplasma gondii. The disease affects almost all warm-blooded animals[3], including approximately two billion people chronically[4]. The parasite infects the cells of the definitive and intermediate hosts in which they perform asexual reproduction, causing the formation of lifelong cysts. Whereas there has been evidence to illustrate that this disease specifically causes rodents to convert their fear of cat odour into attraction, this behaviour is not translatable to humans[11]. However there are correlation studies that indicate that patients with schizophrenia present with an increased number of antibodies to the parasite, so behavioural changes are present in humans as well[12]. A person with a chronic condition of toxoplasmosis will not necessarily present with symptoms, but patients who have a compromised immune system prior to infection may be subject to a more severe onset of symptoms. MRI is helpful in the recognition of toxoplasmosis because it affects the white and gray matter of the brain, creating lesions that are visible through MRI. In figure 3, lesions in the regions of the thalami can be viewed[3]. MRI and CT scans are also able to pick up other brain abnormalities resulting from toxoplasmosis such as hydraencephaly, microencephaly, porencephalic cyst, and periventricular calcification. CT scans are more indicative of calcifications. A major limitation with the MRI method in this case is that it is difficult to tell whether the abnormalities have arisen from the toxoplasmosis infection or from other disturbances. Humans that are more prone to the symptoms of toxoplasmosis are also more prone to other pathologies that compromise immunity, as they generally already have a deteriorated immune system. Severe cases of toxoplasmosis are frequently comorbid with AIDS[3]. 

Behavioural Tests

Rodents are oftentimes used to model toxoplasmosis in humans. After infection with the T. gondii parasite, rodents are subjected to a number of behavioural tests. Hunching is a behaviour that is observed in sick rodents, so analyses are performed to test whether statistically significant amounts of sick rodents display this posture. Healthy mice are known to repeatedly groom themselves throughout the day, so signs for the cessation of grooming are analysed. Neuromuscular and sensorimotor functions are analysed including grip strength and pain sensitivity. The mice are also placed in open-field tests to test for anxiety levels. Through these tests, physical determinants of parasitic manipulation are tested ultimately resulting in a classifiable array of symptoms[4].

Correlation Studies: Evidence Supporting Manipulation Hypothesis

Correlation studies are the only way to provide evidence for the manipulation hypothesis. If there is no evidence directly implying that it is specifically the parasite that is causing the behavioural changes for their own benefit, scientists must account for other possibilities. Correlation studies are used in studying the effects of brain lesions caused by parasites. If lesions begin to disappear upon treatment of the parasite, there is a positive correlation between the presence of the parasite and the onset of the damage. One technique used is the comparison of brain weight to neurological findings. These studies examine whether a parasite causes the loss of brain tissue and therefore a reduction of brain weight, and whether there is a correlation with changes in behaviour[4].

Suicidal Crickets

The hairworm Paragordius tricuspidatus enters into the cricket Nemobius sylvestris and manipulates its behaviour causing it to commit suicide by jumping into water, which is the medium through which the hairworm reproduces. There is a period of time between the point at which the worm enters the cricket and the point at which the cricket actually commits suicide. During this period, the cricket displays aberrant behaviour and is in a manipulated state (Video 2). The duration of this period is dependent upon the balance between the worm's investment of energy and resources in reproductive effort compared to manipulative effort. In order to assess whether the manipulation hypothesis rings true in this case, two correlation studies were performed by Sanchez et al.: 1) whether there was a correlation between infection with the worm and encounter rate with water, and 2) whether the point at which the cricket decides to commit suicide is ideal for optimum parasite fecundity. It was discovered that the timing at which the cricket committed suicide, and subsequently the time at which the hairworm was expelled, was indeed optimum for hairworm reproduction[14].

Video 2: Suicidal Crickets
Hairworm manipulates cricket to commit suicide in order to reach reproductive habitat.
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