Ataxia & Cerebellar function
Ataxia is a lack of coordination in movement, or more specifically: a neurological sign of lack of coordination of muscle movements. It can have a variety of causes and is a symptom of a range of disorders.
To investigate ataxia and related motor disabilities, from neuronal pathways to possible treatments, several animal models and a range of standardized tests are used.
Different forms of ataxia
The cerebellum is responsible for the fine coordination of movement and motor planning. It integrates multimodal neural information to make sure you move smoothly, and respond and adjust your movements in a timely fashion. Say you are walking across your living room in the dark, and you could not see a box hidden in the shadows… luckily you recover quickly, adjusting your stepping pattern and preventing a nasty fall. Thank you, cerebellum.
If the cerebellum is lesioned or otherwise affected, some form of ataxia (see above) is likely. What exactly goes wrong depends upon which part of the cerebellum is affected. When the vestibulocerebellum (flocculonodular lobe) is affected, this manifests in problems with balance and control of eye movements.
Dysfunction of the spinocerebellum (vermis and paravermis) causes people to walk widely, and imbalanced with unequal steps, as if they are drunk. The cerebrocerebellum (lateral parts of the hemispheres) is involved in the accurate timing and planning out of movements, so when something is wrong there it can cause tremors, unequal writing, slurred speech, inability to rapidly alter movements, undershooting or overshooting movement, and more.
While ataxia is often mentioned together with cerebellum, there are also causes of ataxia that originate elsewhere. In sensory ataxia, the lack of coordination can occur due to insufficient sensory input, for example when the patient shuts his eyes and cannot see himself move his legs while walking. Most people are able to still maintain balance in such situations; for sufferers, the sudden lack of sensory input results in poor coordination and balance when visual stimuli are no longer present.
Friedreich’s ataxia is an inherited form in which the damage to the nervous system gets progressively worse. In these patients, the neurons in the spinal cord degenerate, particularly those that are essential for arm and leg movements, connecting with the cerebellum. In addition to gait disturbances, these patients can also suffer from conditions such as heart diseases, but cognitive functions are generally not affected.
Ataxia can affect body and behavior in different ways:
- Hemiataxia – only on one side of the body
- Dystaxia – a mild form, resulting in shaky limb movements and unsteady gait
- Asthenia – general muscular weakness
- Dyschronometria – distorted time perception
- Dysarthria – speech impairments
- Dysphagia – difficulties swallowing
- Hypotonia – low muscle tone
- Dysmetria – undershooting or overshooting movement
- Dysdiadochokinesia – impaired ability to rapidly alternate movements
Causes of ataxia
Ataxia can have a number of different causes. Focal lesions, for example due to a stroke or brain tumor, can cause ataxia. The type of ataxia depends on where the lesion is located in the central nervous system. Metabolic ataxia is caused by substances such as ethanol (alcohol) and certain drugs. Radiation poisoning, hypothyroidism, and even vitamin E and B deficiencies are also known causes of ataxia.
Medication and treatments
There is no cure for ataxia. In some instances, for example when ataxia is caused by vitamin E deficiency, treatment can be targeted at the underlying problem. But in most cases, treatment of ataxia is mostly aimed at relieving symptoms with drugs, physiotherapy, speech therapy, etc. Several medications are used, but ataxia patients are more sensitive to medications as they suffer from a central nervous system disease.
Current disorders and therapies of interest
To be able to provide ataxia patients with more quality of life, several research groups aim their efforts at investigating the genetic background, detailed neurological pathways, possible therapies and drugs that might cause, increase, or decrease symptoms, etc. Ataxia is a common problem in Parkinson’s disease (PD), and Alzheimer's patients also deal with it. In fact, a large part of early onset Alzheimer’s disease patients (AD) have ataxia. Motor skills can also be affected in patients with autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD).
Early onset Alzheimer’s disease
Diego Sepulveda-Falla and his colleagues were part of a study that was described in the media as groundbreaking research. They worked together with a cohort of 25 families from the Antioquia area in Colombia with a high prevalence of early onset familial Alzheimer’s (FAD). While previously it was thought that a gene mutation causes plaques, which in turn causes Alzheimer's symptoms, this study suggests that the mutation causes ataxia in these patients through a different mechanism in the cerebellum (read more in this blog post).
Parkinson’s disease and parkinsonism causes cell death in a specific part of the midbrain (the substantia nigra), as a result the motor system is affected. As a consequence ataxia is often found in Parkinson patients.
Korsakoff syndrome is one of the causes of ataxia that is studied often in rat and mouse models. The long-term overconsumption of alcohol in combination with poor nutrition causes a deficiency in vitamin B (thiamine) in patients that mainly causes memory-problems, but also disturbs balance and motor control.
Vitamin E is neuroprotective, and when the body is unable to use all vitamin E from diet, a deficiency can cause neurological problems such as ataxia. This is called AVED (ataxia with vitamin E deficit). Both laboratory and clinical studies investigate the effects of lifelong high doses of vitamin E and some reports say it may to some extent reverse ataxia. For example, this study shows that alpha-Tocopherol (a form of vitamin E) almost completely prevented the development of neurological symptoms of an alpha-TTP knock-out mouse model of AVED.
Rodent models and tests for ataxia and motor disturbances
To investigate ataxia and related motor disabilities, from neuronal pathways to possible treatments, several animal models and a range of standardized tests are used. Well-known examples include the rotarod, (rotating) beam walk test, treadmills, and complete gait analysis systems such as CatWalk XT. Quite recently, a novel system specifically designed for testing cerebellar functioning (ErasmusLadder) came on the market. Due to the freely adaptable protocol, it is useful to measure a broad range of motor capabilities, including ataxias. First, let’s take a closer look at these other methods.
The beam walk test is pretty self-explanatory. It involves letting the rat or mouse traverse a narrow beam to escape a not-so-pleasantly brightly lit platform onto a nice, dark goal box. This test is one of balance and coordination. It is relatively simple and quite sensitive, but not suitable for severely ataxic animals, as they cannot walk the beam. It is also done completely manually and behavioral measurements can be rather subjective.
The rotarod is, as the name suggests, a rotating rod. The length of time that a mouse or rat is able to stay on the rod is used as a measure of balance and coordination. It is a useful and well-validated test, but again, options to automate this test are limited in that motor learning can not be studied in a sensitive manner. Like the beam walking test, this test cannot be performed by severely ataxic animals.
Just like in the gym, treadmills for rodent research are running belts with an adjustable speed and sometimes even an adjustable slope. Treadmills are used to study motor control (locomotion), but also the muscular system generally. Treadmills (or treadwheels) force animals to walk at a certain speed. While this eliminates speed as a variable, it also elicits an unnatural gait, which may be a problem for certain studies. Additionally, a treadmill causes a visual discrepancy, the animal is moving, but the environment is staying in place. Visual input during movement is important, so compensation or correcting visual acuity might be necessary in these experiments.
Do you remember the old paw-inking method of gait research? With this, you dipped the animal’s feet in ink and let them run over a sheet of paper, then measured print size, step size, etc with a pen and ruler. Technology has brought us a better way to do this, using CatWalk XT. In principle this system is based on the same methodology: it record the footprints of rodents as they walk a straight line. But with CatWalk XT, everything is automated and much more information is brought to the researcher’s attention. Illuminated footprint technology records the dynamic footprints as the animal crosses a dark corridor voluntarily. These prints are then processed within the CatWalk XT software, and calculates a number of statistics based on print size, the distances and amount of time between footprints and footfalls, and so much more. This allows for easy, stress-free testing. For more information, click here.
For example, Elisavet Kyriakou and her colleagues used CatWalk XT to assess the motor function or three rat models of impaired coordination and ataxia. They found differences in both static and dynamic parameters, and they were able to gain useful insights into the effects attributed to intervention, treatment, or injury with CatWalk XT.
While CatWalk XT offers a lot of options to study gait and locomotion, studying motor learning and the specific functioning of the cerebellum requires a more specific test. For this, we present the ErasmusLadder, which gets its name from Erasmus MC (Rotterdam, The Netherlands) where this new test was developed in the lab of Prof. Dr. Chris De Zeeuw.
The ErasmusLadder task allows specific testing of cerebellar locomotion performance and learning. A horizontal ladder with high and low rungs connects two goals boxes. As each rung is touch sensitive, the mouse’s stepping pattern is measured and as time progresses, mice easily learn to traverse the ladder efficiently – using only or mostly the higher rungs, and often jumping over multiple rungs at once.
In a second phase, cerebellar functioning can be specifically tested using an obstacle (announced by a tone); animals with properly functioning cerebellum learn to quickly react and anticipate the obstacle when they hear the tone. In addition, by measuring the time in the box and on the ladder, general cognitive functions such as fear, attention, and motivation can also be investigated.
The great advantage over other methods is that this highly sensitive test can be performed by even the most ataxic mice. In fact, it is both easy enough for ataxic mice to cross, as well as sufficiently challenging for wild types. All animals are able to cross but will make some mistakes in the beginning (such as missteps to the lower rungs). ErasmusLadder is also completely automated, which makes it an objective and easy and efficient way of testing.
Also, alternative specific tests for cerebellar functioning are scarce. Other examples include the well-known Pavlovian eye blink test and adaptation of the vestibulo-ocular reflex, but these tests require surgery and are very low throughput.
Because the non-invasive protocol for ErasmusLadder is adjustable, this test is suitable to study a range of motor performance issues including several ataxias. It is also perfectly suited for longitudinal studies. It is a very robust test, meaning that testing mice over a longer period of time, undergoing several treatments or experiencing the effects of aging over time, provides quality data on the effects of affliction, treatment, recovery, and aging on motor performance and motor learning over time.