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Cognitive Training in HD

Cognitive Training in HD

Huntington’s Disease (HD) is known to cause degenerative changes in three domains: physical, psychological, and cognitive. Although there are no medications currently approved for treating all three domains of HD effects, there are many medications and therapies that can be prescribed for both physical effects (such as chorea) and psychological changes (such as HD related depression). There are, however, fewer options for treating the cognitive changes that arise as a result of HD. One possible option, however, may be cognitive training, which will be explored in this article as it relates to Huntington’s Disease

What is Cognitive Training?

Cognitive training includes mental, intellectual interventions that are designed to target one or more cognitive domains, which have been used by neuropsychology to assess cognitive performance. As defined by the DSM-5, which is used to define and diagnose mental disorders, these domains include executive function, complex attention, social cognition, learning and memory, language, and perceptual-motor function, each with subdomains that allow physicians to more specifically analyze cognitive deficits. 1 Many people affected by HD experience some cognitive symptoms, which can include difficulties with complex problems, thinking through the steps of a problem, and multitasking. In later stages of HD, it may also include the inability to learn new motor tasks due to cognitive symptoms. 2 As cognitive symptoms may greatly affect someone with HD, making the effort to find a solution to these problems is all the more important. An appropriately targeted cognitive training method is one possibility worth exploring. Although not enough research has been done on cognitive training specifically in HD patients to determine whether cognitive training may be beneficial to this population, there have been many studies of cognitive training in other neurodegenerative diseases that suggest that such a result is possible. 

Cognitive Training in other Neurodegenerative Diseases

Over the last few decades, there have been many studies focusing on the effects of cognitive training in neurodegenerative diseases, including Alzheimer’s Disease (AD), non-Alzheimer’s Dementia, the pre-Alzheimer’s Disease state of Mild Cognitive Impairment , and Parkinson’s Disease. A meta-analysis published in 2014 by researchers at King’s College London looked at thirty-three studies of the effects of cognitive training on Alzheimer’s based dementia. 3 Most of the studies in this analysis showed a statistically significant improvement on the mini-mental state evaluation (MMSE) and Alzheimer’s disease Assessment Scale-Cognition (ADAS-Cog) for those who underwent cognitive training as compared to controls. Both the MMSE and ADAS-Cog are well established and widely used by the psychiatric community to measure cognition. Therefore, an improvement on the performance of these assessments after cognitive training suggests that cognitive training may be effective at improving cognition. However, authors of the meta-analysis point out that these results may not be clinically significant; that is, even though they seemed significant in the calculations, that difference may not translate to a noticeable change in the patients’ real life. 

Other studies have focused on the effects of cognitive training in cases of Mild Cognitive Impairment (MCI). Though there is no specific test to diagnose MCI, it has been used for research purposes as a pre-Alzheimer’s state, as many — though not all — cases of MCI later progress to AD. Researchers consider cognitive training as especially relevant to MCI, as these patients have not yet progressed to clinical AD or dementia, and are therefore in a state in which this training may be maximally effective. A different meta-analysis published in 2011 by Li et al. looked at the results of many studies on the effects of cognitive training in MCI. 4 They looked at seventeen studies which, overall, showed significant improvements in various domains of cognition in those who underwent cognitive training. The domains in which they saw improvement included language, episodic memory, semantic memory, executive functioning/working memory, attention, and more. While these results are encouraging, it is important to note that MCI is unique from other neurodegenerative states as it has not yet — and may never — progress to a clinically diagnosed neurodegenerative disease.

There have also been studies on the effects of cognitive training in Parkinson’s Disease (PD), which is important to consider, as PD is considered the most clinically similar to HD out of the neurodegenerative diseases described in this paper. A 2011 study on the effects of cognitive training in PD patients found that those who underwent cognitive training had significantly improved performance in the areas of attention, information processing speed, executive functioning, and more as opposed to those who did not receive cognitive training. 5 A different study from 2015 found that cognitive training in PD patients resulted in beneficial effects on the cognitive deficits in these patients as well as an increase in their brain-derived neurotrophic factor (BDNF) concentration. 6BDNF is an important protein responsible for maintaining adult nerve cells, and has been studied in relation to Huntington’s Disease (for more information on BDNF, visit this page). However, this study emphasizes that they do not know whether an increase in BDNF is beneficial to damaged nerve cells, like those in both PD and HD. 

While none of the neurodegenerative diseases mentioned have the exact same characteristics as HD and are therefore not completely applicable to HD cognitive training research, they do establish a solid foundation for research on cognitive training in HD. Additionally, these studies and more have done a lot to help researchers understand what cognitive training is, how to study it, and how to employ it in the context of a neurodegenerative disease. 

Cognitive Training in Mice Models of HD

More relevant to HD specifically, there have been a few studies over the past few years with the aim of evaluating the efficacy of cognitive training in mice models of HD. One study conducted by researchers at the Cardiff University School of Biosciences in 2016 used HdhQ111/+ knock-in mice  — in which researchers intentionally add a gene to the mouse genome — to simulate HD symptoms in mice models. 7 They randomized both wild-type control mice and the HdhQ111/+  to three different treatment groups to study the effects of cognitive training on the HD mice vs the controls in the different groups. The first group of control and HD mice received cognitive training that involved an attention based task, the second group received a non-attention based cognitive task as training, and the third group received no cognitive training. This study found that both the control and the HD mice in groups one and two (attention and non-attention based cognitive training) performed better on cognitive tasks than the group that received no training. Additionally, the HD mice that received cognitive training showed improved “HD related behavior.” Since the tasks selected were designed to be a representation of HD related cognitive deficits, these results suggest that cognitive training — either attention or non-attention based — has the potential to help those experiencing the cognitive deficits of HD. 

Another study conducted by Curtin et al. and also published in 2016 performed four experiments to test different aspects of cognitive ability in HD mice. 8 The mice were 28-29 weeks old when they were tested, and the studies compared the abilities of mice who received cognitive training when they were 6-9 weeks old to mice who did not receive cognitive training. Using zQ175 mice — another mouse model for HD — the four cognitive skills that they studied in the different experiments were learning and motivation, response inhibition, cognitive flexibility, and memory deficits. In all four experiments, the HD mice who received cognitive training displayed fewer impairments than those who had not. 

Results from both these studies are encouraging for the use of cognitive training to help manage symptoms for HD patients, though it is important to note that results displayed in animal models do not always translate to human patients. 

Cognitive Training in HD Patients

Though there aren’t many studies specifically looking at the effects of cognitive training in Huntington’s Disease patients, there are a few that shed light on this topic. One of these is a clinical trial named CogTrainHD which began in late 2016 and was conducted by researchers at Cardiff University. This study used computerized cognitive training software to determine whether cognitive training is a feasible way of treating HD symptoms. The results of this study have not been posted, but you can find more information here. 9

In addition to the CogTrainHD clinical trial, there are a few studies which look at specific outcomes beyond cognition as the result of cognitive training. For example, a study published in 2020 by Barlett et al. studied the effects of  multidisciplinary training which included cognitive training on the volume of the hypothalamus, levels of BDNF, circadian rhythm, and habitual sleep in people with Huntington’s Disease. 10 These factors are important to study, as changes to the hypothalamus — a region of the brain important in maintaining homeostasis, or internal equilibrium of body processes — have been noted in HD patients. This study found that the HD patients who underwent the multidisciplinary training experienced a smaller loss of brain matter in their hypothalamus than those who did not have the training. Those who had the training also maintained their levels of BDNF, while those who did not have the training experienced a decline in their BDNF following the study period. Although this study included exercise and social interaction in addition to cognitive training in the multidisciplinary training, it supports that a training regimen including cognitive training may encourage positive results for those with HD. 

A specific type of cognitive training that researchers are looking at for its potential to help those afflicted with HD is neurofeedback training. Neurofeedback training differs from traditional cognitive training because it is done while a patient is receiving a real-time functional MRI (fMRI) scan. The training program can use the participant’s response to modify the way the training is given. For example, if the person consistently enters the wrong or correct answer, the program may select easier or more difficult questions, respectively. A study published in 2020 conducted by Papoutsi et al. looked at the feasibility of using neurofeedback training for HD patients by conducting a controlled trial on thirty-two Huntington’s Disease patients. 11 These participants were split into four groups: two conducting neurofeedback training, each with a focus on a different region of the brain, and two control groups that received no neurofeedback intervention. The study found that while there were no significant differences between the results of the two intervention groups that focused on different regions of the brain, both intervention groups performed better on the neurofeedback tasks than the control groups by the end of the intervention. However, neither the intervention nor control groups displayed any improvement in cognitive functioning outside the neurofeedback tasks.

It is evident that more research is needed to determine whether cognitive training is an effective way to treat the cognitive symptoms displayed in Huntington’s Disease. While many of the results on both human and animal models are encouraging, there are many different types of cognitive training that make it difficult to determine what may be the best solution for the most people. Many factors play into whether or not a cognitive training regimen will be effective for an individual: the individual’s medical and mental history, the type of cognitive training, how often one participates in cognitive training (per day, week, etc.), and how long the training period lasts, which is especially important in a study, because if training is not done for long enough to see a result we may be discounting training that may be effective if done for a longer period of time. All of these factors are important to consider when conducting or learning about cognitive training research, and without consideration of all of them, it is difficult to determine what cognitive training therapies actually work. While there are many studies on cognitive training in other neurodegenerative diseases that may serve to guide similar research for the HD community, it is imperative that more research be done on cognitive training in Huntington’s Disease so that HD patients do not miss out on what could potentially be a beneficial form of therapy. 

  1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author. []
  2. https://hdsa.org/what-is-hd/cognitive-symptoms/ []
  3. Huntley JD, Gould RL, Liu K, et al. Do cognitive interventions improve general cognition in dementia? A meta-analysis and meta- regression. BMJ Open 2015;5:e005247. doi:10.1136/bmjopen-2014- 005247 []
  4. Li, H., Li, J., Li, N., Li, B., Wang, P., & Zhou, T. (2011). Cognitive intervention for persons with mild cognitive impairment: A meta-analysis. Ageing research reviews, 10(2), 285-296. []
  5. París, A. P., Saleta, H. G., de la Cruz Crespo Maraver, M., Silvestre, E., Freixa, M. G., Torrellas, C. P., … & Bayés, À. R. (2011). Blind randomized controlled study of the efficacy of cognitive training in Parkinson’s disease. Movement Disorders, 26(7), 1251-1258. []
  6. Angelucci, F., Caltagirone, C., & Costa, A. (2015). Cognitive training in neurodegenerative diseases: a way to boost neuroprotective molecules?. Neural regeneration research, 10(11), 1754. []
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  8. Curtin, P. C., Farrar, A. M., Oakeshott, S., Sutphen, J., Berger, J., Mazzella, M., … & Brunner, D. (2016). Cognitive training at a young age attenuates deficits in the zQ175 mouse model of HD. Frontiers in behavioral neuroscience, 9, 361. []
  9. https://clinicaltrials.gov/ct2/show/NCT02990676 []
  10. Bartlett, D. M., Lazar, A. S., Kordsachia, C. C., Rankin, T. J., Lo, J., Govus, A. D., … & Cruickshank, T. M. (2020). Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington’s disease: A nine-month pilot study. Journal of the neurological sciences, 408, 116522. []
  11. Papoutsi, M., Magerkurth, J., Josephs, O., Pépés, S. E., Ibitoye, T., Reilmann, R., … & Tabrizi, S. J. (2020). Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington’s disease. Brain Communications. []