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Train Your Brain

Although Parkinson’s disease (PD) is traditionally characterized as a movement disorder, researchers have begun to unravel the disease’s profound impact on non-motor domains including mood, sleep and cognition. Indeed, mild cognitive impairment (MCI) has been increasingly recognized as an early state of PD, evident in about 20-30% of early or newly diagnosed patients and impacting up to 50% of patients during the disease course. In fact, subtle cognitive decline can start as early as 6 years before diagnosis in patients with Parkinson’s disease. According to the Movement Disorder Society, the frequency of MCI increases with increasing age, disease duration, and disease severity.

What is Mild Cognitive Impairment (MCI)?

MCI in PD is a varied condition but common deficits include slowness of thought, difficulties with multi-tasking or planning, decreased attention or concentration, disturbances in word finding, memory and visuospatial abilities (the ability to visually perceive objects and the spatial relationships among objects; this skill is used when retracing our steps, for example). Deficits in executive function, which are necessary for goal-directed behavior and regulation of emotion, are associated with functional disability, increased apathy and visual hallucinations. Not surprisingly, therefore, cognitive impairment greatly impacts the quality of life of both patients and their caregivers. Unfortunately, MCI in PD is also a risk factor for developing dementia and dementia is six times more prevalent in PD patients than in the general population. Therefore, PD patients with MCI represent an at-risk group that may benefit from early intervention to slow the onset of dementia.

What are the current treatment approaches?

Although research is active, to date, there are no FDA-approved treatments for MCI in PD. Whether dopamine replacement therapies provide cognitive benefit is inconclusive. Studies of rasagiline and atomexetine, that held promising results in earlier studies have not been reported in recent clinical trials (1, 2). While cholinesterase inhibitors may help those with mild-to-moderate dementia in PD, a Cochrane review found no clear evidence favoring their use in PD patients with MCI. Furthermore, since PD patients may already be taking multiple drugs, adding more drugs to their regimen may not be desirable.

For this reason, there is a great interest in non-pharmacological approaches to stave off worsening cognitive disability. Indeed, there is evidence for the effectiveness of cognitive training programs in healthy people and non-PD patients with MCI. Researchers believe that cognitive training may slow down the progression of cognitive manifestations of PD by activating mechanisms of neural plasticity, which allows the brain to reorganize its pathways to adjust to new situations and compensate for injury or disease.

Patients should note that if the onset of cognitive disturbances is sudden, they should first be screened for underlying metabolic disorders (thyroid or hepatic), infections (urinary) and vitamin deficiencies, as well as medications.

Does cognitive training work?

In recent years, there has been an explosion of clinical trials investigating the merits of cognitive training. Various forms of cognitive training have been reported to have positive effects on cognitive domains that are commonly impaired in PD, such as executive functions, attention, memory, information processing speed and visual spatial abilities.

Several factors preclude the recommendation of one cognitive training over another, including the small number of participants included in the trials and imperfect study designs. Furthermore, the studied interventions differ in content, duration and outcomes measured. Some programs required homework, while others did not. Some assessed computer-based training alone, with others in combination with paper-based exercises or motor training. Some studies included patients with MCI and others included only cognitively healthy PD patients. Therefore, comparisons across studies are difficult.

Several systematic reviews (1, 2) have concluded that cognitive training is at least moderately effective in improving some cognitive functions for mild-to-moderate PD patients in the immediate or short-term. A recent study concluded that cognitive training leads to clinically meaningful improvements in overall cognition, as well as moderate to large effect sizes on measures of working memory, processing speed and executive functions. However, there was no effect on memory, attention or visuospatial skills. Unable to recommend one program over another, researchers urge for larger randomized controlled trials to provide answers. In awaiting those, what does the literature tell us?

Who would benefit most from cognitive training?

Depending on the stage of the disease, PD patients differ in their cognitive abilities. It is likely that patients with MCI will benefit more from cognitive training than would patients who are more advanced in the disease because they are capable of better understanding the directions the training program. In general, certain patient types may respond more strongly to cognitive training than others, given that differences exist in their predisposition to cognitive decline already in early stages of PD. Specifically, patients who are non-tremor dominant exhibit greater cognitive impairment than the other subgroups.

Research is still needed to identify which intervention is more suitable for unimpaired vs. more severely impaired patients. As of now, there are no studies of cognitive rehabilitation in PD patients with established dementia. However, a study is currently underway to answer this very question.

Certain cognitive training programs may also be more beneficial to certain subsets of PD patients. For instance, one study demonstrated that patients with longer disease duration, earlier age at diagnosis or higher L-dopa equivalent doses tended to experience greater training gains from cognitive speed of processing training. More research is needed to identify which patients would benefit most from a specific training approach.

Should the cognitive training program be tailored to the PD patient?

It is still unclear which cognitive training program, tailored or standardized, is superior for PD patients. In tailored approaches, patients are tested using neuropsychological tests prior to initiating an intervention to assess their strengths and weaknesses; subsequently, the program is tailored to meet their needs. In the standardized approach, all patients are administered the same intervention. In theory, personalization should lead to better outcomes. However, its superiority has not been empirically proven. Indeed, there are studies that show that standardized approaches, too, improve certain aspects of cognition.

Because personalizing the program is time-consuming and costly, it may be best to tailor the program not to the specific PD patient, but to the gamma of deficits that PD patients typically experience, such as in episodic memory (affecting 69% of patients), in executive functions (54%), in visuospatial/construction (46%) and in working memory/attention.

However, testing patients prior to starting the training may provide important information. For instance, it may determine whether an intervention will be effective for a patient with specific impairments. Poor performance on a motor sequence task, such as pressing buttons to reproduce a number series, was shown to lead to greater improvements in sequencing tasks requiring executive function in comparison to unimpaired or control patients. Interestingly, the results of baseline testing and psychologist’s training suggestions may be often concordant with the requests of patients, so having a discussion with a patient in lieu of testing may answer some questions and identify the best treatment approach.

Should the program target specific PD dysfunctions?

Cognitive training can be structured, targeting cognitive domains specifically impaired by the disease, or unstructured, composed of general cognitively stimulating activities. Two studies demonstrated that structured cognitive training appears to be more beneficial than interventions not explicitly focused on cognitive improvement. For instance, one study showed that the structured program (NEUROVitalis) had more benefit for short-term and working memory, a domain of executive function, than did the unstructured Mentally Fit program that focused on language, creative thinking and general group discussions. Similarly, a structured program was more effective on measures of processing speed, visual memory and functional disability than a general program consisting of reading, drawing and arts and crafts. It is still unclear whether cognitive training is more effective when it targets specific dysfunctions (e.g., memory) individually or tackles multiple PD-related dysfunctions at once. A Cochrane Review is currently being conducted, which will attempt to answer this question.

However, there is increasing evidence that unstructured programs, like puzzles (e.g., Sudoku) or video games, may also improve cognitive function. Following six months of daily Sudoku puzzles, patients improved in reaction time, the number of correct answers and missed answers on an attention task correlated to improvements in executive function and logical reasoning, as compared to baseline and untrained PD patients. Furthermore, exergaming, which combines exercise with simultaneous processing of virtual reality cognitive challenges, may also improve certain measures of executive function. In a study of Wii video games, researchers found benefit for patients in overall function, which the authors related to cognition, as well transfer of learning to untrained tasks and a retained benefit at two months. When comparing WiiSports to a more structured program, researchers of one study even found that both programs offered similar cognitive benefits. In fact, patients trained with WiiSports showed even more improvement in attention than those trained with CogniPlus, as well as a trend towards improving visuoconstruction and episodic memory.

Does exercise improve cognition?

The videogame studies suggest that programs that incorporate elements of exercise may provide added benefit than do programs that are purely cognitive in nature. Indeed, one study demonstrated that patients who received a multifaceted program comprising cognitive, transfer and motor elements improved over those receiving cognitive training alone or cognitive plus transfer training only. Specifically, they improved more on cognitive and executive function tests both in the short-term and remained stable over 6 months, reported a better quality of life and felt more confident in activities of daily living. The motor training helped patients improve even in the most challenging executive tasks regarding rule cognition, set shifting, and decision-making. A more diversified and challenging training appears to more effective at improving cognition.

Indeed, numerous studies have demonstrated the therapeutic effect of exercise on PD patients’ cognition. A recent study demonstrated that three months of aerobic training using a stationary bike improved executive function of PD patients, specifically their cognitive inhibition (the ability to tune out stimuli that are irrelevant to the task at hand). For more impaired patients, even bouts of passive cycling may improve executive function. Resistance training, too, has been reported to improve attention and working memory in mild-to-moderate PD patients. Multimodal exercise with both aerobic and progressive strength training elements improves executive function, as well as verbal fluency, spatial working memory and possibly semantic fluency.

Is there evidence that cognitive training leads to lasting benefits?

While most studies examined only short-term benefit, several studies were able to demonstrate a retention of benefit following the program completion. Most recently, researchers were able to show that cognitive training may result in stable improvements that prevent further cognitive decline 12 months following training. Participants who completed a structured or unstructured program were both able to maintain their levels of cognitive functioning, while those in the control group showed significant declines, as well as an increased risk of developing MCI during this time. Another study, although uncontrolled, documented animprovement in verbal processing and fluency, logic and verbal memory and abstract reasoning following 6 weeks of motor plus cognitive training using a computer-based program (Neuropsicologico) with a retention of these benefits even after 6 months following the program’s end.

Should cognitive training be performed regularly?

Some researchers believe that cognitive training may either briefly stabilize cognitive decline or slow the rate of decline. Given the progressive nature of PD, sustaining long-term improvement following cognitive training is unlikely. For example, one study documented significant improvements in visual short-term memory and verbal long-term memory in PD patients following a computer-based program (BrainStim) that targets working memory that lasted up to 3 months. Since this benefit diminished with time in both PD patients and healthy controls, the researchers argued that cognitive training should be incorporated as a regular component of the treatment approach in PD. “Booster” cognitive training may also extend improvements in cognition for a longer period, potentially delaying dementia.

Fortunately, across the studies, patients adhered well to the programs even when faced with more time-consuming interventions. This likely reflects a combination of factors, including the high motivation of the PD community, as well as the acceptability of the cognitive training programs, proving them to be practical and easily implemented. For instance, in one study, patients perceived a one month-long in-clinic standardized program of audio CDs and worksheets (Attention Process Training II) to require moderate-to-high level of effort, without being exceedingly exhausting or effortful, at least somewhat enjoyable and effective in improving their attentional abilities. The authors also reported that those with better cognitive abilities may be more motivated to engage in the program. A recent study& found that patients were satisfied with an even longer (6-15 week) at-home one-on-one cognitive training program, rating its quality and value highly. The participants maintained high levels of effort and enjoyment during the treatment and most had high homework adherence.

How can patients motivate themselves to regularly engage in cognitive training?

Including partners into cognitive training interventions may be one way to increase adherence to the program. In one study, researchers included spouses/caregivers into the training program to promote continued at-home training. According to the questionnaires sent to patients and their partners, social aspects are very important for PD patients. Concordantly, patients adhered better to the training program when their partners participated actively in the sport programs.

Another way to enhance motivation is to engage in a more diverse training program. As compared to patients assigned to cognitive training alone or those assigned to bimodal training involving cognitive and transfer training, patients assigned to multimodal training composed of cognitive, transfer and motor training exercised more physically and conducted more paper and pencil excises at home.

Along with cognitive training, education regarding healthy brain aging and risk factors that contribute to cognitive decline such as depression, anxiety, sleep, vascular risk factors, diet and exercise may also render a program more appealing and provide greater long-term benefits.

Other factors may also affect adherence to the program. Interventions that are administered in-person may be time-consuming, expensive and/or challenging for patients who have mobility difficulties. Many of the studied computer-based programs (Attention Processing Training II; Insight; SmartBrain; COGPACK; BrainTrainer; NEUROVitalis; CogniPlus; Rehacom; BrainStim; REHACOP, currently in Spanish only; Training Neuropsicologico, currently in Italian only), on the other hand, are commercially available and therefore, may be more accessible at home. However, many patients find technology to be daunting. Patients should also beware of the many commercially available “brain training” products on the market that are based on poor or flawed evidence.

How does cognitive training affect the brain?

Some researchers believe that cognitively stimulating activities, as delivered by cognitive training for example, may allow patients to clinically overcome some of the underlying PD pathology in the brain. Supporting this hypothesis, several studies have actually recorded changes in the brain following cognitive training.

Following six months of daily Sudoku puzzles, patients demonstrated significant reductions in the patterns of their brain activation as compared to the untrained PD patients, which the authors interpreted as improved cortical efficiency. Similarly, researchers demonstrated the effect of training on the brain’s functional organization following REHACOP (training attention, memory, processing speed, language, executive functioning and social cognition) and RehaCom programs (training attention and information processing). Another study demonstrated that cognitive training focused on executive functioning increases levels of BDNF, a neurotrophic factor involved in dopaminergic neuron protection and hippocampal neurogenesis, in PD patients with MCI.

The findings suggest that cognitive training may lead to brain changes that potentially normalize activation and connectivity patterns and/or increase neuroprotective compounds in the brain that may delay and/or alter the progression of PD. Whether these changes are long lasting and correlated with improvements in daily tasks is yet to be determined.

Does cognitive training improve patients’ day-to-day lives?

An important aspect to consider is whether the training effect generalizes to untrained tasks and ultimately, translates into improvements in the performance of everyday activities. Although weak, some research suggests that there is some degree of transfer to untrained measures of cognition (1, 2, 3) and related cognitive tasks (1, 2).

While one group did not report a benefit in cognitive difficulties in activities of daily living following training using SmartBrain software and paper/pen exercises, another group demonstrated improvement on the functional disability scale following a structured, pen and paper cognitive training program (REHACOP), suggesting that the training may generalize to functional activities. Nonetheless, given the current body of evidence, a recent review of existing randomized trials concluded that cognitive training did not have an effect on activities of daily living.

As demonstrated by one study, incorporating transfer training into the intervention may be necessary to achieve such results. Here, one group received cognitive training alone, while two other groups received cognitive plus transfer training, in which they used strategies like mnemonics, decision-making and reading comprehension to practice skills in real-world situations such as preparing a meal or paying a bill. All groups showed improvement on the outcome measures; however, patients who received transfer training reported greater improvements in activities of daily living, suggesting that the program generalized to improvements on untrained but similar cognitive tasks. Washington University and Mercy College are planning a study of a cognitive training intervention that will explicitly train for transfer of strategies to real-world activities and environments.

A recent review of existing randomized trials concluded that cognitive training did not improve depression or quality of life. However, only a few studies assessed the effect of cognitive training on these measures. The two studies that did report improvements in depression or quality of life involved a large socialization component. For instance, while an unstructured program (Mentally Fit) focused on language, creative thinking and general group discussions did not improve patients’ cognitive performance, it did improve their depression scores, possibly owing to increased social interaction. The lack of effect on depression in most studies may be due to the fact that the studies recruited patients’ who had low depression scores from the beginning. Therefore, cognitive training may be most effective in PD patients with established clinical depression. Alternatively, it is possible that it may take a longer time (longer than the study duration) to measure changes in depression.

Final Remarks

In order for cognitive training to be considered effective, it should lead to the acquisition of general skills or functions that optimize performance of different everyday tasks. Clearly, this has yet to be demonstrated convincingly. Although questions remain, cognitive training is gaining recognition as a promising approach for maintaining cognition in PD. The current body of evidence is compelling and warrants head-to-head trials aimed at establishing clinical standards for cognitive training in PD patients.

Furthermore, there is some evidence that cognitive training may improve other areas impacted by PD in addition to cognition. For instance, one study demonstrated that cognitive training has carryover effects to certain aspects of mobility, which is known to require attention and executive functioning to perform. A study is currently underway assessing whether cognitive training may improve freezing of gait, which targets cognitive systems such as attentional set-shifting, processing speed and working memory.

On a side note, neural stimulation is another approach that is being explored as a method of improving cognition in PD patients. According to a recent review, studies of noninvasive techniques (repetitive direct current stimulation, rDCS, and repetitive transcranial magnetic stimulation, rTMS) have yielded variable results. Only one randomized control study exists that has demonstrated positive effects on attention and executive functioning following left prefrontal rTMS. Although there are no high quality studies of DBS for improving cognition, one case report described its success following DBS in a PD patient with dementia. Thus while there is some preliminary evidence that neural stimulation may be an effective treatment for cognitive impairment, further research is warranted. The University of Colorado at Denver is currently conducting a randomized control trial to determine to assess the therapeutic potential of bifrontal rTMS in modulating cortical activity and improving cognitive function in PD patients with MCI.

Take-Away for Patients

Although the literature provides more questions than answers regarding cognitive training – which program is best? At what stage of the disease? For how long? What about “booster” sessions?—what patients can take away is this: leading a cognitively challenging lifestyle is important! Supporting this conclusion is the finding that higher levels of education, as a proxy for cognitive reserve (or the brain’s ability to optimize performance through differential recruitment of brain networks and/or strategies), is significantly associated with cognitive performance in PD and a small but significant slowing in cognitive decline.

This means that patients should engage in activities that challenge their brain to learn new things, think creatively, solve problems and achieve goals. Activities such as exercising, reading, using the computer, solving puzzles, playing games, engaging in social interactions and even performing household chores may promote cognitive preservation in PD. To stay sharp, patients should stay active socially, physically and mentally.

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