Leigh E. Carvet, PhDLeigh E. Carvet, PhD
Patients with multiple sclerosis (MS) experience not only physical symptoms but also an elevated risk of psychiatric comorbidities and cognitive dysfunction, according to the findings of various studies. In a systematic review published in 2015, rates of depression and anxiety were 23.7% (95% CI, 17.4%-30.0%) and 21.9% (95% CI, 8.76%-35.0%), respectively, among patients with MS.1 In other research, depression was 2 to 5 times more common among people with MS compared with the general population.2 Additional findings suggest a greater prevalence of bipolar disorder and other psychiatric illnesses in this group, as well, although research has been limited and results have been variable overall.

The authors of the 2015 review noted that the “prevalence of psychiatric comorbidity is high even at the time of MS diagnosis and rises over the course of the disease.”1 The mechanisms underlying these associations are likely multifactorial, reflecting pathophysiology of the disease—such as immunological and inflammatory changes or structural brain abnormalities that may lead to depression—and therapies used in MS treatment, along with psychosocial and other factors.

Bridging Gaps in Psychiatric and Cognitive Care

Comorbid mental illness in MS has been linked to lower adherence to disease-modifying therapy, higher levels of fatigue and pain, reduced quality of life, and increased disability progression and mortality.1,3 In research published in 2018 in Multiple Sclerosis and Related Disorders, approximately one-third of patients with MS reported a need for mental health treatment.3 However, factors such as time, cost, transportation, and mobility limit patients’ access to traditional in-person services, highlighting the need for more accessible modes of treatment delivery. To that end, emerging approaches using digital technology have shown promise in improving both mental health symptoms and cognitive dysfunction, which is estimated to affect more than 50% of people who have MS.4

“I believe that we are on the cusp of major innovations in this space for improving both mental health and cognitive function for people living with MS,” Leigh E. Charvet, PhD, associate professor of neurology and director of MS research at NYU Langone Health’s Multiple Sclerosis Comprehensive Care Center in New York, New York, told NeurologyLiveTM. She described a few key areas of development in this setting: “First, the platforms for online connection and support are rapidly developing to provide very targeted symptom management, sometimes even in conjunction with the health care team. Second, there are increasingly sophisticated online and app-based programs that can be used for symptom reduction that have a growing body of research supporting their use.”

For example, a sizable body of research supports the benefits of mindfulness-based meditation (for which numerous digital tools are available) for people living with MS, both in reducing distress and improving mood and cognitive focus. Authors of a systematic review published in 2019 reported that mindfulness-based interven- tions were associated with statistically significant benefits related to mental health, quality of life, and certain measures of physical health in patients with MS.5 These effects were sustained at 3-and 6-month follow-up assessments. There are also well-developed digital pain-management programs that may be useful to patients.

Remote Cognitive Rehab and tDCS

Charvet believes that patients will soon be able to have symptoms routinely monitored from home and that telemedicine will facil- itate greater access to providers and enable in-home delivery of therapies and rehabilitation. Research by Charvet and colleagues indicates that “brain training” programs can improve aspects of cognitive functioning over time. In a double-blind, randomized trial published in 2017, the team investigated the effects of an adaptive online cognitive remediation program called BrainHQ in 135 patients with MS.4 Their results show that 12 weeks (60 sessions) of home-based training with BrainHQ improved cognitive functioning to a greater degree than an active control condition involving ordinary computer games (mean change in composite z score ± SD, 0.25 ± 0.45 vs 0.09 ± 0.37; P = .03; estimated difference = 0.16; 95% CI, 0.02–0.30 [FIGURE]).

“[I subsequently] became very interested in the emerging technol- ogies to provide noninvasive brain stimulation to rehabilitate and manage symptoms in MS and, specifically, transcranial direct current stimulation [tDCS], due to its extensive safety and tolerability profile and portability of devices,” Charvet said. “To be effective, tDCS and most rehabilitative therapies must be repeated near daily across multiple sessions, and it is usually too much of a burden for patients to come to a clinic to receive this frequency and duration of treatment. We recently published a study demonstrating this need.”6

To address the issue, she and her team developed remotely supervised tDCS (RS-tDCS), a home-based model that can be paired with cognitive or motor rehabilitation. They verified the feasibility of the approach in patients with MS, including those with greater disability who are typically unable to participate in rehabilitation studies, and found that RS-tDCS combined with home-based brain training can reduce MS fatigue and improve the effects of cognitive training.7,8

Among the group’s additional studies under way is a large trial comparing RS-tDCS to sham stimulation for the treatment of MS fatigue and cognitive impairment. The randomized controlled trial, funded by the National Multiple Sclerosis Society, is being completed. Overall, the investigators have delivered >3500 RS-tDCS and rehabilitation sessions to patients at home thus far. “I believe that neuromodulation with noninvasive brain stimulation is a very promising nondrug option for the management and rehabilitation of MS symptoms, but careful and controlled research is still needed to provide parameters and guidelines for optimal clinical implementation,” Charvet said.

Digital Tools for Assessment and Symptom Improvement

Another development on the horizon is a collaboration between Sanofi and Happify Health to create and study a digital app based on cognitive behavioral therapy to help improve mental health symptoms in people with MS.9 “Happify Health has a successful mental health digital solution that has more than 5 years of scientific evidence showing it can reduce depression and anxiety through innovative user experiences and gamification,” a Sanofi spokesperson told NeurologyLiveTM. “This collaboration will build on its existing product to create a product specifically for people living with MS, which Sanofi aims to have validated clinically.” The company will then submit the product for approval by the FDA as a medical device that would be available by prescription.9 Patients are becoming increasingly interested in selfmanagement solutions, and “Sanofi has successfully implemented digital solutions across the business and has a deep understanding of MS therapeutic development and commercialization,” the spokesperson added.

Digital health offers a “particularly exciting” opportunity to enhance continuity of care, according to Charvet: “For instance, the MS Performance Test is an iPad assessment that can be integrated into the clinical visit to provide more comprehensive assessment for monitoring cognitive and motor functioning, as well as quality of life over time.”10

Meghan L. Beier, MA, PhD, a rehabilitation neuropsychologist and an assistant professor of physical medicine and rehabilitation at The Johns Hopkins University School of Medicine in Baltimore, Maryland, further elaborated on digital tools that may be used to assess cognition in patients with MS. A range of computerized cognitive test batteries have been examined in this population, such as the Cognitive Drug Research battery, NeuroTrax (previously known as MindStreams)/BrainCare, Cogstate Brief battery, and CNS Vital Signs.

Single domain screeners are also being used, including the processing speed test.11 “These instruments are generally self-administered, meaning that patients can take them without the assistance of a testing technician, and they do very well at detecting difficulties with processing speed, the primary area of cognitive difficulty in people with MS,” Beier told NeurologyLiveTM.

She noted that gaps remain in the use of computerized cognitive assessments, including the issue of ecological validity. Further validation research will be needed before the results of existing cogni- tive assessments can be fully understood and applied. One shortcoming of the current tools is that they do not adequately assess the learning of new information, which is impaired in MS more often than the recall or recognition of previously learned information. In the future, voice recognition may be used help to overcome this limitation as the technology improves.

“The iCAMS, developed by our research team, requires the use of a testing technician, which could be a barrier to adoption; however, it accurately assesses for processing speed and learning new information,” Beier said. In a study reported in the International Journal of MS Care, she and colleagues found no significant difference in scores when comparing the iCAMS—a tablet-based version of the paper-based Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)—to the BICAMS, and the iCAMS took roughly 10 minutes less to administer.12

They are also investigating the use of TestMyBrain.org compared with gold standard assessments like the BICAMS, Beier said. “The TestMyBrain.org platform is promising because the tests are free and can be accessed by anyone with a computer, and they have been validated on a minimum of 5,000 to 10,000 individuals.”13 The preliminary pilot study (which is expected to be published in the near future) demonstrated promising test-retest reliability, known-groups validity, and concurrent validity, and the team is now conducting a follow-up study to establish ecological validity.

Beier recommends that clinicians use computerized cognitive testing as screening tools but notes that, unlike a full neuropsychological evaluation, these do not adequately assess factors such as motivation, effort, and the influence of mood and fatigue. “Therefore, until these instruments are improved or refined, positive findings on computerized cognitive testing should trigger a referral to neuropsychology, as available,” she advised. “If a neuropsychologist is not available in one's area, I would consider adding standardized instruments to assess for mood and fatigue so that these elements can be captured by the clinical team.”

Challenges and Future Directions

Telephone- and web-based mental health interventions represent another promising area of development in MS care. Dawn M. Ehde, PhD, a clinical psychologist and professor of psychology and rehabilitation medicine at University of Washington Medicine in Seattle, and colleagues have studied interventions for issues including depression and pain interference using one-on-one treatment delivered by phone14 and group-based interventions15 via online platforms such as Zoom. “They have found significant results in all their studies, and individuals tend to miss fewer of the study visits and report positive experiences with the interventions,” Beier said.

The evidence thus far indicates that distance-based mental health interventions are effective and well accepted by MS patients, according to Beier. “These low-cost interventions break down the barriers that traditional psychotherapy might impose—for example, missing a significant amount of time from work to travel to in-person appointments—and allow for people to attend even if they have geographic, mobility-related, fatigue-related, or transportation-related barriers.” Some of the roadblocks to widespread adoption pertain to payer reimbursement, differences in state regulations, and ethical concerns such as how to address suicidal ideation expressed by a remote patient.

Investigators also continue to explore the use of computerized cognitive interventions. In the meantime, in-person cognitive rehabilitation remains the gold standard in this area. Therefore, if there is no notable improvement in function with computerized interventions, assessment by a neuropsychologist and/or speech pathologist could be helpful. “Again, contributing factors such as mood, fatigue, or motivation could impede progress or improvement in symptoms,” Beier said.

Charvet cautioned that many technologies on the market do not have demonstrated benefits, and those used in clinical care, as well as the assessment or therapy they deliver, should be verified first by research. “Any new technology needs to have demonstrated ability to be accessed by patients, preferably including those living with MS and including adaptation for those living with higher levels of disability,” she said. For example, the telerehabilitation platform used in her team’s research has been extensively developed and tested for its feasibility for access by people with MS across disability levels. In terms of online communities for people with MS, Beier said that it is “important that the community is based on research-validated information and therapeutic tenets and monitored for content, and preferably endorsed by the National MS Society.”
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