Data for the current study were obtained during the course of a multi-arm, randomized, blinded, sham-controlled trial that includes a follow-up period. The parent study includes four arms with different combinations of Cognitive Rehabilitation (CR), Exercise (EX), Sham Cognitive Rehabilitation (CR-S), and sham exercise (EX-S). Participants are randomized to a study arm upon completion of baseline testing. Data are collected at 11 sites in 6 countries [Canada (1 site), US (2 sites), UK (2 sites), Denmark (1 site), Belgium (1 site), and Italy (4 sites)]. Outcome measures include neuropsychological assessment, Patient-Reported Outcomes (PROs), and neuroimaging. See Feinstein et al.  for the full study protocol.
Participants included 131 individuals with a clinically definite diagnosis of PMS (primary or secondary) of the 138 participants enrolled in the parent RCT. The mean age of the sample was 52 years (SD = 6.9), with a mean disease duration of 14.4 years (SD = 9.1). See Table 1 for demographic data. Given that these patients are generally the most impaired subtype of MS patients, they are thus the most likely to develop psychiatric symptomatology when facing a pandemic.
Patients were recruited via specialized in and outpatient MS clinics, as well as via media advertising prior to the COVID-19 pandemic, and were at various points in study participation when study procedures were stopped at all sites due to the pandemic. Prior to initial study enrollment, all potential subjects completed a two-step screening procedure, including a pre-screening examination in person or via telephone to collect basic information and a detailed face-to-face screening for neurological, psychiatric, cognitive, and medical variables. Inclusion and exclusion criteria are summarized in Table 2 by the screening step.
The parent RCT received ethics approval at all institutions and a modification was approved at all institutions for additional PROs, including a COVID Impact Survey, to be administered during lockdown.
Ongoing study procedures were interrupted at each individual data collection site in accordance with governmental restrictions as COVID-19 spread worldwide and all data collection sites were under lockdown orders. During the study closure, all sites contacted participants by telephone on a weekly basis to maintain contact with the participants and update them on any new information regarding the anticipated continuation of study procedures.
During this time, the study team developed a COVID Impact Survey, which was administered by a data collector via telephone or email to all enrolled participants between May 4, 2020 and July 5, 2020. All participants additionally completed selected Patient-Reported Outcomes (PROs) that were previously administered at study enrollment (baseline) to evaluate changes in depression, anxiety, quality of life (QOL), and MS symptomatology during the time period in which lockdown restrictions were in place. Survey administration occurred after lockdown orders and the resultant implications were evident across all data collection centers as lockdown was in place; this is an important methodological detail due to the fact that higher mean levels of psychiatric symptoms (stress, anxiety, and depression) have been observed after the sampled population began to experience the effects of stay at home orders . The time between baseline PRO completion and lockdown survey completion varied (M = 9.5 months, SD = 4.1 months).
Assessments in the current study included the COVID Impact Interview and several PROs administered at baseline and re-administered during lockdown.
The COVID Impact Interview was developed by the study team specifically for use in this study in an effort to evaluate the impact of the COVID-19 pandemic and lockdown orders on individuals with PMS across the participating 11 centers, representing 6 countries in North America and Europe. It consists of 22 questions related to self and family exposure to COVID-19, length of time under lockdown orders, activities during lockdown, disease symptomatology, and interactions with healthcare providers. A set of questions assessing the impact of the pandemic on psychological, financial, and physical well-being were included with responses recorded on an integer scale (0–10, with 0 being no impact and 10 being maximal impact). The survey was administered in the individual’s native language. Results were examined in response to each specific question.
The Hospital Anxiety Depression Scale (HADS) is widely used to assess psychological distress in non-psychiatric patients. It consists of two subscales, measured via 14 items, seven items for the anxiety subscale (HADS-Anxiety) and seven for the Depression (HADS-Depression) subscale . Overall, it has demonstrated satisfactory psychometric properties in several different populations, including MS [23,24,25,26]. Each item is scored on a response scale with four alternatives ranging between 0 and 3 and a higher score indicates greater anxiety or depression. The HADS-depression cut-off for clinical depression was defined as scores ≥ 8.0 .
The Beck Depression Inventory -II (BDI-II)  is an easily administered, 21-item scale that assesses various aspects of depression, useful in determining the presence and severity of depressive symptoms. Each item is concerned with a specific aspect of depression (mood, motivation, and appetite) and contains four statements of graded severity expressing how a person might think or feel about that particular aspect of depression. The total score is the sum of all statements endorsed by the participant. A higher score indicates greater depression.
The Multiple Sclerosis Impact Scale (MSIS-29) is a disease-specific measure of the impact of MS. It consists of 29-items, 20 associated with a physical scale, and 9 associated with a psychological scale; the sum of each scale is transformed to a scale of 0–100 and higher scores indicating worse health . Items ask about the impact of MS on day-to-day life in the past 2 weeks, rated on a five-point Likert scale. The MSIS-29 has strong reliability and validity in MS samples , with existing evidence supporting its responsiveness in rehabilitation trials .
The EuroQol (EQ5D)  is a widely used measure of QOL developed in Europe, often used in cost-effectiveness analyses. It evaluates QOL across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Changes in responses from baseline to lockdown were evaluated using paired t tests and Wilcoxon signed-rank tests. Independent sample t tests were utilized to examine sex differences (male versus female) in response patterns. Pearson (or Spearman, when appropriate) correlation coefficients examined the relationships between the COVID-19 Impact Interview and changes in specific PROs as well the relationship between EDSS, MS-disease duration, baseline processing speed scores and changes in depression and anxiety.