Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research
Table 4
Clinical measures employed in studies.
Clinical measure
Test characteristics
Studies utilizing
Disease severity
Expanded Disability Status Scale (EDSS)
Ordinal scale based on observations concerning gait and use of assistive devices. Rated from 0.0 to 10.0, in increments of 0.5, where 0.0 indicates no disability, 1.0-4.5 describes persons who can walk without mobility aids, 5.0-9.5 refers to impairments in walking, ranging from being able to walk 200 m without aid (5.0) to being confined to bed and unable to communicate or swallow (9.5), and 10.0 indicates the person has died [51, 55, 67].
Set of eight ordinal subscales based on the standard neurological examination. Each is rated from 0 to 9 in discrete increments of 1, where greater score denotes more severe disability. Subscales include pyramidal function, cerebellar function, brainstem function, sensory function, bowel and bladder function, visual function, cerebral/mental function, and other features noted by the examiner. Scores can be reported separately or as a composite [159].
Battery containing the Timed 25-foot Walk (T25FW), Nine-hole Peg Test (9HPT), and Paced Auditory Serial Addition Test-3 seconds (PASAT3) to assess leg function/ambulation (T25FW), arm/hand function (9HPT), and cognitive function (PASAT3), respectively. Each item can be scored separately or combined [160].
Includes elements of the selective reminding test (SRT) (verbal memory), Spatial Recall Test (SPART) (visual memory), Symbol Digit Modalities Test (SDMT) (attention, visual precision search, processing speed, and executive functions), paced auditory serial addition test (PASAT) (maintenance of attention, processing speed, and working memory), world list generation (WLG) (associative verbal fluency), and Stroop test (ST) (selective attention). Subscales can be scored independently, collapsed across specific cognitive domains (i.e., verbal memory and visual memory), or combined [54, 161].
Test of episodic verbal learning and memory. A list of nouns is read aloud over several trials, after each of which the participant attempts to recall as many nouns as possible. Participants are also provided with an interference list of words with similar meaning. Recall and recognition of the original list are tested at different intervals. A learning curve with learning parameters, response errors, and interference effects is used for scoring [162–164].
Test of short-term verbal memory. Sequences of digits are presented in forward and reverse order, and the participant recalls the sequences. Two trials are presented at each sequence length, beginning with two digits, until either the participant fails to recall the trial or the maximal span length is reached (nine forward and eight backward). The total number of lists recalled correctly is combined across forward span and backward spans to give a total correct score [165–167].
Test of frontal lobe dysfunction. Utilizes six subscales that examine conceptualization (similarities test), mental flexibility (verbal fluency test), motor programming (Luria motor sequences), sensitivity to interference (conflicting instructions), inhibitory control (go-no-go test), and environmental autonomy (prehension behaviour). Each subscale is rated from 0 to 3, and the sum of the scores is interpreted; 18 is the maximum (best) score, and <12 indicates cognitive impairment [168].
Test of information processing speed and visual or auditory memory. Administered in a visual or auditory format, digits 1 to 9 are associated with a corresponding letter. Participants must replace randomized letters with the appropriate digit as quickly as possible. Scoring is based on the number of correct letter-digit substitutions made in 60 seconds [169, 170].
Test of visuospatial learning and memory. Participants are shown an array of images several times for 30 seconds at a time. After each presentation and 15 minutes after the last presentation, participants must relocate the images to their correct position on an empty grid. For every trial, a displacement score is measured consisting of the sum of the errors made for each object placement on that trial, a total displacement score combines the individual displacement scores from the learning trials, a learning index represents the relative difference in performance between trials, and a delayed recall score considers the difference between last trial and delayed trial [171, 172].
Test of auditory or visual working memory and attention. In either auditory or visual form, the participant is presented a series of letters and digits in a nonsystematic order. Following the presentation, the participant must report back the stimuli, with the letters in alphabetical order and the digits in ascending order. Scoring is based on correctness of responses [165, 173, 174].
Thirty-point questionnaire examining aspects of cognitive function including registration, attention, calculation, recall, language, ability to follow simple commands, and orientation. Scoring is relative to age- and education-based norms [175, 176].
Test of processing speed and working memory. Computer task whereby participants press one of two buttons, denoting target and nontarget, in response to a target (letter) that matches a stimulus presented zero, one, two, or three stimuli previously. Scoring is based on reaction time and correctness of responses in each condition [177, 178].
Paced Auditory Serial Addition Test (PASAT-2/PASAT-3)
Test of processing speed and working memory. A series of digits is presented, either visually or aurally, and the two most recent digits must be summed. An interval of 2 (PASAT-2) or 3 seconds (PASAT-3) separates each digit. Scoring is based on the number of correct responses for each trial or the total number of correct responses over all trials. The PASAT is part of the MSFC and BRB [160, 161, 179].
Test of attention. Computer task involving responding to visual stimuli presented in one of two possible locations on the computer screen. Prior to the stimulus, a visual cue directs the participant’s attention either to the correct location (valid cue) or an incorrect location (invalid cue). There are a proportionate number of valid and invalid cues and noncued stimuli, which are randomly interspersed. Performance is based on correct responses and reaction time and can be compared across cue conditions [8, 180].
Test of verbal memory and learning. The participant hears a list of unrelated words and must recall as many words as possible. Every subsequent trial involves the administrator reminding the participant only of those words the participant did not recall on the previous trial. Trials of recall and selective reminding continue until the participant can correctly recall all words on three consecutive trials or until all trials have been completed. Scores are provided for words recalled from long-term storage (SRT-LTS), consistently from long-term retrieval (SRT-CLTR), and delayed recall (SRT-D). The SRT is part of the BRB [161].
Test of visuospatial learning. A checkerboard displaying a pattern of checkers is placed in front of the participant for 10 seconds. The participant tries to reproduce the pattern. This occurs for multiple trials, plus a 15-minute delayed-recall trial. Scoring is based on the number of correctly placed checkers over the first trials (SPART), as well as during the delayed-recall trial (SPART-D). The SPART is part of the BRB [161, 181].
Test of selective attention. Participants are instructed to read aloud a list of colour names as quickly as possible, leaving no errors uncorrected. The task utilizes five words (red, blue, green, brown, and purple) and their matching ink colours. Each ink colour appears twice in each row and column on card. The task examines the effect of incompatible ink colour on reading words aloud and measures response time. The Stroop test is a component of the BRB [54, 161, 182].
Test of attention, visual precision search, processing speed, and executive function. participant is given 90 seconds to pair specific numbers with given geometric figures, based on a reference key provided by the experimenter. Scoring is based on a predetermined scoring form. The SDMT is a component of the BRB [161, 183, 184].
Test of verbal fluency, including category fluency (ability to list objects in different categories) and letter fluency (ability to list different words beginning with the same letter), semantic memory, and retrieval from long-term memory storage. Participants are asked to say as many different words as possible that begin with a specific letter (letter fluency) in 60 seconds. Participants cannot say proper nouns nor variations of the same word root. Next, participants must say as many words as possible from a specific category (category fluency) in 60 seconds. This test is part of the BRB [161, 185–187].
Used to describe hand function and to index overall body strength. Using a standard protocol, a handgrip dynamometer is used to measure handgrip strength. Results can be compared to norms, between individuals, or across limbs. Grip strength can also be measured as pinch grip strength or as a maximum voluntary isometric contraction (MVC) [188].
Ordinal scale used to examine muscle strength, based on a standard neurological examination. The experimenter grades muscle strength on a scale of 0-5, relative to the maximum expected strength. A score of 0 indicates no contraction of the muscle, while 5 indicates normal strength [82, 189, 190].
Ordinal scale used to assess spasticity, based on a standard neurological examination. Uses discrete ratings of 1 and is scored from 0 to 4; 0 reflects normal tone3z and 4 indicates that the tested muscle is rigid during flexion or extension. The examiner passively flexes and extends joints of interest, providing a rating for each [189, 191].
Used to examine finger dexterity. The participant sits at a table with a small, shallow container holding nine pegs and a block containing nine empty holes. On a start command, the participant picks up and places each of the nine pegs in the nine holes as fast as possible, one at a time. The participant then removes them as quickly as possible, placing them into their container. The total time to complete the task is recorded. Two consecutive trials with the dominant hand are immediately followed by two consecutive trials with the nondominant hand. Both trials for each hand are averaged and reported separately. The 9HPT is part of the MSFC [160].
Ordinal scale used to assess the presence or severity of “upper” versus “lower” motor neuron lesions, based on a standard neurological examination. A tendon is tapped briskly by a reflex hammer, and the resultant muscle contraction is given a score of 0-4, where 0 reflexes abnormal hyporeflexia, 2 is normal, and 4 denotes abnormal hyperreflexia [82, 189, 192].
Used to assess walking performance and lower extremity function. The participant is instructed to walk as fast and safely as possible across a marked 25-foot linear course, using an assistive device if necessary. The participant is timed walking the course twice, and the two trials are averaged. Scoring is expressed as time or speed or as part of the ambulatory index, a 10-point scale that assesses mobility based on time and degree of assistance required during the T25FW. The T25FW is a component of the MSFC [160, 193, 194].
Self-report measure used to examine participants’ perceptions of how fatigue impacts their quality of life. The scale is comprised of 40 items that are scored from 0 (no problem) to 4 (extreme problem), providing a total composite score of 0-160, and contains subdomains that reflect perceived impact on cognitive (concentration, memory, thinking, and organization of thoughts), physical (motivation, effort, stamina, and coordination), and psychosocial functioning (isolation, emotions, workload, and coping) (10 items/40 points each) [195].
Self-report measure that uses a series of 7-point scales to examine the severity and impact of subjective feelings of fatigue. In response to each of the nine statements provided, a rating of 1 indicates strong disagreement while 7 refers to strong agreement. A indicates that the individual may not be suffering fatigue, whereas >36 suggests that one may be experiencing fatigue and should seek medical counsel [196].
Abbreviated version of the FIS that has been adapted for persons with MS. This scale contains cognitive (9 items/36 points), physical (10 items/40 points), and psychosocial (2 items/8 points) subscales; however, this test only contains 21 items and can be rated out of a total 0-84 points [195, 197].
