Visual Analysis in Single Case Experimental Design Studies Brief Review and Guidelines

Introduction

Due to the large proportion of people living with chronic neurological impairments, not-invasive brain stimulation (NIBS) was developed equally a potential adjuvant to heighten neurological rehabilitation. NIBS techniques such as transcranial straight current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS) have been proposed to temporarily attune neural excitability in a given direction based on the blazon of stimulation used. For example, seminal studies in tDCS reported that anodal tDCS over the motor cortex (M1) increased corticomotor excitability, whereas M1 cathodal tDCS decreased corticomotor excitability, for up to an 60 minutes (Nitsche and Paulus, 2001; Nitsche et al., 2003). The polarity dependent changes in corticomotor excitability were suggested to represent up-regulation or down-regulation of neural plasticity (Nitsche and Paulus, 2001; Nitsche et al., 2003) and depend on several stimulation parameters (Woods et al., 2016). When delivered before or during rehabilitation NIBS may increase the beneficial neuroplastic furnishings of rehabilitation solitary.

Afterwards, the field of NIBS grew rapidly. Many researchers applied tDCS or rTMS to a broad range of clinical populations and explored many variations in experimental parameters. Well-nigh ordinarily, researchers opted to employ a randomized controlled trial (RCT) report design, allocating participants to either; real vs. sham stimulation, facilitatory vs. inhibitory stimulation (e.yard., anodal vs. cathodal tDCS), stimulation alone vs. stimulation with therapy, or some combination of the above in a multi-arm trial. In addition, NIBS trials have typically used functional and/or neurophysiological outcomes (such as motor learning tasks or measures of corticomotor excitability after M1 stimulation) to make up one's mind the afterwards-effects of stimulation, often followed upward at multiple time-points to decide the duration of effects. The ease and reported effectiveness of sham stimulation (e.1000., fade in-fade out protocol for tDCS, or sham coil rTMS) (Gandiga et al., 2006; Mennemeier et al., 2009) allows robust methodological written report designs such every bit double-blinded cross-over RCTs frequently used in NIBS research.

However, despite the rapid rise of NIBS inquiry over the by 20 years, electric current evidence has largely not supported translation into clinical practise, with just rTMS as a treatment for drug-resistant low adopted clinically so far (O'Connell et al., 2018; Elsner et al., 2020). 1 of the major criticisms of NIBS that likely acts as a barrier to translation is the substantial between-subject variability observed in response to stimulation (López-Alonso et al., 2014; Wiethoff et al., 2014; McCambridge et al., 2015). With some causal studies of salubrious participants showing that merely half of participants reply to NIBS equally expected (López-Alonso et al., 2014; Wiethoff et al., 2014). Therefore, when investigating group-level changes in outcomes the results are unlikely to show statistical or clinically meaningful differences and may mask the positive benefits experienced past some participants. Notwithstanding, it is not surprising that substantial between-discipline variability exists given the lack of precision in current NIBS studies that typically prefer a "one-size-fits-all" approach to delivery of the intervention.

In the literature, several determinants of NIBS are known to influence stimulation response, both interventional (east.thousand., type and location of stimulation) and biological factors (eastward.g., skull thickness, brain morphology and neurochemistry) (Filmer et al., 2019; Hordacre et al., 2021) that should be taken into consideration when delivering NIBS. Researchers take discussed the demand for individualized or tailored stimulation protocols, using known determinants of NIBS to guide stimulation protocols to help address wide-scale variability in responses (Di Pino et al., 2014; McCambridge et al., 2018; Hordacre et al., 2021). For example in tDCS inquiry, individualized stimulation could tailor the stimulation protocol based on clinical characteristics of the patient (e.thou., lesion location, structural integrity of neural pathways) (Di Pine et al., 2014) or individually modeled electrical fields (Antonenko et al., 2019) or a combination of many factors including methodological (east.yard., dosage and biological factors) (Hordacre et al., 2021) (Figure 1). Patient-tailored brain stimulation would be a sensible arroyo, though the feasibility of conducting a large-calibration RCT with highly-precise individualized stimulation protocols for each participant would be difficult, especially in a clinical population. Therefore, in this opinion article, we consider if an alternating methodological approach to investigating the effectiveness of NIBS in lab-based or clinical settings would be of involvement to the field.

Effigy i. (A) Example of individualized transcranial direct current stimulation (tDCS) that could be tested using SCED methodology. (B) Hypothetical information for an A-B-C-B-C-A design where five measurements are taken in each of the 6 phases so that three phase changes betwixt B and C can be reported on (e.g., B → C, C → B, and B → C again).

Single-Example Experimental Designs

To our knowledge, a study design that has not withal been employed in NIBS research is a single case experimental design (SCED). SCEDs are clinical trials of an private (or several individuals each studied as a single instance), in dissimilarity to trials of groups of participants (Tate and Perdices, 2019). They have also been called unmarried-system designs, single-subject designs, single-case research designs, single participant designs, interrupted fourth dimension-series designs, and N-of-1 trials. Every bit with many other study designs, the results of SCEDs can be included in systematic reviews (Tanious and Onghena, 2020). To establish a causal relationship between a target beliefs and an intervention, SCEDs have four essential elements: (1) the participant is their own control, (2) a priori methods are used, (iii) the target behavior is repeatedly measured before, during and subsequently an intervention, and (4) the intervention is systematically manipulated (Tate and Perdices, 2019). Inferences nigh the intervention are then drawn from the repeated demonstration of the intervention effect on the outcome. Table 1 shows the four classifications of SCED designs: (1) withdrawal/reversal designs, (2) multiple-baselines designs, (3) alternating-treatments designs, and (four) changing-benchmark designs. A range of modifications and combinations of these four approaches accept been used to date (Shadish and Sullivan, 2011), with some designs better suited to particular type of inquiry questions (come across Table ane). Ane key entreatment of a SCED is the power to individualize an intervention to a given participant, equally would be done in many clinical practice settings. For health research, SCEDs are considered Level ane evidence (OCEBM Levels of Evidence Working Group, 2011) and the methodological quality of SCEDs tin can be assessed and guided by the recently developed Single-Instance Reporting guideline In BEhavioural interventions (SCRIBE) 2016 checklist (Tate et al., 2016a,b).

Table ane. Classification of SCED designs adapted from Chapter 1 of Tate and Perdices (2019).

Instance Protocol for Non-Invasive Encephalon Stimulation

Planning

To farther elaborate on SCEDs and the potential utility for NIBS inquiry, nosotros propose an example SCED protocol to respond the research question "Is motor cortex anodal tDCS more effective than sham tDCS at increasing corticomotor excitability in chronic stroke participants?" To respond this question, a withdrawal multiple handling design is appropriate (encounter Tabular array 1). In this example, an A-B-C-B-C-A blueprint could be used where A = baseline or follow-up with no stimulation, B = sham tDCS, and C = existent tDCS. This design provides iii opportunities to examine the experimental effect between B and C. To establish the absolute effectiveness of B or C compared to baseline, the design would require at least three phase changes involving A and C, and three involving A and B. This is a very cumbersome design [e.g., A-B-C-B-C-A-B-A-C-A (Tate and Perdices, 2019)]. Ane upstanding and practical consideration here is whether the design should stop on an active intervention phase so that the study ends on a potentially beneficial handling for the patient. The appropriate elapsing of each phase is dependent on the "wash-out" period needed subsequently stimulation, estimated to be 1–one.five h for anodal tDCS (Nitsche and Paulus, 2001) thereby minimizing possible confounding "alternation furnishings" (Tate and Perdices, 2019). Within each stage, at to the lowest degree five measurements of the outcome measure should be taken (run into Figure 1B for hypothetical data) to account for possible variability (Kratochwill et al., 2013). In this example, 10 TMS-pulses could be delivered every iv–5 s at each measurement to provide a total of five average MEP amplitudes per phase.

Randomization and blinding are important for the internal validity of a SCED. Randomization tin can be achieved in some SCED classifications by randomizing the phases, or randomizing the onset in a multiple-baseline study. In our A-B-C-B-C-A example, the sequence of phases is not randomized. However, blinding could be achieved by concealing the stimulation type (real, sham) to the participants and the result assessors and not revealing the guild of phases or having a divide researcher administrate the intervention that is not involved in data collection or analysis. For instance, sham tDCS protocols set up the electrodes the same as in real stimulation except the current is ramped up to provide sensory stimulation on the scalp then ramped down once more to no stimulation. Some tDCS machines can also be pre-programmed to do the "fade in-fade out" protocol without the experimenter'south knowledge or use a separate experimenter deliver the stimulation. In add-on, blinding during the analysis could be achieved by non disclosing the stage (baseline, real, sham, follow upward) to the statistician analyzing the information until all analyses are complete.

Considerations

In terms of reporting on a SCED report, information technology is important to thoroughly report the selection criteria, participant characteristics, setting, outcome measures, equipment, intervention details, and the procedural fidelity of the intervention. A thorough description is required for replication and to maximize the external validity of the written report, for example, researchers may want to repeat the trial on three or more participants that represent the clinical population (i.e., young and onetime, male and female, unlike settings etc.).

Detailed descriptions of all phases of the intervention are required (i.e., baseline, real, sham) in SCED studies. If the written report uses patient-tailored encephalon stimulation then a comprehensive description should be given well-nigh how stimulation is individualized (i.e., based on what parameters) so that replication of the intervention awarding and how it was individualized could be accomplished in subsequent trials. Reporting how and when the intervention was delivered also as the intervention dosage (e.g., current strength, duration of stimulation, electrode size and placement etc.) is of particular importance. Similar detail should be given to describing the sham intervention, for example the current strength and elapsing of the tDCS fade in-fade out protocol (Ambrus et al., 2012).

Analysis

To begin planning a SCED information analysis, it is important to first determine if changes in level, trend, and/or variability of the result measure are indicative of a treatment effect. For case, if the outcome measure was corticomotor excitability assessed with TMS–induced motor evoked potentials (MEP), then a change in the level of corticomotor excitability (i.e., amplitude of the MEPs) with real NIBS compared to sham and baseline would betoken stimulation was constructive. Similarly, if the result was a motor learning task yous may hypothesize a modify in the trend (i.due east., rate of improvement) with real NIBS would indicate that the handling was effective. Visual and statistical analysis supplement each other in SCED studies and demand to exist utilized in conjunction (Tate and Perdices, 2019), though controversy most analysis procedures be.

The approach selected for visual and statistical assay is essential to consider. Kratochwill et al. (2013) includes four steps in visually evaluating the phases of a SCED written report which can exist summarized every bit: (1) "Is the data stable at baseline?" (2) "Are there whatever trends or variability?" (3) "How long until at that place is an effect?" and (4) "Did the command piece of work?" Various techniques be to visually analyse information in a systematic and objective fashion, including descriptive statistics, level changes, split-middle trend lines, variability and evaluating trends in each stage (Parsonson et al., 1992; Lane and Gast, 2014; Barton et al., 2018). For statistical analysis methods, detailed guides are available (Manolov and Solanas Pérez, 2018) considering a range of issues may influence the validity of statistical tests (Parker et al., 2011; Velicer and Molenaar, 2013; Harrington and Velicer, 2015). Statistical analyses are valuable (i) when variability appears large upon visual inspection, (2) when effects of interventions are non yet well-understood, (iii) when small but important changes in target behaviors cannot be detected past visual analysis, or (iv) to enhance replication studies (Kazdin and Tuma, 1982).

Advantages and Challenges

SCEDs are a useful study pattern to further explore NIBS, particularly for patient-tailored NIBS protocols. Similar to a RCT, SCEDs are considered Level 1 bear witness for health interventions (OCEBM Levels of Bear witness Working Group, 2011). One advantage of a SCED over a big-scale RCT is that it is more cost constructive, because it requires fewer participants and resources. Not requiring large sample sizes to accomplish statistical ability may be of particular importance for low-incidence patient populations that oft suffer from being under-powered. In addition, because SCEDs use an individual equally their own control, issue measures can exist interpreted as accented values relative to the participant'due south baseline. Interpretation of absolute values would avoid not-validated normalization procedures used in some neurophysiological research (e.m., pre-post, pre-post/mail, pre-post/pre+post). Although tailored-interventions tin exist used in RCTs, SCEDs are also suitable for patient-tailored treatments that may involve clinical judgements that are commonplace in clinical exercise. In a SCED study, private modifications to the protocol can exist extensively explained for each participant and then that replication is possible. Furthermore, exploring patient-tailored NIBS with a SCED design tin also inform how a tailored intervention could be farther tested in a large-scale RCT.

However, in that location are some important challenges that should be considered. A electric current claiming to SCED inquiry is the generalizability of findings, especially for very heterogenous patient populations (east.thou., stroke, dystonia). Replication is therefore required, though guidance on how many participants are needed for acceptable replication is lacking. SCED's tin can besides exist burdensome to participants because they require all-encompassing data drove. Another challenge is that SCED's are vulnerable to plausible rival hypotheses that may explicate the outcomes such as, maturation, regression to the mean and external factors (Caneiro et al., 2019). Further, there are currently no agreed upon statistical assay procedures. Criticism of the subjective nature of visual inspection, and hence acceptability of SCEDs equally Level 1 evidence by the field, could also exist a bulwark to translation.

Summary

In summary, the central aspects of NIBS announced to be suitable for studies using SCED methodology. This approach may be a useful avenue to farther investigate inter-individual variability and more advanced individualized stimulation protocols. In add-on, due to the relative ease and safety of modulating the independent variable in NIBS research, NIBS may also be a candidate field to ameliorate and develop SCED methodology.

Author Contributions

AM: formulation of the idea. AM and JP: manuscript preparation and approval of last paper. Both authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the inquiry was conducted in the absence of any commercial or financial relationships that could be construed as a potential disharmonize of interest.

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Source: https://www.frontiersin.org/articles/10.3389/fnrgo.2021.678579/full