Brain stimulation is a rapidly expanding field, in which a wide variety of stimulation techniques can be used to modify brain activity in order to promote neuroplasticity. A few decades after its introduction, brain stimulation has gained support as a major technique used in human neuroscience. It has been used to modulate cognitive processes, motor function and even network‐level brain connectivity. A long‐term goal of brain stimulation research is to develop novel treatments for neurological and psychiatric disorders. However, a major issue preventing the attainment of this goal is that brain stimulation protocols do not produce the same physiological or behavioural effects in every individual. In addition, the effects of stimulation can even vary within an individual when tested during different sessions. This problem has been aptly termed the ‘variability problem’, and although some sources of this variability are known (such as age, attention, genetic factors, physical activity and circadian influences; Ridding & Ziemann, 2010) others are not. Sources of variability across studies may be related to subject‐specific differences (such as age, sex and cortical anatomy), while others could be related to differences in stimulation parameters and measurement techniques (such as stimulation intensity and duration, as well as how the effects of stimulation are assessed). Importantly, there is currently no consensus regarding which stimulation parameters are most effective for inducing specific neurophysiological and/or behavioural changes, so stimulation parameters often vary across studies. This makes it challenging to determine the general sources of variability in response to different brain stimulation techniques. In order to resolve these issues, systematic exploratory studies of different stimulation parameters and measurement techniques and their influence on the effects of the stimulation protocol are needed.
In this issue of The Journal of Physiology, Jamil and colleagues used this type of systematic exploratory approach to study the impact of stimulation intensity during transcranial direct current stimulation (tDCS) on the neurophysiological effects of the stimulation (Jamil et al. 2017). tDCS is a brain stimulation technique in which low‐level direct current is applied through two electrodes to the scalp. If the anode is located over the primary motor cortex (M1), corticospinal excitability can increase, whereas if the cathode is located over M1, corticospinal excitability in some circumstances can decrease (Nitsche & Paulus 2001). Jamil and colleagues systematically varied stimulation intensity during 15 min of M1 tDCS and measured the effect of this variation on corticospinal excitability. Specifically, they tested two groups of individuals (a group that received anodal stimulation and a group that received cathodal stimulation) in which each individual was exposed to five different stimulation intensities including sham during different testing sessions. Interestingly, varying the stimulation intensity did not significantly affect the observed post‐stimulation increases in corticospinal excitability due to anodal stimulation, whereas only one mid‐range stimulation intensity produced significant post‐stimulation decreases in corticospinal excitability due to cathodal stimulation. The authors also performed additional post hoc exploratory analyses in order to identify potential sources of response variability across individuals. Using this exploratory approach, they found that sensitivity to transcranial magnetic stimulation predicted the response to anodal but not cathodal stimulation. The study by Jamil and colleagues is a good example of an exploratory investigation aimed at shedding light on the potential mechanisms and determinants of variability in responsiveness to brain stimulation. Specifically, discovering the optimal stimulation parameters as well as potential predictors of responsiveness through exploratory studies is the first step towards the rational design of well‐defined, hypothesis‐driven and properly powered investigations aimed at promoting neuroplasticity and behavioural change.
This type of exploratory work is invaluable in all fields of scientific inquiry. In its absence, it would be impossible to design studies that require preliminary data in order to correctly power pre‐registered, hypothesis‐driven confirmatory investigations. It is regrettable that exploratory studies are often discouraged by journals or study sections as ‘fishing expeditions’ or ‘low impact’. Well‐designed, systematic and transparently reported exploratory studies, when identified as such by the investigators and cautiously interpreted, like the study by Jamil and colleagues, have great potential to feed confirmatory hypothesis‐driven investigations and lead to significant advancements in physiological understanding (Buch et al. 2016).
Some of the most impactful work in neuroscience in recent years has been exploratory in nature: consider the identification of resting‐state networks in fMRI and the generation of updated cortical maps using multi‐modal imaging parcellation techniques (Glasser et al. 2016). Jamil and colleagues applied this philosophy to study the parameter space of tDCS application over the motor cortex. These types of investigations are an important first step towards hypothesis‐driven confirmatory studies as they identify potentially valuable lines of scientific inquiry. We therefore look forward to the publication of well‐designed, systematic, exploratory investigations and feel excited for the new scientific directions and physiological insights these works will bring.
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Competing interests
The authors declare no competing interests.
Author contributions
Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
Linked articles This Perspective highlights an article by Jamil et al. To read this article, visit https://doi.org/10.1113/JP272738.
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