Transcranial direct current stimulation (tDCS) A general purpose neuromodulator?

Dan Ofer. Hebrew University of Jerusalem. ddofer@gmail.com 21.9.2013

Introduction:
The goal of this paper is to present transcranial direct current stimulation (tDCS) and to argue that it is a general modulator of neuronal excitability and plasticity, as evidenced by the extremely diverse mental functions and neuroanatomical regions affected by tDCS in varied studies. This, as opposed to being specific to only a single domain, cortical network, region or mental function. Towards this argument, I shall present a wide array of different cortical regions and effects modulated in tDCS experiments.

What is tDCS?
Transcranial direct current stimulation (tDCS) is a form of non-invasive external electric stimulation of the cortex. It works via a weak electrical current (typically 0.5-2 mA) passed between electrodes attached to the scalp, polarizing the underlying brains cortex tissue with an electrical field. (The following wording is adapted from reviews14): "tDCS can modulate cortical excitability and spontaneous firing activities in the stimulated region by shifting the resting membrane potential, thus altering the intrinsic neuronal excitability. Depending on the polarity of the current flow, cortical excitability can be increased via anodal stimulation or decreased via cathodal stimulation. " tDCS induces cortical and neural plasticity via subthreshold polarization of the neuronal membrane via weak direct electrical currents and induced electric fields.57

tDCSs Physical Basis - What it Does:

In terms of its relationship to neuroelectric activity, tDCS is a neuromodulator it alters excitability, increasing or decreasing the threshold of excitation and thus the firing rate and activity of affected neurons. However, it does not cause neurons to fire "independently"; that is, it modulates existing activity but does not induce independent firing. In contrast, in TMS (Transcranial Magnetic Stimulation) or electric shocks 40, resting or non-active neurons are induced to fire, independently of natural activity because (static) electrical fields in this range do not yield the rapid depolarization required to produce action potentials in neural membranes 2. The effects

of tDCS on cortical excitability can last for a varying amount of time8, depending on the region affected, the function involved, and the strength and duration of the tDCS stimulus itself. Hence, tDCS is a neuromodulatory intervention. The tissue is polarized9 and tDCS modifies spontaneous neuronal excitability and activity by depolarization or hyperpolarization of the resting membrane potential (Vmr). The extent of tDCS's effect depends on a number of factors2: i. Current density (dependent on current strength and the size of the electrode). This determines the strength of the induced electrical fields. It has been shown that higher current densities result in stronger effects1014. ii. Duration - Longer stimulus' durations (all other factors being equal) determine the occurrence and duration of effects in humans and animals2,1420. It should be noted that there can be significant differences in effects in cases where tDCS treatments are spaced out at intervals, rather than a single exposure2,3,2023. Multiple spaced exposures tend to have longer lasting and more potent effects than a single exposure 3,24. However, the mechanisms underlying these changes are not well understood, as is any possible relation to long term potentiation [LTP].25,26 It is currently unknown whether using spaced intervals would result in greater (or longer lasting) effects for other studied phenomena. The exact underlying differences between effects that last for days, weeks, months or hours are as yet unknown. iii. Orientation of the induced electric field set by the electrodes positions and polarity (Anodal or Cathodal stimulation). The positioning determines the areas of the

cortex affected by the current flow and the induced electric field, while the polarity determines the effect (increased or decreased excitability due to depolarization or hyperpolarization respectively). (3:)Early studies in animals15,27 [] using direct cortical stimulation showed that if the anode was placed above or within the cortex, spontaneous neuronal activity was increased, whereas cathodal polarity resulted in reduced spontaneous unit discharges due to subthreshold changes in membrane polarization. [] However, neurons throughout the cortex were not modulated in a homogenous manner. [] different subpopulations of neurons appear to have different thresholds for modulation.27 It must be noted that the mechanisms underlying the changes in cortical excitability induced by tDCS are different for those effects seen during stimulation and those induced after the stimulation has stopped 3 meaning, that there are differences in the physiological effects and underlying facilitating mechanisms involved, depending on the timeframe i.e. - during or after the tDCS stimulation. Effect of tDCS on Neurons during Stimulation: Vmembrane (3:)The effects of anodal {= increased excitability9} tDCS during stimulation appear to be solely dependent on {depolarizatory} changes in membrane potential. This was established by Nitsche et al6, using pharmacological methods (flunarizine and carbamezipine) that blocked calcium 105 (Ca2) or sodium (Na+) channels, reducing or abolishing (respectively) the effects of anodal stimulation for the treated neurons. 9

During cathodal stimulation, the reduction in excitability caused is seemingly unhindered6 by calcium or sodium channel blockers, as would be expected3 if the neurons membrane is indeed hyperpolarized by the cathodal tDCS. NMDA and GABA receptor antagonists had no effect on the immediate effects of either anodal or cathodal tDCS, as would be expected from a shift in Vmembrane/the resting membrane potential (as opposed to an effect exclusively dependent on synaptic plasticity) 26,3,6,7 After-effects of tDCS on Neurons post Stimulation: The mechanisms involved in tDCS effects lasting after the stimulation has passed are more complicated and less understood. Generally speaking, the effects of a single tDCS stimulation can last for hours18,28 or longer, in the case of multiple spaced treatments, with some cognitive effects seen to persist for days or weeks after. 13,22,2932 It seems that the long term effects are the result of GABAergic (for anodal tDCS1) and/or glutamergic (ex: NMDA receptors) modulation, with a major component in lasting effects being synaptic plasticity and interneurons.1,3,5,6,8,9,22. It also appears that tDCS promotes changes in levels of brain-derived neurotrophic factor (BDNF), an important element for neuronal proliferation and survival. 1, 100

To summarize, these match what might be expected from a neuromodulator, with immediate stimulation causing a moderate shift in the neuron's membrane potential (hyperpolarization or depolarization, depending on the polarity), but said Vmembrane shift

is not sufficient in itself to induce neurons to fire spontaneously, or to prevent their activity altogether. However, it does affect the critical threshold of input from external stimuli required in order for the neuron to fire an action potential. In the long run, we would indeed expect any lasting effects to be similar to those seen in normal long term changes in plasticity, but accelerated due to the facilitation of activity and thus excitability. We might as well postulate as an extension of Hebbs law that Neurons that fire together wire together" 33, that increased/accelerated or decreased firing of the functionally related neurons found together in a network or region, would likely lead to an increase or decrease respectively in the strength of the relevant intersynaptic and/or intra-network connections at a faster rate than the baseline, possibly via theorized LTP/LTD like mechanisms1,26,34,, strengthening the neuronal synaptic connections and making them more efficacious35 tDCS as a Research Tool Recent years have seen tDCS reintroduced (study of the effects of electricity on the brain is quite ancient) as a noninvasive research tool for altering neuroplasticity, modulation of cortical function, neurorehabilitation, and in linking between behaviors & mental functions to varied regions of the brain 65. Its exponentially increasing popularity in recent years 92 is derived from a number of characteristics 2: 1. Rapid effect. 2. Exact neuroanatomical targeting (as opposed to pharmacological means), albeit at a relatively coarse scale. 3. Cheap. 4. Relatively easy to use and safe. 5. Noninvasive and can be used in conjunction with other tasks. 6. Flexibility can be used to investigate an extremely large variety of brain regions, behaviors and mental functions. 7. Potential uses in healthy subjects.

5,10,12,13,17,19,2124,26,2932,46,47,57,58,66,67,70,77,78,81,86,87,89,91,92

. 8. Ability to serve as a tool for

linking neuroanatomical regions to behavioral functions.37 See Figure 1, supplementary material.

tDCS Effects on Mental Functions:

As mentioned in prior reviews, tDCS has been shown to have an effect on a very wide range of mental functions and behaviors 1,2,3. In the following section, I shall present a sampling of different effects, covering different behavioral and cognitive functions, achieved using tDCS stimulation (anodal or cathodal, depending on the specifics) on different neuroanatomical regions in humans, or different effects seen from stimulating the same regions of the brain (in other studies which stimulated that region). To reiterate, the overall goal of this paper is to argue that tDCS is a general mental neuromodulator (via its modulation of neuronal excitability), rather than being a domain specific effect36 limited to only a single modulara mental function.

The majority of tDCS experiments focusedb on the prefrontal cortexc (PFC), the dorsolateral prefrontal cortex region (dlPFC) and the motor cortexd, particularly the

a http://www.cognitiveatlas.org/concept/domain_specificity36 b Source: Probable association by Brainscanr, and overview of the review article, in particular 2. http://www.brainscanr.com/Search?term_a=TDCS

primary motor cortex (M1). A number of other regions are also examined, in particular the primary somatosensory cortex (S1) and visual cortex. 2 While most of the studies presented here focus on the effects on functions evoked by tDCS, it must be noted that a major and growing use of tDCS is to infer the involvement of neural regions in varied functions, such as for example; the role of the cerebellum in verbal working memory37, or suppression of the non-dominant hand's motor cortex by the M1 region controlling the dominant hand38,39. In the aforementioned cases, this was investigated via inhibitory/cathodal tDCS on those regions in conjunction with tasks involving the functions studied. Furthermore, in these studies, impairment of a function following modulation of a neuroanatomical area, typically in the form of cathodal tDCS "inhibition", is used as supporting evidence towards the hypothesis that it does indeed play a role in the affected function, whether directly or indirectly. The inclusion of a number of cortical structures and associated effects was inspired by both articles2,3,24,26,40, and the brainSCANr engine (Brain Systems, Connections, Associations, and Network Relationships). http://www.brainscanr.com/Search?term_a=TDCS. 41 See Figure 2 & 3, supplementary material.

c This often includes, roughly speaking, the prefrontal (anterior and rostral) cortex itself (PFC), the Orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (dlPFC). d This includes the primary motor cortex (M1), the premotor cortex, and supplementary motor cortex

Motor Cortex Studies:

tDCS studies involving the motor cortex have shown potentially beneficial effects which can be attained using tDCS even in healthy individuals42. The primary motor cortex (M1) is a popular target in studies involving motor learning due to its suspected role in the initial encoding of motor skills (initial formation of memory)43, 24, the relative ease of quantifying results, and its being one of the earliest most studied areas in the field14,27,44. M1 modulation may also affect other areas such as the premotor cortex 24,45,46. In addition, there is a distinction24 between learning new motor skills and improving performance of existing motor skills'.10,24,42,47 Review and meta-analysis studies have shown that anodal tDCS increased corticomotor excitability.10,24 In regards to (lasting) effects; tDCS produces lasting effects in the human motor cortex. These are stable for up to about an hour if tDCS is applied for 9-13 minutes. Anodal stimulation enhances, whereas cathodal tDCS diminishes excitability, as measured by motor-evoked potential (MEP) amplitude2,18

Hand Motor Performance: A study of non-dominant hand motor performance and control48, as measured with the Jebsen Taylor Hand Function Test (JTT), reported the following: Anodal (excitatory) tDCS stimulation of theM1 contralateral to the non-dominant hand, (= the Left hemisphere, for the right handed subjects), resulted in significant enhancement of JTT performance after 1mA anodal tDCS of M1 (mean improvement of

9.41%), but not after sham 48. The study reported improvement in the non-dominant hand, but not the dominant hand. This seeming contradiction with other studies reporting all-around improvement is explained by the fact that the JTT task examines motor performance and control, rather than motor learning. As the author notes, the nondominant hands governing motor cortex region is characterized by having a higher motor threshold and lower motor evoked potential [MEP], as a corollary to its relatively lower intrinsic excitability48,49 compared to the dominant hands motor cortex. Motor Learning: A number of studies have shown tDCS evoked enhancement of motor learning, in both healthy and sick individuals. Reported results vary due to the differences between tasks, the complexity of the tasks and stages of learning studied 24, as well as possible methodological inconsistencies1,2 (for example, differences in: electrode montage placement and electrical field orientation, stimulation duration, and current strength). Still, a number of studies16,24,26,38,39,4246,48,5053 have shown improvements in motor learning and/or rehabilitation with tDCS stimulation. A typical example is a study of non-dominant hand motor function enhancement via (unilateral) anodal stimulation of the contralateral motor cortex 24,44,51, or/and47,53 inhibition of the opposing hemispheres motor cortex via cathodal stimulation.38 The wide range of effects, most of which showed improvements (as measured by varying criteria) include better results in recovering motor skills among stroke patients10,47,50,54, enhanced retention of motor skills, 44,51 , the previously mentioned effects24 on (non-dominant) hand motor skills' performance
38,39,48,54

, implicit motor-

sequence learning24,44,35, modulation of long term motor memory, implicit and procedural

skills learning, retention and consolidation 3,55,104, explicit sequence learning (in a bilateral stimulation experiment) 53, increased practice-dependent plasticity i.e. magnitude and duration of newly acquired motor memories51 and visuomotor tracking/coordination task performance following a-tDCS stimulation of the contralateral M1 or extrastriate visual cortex area MT+/V5 (but not of the primary visual cortex) 52 Motor Studies Discussion: To summarize, the overall consensus 42, 20 would seem to be that tDCS {is} [] capable of inducing lasting improvements in motor function. [and] has shown preliminary success in improving motor performance and motor learning in healthy individuals, and restitution of motor deficits in stroke patients.42 An aspect worthy of reemphasis is the two types of functional enhancements seen in the aforementioned studies (and the following section): (1) Immediate performance enhancement; for example, increased dexterity and control in the JTT test48 (these effects are seen in tasks where tDCS improves performance, even without training56) (2) Faster/enhanced learning and/or plasticity, as seen in memory retention and formation44,51, reconstruction of (motor) skills in stroke patients10,10,47,50,54,57, or effects seen when tDCS is applied during training24,46,58. The connection or causation between these two effects', if there is one, is unclear20,24,28, and requires further study beyond the scope of this work. While it might seem likely that a positive link exists, evidence is currently sparse, with some negative

examples showing a negative correlation between the learning slope, reaction time and/or accuracy or control26, 44. In addition, some effects or changes might be network specific, or due to stimulation of competing or inhibiting neighboring regions, thus impacting various performance criteria for some tasks, but not others. For example, cathodal stimulation of the opposing hemisphere-motor cortex region, rather than anodal stimulation of the contralateral M1 hand region, has a similar but not identical facilitatory effect 47,53,56,59. Repeating previous experiments with fresh experimental paradigms may well add new insight to this issue. These measures might include: Left/Right/dual hemisphere stimulation anodal cathodal, larger samples, different tasks (measuring the learning or performance rates improvements, increases above the baseline and retention), uniform stimulation intensity/current strength2 and improved neuroanatomical resolution via new high definition tDCS techniques5 which allow stimulation of smaller, more focused regions.

Cognitive Studies:
A great many tDCS studies on higher mental functions or cognitive effects have focused on stimulation or suppression of the prefrontal cortex (PFC) and its connected regions, especially the dorsolateral prefrontal cortex (dlPFC)30,60 and the orbitofrontal cortex (OFC)6163. Interest in these regions is primarily due to their suspected roles in the highest mental and cognitive functions such as planning64, executive functions64, working memory [WM]20,30,32,6568, behavioral regulation69 and decision making62,7072;

the most advanced and intellectual mental functions that we possess as intelligent beings.

A diverse array of mental functions show potential for modulation by tDCS. Many even show enhancement i.e. improvement beyond the baseline in healthy individuals. Among the best established and most documented of tDCS evoked effects is improved WM, via anodal-tDCS [a-tDCS] stimulation of the dlPFC 26,30,32,66,67,73. WM is the limited capacity storage system involved in the maintenance and manipulation of information over short periods of time. WM plays a key role in a wide rangee of higher order cognitive functions74. WM is one of the few known transferable75 elements of general or fluid intelligence76, with a wide array of cognitive functions benefiting from it.74 It is typically measured using a n-back task30, and is suspected to be malleable with training30,75,76. Anodal {excitatory} tDCS stimulation [a-tDCS] over the dlPFC has been shown to improve verbal and visuospatial32 working memory30,67,77, both in patients (poststrokes24,32,54,65,75, Parkinsons disease73 or Alzheimers disease78), and in healthy30,32,66,67 or elderly12,78,79 adults. Stimulation of the left PFC is associated with

e Examples of WM associated functions: http://www.brainscanr.com/Search?term_a=working+memory

verbal WM17 and naming ability improvement, while a-tDCS of the right PFC is associated with improving visuospatial WM. 32

Other cognitive effects: Explicit motor learning as noted in the previous, motor section, with dlPFC modulation was also seen to have an effect in some cases 24,78,80. Improved retention, consolidation21,55,80 and reconsolidation23 of (verbal) declarative memories17,21,26,77 , following unilateral-left dlPFC a-tDCS. At the same time, M1 stimulation was not found to affect verbal memory performance77.

Anecdotally, strongly reported positive feelings of improved focus, clarity29,

concentration29,81 and a state of flow82,40,83 (flow is a state of concentration or complete absorption with the activity at hand and the situation.84). The aforementioned effects make tDCS a potential tool for speeding up learning,2,51,58,67,77,82,83,85,29,40, in a variety of real world tasks 86.For example, training for complex threat detection, found a 2.3 fold improvement in the training time required, via improved alertness-attentional control81, following atDCS of the right inferior frontal cortex during training29. The difference between the test and sham groups was retained for over 24 hours after the training ended.

Creativity and novel-insights 87: participants who underwent cathodal

stimulation of the left anterior temporal lobe (ATL) together with anodal stimulation of the right ATL were three times as successful at solving an insight/creativity task (matchstick arithmetic) compared to a control group

(reversing the hemispherical A/C stimulation showed less of an effect, possibly due to a ceiling effect, reminiscent of the aforementioned M1 hand studies).48

Long-lasting changes in numerical competence: in this study, healthy adults

were stimulated via tDCS while learning artificial numerical valuesf. They were later tested for numerical competency. The group which had anodal and cathodal tDCS stimulation to the right and left (respectively) parietal lobes during training showed better and more consistent performance in both numerical tasks compared with the control group. Interestingly, six months after the experiment, that group still showed improvement. Another group with reversed stimulation polarity showed reduced performance. The training derived effect was seemingly task-specific, with performance in the tasks using normal numbers not showing change. 22 Inhibitory control of voluntary actions was enhanced or impaired via a-tDCS or cathodal tDCS (respectively) to the pre-supplementary motor area. 106 Verbal & Lingual abilities: in addition to the aforementioned effects of left dlPFC atDCS on verbal working memory, other studies have shown that:

f They were stimulated for 20 minutes at the start of the 90-120 minute learning phase. They were not stimulated during the testing.

oA-tDCS over the right temporal-parietal cortex combined with language training significantly improved naming ability in patients suffering from chronic anomic aphasia (severe problem with recalling words or names)88.
o

a-tDCS of the left posterior perisylvian region (included Wernicke's area) in

healthy subjects, during a visual picture naming task also showed significantly faster and equally accurate naming responses following stimulation.89 oCathodal tDCS over the Cerebellum impairs verbal working memory37, implying cerebellar involvement in the function (excitatory/a-tDCS was not tested). odlPFC a-tDCS affects long term verbal memory consolidation17 (initial memorization) and reconsolidation23,23 (renewed consolidation/storing of a memory following its retrieval), with both showing enhancement i.e. Improved speed and recognition accuracy when tested on verbal memories17. oA-tDCS over Brocas area was shown to enhance implicit learning of an artificial grammar. 90 The effects were seen to be specific to rule-based knowledge of the artificial grammar and detection of syntactic violations and were not the result of differences in W M.

A-tDCS stimulation of the auditory cortex was found to improve the abilities of

healthy subjects in temporal auditory processing abilities, as measured by the subjects ability to discern auditory temporal resolution. Cathodal tDCS reduced performance compared to the control group.91

tDCS experiments with aged, healthy subjects have shown reversal of some agerelated impairments in mental abilities to a more youthful12 state92. Known effects include: Right temporoparietal cortex stimulating leading to improved object-location learning (learning the positions of buildings on a street map), with improved recall lasting for at least one week93. M1 stimulation affecting acquisition of complex motor skills, lasting for over 24 hours 94. Age related hyperactivity in a number of neural networks involved in semantic word generationg was notably reduced with improved task performance, following a-tDCS of the left inferior frontal gyrus.12 Other age related declines have been noted to be alleviated by tDCS in studies focusing on patients suffering from Alzheimers disease (for example, object recognition).78,92 Additional Behavioral Effects: Cathodal tDCS over M195 or primary somatosensory cortex (S1) has been shown to reduce induced pain sensations/nociception. 96 dlPFC tDCS stimulation has also been found to reduce craving for specific foods97 and alcohol98, to alter probabilistic thinking 68, probabilistic forecasting (switching between frequency matching and expectancy maximization strategies70) and risk-taking ('risk-appetite') behavior71,72. Polarization of the visual or parietal cortexes modulates the threshold for motion or tactile perception, respectively (i.e increased or reduced sensitivity). 101-103
g

This included the PFC and anterior cingulate gyrus

tDCS applied during slow wave sleep affects verbal declarative memory, improving retention of 'word pairs'21, and also facilitates "sleep dependent consolidation" of procedural motor memories enhancing retention (consolidation) of these none-declarative memories 94,92. Different sleep frequency bands were also affected 21.

Discussion
tDCS has a number of different modulatory effects on various mental, cognitive, behavioral and neurobiological processes.. It is capable of inducing modulatory changes in many different systems, and neural regions 1. tDCS induced physiological changes may result in both local and distant changes in excitability, inhibition and potentially changes in plasticity (local or synaptic). The effects underlying the immediate or lasting effects involved in tDCS, and the changes derived from and affected by it cannot be simplified narrowed down to only one basic mechanism such as reduced dopamine reuptake or spontaneous motor activity induced by strong electrical shocks of the motor nerves. As has been noted here previously, effects differ in regards to: i) The mental, behavioral or cognitive functions affected. Effects modulated include declarative memory 21,77, motor performance and control 38,39,48, consolidation 55,104 and reconsolidation 23,24 of memories, attentional control 56,81, visual and tactile-sensory perception and sensitivity 56,101,103, visuomotor tracking 52,101, working memory 30,32,37,66,67, risk appetite behavior 70-72, cravings 97,98, creativity 87, planning ability19 , language and artificial grammar rule-learning90-92, and the many other effects previously listed in both this text and existing literature 1-3,92. ii) The cortical area(s) affected:1-3. Stimulation of different regions of the brain can affect the same functions and/or different functions, depending on the areas, their roles and the functional network involved in a function.

Given examples include: WM modulation via the cerebellum 25,37 or dlPFC, and involvement of both M1 and the PFC in implicit learning of motor skills 20,30,35,39,42,45,48,51. This as opposed to tasks found to be unaffected by stimulation of one of the generally involved areas (V1, M1, dlPFC in the case of motor related tasks), in cases such as taskspecific differential effects on task switching performance 46 or visuomotor tracking 52,101. iii) While most investigated functions can be impaired, usually but not exclusively, by cathodal tDCS, far fewer functions can be enhanced. For example, dominant hand motor performance in healthy individuals, (at least in existing studies) 48. That said, a large number of effects show enhancement in healthy adults10,19,24,38,67,68,70,87,89 or improved restoration (sometimes when combined with training 74,88) towards healthy or normal levels in the case of the elderly 92-94, post-stroke patients 47,50,54,65,and Alzheimer's or Parkinson's disease's patients 73,78. These effects typically involve: A) broad, trainable ("training dependent plasticity" = interactions between training with or without tDCS) mental functions such as WM 74-76 or other effects of executive planning' and so called 'higher mental functions' 56,58,80-87. B) The other type that seems most 'amenable' to 'enhancement' are functions controlled by regions which have deteriorated and have reduced plasticity or excitability. Examples include age related decline in cognition and mental capabilities. tDCS has been shown temporary reversal of many of the aforementioned age related symptoms or connectional characteristics 12,92-94 and enhancement of motor control and performance in the nondominant hand38 (which is theorized to be 'suppressed' by the dominant hand 49). In all these cases, the tDCS "resets" excitability towards what is likely the 'healthy baseline'. What exactly determines if a function can be enhanced, with or without training or enhanced in a lasting, training dependent or independent fashion29,40,56,58,83, is beyond the scope of this work, save for speculation.

i)

The duration of effects after the stimulation has ended can vary immensely, both in regard to the post-immediate effects following the end of the stimulation (typically occurring over hours 14,15,18,34), and in regards to the duration of the functional changeswhich can persist for days 29 or even months! 19,22 Multiple mechanisms are possibly involved in such long lasting effects, likely including (but not necessarily identical to) neural and/or synaptic plasticity 1,28,100 + LTP and/or LTD like effects 13,6,7,27,28

, modulation of GABA, Glutamate and/or NMDA

receptors1,6,7,13,105,106-108, involvement of regulation/effects from related neural networks 1,3,107 and regulatory factors, such as BDNF 100. ii) The numerous cases of left/right specificity of effects, not just for motor effects 39,42,53 but also for abstract mental functions (such as declarative verbal memory77 or working memory67) is somewhat peculiar. Perhapsthis might prove to be an artifact of current leakage affecting surrounding structures or shared inhibitory interneuronal networks, with bilateral atDCS+ cathodal tDCS inadvertently focusing the effects to sub-structures.

Claims of tDCS being domain specific or a modulator of only a single effect appear invalid, given the numerous listed examples of different effects for different regions, and the wide range of effects. Modulation of WM and attention could possibly have an influence on a number of the effects 60,74,76 and possibly even some of the behavioral effects, such as reduced risk appetite behavior being a consequence of improved probabilistic thought/numerical competency, and that being somehow derived from a boost to WM but it still fails to explain all the dlPFC related effects (cravings97,98 for example), and completely fails at explaining effects evoked from stimulation of regions remote from the PFC. Still, the possibility of WM as an underlying 'cause' behind many known cognitive and behavioral effects seen as a result of imprecise/"conventional"5 tDCS currents applied to the dlPFC 'leaking' is an interesting one, and could easily be investigated as a confounding effect via

testing for changes in WM using an n-back test, and examining the r-Pearson's correlation for WM changes relative to whichever effects are being primarily examined. The possibilities for further research are vast. A number of interesting questions include: what other cognitive effects show lasting changes (relative to a control group) for weeks or months following tDCS stimulation? Are any such effects training independent (all given examples of long lasting effects have involved training88, albeit with differential effects seen for novices in some cases 86)? Can effects from different brain regions or networks "overlap" in an additive manner? (For example, this is examinable via simultaneous a-tDCS of the dlPFC and other areas known to be involved in a task, and comparison of results to see if interaction or additive effect(s?) exist). Stimulation of novel areas and investigation at higher resolutions for which regions within structures are involved in modulation of functions associated with the entire region (sub-regions of the dlPFC and WM for example). The potential "real world" uses are known, in particular for rehabilitation 2,16,50,65, but the potential use as a so called "thinking cap"87 for healthy individuals is even more exciting. Studies have already taken place in the real world with healthy individuals
29,40,81,82,83

, but more are needed to help establish the generalizability of the potential

effects, to help establish the safety of long term use 2,11 and optimize parameters for such usage (in terms of electrode orientation and location, current intensity and 'side-effects'
99

). Two interesting ways to test this, with a large study group of healthy adults, would be

to try the following: i) A study of the effects of a-tDCS on language learning; given stimulation of a combination (requiring an additional 'additive' experiment to establish the most effective combination) of Broca's area, Wernicke's area and/or the dlPFC. This could be applied in conjunction with an existing language course, or even a code/programming language course. ii) Another idea is a-tDCS of the dlPFC, and/or the anterior temporal lobes ("insight facilitation"87) with volunteers in an academic environment, such as a theoretical training course or academic class, applied at the midpoint of a course, so as to observe the effects on learning 40,82,83. Given such a large group (even a sub-section of volunteers from one), any effects in grades or improvements for the non-sham group can be easily compared to the rest of the class, and their own previous performance.

This would be an excellent way to test applicability and potentially enhancing effects with a large group of healthy subjects, and would not be overly expensive given the relative simplicity and compactness of a basic tDCS kit. This would help in testing the effects in challenging, noisy environments with a focus on uses that would have far reaching implications for healthy people, while the large test groups would help in establishing effects, as opposed to the large number of existing experiments with their small sample sizes, a fact that makes rigorously testing something with multiple A/B/C combinations statistically problematic. This could have obvious benefits 87 for consumers, with the added benefit of massively expanding the data available for use in future rehabilitative or restorative92 studies, as well as other studies in the field, such as examining neuroanatomical networks or the long term effects (and side-effects99).

Conclusion
tDCS modulates neural excitability1,2,6, increasing calcium levels at site of anodal stimulation 5,7,92, altering the 'resting' electrical potential of neurons' membranes 1,3,14,27 , and possibly changing neuroplasticity and/or synaptic plasticity via inducing LTP or LTD like changes6,34,38. Anodal tDCS creates an electric field, inducing a slight depolarization, increasing the intrinsic excitability of neurons while cathodal tDCS decreases neuronal excitability due to hyperpolarization. The after-effects of both anodal and cathodal tDCS are influenced by glutamatergic receptors 1,3,6,7, and a-tDCS is influenced by "GABAergic neurotransmission via interneurons" 92,106. tDCS has been shown to affect a heterogonous array of different mental, behavioral, cognitive and neurobiological functions. The mental and behavioral effects of tDCS depend on the stimulation's parameters, cortical region(s) stimulated, the mental function itself, and possible interactions with other factors, such as damage (in the case of strokes), or decline (in the case of age related decline). Not all effects can be "enhanced"

beyond baseline abilities, and not all such effects (whether "enhancing" or "inhibitory") are retained after the stimulation has ceased, though some tDCS-evoked effects may persist for months. Some capabilities are "enhanced" (during stimulation) via increased intrinsic excitability, while others benefit from cathodal tDCS reducing "noise"30. tDCS should not be regarded as affecting only a single effect, function or region, but rather as a general purpose neuromodulator that has different effect depending on the variables at play, in particular the region of the brain stimulated, the polarity of the induced electrical field, the mental or behavioral function involved and the time-period of the stimulation.

I wish to thank everyone who helped with this paper, in particular my friends and family, and my academic advisor.

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Supplementary Material
Fig.1 :

Source: (92) Voytek, B., & Gazzaley, A. (2013). Stimulating the aging brain. Annals of neurology, 73(1), 13. doi:10.1002/ana.23790 Fig 2: tDCS & TMS associations:

Source: 41 - http://www.brainscanr.com/Search?term_a=tDCS

Fig 3:

Source: 41 - http://www.brainscanr.com/Search?term_a=working+memory