Quantifying error in effect size estimates in attention, executive function, and implicit learning.

Accurate quantification of effect sizes has the power to motivate theory and reduce misinvestment of scientific resources by informing power calculations during study planning. However, a combination of publication bias and small sample sizes (∼N = 25) hampers certainty in current effect size estimates. We sought to determine the extent to which sample sizes may produce errors in effect size estimates for four commonly used paradigms assessing attention, executive function, and implicit learning (attentional blink, multitasking, contextual cueing, and serial response task). We combined a large data set with a bootstrapping approach to simulate 1,000 experiments across a range of N (13-313). Beyond quantifying the effect size and statistical power that can be anticipated for each study design, we demonstrate that experiments with lower N may double or triple information loss. We also show that basing power calculations on effect sizes from similar studies yields a problematically imprecise estimate between 40% and 67% of the time, given commonly used sample sizes. Last, we show that skewness of intersubject behavioral effects may serve as a predictor of an erroneous estimate. We conclude with practical recommendations for researchers and demonstrate how our simulation approach can yield theoretical insights that are not readily achieved by other methods such as identifying the information gained from rejecting the null hypothesis and quantifying the contribution of individual variation to error in effect size estimates. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Stimulating prefrontal cortex facilitates training transfer by increasing representational overlap.

A recent hypothesis characterizes difficulties in multitasking as being the price humans pay for our ability to generalize learning across tasks. The mitigation of these costs through training has been associated with reduced overlap of constituent task representations within frontal, parietal, and subcortical regions. Transcranial direct current stimulation, which can modulate functional brain activity, has shown promise in generalizing performance gains when combined with multitasking training. However, the relationship between combined transcranial direct current stimulation and training protocols with task-associated representational overlap in the brain remains unexplored. Here, we paired prefrontal cortex transcranial direct current stimulation with multitasking training in 178 individuals and collected functional magnetic resonance imaging data pre- and post-training. We found that 1 mA transcranial direct current stimulation applied to the prefrontal cortex paired with multitasking training enhanced training transfer to spatial attention, as assessed via a visual search task. Using machine learning to assess the overlap of neural activity related to the training task in task-relevant brain regions, we found that visual search gains were predicted by changes in classification accuracy in frontal, parietal, and cerebellar regions for participants that received left prefrontal cortex stimulation. These findings demonstrate that prefrontal cortex transcranial direct current stimulation may interact with training-related changes to task representations, facilitating the generalization of learning.

Intensity-dependent effects of tDCS on motor learning are related to dopamine.

Non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), are popular methods for inducing neuroplastic changes to alter cognition and behaviour. One challenge for the field is to optimise stimulation protocols to maximise benefits. For this to happen, we need a better understanding of how stimulation modulates cortical functioning/behaviour. To date, there is increasing evidence for a dose-response relationship between tDCS and brain excitability, however how this relates to behaviour is not well understood. Even less is known about the neurochemical mechanisms which may drive the dose-response relationship between stimulation intensities and behaviour. Here, we examine the effect of three different tDCS stimulation intensities (1 mA, 2 mA, 4 mA anodal motor cortex tDCS) administered during the explicit learning of motor sequences. Further, to assess the role of dopamine in the dose-response relationship between tDCS intensities and behaviour, we examined how pharmacologically increasing dopamine availability, via 100 mg of levodopa, modulated the effect of stimulation on learning. In the absence of levodopa, we found that 4 mA tDCS improved and 1 mA tDCS impaired acquisition of motor sequences relative to sham stimulation. Conversely, levodopa reversed the beneficial effect of 4 mA tDCS. This effect of levodopa was no longer evident at the 48-h follow-up, consistent with previous work characterising the persistence of neuroplastic changes in the motor cortex resulting from combining levodopa with tDCS. These results provide the first direct evidence for a role of dopamine in the intensity-dependent effects of tDCS on behaviour.

Assessing the influence of dopamine and mindfulness on the formation of routines in visual search.

Given experience in cluttered but stable visual environments, our eye-movements form stereotyped routines that sample task-relevant locations, while not mixing-up routines between similar task-settings. Both dopamine signaling and mindfulness have been posited as factors that influence the formation of such routines, yet quantification of their impact remains to be tested in healthy humans. Over two sessions, participants searched through grids of doors to find hidden targets, using a gaze-contingent display. Within each session, door scenes appeared in either one of two colors, with each color signaling a differing set of likely target locations. We derived measures for how well target locations were learned (target-accuracy), how routine were sets of eye-movements (stereotypy), and the extent of interference between the two scenes (setting-accuracy). Participants completed two sessions, where they were administered either levodopa (dopamine precursor) or placebo (vitamin C), under double-blind counterbalanced conditions. Dopamine and trait mindfulness (assessed by questionnaire) interacted to influence both target-accuracy and stereotypy. Increasing dopamine improved accuracy and reduced stereotypy for high mindfulness scorers, but induced the opposite pattern for low mindfulness scorers. Dopamine also disrupted setting-accuracy invariant to mindfulness. Our findings show that mindfulness modulates the impact of dopamine on the target-accuracy and stereotypy of eye-movement routines, whereas increasing dopamine promotes interference between task-settings, regardless of mindfulness. These findings provide a link between non-human and human models regarding the influence of dopamine on the formation of task-relevant eye-movement routines and provide novel insights into behavior-trait factors that modulate the use of experience when building adaptive repertoires.

Neurochemical Predictors of Generalized Learning Induced by Brain Stimulation and Training.

Methods of cognitive enhancement for humans are most impactful when they generalize across tasks. However, the extent to which such "transfer" is possible via interventions is widely debated. In addition, the contribution of excitatory and inhibitory processes to such transfer is unknown. Here, in a large-scale neuroimaging individual differences study with humans (both sexes), we paired multitasking training and noninvasive brain stimulation (transcranial direct current stimulation, tDCS) over multiple days and assessed performance across a range of paradigms. In addition, we varied tDCS dosage (1.0 and 2.0 mA), electrode montage (left or right prefrontal regions), and training task (multitasking vs a control task) and assessed GABA and glutamate concentrations via ultrahigh field 7T magnetic resonance spectroscopy. Generalized benefits were observed in spatial attention, indexed by visual search performance, when multitasking training was combined with 1.0 mA stimulation targeting either the left or right prefrontal cortex (PFC). This transfer effect persisted for ∼30 d post intervention. Critically, the transferred benefits associated with right prefrontal tDCS were predicted by pretraining concentrations of glutamate in the PFC. Thus, the effects of this combined stimulation and training protocol appear to be linked predominantly to excitatory brain processes.

Exploring the intra-individual reliability of tDCS: A registered report.

Transcranial direct current stimulation (tDCS), a form of non-invasive brain stimulation, has become an important tool for the study of in-vivo brain function due to its modulatory effects. Over the past two decades, interest in the influence of tDCS on behaviour has increased markedly, resulting in a large body of literature spanning multiple domains. However, the effect of tDCS on human performance often varies, bringing into question the reliability of this approach. While reviews and meta-analyses highlight the contributions of methodological inconsistencies and individual differences, no published studies have directly tested the intra-individual reliability of tDCS effects on behaviour. Here, we conducted a large scale, double-blinded, sham-controlled registered report to assess the reliability of two single-session low-dose tDCS montages, previously found to impact response selection and motor learning operations, across two separate time periods. Our planned analysis found no evidence for either protocol being effective nor reliable. Post-hoc explorative analyses found evidence that tDCS influenced motor learning, but not response selection learning. In addition, the reliability of motor learning performance across trials was shown to be disrupted by tDCS. These findings are amongst the first to shed light specifically on the intra-individual reliability of tDCS effects on behaviour and provide valuable information to the field.

Dopamine Increases Accuracy and Lengthens Deliberation Time in Explicit Motor Skill Learning.

Although animal research implicates a central role for dopamine in motor skill learning, a direct causal link has yet to be established in neurotypical humans. Here, we tested if a pharmacological manipulation of dopamine alters motor learning, using a paradigm which engaged explicit, goal-directed strategies. Participants (27 females; 11 males; aged 18-29 years) first consumed either 100 mg of levodopa (n = 19), a dopamine precursor that increases dopamine availability, or placebo (n = 19). Then, during training, participants learnt the explicit strategy of aiming away from presented targets by instructed angles of varying sizes. Targets jumped mid-movement by the instructed aiming angle. Task success was thus contingent upon aiming accuracy and not speed. The effect of the dopamine manipulations on skill learning was assessed during training and after an overnight follow-up. Increasing dopamine availability at training improved aiming accuracy and lengthened reaction times, particularly for larger, more difficult aiming angles, both at training and, importantly, at follow-up, despite prominent session-by-session performance improvements in both accuracy and speed. Exogenous dopamine thus seems to result in a learnt, persistent propensity to better adhere to task goals. Results support the proposal that dopamine is important in engagement of instrumental motivation to optimize adherence to task goals, particularly when learning to execute goal-directed strategies in motor skill learning.

Neural substrates of individual differences in learning generalization via combined brain stimulation and multitasking training.

A pervasive limitation in cognition is reflected by the performance costs we experience when attempting to undertake two tasks simultaneously. While training can overcome these multitasking costs, the more elusive objective of training interventions is to induce persistent gains that transfer across tasks. Combined brain stimulation and cognitive training protocols have been employed to improve a range of psychological processes and facilitate such transfer, with consistent gains demonstrated in multitasking and decision-making. Neural activity in frontal, parietal, and subcortical regions has been implicated in multitasking training gains, but how the brain supports training transfer is poorly understood. To investigate this, we combined transcranial direct current stimulation of the prefrontal cortex and multitasking training, with functional magnetic resonance imaging in 178 participants. We observed transfer to a visual search task, following 1 mA left or right prefrontal cortex transcranial direct current stimulation and multitasking training. These gains persisted for 1-month post-training. Notably, improvements in visual search performance for the right hemisphere stimulation group were associated with activity changes in the right hemisphere dorsolateral prefrontal cortex, intraparietal sulcus, and cerebellum. Thus, functional dynamics in these task-general regions determine how individuals respond to paired stimulation and training, resulting in enhanced performance on an untrained task.

Individual Differences in Decision Strategy Relate to Neurochemical Excitability and Cortical Thickness.

The speed-accuracy trade-off (SAT), whereby faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during the performance of almost all daily tasks. To date, computational modeling has implicated the latent decision variable of response caution (thresholds), the amount of evidence required for a decision to be made, in the SAT. Previous imaging has associated frontal regions, notably the left prefrontal cortex and the presupplementary motor area (pre-SMA), with the setting of such caution levels. In addition, causal brain stimulation studies, using transcranial direct current stimulation (tDCS), have indicated that while both of these regions are involved in the SAT, their role appears to be dissociable. tDCS efficacy to impact decision-making processes has previously been linked with neurochemical concentrations and cortical thickness of stimulated regions. However, to date, it is unknown whether these neurophysiological measures predict individual differences in the SAT, and brain stimulation effects on the SAT. Using ultra-high field (7T) imaging, here we report that instruction-based adjustments in caution are associated with both neurochemical excitability (the balance between GABA+ and glutamate) and cortical thickness across a range of frontal regions in both sexes. In addition, cortical thickness, but not neurochemical concentrations, was associated with the efficacy of left prefrontal and superior medial frontal cortex (SMFC) stimulation to modulate performance. Overall, our findings elucidate key neurophysiological predictors, frontal neural excitation, of individual differences in latent psychological processes and the efficacy of stimulation to modulate these.SIGNIFICANCE STATEMENT The speed-accuracy trade-off (SAT), faster decisions increase the likelihood of an error, reflects a cognitive strategy humans must engage in during most daily tasks. The SAT is often investigated by explicitly instructing participants to prioritize speed or accuracy when responding to stimuli. Using ultra-high field (7T) magnetic resonance imaging (MRI), we found that individual differences in the extent to which participants adjust their decision strategies with instruction related to neurochemical excitability (ratio of GABA+ to glutamate) and cortical thickness in the frontal cortex. Moreover, brain stimulation to the left prefrontal cortex and the superior medial frontal cortex (SMFC) modulated performance, with the efficacy specifically related to cortical thickness. This work sheds new light on the neurophysiological basis of decision strategies and brain stimulation.

Dopamine Alters the Effect of Brain Stimulation on Decision-Making.

Noninvasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS), show promise in treating a range of psychiatric and neurologic conditions. However, optimization of such applications requires a better understanding of how tDCS alters cognition and behavior. Existing evidence implicates dopamine in tDCS alterations of brain activity and plasticity; however, there is as yet no causal evidence for a role of dopamine in tDCS effects on cognition and behavior. Here, in a preregistered, double-blinded study, we examined how pharmacologically manipulating dopamine altered the effect of tDCS on the speed-accuracy trade-off, which taps ubiquitous strategic operations. Cathodal tDCS was delivered over the left prefrontal cortex and the superior medial frontal cortex before participants (N = 62, 24 males, 38 females) completed a dot-motion task, making judgments on the direction of a field of moving dots under instructions to emphasize speed, accuracy, or both. We leveraged computational modeling to uncover how our interventions altered latent decisional processes driving the speed-accuracy trade-off. We show that dopamine in combination with tDCS (but not tDCS alone nor dopamine alone) not only impaired decision accuracy but also impaired discriminability, which suggests that these manipulations altered the encoding or representation of discriminative evidence. This is, to the best of our knowledge, the first direct evidence implicating dopamine in the way tDCS affects cognition and behavior.SIGNIFICANCE STATEMENT tDCS can improve cognitive and behavioral impairments in clinical conditions; however, a better understanding of its mechanisms is required to optimize future clinical applications. Here, using a pharmacological approach to manipulate brain dopamine levels in healthy adults, we demonstrate a role for dopamine in the effects of tDCS in the speed-accuracy trade-off, a strategic cognitive process ubiquitous in many contexts. In doing so, we provide direct evidence implicating dopamine in the way tDCS affects cognition and behavior.

Task difficulty and private speech in typically developing and at-risk preschool children.

Private speech is a cognitive tool to guide thinking and behavior, yet its regulatory use in atypical development remains equivocal. This study investigated the influence of task difficulty on private speech in preschool children with attention or language difficulties. Measures of private speech use, form and content were obtained while 52 typically developing and 25 developmentally at-risk three- to four-year-old children completed Duplo construction and card sort tasks, each comprising two levels of challenge. In line with previous research, developmentally at-risk children used less internalized private speech than typically developing peers. However, both typically developing and at-risk children demonstrated a similar regulatory private speech response to difficulty with no systematic evidence of group difference. This was captured by an increase in all utterances, reduced private speech internalization, and more frequent forethought and self-reflective content. Results support the hypothesis of delayed private speech internalization but not regulatory deviance in atypical development.

The causal role of the prefrontal and superior medial frontal cortices in the incidental manipulation of decision strategies.

A key strategic decision one must make in virtually every task context concerns the speed accuracy trade-off (SAT). Experimentally, this ubiquitous phenomenon, whereby response speed and task accuracy are inversely related, is typically studied by explicitly instructing participants to adjust their strategy: by either focusing on speed, or on accuracy. Computational modelling has been applied to deconvolve the latent decision processes involved in the SAT, with considerable evidence suggesting that response caution (the amount of evidence needed for a decision to be reached) is a key variable in the setting of SAT strategy. Neuroimaging has implicated the prefrontal cortex, the pre-supplementary motor area (preSMA), and the striatum in the setting of response caution. In addition, brain stimulation has provided causal evidence for the involvement of the left prefrontal cortex and superior medial frontal cortex (SMFC, which includes the preSMA) in adjustments of response caution following explicit instructions, although stimulation of the two regions has dissociable effects. Here, in a double-blind and preregistered study we investigated the role of these two regions using an incidental manipulation of SAT strategy - via stimulus signal variability - which has previously been shown to influence decision confidence. We again found tDCS applied to both regions modulated response caution, and there was a dissociation: stimulating prefrontal cortex increased, and stimulating SMFC decreased, response caution. These findings provide further support for key, but dissociable, roles of these brain regions in decision strategies whether they are implemented explicitly or incidentally.

Knowledge generalization and the costs of multitasking.

Humans are able to rapidly perform novel tasks, but show pervasive performance costs when attempting to do two things at once. Traditionally, empirical and theoretical investigations into the sources of such multitasking interference have largely focused on multitasking in isolation to other cognitive functions, characterizing the conditions that give rise to performance decrements. Here we instead ask whether multitasking costs are linked to the system's capacity for knowledge generalization, as is required to perform novel tasks. We show how interrogation of the neurophysiological circuitry underlying these two facets of cognition yields further insights for both. Specifically, we demonstrate how a system that rapidly generalizes knowledge may induce multitasking costs owing to sharing of task contingencies between contexts in neural representations encoded in frontoparietal and striatal brain regions. We discuss neurophysiological insights suggesting that prolonged learning segregates such representations by refining the brain's model of task-relevant contingencies, thereby reducing information sharing between contexts and improving multitasking performance while reducing flexibility and generalization. These proposed neural mechanisms explain why the brain shows rapid task understanding, multitasking limitations and practice effects. In short, multitasking limits are the price we pay for behavioural flexibility.

tDCS augments decision-making efficiency in an intensity dependent manner: A training study.

The application of transcranial direct current stimulation (tDCS) to the prefrontal cortex has the potential to improve performance more than cognitive training alone. Such stimulation-induced performance enhancements can generalize beyond trained tasks, leading to benefits for untrained tasks/processes. We have shown evidence that stimulation intensity has non-linear effects on augmenting cognitive training outcomes. However, it is currently unclear how stimulation intensity augments cognitive processing to impact training and transfer effects. Here, we applied decision-making modelling via the linear ballistic accumulator framework to understand what aspects of cognitive processes underlying speeded single-/dual-task decision-making performance change with tDCS intensity. One hundred and twenty-three participants were split into four groups: sham, 0.7 mA, 1.0 mA and 2.0 mA stimulation intensities. Participants completed four training sessions whilst tDCS was delivered. The 0.7 mA & 1.0 mA intensities provided the greatest benefit for performance (increased decision-making efficiency as measured by drift rates) on the trained task - more than sham or 2.0 mA stimulation. The latent decision components integrated both accuracy and reaction times to estimate performance more broadly. We see an inverted u-shaped function of stimulation intensity and cognitive performance in the trained-on task, where either no stimulation or too much stimulation is sub-optimal for performance. By contrast, 1.0 mA and 2.0 mA intensities led to increased drift rates in an untrained (transfer) single task. In sum, tDCS intensity non-linearly modulates cognitive processes related to decision-making efficiency.

The influence of self-reported history of mild traumatic brain injury on cognitive performance.

The long-term cognitive consequences of mild traumatic brain injury (mTBI) are poorly understood. Studies investigating cognitive performance in the chronic stage of injury in both hospital-based and population-based samples have revealed inconsistent findings. Importantly, population-based mTBI samples remain under-studied in the literature. This study investigated cognitive performance among individuals with a history of self-reported mTBI using a battery of cognitively demanding behavioural tasks. Importantly, more than half of the mTBI participants had experienced multiple mild head injuries. Compared to control participants (n = 49), participants with a history of mTBI (n = 30) did not demonstrate deficits in working memory, multitasking ability, cognitive flexibility, visuospatial ability, response inhibition, information processing speed or social cognition. There was moderate evidence that the mTBI group performed better than control participants on the visual working memory measure. Overall, these findings suggest that even multiple instances of mTBI do not necessarily lead to long-term cognitive impairment at the group level. Thus, we provide important evidence of the impact of chronic mTBI across a number of cognitive processes in a population-based sample. Further studies are necessary to determine the impact that individual differences in injury-related variables have on cognitive performance in the chronic stage of injury.

On the Influence of Spatial and Value Attentional Cues Across Individuals.

The visual world provides a myriad of cues that can be used to direct information processing. How does the brain integrate predictive information from disparate sources to modify visual priorities, and are combination strategies consistent across individuals? Previous evidence shows that cues predictive of the value of a visually guided task (incentive value) and cues that signal where targets may occur (spatial certainty) act independently to bias attention. Anticipatory accounts propose that both cues are encoded into an attentional priority map, whereas the counterfactual account argues that incentive value cues instead induce a reactive encoding of losses based on the direction of attention. We adjudicate between these alternatives and further determine whether there are individual differences in how attentional cues are encoded. 149 participants viewed two coloured placeholders that specified the potential value of correctly identifying an imminent target. Prior to the target's presentation, an endogenous spatial cue indicated the target's likely location. The anticipatory and counterfactual accounts were used to motivate parametric regressors that were compared in their explanatory power of the data, at the group level and on data stratified by a clustering algorithm. Clustering revealed 2 subtypes; whereas all individuals use spatial certainty cues a subset does not use incentive value cues. When incentive value cues are used their influence reflects a counterfactual loss function. The data support the counterfactual account and show that theories of motivated attention must account for the non-uniform influence of incentive value on visual priorities.

Making a HIIT: study protocol for assessing the feasibility and effects of co-designing high-intensity interval training workouts with students and teachers.

BACKGROUND: High-intensity interval training (HIIT) is an effective strategy for improving a variety of health outcomes within the school setting. However, there is limited research on the implementation of school-based HIIT interventions and the integration of HIIT within the Health and Physical Education (HPE) curriculum. The aims of the Making a HIIT study are to: 1) describe the methodology and evaluate the feasibility of co-designing HIIT workouts with students and teachers in HPE; 2) determine the effect of co-designed HIIT workouts on cardiorespiratory and muscular fitness, and executive function; 3) understand the effect of co-design on students' motivation, enjoyment, and self-efficacy towards the workouts; and 4) evaluate the implementation of the intervention. METHODS: Three schools will participate. Within each school, three different groups will be formed from Year 7 and 8 classes: 1) Co-Designers; 2) HIIT Only; and 3) Control. The study will include two phases. In phase one, Group 1 will co-design HIIT workouts as part of the HPE curriculum using an iterative process with the researcher, teacher, and students as collaborators. This process will be evaluated using student discussions, student surveys, and teacher interviews. In phase two, Groups 1 and 2 will use the co-designed 10-minute HIIT workouts in HPE for 8-weeks. Group 3 (control) will continue their regular HPE lessons. All students will participate in cardiorespiratory fitness, muscular fitness, and executive function assessments before and after the HIIT program or control period. Students will complete questionnaires on their motivation, enjoyment, and self-efficacy of the workouts. Differences between groups will be assessed using linear regressions to account for covariates. Heart rate and rating of perceived exertion will be collected during each HIIT session. The implementation will be evaluated using the Framework for Effective Implementation. Ethical approval was granted by the University of Queensland Human Research Ethics Committee and other relevant bodies. DISCUSSION: This study will be the first to co-design HIIT workouts with teachers and students within the HPE curriculum. As this study relies on co-design, each HIIT workout will differ, which will add variability between HIIT workouts but increase the ecological validity of the study. TRIAL REGISTRATION: ACTRN, ACTRN12622000534785, Registered 5 April 2022 - Retrospectively registered, https://www.anzctr.org.au/ACTRN12622000534785.aspx.

Intervention is a better predictor of tDCS mind-wandering effects than subjective beliefs about experimental results.

Blinding in non-invasive brain stimulation research is a topic of intense debate, especially regarding the efficacy of sham-controlled methods for transcranial direct current stimulation (tDCS). A common approach to assess blinding success is the inclusion of correct guess rate. However, this method cannot provide insight into the effect of unblinding on observed stimulation outcomes. Thus, the implementation of measures to systematically evaluate subjective expectation regarding stimulation is needed. Previous work evaluated subjective effects in an earlier study which reported a mind-wandering and tDCS data set and concluded that subjective belief drove the pattern of results observed. Here we consider the subjective and objective intervention effects in a key contrast from that data set-2 mA vs. sham-which was not examined in the reanalysis. In addition, we examine another key contrast from a different tDCS mind-wandering study that employed similar methodology. Our findings support objective intervention as the strongest predictor of the observed effects of mind-wandering in both re-analyses, over and above that of subjective intervention. However, it is important to control for and understand the possible inadequacies of sham-controlled methods.

State-dependent effects of neural stimulation on brain function and cognition.

Invasive and non-invasive brain stimulation methods are widely used in neuroscience to establish causal relationships between distinct brain regions and the sensory, cognitive and motor functions they subserve. When combined with concurrent brain imaging, such stimulation methods can reveal patterns of neuronal activity responsible for regulating simple and complex behaviours at the level of local circuits and across widespread networks. Understanding how fluctuations in physiological states and task demands might influence the effects of brain stimulation on neural activity and behaviour is at the heart of how we use these tools to understand cognition. Here we review the concept of such 'state-dependent' changes in brain activity in response to neural stimulation, and consider examples from research on altered states of consciousness (for example, sleep and anaesthesia) and from task-based manipulations of selective attention and working memory. We relate relevant findings from non-invasive methods used in humans to those obtained from direct electrical and optogenetic stimulation of neuronal ensembles in animal models. Given the widespread use of brain stimulation as a research tool in the laboratory and as a means of augmenting or restoring brain function, consideration of the influence of changing physiological and cognitive states is crucial for increasing the reliability of these interventions.

On the relationship between GABA+ and glutamate across the brain.

Equilibrium between excitation and inhibition (E/I balance) is key to healthy brain function. Conversely, disruption of normal E/I balance has been implicated in a range of central neurological pathologies. Magnetic resonance spectroscopy (MRS) provides a non-invasive means of quantifying in vivo concentrations of excitatory and inhibitory neurotransmitters, which could be used as diagnostic biomarkers. Using the ratio of excitatory and inhibitory neurotransmitters as an index of E/I balance is common practice in MRS work, but recent studies have shown inconsistent evidence for the validity of this proxy. This is underscored by the fact that different measures are often used in calculating E/I balance such as glutamate and Glx (glutamate and glutamine). Here we used a large MRS dataset obtained at ultra-high field (7 T) measured from 193 healthy young adults and focused on two brain regions - prefrontal and occipital cortex - to resolve this inconsistency. We find evidence that there is an inter-individual common ratio between GABA+ (γ-aminobutyric acid and macromolecules) and Glx in the occipital, but not prefrontal cortex. We further replicate the prefrontal result in a legacy dataset (n = 78) measured at high-field (3 T) strength. By contrast, with ultra-high field MRS data, we find extreme evidence that there is a common ratio between GABA+ and glutamate in both prefrontal and occipital cortices, which cannot be explained by participant demographics, signal quality, fractional tissue volume, or other metabolite concentrations. These results are consistent with previous electrophysiological and theoretical work supporting E/I balance. Our findings indicate that MRS-detected GABA+ and glutamate (but not Glx), are a reliable measure of E/I balance .