Research

Enhancing visual-spatial learning by focalized transcranial direct current stimulation

Visual-spatial episodic memory formation, including object-location memory, is crucial for adapting to changing environments throughout life, and is known to decline in aging and aging-associated diseases. Given that this type of memory is inherently ecologically relevant and necessary for a variety of tasks in everyday life, this project will specifically investigate the neural mechanisms and predictors underlying enhancement of this process by individualized, focal transcranial direct current stimulation (tDCS). In the long-run, outcomes of this project will contribute to improving treatment of patients with neurodegenerative diseases (e.g., dementia and its precursors) or neurological injury (post-stroke visuo-spatial deficits). Within the broader context of the Research Unit, the present study is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8). The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioural stimulation response not only within each project, but also across the different tasks and functional domains (in Project 9). The current project will contribute unique information on how tDCS modulates spatial episodic memory formation, thereby complementing the investigation of tDCS-induced enhancement of spatial working memory in Project 2 (PI Blankenburg). Comparison with results obtained from Project 3, that uses a similar learning paradigm to investigate verbal episodic memory formation (PI Meinzer), will allow to investigate domain specificity of outcomes. Collectively, the results of the empirical projects of the Research Unit will increase our current understanding of tDCS-induced neural network effects, their regional specificity and the mechanisms underlying inter-individual variability of stimulation effects. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9+10), thereby advancing future experimental and translational applications of tDCS in health and disease.

Enhancing novel word learning by focalized transcranial direct current stimulation

The ability to learn new words is a crucial aspect of language acquisition in the developing and adult brain and known to decline in normal aging and age-associated disease. Because of the high ecological validity and relevance of novel word learning for everyday life in work and leisure contexts, this project will specifically investigate the neural mechanisms and predictors underlying enhancement of this process by individualized, focal transcranial direct current stimulation (tDCS). In the long-run, outcomes of this project will contribute to improving treatment of patients with neurodegenerative diseases (e.g., dementia and its precursors) or neurological injury (post-stroke aphasia) affecting language (re-)learning.

Within the broader context of the Research Unit (RU), the present study is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8) and the healthy human lifespan. The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioural stimulation response not only within each project, but also across the different tasks and functional domains (Project 9).

The current project will contribute unique information on how tDCS modulates verbal episodic memory formation, thereby complementing the investigation of tDCS-induced enhancement of verbal working memory in Project 4 (PI Hartwigsen). Comparison with results obtained from Project 1, that uses a similar learning paradigm to investigate visuo-spatial episodic memory formation (PI Flöel), will allow to investigate domain specificity of the respective outcomes.

Collectively, the results of the empirical projects of the RU will increase our current understanding of tDCS-induced neural network effects, their regional specificity, the mechanisms underlying inter-individual variability of stimulation effects, and potential changes due to chronological age. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9+10), thereby advancing future experimental and translational applications of tDCS in health and disease. 

Enhancing verbal working memory by focalized tDCS

Verbal working memory, the temporary maintenance of verbal information, is a key capacity of human cognition which is particularly relevant for successful and efficient every-day communication. This faculty is often affected by normal aging and in neurological and psychiatric disorders. The planned project will investigate the neural mechanisms and predictors underlying enhancement of verbal working memory by individualized, focal transcranial direct current stimulation (tDCS). To this end, we will combine individualized tDCS with a well-established n-back paradigm in healthy volunteers. We will complement univariate functional neuroimaging analyses with advanced functional and effective connectivity measures as well as graph theoretical approaches to map stimulation induced changes at the neural network level and relate them to behavioral changes. A better understanding of the neural underpinnings of modulatory tDCS effects on verbal working memory function will help to refine current models of verbal working memory and ultimately increase treatment efficacy of neurostimulation protocols in individuals with verbal working memory deficits.

Within the broader context of the Research Unit (RU), the present study is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8) and the healthy human lifespan. The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioural stimulation response not only within each project, but also across the different tasks and functional domains (in Project 9).

The current project will contribute unique information on how tDCS modulates verbal working memory, thereby complementing the investigation of tDCS-induced enhancement of verbal episodic memory formation in Project 3 (PI Meinzer). Collectively, the results of the empirical projects of the RU will increase our current understanding of tDCS-induced neural network effects, their regional specificity, the mechanisms underlying inter-individual variability of stimulation effects, and potential changes due to chronological age. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9+10), thereby advancing future experimental and translational applications of tDCS in health and disease. 

Enhancing motor sequence learning by focalized transcranial direct current stimulation

The ability to learn motor sequences is a crucial aspect of motor learning in the developing and adult brain and known to decline in normal aging and age-associated diseases. Motor learning is highly relevant for everyday life in work and leisure contexts. This project will thus specifically investigate the neural mechanisms and predictors underlying enhancement of this process by individualized, focal transcranial direct current stimulation (tDCS). In the long-run, outcomes of this project will contribute to improving treatment of patients with neurological diseases (e.g., stroke, Parkinson´s disease) affecting motor learning, and requiring it in the context rehabilitation.

Within the broader context of the RU, the present study is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8). The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioural stimulation response not only within each project, but also across different tasks and functional domains (in Project 9).

The current project will contribute unique information on how tDCS modulates motor sequence learning, which primarily depends on cortico-striatal loops, thereby complementing the investigation of tDCS-induced enhancement of cerebellar-dependent motor learning in Project 6 (PI Timmann). Collectively, the results of the empirical projects of the RU will increase our current understanding of tDCS-induced neural network effects, their regional specificity and the mechanisms underlying inter-individual variability of stimulation effects. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9+10), thereby advancing future experimental and translational applications of tDCS in health and disease.

Enhancing cerebellar-dependent motor learning by focalized tDCS

There is significant interest to use cerebellar transcranial direct current stimulation (cerebellar tDCS) as a tool to understand cerebellar function and to treat cerebellar disease. Cerebellar tDCS effects, however, are often difficult to replicate even within the same laboratory, indicating considerable variability between individual participants and hampering more widespread use. The aim of the present project is to test whether focalized tDCS based on the individual cerebellar anatomy reliably enhances cerebellar-dependent motor learning, to understand the neuronal mechanisms underlying focalized cerebellar tDCS effects and to identify the predictors of individual cerebellar tDCS effects in a highly systematic and comprehensive manner. We will use eyeblink conditioning to study cerebellar tDCS effects on motor learning because it is strongly cerebellar-dependent and the associated cerebellar areas are well known. Furthermore, the ability to acquire conditioned eyeblink responses declines with increasing age and is impeded by cerebellar disease.Importantly, the initially described enhancing effects of anodal cerebellar tDCS on the acquisition of conditioned eyeblink responses were difficult to replicate in later studies. Therefore, eyeblink conditioning is an excellent model to optimize cerebellar stimulation protocols on an individual level in order to increase efficacy of the intervention, and to better understand possible predictors of cerebellar tDCS effects on motor learning in individual participants.

Within the broader context of the RU, the present study (Project 6) is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8) and the healthy human lifespan. The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioral stimulation response not only within each project, but also across the different tasks and functional domains (in Project 9).

The current project will complement the investigation of tDCS-induced enhancement of motor sequence learning in Project 5 that also investigates behavioral and neural modulation of individualized, focal tDCS in the motor domain, but with the primary motor cortex as the relevant hub in this paradigm. Collectively, the results of the empirical projects of the RU will increase our current understanding of tDCS-induced neural network effects, their regional specificity, the mechanisms underlying inter-individual variability of stimulation effects, and potential changes due to chronological age. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in Projects 9+10), thereby advancing future experimental and translational applications of tDCS in health and disease.

Enhancing learning-based cognitive control by focalized transcranial direct current stimulation

Adaptive cognitive control – as the human capacity to pursue goal-directed behavior in dynamically changing environments – forms the basis for cognitive and behavioral flexibility in everyday life. Recent research has highlighted associative learning mechanisms and the role of episodic memory as basic mechanisms underlying adaptive cognitive control. Because adaptive cognitive control shows a decline in normal aging and its malfunction is closely related to neurological and psychiatric conditions, this project will specifically investigate the neural mechanisms and predictors underlying enhancement of this process by individualized, focal transcranial direct current stimulation (tDCS). In the long-run, outcomes of this project will contribute to improving treatment of patients with deficits in self-control and disadvantageous decision making (e.g., addiction, eating disorders).

Within the broader context of the Research Unit (RU), the present study is one of eight projects investigating tDCS effects on learning and memory formation across functional domains (Projects 1-8) and the healthy human lifespan. The highly systematic and coordinated approach pursued by these empirical projects will allow for the first time analyzing the underlying neural mechanisms and predictors of behavioral stimulation response not only within each project, but also across the different tasks and functional domains (in Project 9).

The current project will contribute unique information on how tDCS modulates learning-based adaptive cognitive control, thereby complementing the investigation of tDCS-induced enhancement of sequential decision making in Project 8 (PI Li). Collectively, the results of the empirical projects of the RU will increase our current understanding of tDCS-induced neural network effects, their regional specificity, the mechanisms underlying inter-individual variability of stimulation effects, and potential changes due to chronological age. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9+10), thereby advancing future experimental and translational applications of tDCS in health and disease. 

Enhancing value-based learning by focalized tDCS (transcranial direct current stimulation)

Adaptive behaviour requires individuals to learn and represent contingencies between their choices and the outcomes of their decisions to adjust behaviour according to situational demands. Such value-based learning also underlies sequential decision making, in which the outcome of a current choice only becomes apparent after a few decision stages. Value-based learning is crucial for adapting to changing environments throughout life and is known to decline in aging and aging-associated diseases. Given that value-based sequential decision is an ecologically relevant task in everyday life for people of different ages, this project will specifically investigate the neural mechanisms and predictors underlying enhancement of this process by individualized, focal transcranial direct current stimulation (tDCS). In the long-run, outcomes of this project will contribute to improving treatment of patients with neurodegenerative diseases (e.g., dementia and its precursors) for whom the abilities of value-based learning and decision making are also impaired.

Within the broader context of the Research Unit, the present study is one of eight empirical projects investigating tDCS effects on learning and memory formation across functional domains and the healthy human lifespan. The highly systematic and coordinated approach pursued by these empirical projects will allow us, for the first time, to analyse the underlying neural mechanisms and predictors of behavioural stimulation response not only within each project, but also coordinate with method-oriented projects in the research unit to study relations between different tasks and functional domains.

This project will contribute unique information on how tDCS modulates value-based sequential decision making, thereby complementing the investigation of tDCS-induced enhancement of learning-based adaptive control in Project 7 (PI Fischer). Collectively, the results of the empirical projects of the Research Unit will increase our current understanding of tDCS-induced neural network effects, their regional specificity, the mechanisms underlying inter-individual variability of stimulation effects, and potential changes due to chronological age. From a methodological point of view, data acquired in these projects will contribute to optimizing and validating biophysical models of current flow (in P9 and P10), thereby advancing future experimental and translational applications of tDCS in health and disease.

Optimization of focal brain stimulation by individualized electric field simulations: Implementation and assessment of effects across sites and functional domains

Advanced computational modeling approaches have been developed to estimate the strength and distribution of the electric field induced by brain stimulation. By using magnetic resonance imaging (MRI) based head models, these approaches allow individualized simulations of current flow. Previous studies have revealed considerable inter-individual variability in the strength and distribution of the electric field induced in the brain and have linked it to the variability of the stimulation outcome. Similarly, functional and microstructural properties of the stimulation targets were linked to variable stimulation effects. However, the predictive value of individually induced electric fields in the human brain for behavioral and neurophysiological stimulation outcomes and their variability still needs to be established. Additionally, while methods for tDCS current flow optimization are being developed, current knowledge about dose-response relationships is rudimentary and little is known about potential differences between cortical areas, functional domains, changes across the healthy human lifespan and other modulating factors. This will be addressed for the first time by the highly coordinated and optimized stimulation approach implemented in the Research Unit (RU).

To meet these challenges, Project 9 (P9) of the RU will (A) fulfill a service function for the empirical projects (P1-8) by providing the methodology required for a reliable personalized targeting. Based on structural MRI data acquired in the empirical projects, we will develop an individualized and focal stimulation approach to enable optimized and coordinated stimulation protocols in P1-8 of the RU. Further, we will complement research in these individual projects by examining sources of variability in behavioral and neural tDCS responses using a hypothesis-driven approach within and across projects: (B.1) collaborating with P1-8 to determine the effect of simulated electric fields on behavioral and neuronal outcomes in a domain specific way (within projects), and (B.2) investigating cross-project consistency of the effects, thereby leveraging the unique large and coordinated dataset that will be acquired by the RU, to assess the relationship between inter-individual variability in electric fields and stimulation effects across brain sites and functional domains.

In the long run, this project will enable future studies to systematically plan and implement individually optimized tDCS interventions. Moreover, the potential second phase of the RU will explore how age-associated brain changes impact cortical-dose relationships as well as their mediators. Therefore, the results of the project will lay the foundation for individually optimized stimulation protocols across the human lifespan, with the ultimate goal to optimize stimulation outcome for the individual.

Validating and optimizing personalized current flow simulations across the human lifespan using in-vivo magnetic resonance current density imaging

Computer simulations have become an important tool for characterizing and optimizing the electric field distribution induced by transcranial electric stimulation (tES) in the human brain. Simulations also enable personalized stimulation approaches that control for the impact of different head and brain anatomies on the individual field distribution, and they are an integral component of the research strategy of the research unit (RU). However, as simulations estimate the electric fields based on potentially uncertain information about head anatomy and tissue conductivities, validating their accuracy is highly important. Critically, theoretical analyses and invasive electrode recordings in selected human patients undergoing surgery showed that the accuracy of field simulations can vary strongly between individuals. This generates the risk that potential associations between the estimated fields and the recorded physiological responses are obscured.

In project 10 (P10) of the RU, we will for the first time apply magnetic resonance current density imaging (MRCDI) to a large group of subjects in order to systematically and non-invasively validate the electric field simulations used in the RU. The planned work will leverage our recent, comprehensive work on MR acquisition schemes, optimized tES hardware and analytical methods, which helped to mature MRCDI and make it ready for the envisioned large-scale application in humans. We will start by collecting MRCDI data of 40 healthy participants for all target regions used in the RU. We will use this data in a new Bayesian analysis framework to systematically optimize the tissue conductivities of the personalized head models. Employing a Bayesian framework will reveal the uncertainty of the estimated conductivities in a principled manner, and give insight into which conductivities benefit from the optimization by MRCDI. As second step, we aim to extend this approach towards the comparison of head models of varying anatomical complexity using Bayesian model selection. Finally, we will test the impact of anatomical features (skull thickness, CSF volume) and selected demographic variables (age, sex) on the simulation accuracy at the individual level. These results will be used for the development of an optimized head modelling pipeline with improved accuracy which will be implemented in the post-hoc analyses in projects P1-9 of the RU and also provided open source for broad use.

Complementing the above work, we will streamline the MRCDI acquisition procedures that currently require expert knowledge. The improved procedures will be pilot-tested within four projects of the RU, making MRCDI ready for a broader usage. In particular, this work will prepare MRCDI for its general use across all projects in the potential second phase of the RU, where changes in skull composition and brain anatomy at old age might require further adaptations of the simulations to ensure accurate field estimates.