This study aims to investigate which of two brain regions is important for which decision-making strategy. The investigators suppose that one brain region - the \*striatum\* - is important for repeatedly choosing objects that have previously been paired with rewards (strategy 1). They suppose that a different region - the \*hippocampus\* - is important for extending such reasoning to RELATED objects (strategy 2). The investigators will repeatedly ask young and healthy subjects to choose between two objects. The two objects are repeatedly drawn from a pool of seven. Relations between the seven objects have been learned on the first day of the experiment. The investigators will record subjects' choices and will use an automated way to assess the extent to which any given subject uses either decision-making strategy. * On one day, subjects will perform the task while their right hippocampus is being stimulated with non-invasive electrical stimulation ("condition A"). * On another day, subjects will perform the same task but with their striatum being stimulated ("condition B"). * On yet another day, a control stimulation ("condition C") will be applied that looks and feels like the real stimulation but does not influence brain activity. Which stimulation (A, B, C) happens on which day is assigned by computer code and differs between subjects. Subjects do not know, and investigators mostly do not know, whether real or control stimulation is applied on each day. The investigators will check whether subjects use strategy 1 more when their striatum is being stimulated and strategy 2 more when their hippocampus is being stimulated, as compared to when the control stimulation is applied.
The purpose of this study is to isolate the roles of hippocampal formation versus striatum in cognitive map-based versus stimulus-outcome learning-based decision-making. The study consists of four sessions on four consecutive days: an initial learning session and three decision-making sessions under three different non-invasive brain stimulation conditions. Decision-making will be observed in a choice task, where young and healthy adults will be presented with two out of seven stimuli on any given trial. They will be asked to choose one of both so as to maximize their reward. The reward value of the chosen stimulus is displayed after the choice has been made. Different stimuli's reward values are related to each other following latent relations between stimuli learned during the subject's first experimental session. Throughout the choice task, reward values shift from time to time without notice, but always respecting the latent structure between stimuli. Subjects can most successfully adapt to these spontaneous shifts if they use the relational knowledge acquired during session 1 (map-based generalization), whereas learning the new reward values one-by-one will cost more time/trials (stimulus-outcome association learning). During the choice task, neural activity will be upregulated using transcranial temporal interference stimulation (tTIS; Grossman et al., 2017; Vassiliadis et al., 08/2024), specifically, intermittent theta-burst stimulation (iTBS; Beanato, Moon et al., 2024; Wessel, Beanato et al., 2023). Subjects will undergo hippocampal tTIS in one session, striatal tTIS in another session, and high-frequency control stimulation in yet another session. The order of conditions is pseudorandomized and counterbalanced across subjects. For blinding, see "Study Design". Shifts in cognitive map-based versus stimulus-outcome association-based decision-making will be analyzed as a function of stimulation condition using computational modeling of choice data. Assuming a causal role of the hippocampal formation in cognitive map-based behavior (Garvert et al., 2017) and of the striatum in stimulus-outcome learning (Gläscher et al., 2010), a double dissociation may be expected: upregulating hippocampal activity should boost map-based over stimulus-outcome association-based decision-making, whereas upregulating striatal activity should produce the opposite effect (always as compared to the high-frequency control stimulation). Hypotheses formulated in this registration are theoretically motivated and partly supported by online behavioral pilot data that will not be included in any analyses. At first submission of this registration, data collection is ongoing. The collected data has been inspected for quality control but has neither been used to generate hypotheses nor to test these (except navigation and proximity judgment task accuracy has been inspected to ensure successful learning). Investigators are partly blind to stimulation condition (see "Study Design"), and no stimulation condition-dependent analyses have been conducted before submission of this registration.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
36
Transcranial temporal interference stimulation using intermittent theta-burst protocol and targeting right hippocampus. Unlike the striatal set-up, the hippocampal electrode set-up is asymmetrical and can only stimulate unilaterally (Beanato, Moon et al., 2024; Violante et al., 2023). In the present study, \*right\* hippocampus is targeted because it showed cognitive map-compatible activity in a similar task in a previous study (Garvert et al., 2023) and because it has been suggested to be involved in map-based navigation (Iglói et al., 2010).
Transcranial temporal interference stimulation using intermittent theta-burst protocol and targeting bilateral striatum.
Analoguous to transcranial temporal interference stimulation except both high-frequency electric fields are oscillating at the exact same frequency, meaning there is no biologically active envelope modulation. This high-frequency stimulation is applied with the striatal electrode set-up in 50 % of the subjects (hippocampal set-up in the other 50 %). No stimulation actually occurs because the stimulation frequency is too high to be biologically active (Grossman et al., 2017).
Analoguous to transcranial temporal interference stimulation except both high-frequency electric fields are oscillating at the exact same frequency, meaning there is no biologically active envelope modulation. This high-frequency stimulation is applied with the hippocampal electrode set-up in 50 % of the subjects (striatal set-up in the other 50 %). No stimulation actually occurs because the stimulation frequency is too high to be biologically active (Grossman et al., 2017).
University Hospital Würzburg (UKW)
Würzburg, Bavaria, Germany
RECRUITINGWeight between map-based generalization and stimulus-outcome association-based decision-making
"Weight" references a parameter that is extracted from recorded choice behavior by means of computational modeling. Three basic models (one map-based, two stimulus-outcome association-based) are fit to each subject's choice data from each session. Two hybrid models - combining the map-based with either of the stimulus-outcome association-based components - are also fit. The weight parameter will be extracted from the hybrid model that fits most subjects' behavior best under the control condition (high-frequency stimulation). It describes the extent to which the subject relies on the map-based relative to the association-based component/strategy for making their choices. Given the presumed roles of hippocampus in map-based and striatum in association-based decision-making, the investigators expect the weight parameter to increase under hippocampal tTIS and to decrease under striatal tTIS relative to high-frequency control stimulation.
Time frame: Days 2-4.
Choice accuracy
Whether, out of two simultaneously presented stimuli, the one associated with the higher reward has been chosen on a given trial. Early after a shift in reward contingencies, using a map-based strategy should increase the probability of choosing correctly. This is because the new reward contingencies may not have been experienced yet (disabling association-based strategies) and so can only be inferred (requiring map-based strategies). Both strategies should be equally successful later after a shift once all new contingencies have been experienced. Averaged across all trials, the investigators therefore expect to observe higher accuracy under hippocampal and lower accuracy under striatal tTIS as compared to control stimulation. The investigators also expect subjects' individual choice accuracies to positively correlate with their map-based weight parameter estimates.
Time frame: Days 2-4.
Choice response time
Time between presentation of the two stimuli for the present trial and the subject's choice of one of the two stimuli. The investigators will analyze the effects of hippocampal and striatal tTIS as compared to control stimulation on response time in an exploratory manner.
Time frame: Days 2-4.
Proportion of subjects best fit by different computational models
Different candidate models are fit to the recorded choice data, two of which are on the "stimulus-outcome association-based" and one on the "map-based generalization" side. Hybrid models (= weighted sum of one stimulus-outcome association-based element and the map-based generalization element) are also fit. WAIC (Watanabe, 2010) will be used to determine which model fits which subject best under any given stimulation condition. The investigators expect the proportion of subjects best described by the map-based (association-based) model(s) to increase (decrease) under hippocampal tTIS as compared to control stimulation, with the opposite pattern showing under striatal tTIS. Note: Should ≥ 50 % of subjects perform at chance level in the proximity judgments in the first session (last eight blocks), the investigators will use subjects' \*subjective\* representations (as collected at the end of the last choice task session) instead of the objective ones as a basis for the map-based model.
Time frame: Days 2-4.
Influence of true and past rewards on choice
The investigators will use (a) the difference in the most recently observed values of the stimuli presented to the subject's left vs. right and (b) the difference between the actual, current values of these stimuli (which may not have been observed yet) to predict whether the subject will have chosen the left vs. right stimulus. Subjects pursuing a stimulus-outcome association-based strategy will exclusively rely on directly experienced reward contingencies (strong regression weight of (a) but not (b)). Subjects generalizing across related stimuli will be able to infer a stimulus' current value even if that one has not been observed recently (strong regression weight of (b) but not (a)). The investigators expect the regression weights of (a) to increase and (b) to decrease under striatal tTIS (opposite under hippocampal tTIS) as compared to control stimulation.
Time frame: Days 2-4.
Influence of true and past rewards on choice response time
The investigators will use (a) the difference in the directly experienced past values of left vs. right stimuli and (b) the difference in the actual, current reward values of left vs. right stimuli (which may not have been observed yet) as predictors of response time. Subjects should respond more quickly if the value difference is larger (less conflict). Under this assumption, a comparison of regression weights (a) and (b) will reveal whether subjects' behavior is more strongly governed by (differences in) experienced values or by (differences in) inferred true values. The investigators will analyze the effects of striatal and hippocampal tTIS as compared to control stimulation on the regression weights in an exploratory manner.
Time frame: Days 2-4.
Proximity judgment task accuracy
Subjects will learn the latent relations between stimuli on the first day by means of a navigation task and a proximity judgment task (among two stimuli, identifying the one that is closest to a third). Both tasks are presented in an alternating manner. Proximity judgment task accuracy is the proportion of trials on which the closer stimulus was correctly identified. Proximity judgment task accuracy in the last 8 blocks is expected to be above chance and to increase over blocks as subjects learn the relations between stimuli. Proximity judgments are additionally collected at the beginning of the second, third, and fourth sessions \*before\* stimulation onset to determine subjects' current knowledge of the latent relations. Stable performances are expected across sessions 2 through 4 and between stimulation conditions. Supplementary analyses of choice behavior will be constrained to subjects with above-chance proximity judgment accuracy or include this accuracy as a covariate.
Time frame: Days 1-4.
Proximity judgment task response time
Time between presentation of the three stimuli for the present trial and the subject's response as to which of the two options they believe to be closest to the third stimulus. This measure will be analyzed in an exploratory manner.
Time frame: Days 1-4.
Stimulation tolerability
* Which sensations do subjects report during familiarization with the stimulation? In the familiarization, the investigators will gradually expose the subject to a current intensity of 1, 2, 3, 4 mA (summed across both channels) both for tTIS and for high-frequency control stimulation (order counterbalanced between subjects and subjects blind to type of stimulation). Subjects are asked to report the strength and type of any sensations they may experience. * Which side effects do subjects report relating to each of the three stimulation sessions? The investigators expect tTIS and high-frequency control stimulation to be tolerable (Vassiliadis et al., 03/2024).
Time frame: Days 2-4.
Stimulation blinding
Are subjects' classifications of real vs. placebo stimulation for each session (as collected after the final stimulation session) correct above chance? The investigators expect tTIS and high-frequency control stimulation to be indistinguishable from subjects' point of view, ensuring successful blinding (Vassiliadis et al., 03/2024).
Time frame: Day 4.
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