Biology subjects

den Ouden, H. E. M.

Publications and source records attributed to den Ouden, H. E. M..

15 recordsLinked to original sources

bioRxiv2026

Dopamine modulates striatal activity when controlling the output of working memory

Cognitive control depends on capacity-limited mechanisms that require selection. Working memory (WM) therefore relies on an input-gate to filter information into WM and an output-gate to transform current WM representations into a prioritised state to guide behaviour. According to current theory, such WM gating processes are modulated by dopamine in the striatum, yet empirical evidence for this hypothesis remains sparse. We fill this gap by directly testing the role of dopamine for both WM input-and output-gating in a double-blind, placebo-controlled within-subject fMRI study (N = 34; 23 female, 11 male human subjects), using a 400 mg oral dose of the dopamine D2 receptor antagonist sulpiride. In our cued delayed-response task, which separated input-from output-gating, sulpiride altered neural activity in the striatum during output-gating. This effect was accompanied by a sulpiride-induced de-crease in the neural stimulus selectivity of gated sensory representations in visual association cortex, with greater decreases in stimulus selectivity correlating with reduced behavioural accuracy in the task. Together, the results establish a role for striatal dopamine during the control of cortical outflow of WM. Significance StatementTo act on a goal, the brain holds information in mind and brings the important parts into focus to guide what we do next. Scientists believe that this "selection" process involves dopamine, a chemical messenger, in a brain area called the striatum. We tested this by giving people a drug that alters dopamine activity in the brain. The drug changed how the striatum reacted when people selected information from memory. It also made the brains visual areas represent this information less clearly, and this change affected peoples behaviour. Therefore, we conclude that dopamine in the striatum plays a role when our brain controls which information in working memory is sent to other parts of the brain to guide actions.

neuroscience↗

bioRxiv2025

Dissecting the contribution of recent reward versus recent performance history on cognitive effort allocation

An extensive body of literature has shown that humans tend to avoid expending cognitive effort, just like for physical effort or financial resources. How then, do we decide whether to put this effort in? Decision-making not only involves choosing our actions, but also the meta-decision of how much cognitive effort to invest in making this choice, weighing the costs of cognitive effort against potential rewards. Popular recent theories, grounded in the field of reinforcement learning, suggest that this cost-benefit trade-off can be informed by the opportunity costs of effort investment, which the brain may approximate by the estimated average reward rate per unit time. It follows from intuition that in a low reward environment, investing cognitive resources in the task at hand will less likely lead to missed opportunities. Recent studies provided support for this idea, showing that people exert more cognitive effort when reward rate is low. Here, we replicate one of the key previous findings but provide an important nuance to this result. Cognitive effort allocation was better explained by participants recent performance history (i.e. accuracy rate) than average reward rate. In combination with the observation that participants were insensitive to the reward currently at stake, this invites a reinterpretation of these previous findings and suggests the need for further studies to assess whether environmental richness may indeed serve as a heuristic to modulate cognitive effort allocation.

neuroscience↗

bioRxiv2025

Ultrasound neuromodulation reveals distinct roles of the dorsal anterior cingulate cortex and anterior insula in Pavlovian biases

Pavlovian biases reflect the notorious influence of hard-wired, evolutionarily conserved cue-response tendencies on instrumental action selection: people show automatic action invigoration in face of potential rewards, but action suppression in face of potential punishments. The neural origin of these biases is unclear. Past evidence suggests dorsal anterior cingulate cortex (dACC) and anterior insula (aIns) as part of a "reset network" that rapidly responds to salient information and might contribute to these biases. We used transcranial ultrasonic stimulation (TUS) in 29 healthy participants to interfere with neural activity in these regions and test their causal role in a within-subject, counter-balanced design across three sessions (sham, TUS-dACC, TUS-aIns). Computational modelling revealed a double dissociation, with distinct roles of both regions in Pavlovian biases: while TUS to the aIns decreased peoples tendency to overly take credit for rewards following action and to ignore punishments following inaction, TUS to dACC increased participants tendency to take the cue valence as a reinforcer signal. Although the dACC and aIns are part of the same network and often co-activate during decision-making tasks, TUS interference reveals their distinct roles: the dACC mediates cue-dependence persistence while the aIns is critical for inferring whether outcomes are self-caused.

neuroscience↗

bioRxiv2025

Parameter optimisation for mitigating somatosensory confounds during transcranial ultrasonic stimulation

Transcranial ultrasonic stimulation (TUS) redefines what is possible with non-invasive neuromodulation by oaering unparalleled spatial precision and flexible targeting capabilities. However, peripheral confounds pose a significant challenge to reliably implementing this technology. While auditory confounds during TUS have been studied extensively, the somatosensory confound has been overlooked thus far. It will become increasingly vital to quantify and manage this confound as the field shifts towards higher doses, more compact stimulation devices, and more frequent stimulation through the temple where co-stimulation is more pronounced. Here, we provide a systematic characterisation of somatosensory co-stimulation during TUS. We also identify the conditions under which this confound can be mitigated most eaectively by mapping the confound-parameter space. Specifically, we investigate dose-response eaects, pulse shaping characteristics, and transducer-specific parameters. We demonstrate that somatosensory confounds can be mitigated by avoiding near-field intensity peaks in the scalp, spreading energy across a greater area of the scalp, ramping the pulse envelope, and delivering equivalent doses via longer, lower-intensity pulses rather than shorter, higher-intensity pulses. Additionally, higher pulse repetition frequencies and fundamental frequencies reduce somatosensory eaects. Through our systematic mapping of the parameter space, we also find preliminary evidence that particle displacement (strain) may be a primary biophysical driving force behind peripheral somatosensory co-stimulation. This study provides actionable strategies to minimise somatosensory confounds, which will support the thorough experimental control required to unlock the full potential of TUS for scientific research and clinical interventions. Highlights- Tactile, thermal, and even painful somatosensory confounds may occur during TUS. - Confounds can be mitigated via pulse shaping & transducer-specific parameters. - Valid and replicable TUS research requires control for peripheral confounds. - Particle displacement may be a primary driving force for somatosensory confounds.

neuroscience↗

bioRxiv2025

Rapid modulation of choice behavior by ultrasound on the human frontal eye fields

A fundamental challenge in neuroscience is establishing causal brain-function relationships with spatial and temporal precision. Transcranial ultrasonic stimulation (TUS) offers a unique opportunity to modulate deep brain structures non-invasively with high spatial resolution, but temporally precise effects and their neurophysiological foundations have yet to be demonstrated in humans. Here, we develop a temporally precise TUS protocol targeting the frontal eye fields (FEFs) -- a well-characterized circuit critical for saccadic eye movements. We demonstrate that TUS induces robust excitatory behavioral effects. Importantly, individual differences in baseline GABAergic inhibitory tone predict response magnitude. These findings establish TUS as a reliable tool for chronometric circuit interrogation and highlight the importance of neurophysiological state in neuromodulation. This work bridges human and animal research, advancing targeted TUS applications in neuroscience and clinical settings. HighlightsO_LIFocused ultrasound modulates saccades with high spatial and temporal precision C_LIO_LIInhibitory circuits in the frontal eye fields shape choice computations C_LIO_LIGABA levels predict individual variability in ultrasound-induced behavioral changes C_LIO_LIUltrasound can be used to probe fast neural dynamics and individual differences C_LI

neuroscience↗

bioRxiv2024

Abstract rule generalization for composing novel meaning recruits the frontoparietal control network

The ability to generalize previously learned knowledge to novel situations is crucial for adaptive behavior, representing a form of cognitive flexibility that is particularly relevant in language. Humans excel at combining linguistic building blocks to infer the meanings of novel compositional words, such as "un-reject-able-ish". How do we accomplish this? While recent research on compositional generalization in relational memory, action planning and vision strongly implicates a medial prefrontal-hippocampal network (Baram et al., 2021; Barron et al., 2020; Schwartenbeck et al., 2023), it remains unclear whether the same network supports compositional inference in language. To this end, we trained participants on an artificial language in which the meanings of compositional words could be derived from known stems and unknown affixes, using abstract affixation rules (e.g., "good-kla" which means "bad", where "-kla" reverses the meaning of the stem word "good"). According to these rules, word meaning depended on the sequential relation between the stem and the affix (i.e., pre- vs. post-stem). During fMRI, participants performed a semantic priming task, with novel compositional words as either sequential order congruent (e.g., "white-kla") or incongruent primes (e.g., "kla-white"), and synonyms of the composed meaning as targets ("black"). Our results show that the compositional process engages a broad temporoparietal network, including the hippocampus, while the composed meanings are represented in left-lateralized language areas. Notably, newly composed meanings were decodable already at the time of the prime. Finally, we found that the composition process recruits abstract structure rule representations in a lateral frontoparietal network, rather than the predicted medial frontotemporal network, perhaps because abstract rules in language are more readily formatted as production rules rather than as relational map structures.

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bioRxiv2023

Pupil dilation reflects effortful action invigoration in overcoming aversive Pavlovian biases

"Pavlovian" or "motivational" biases describe the phenomenon that the valence of prospective outcomes modulates action invigoration: Reward prospect invigorates action, while punishment prospect suppresses it. The adaptive role of these biases in decision-making is still unclear. One idea is that they constitute a fast-and-frugal decision strategy in situations characterized by high arousal, e.g., in presence of a predator, which demand a quick response. In this pre-registered study (N = 35), we tested whether such a situation--induced via subliminally presented angry vs. neutral faces--leads to increased reliance on Pavlovian biases. We measured trial-by-trial arousal by tracking pupil diameter while participants performed an orthogonalized Motivational Go/NoGo Task. Pavlovian biases were present in responses, reaction times, and even gaze, with lower gaze dispersion under aversive cues reflecting "freezing of gaze". The subliminally presented faces did not affect responses, reaction times, or pupil diameter, suggesting that the arousal manipulation was ineffective. However, pupil dilations reflected facets of bias suppression, specifically the physical (but not cognitive) effort needed to overcome aversive inhibition: Particularly strong and sustained dilations occurred when participants managed to perform Go responses to aversive cues. Conversely, no such dilations occurred when they managed to inhibit responses to Win cues. These results suggest that pupil diameter does not reflect response conflict per se nor the inhibition of prepotent responses, but specifically effortful action invigoration as needed to overcome aversive inhibition. We discuss our results in the context of the "value of work" theory of striatal dopamine.

neuroscience↗

bioRxiv2023

High stakes slow responding, but do not help overcome Pavlovian biases in humans

"Pavlovian" or "motivational" biases are the phenomenon that the valence of prospective outcomes modulates action invigoration: the prospect of reward invigorates actions, while the prospect of punishment suppresses actions. Effects of the valence of prospective outcomes are well established, but it remains unclear how the magnitude of outcomes ("stake magnitude") modulates these biases. In this pre-registered study (N = 55), we manipulated stake magnitude (high vs. low) in an orthogonalized Motivational Go/NoGo Task. We tested whether higher stakes (a) strengthen biases or (b) elicit cognitive control recruitment, enhancing the suppression of biases in motivationally incongruent conditions. Confirmatory tests showed that high stakes slowed down responding, especially in motivationally incongruent conditions. However, high stakes did not affect whether a response was made or not, and did not change the magnitude of Pavlovian biases. Reinforcement-learning drift- diffusion models (RL-DDMs) fit to the data suggested that response slowing was best captured by stakes prolonging the non-decision time. There was no effect of the stakes on the response threshold (as in typical speed-accuracy tradeoffs). In sum, these results suggest that high stakes slow down responses without affecting the expression of Pavlovian biases in behavior. We speculate that this slowing under high stakes might reflect heightened cognitive control, which is however ineffectively used, or reflect positive conditioned suppression, i.e., the interference between goal-directed and consummatory behaviors, a phenomenon previously observed in rodents that might also exist in humans. Pavlovian biases and slowing under high stakes may arise in parallel to each other.

neuroscience↗

bioRxiv2023

Auditory confounds can drive online effects of transcranial ultrasonic stimulation in humans

Transcranial ultrasonic stimulation (TUS) is rapidly emerging as a promising non-invasive neuromodulation technique. TUS is already well-established in animal models, providing foundations to now optimize neuromodulatory efficacy for human applications. Across multiple studies, one promising protocol, pulsed at 1000 Hz, has consistently resulted in motor cortical inhibition in humans (Fomenko et al., 2020). At the same time, a parallel research line has highlighted the potentially confounding influence of peripheral auditory stimulation arising from TUS pulsing at audible frequencies. In this study, we disentangle direct neuromodulatory and indirect auditory contributions to motor inhibitory effects of TUS. To this end, we include tightly matched control conditions across four experiments, one preregistered, conducted independently at three institutions. We employed a combined transcranial ultrasonic and magnetic stimulation paradigm, where TMS-elicited motor-evoked potentials (MEPs) served as an index of corticospinal excitability. First, we replicated motor inhibitory effects of TUS but showed through both tight controls and manipulation of stimulation intensity, duration, and auditory masking conditions that this inhibition was driven by peripheral auditory stimulation, not direct neuromodulation. Further, we consider neuromodulation beyond driving overall excitation/inhibition and show preliminary evidence of how TUS might interact with ongoing neural dynamics instead. Primarily, this study highlights the substantial shortcomings in accounting for the auditory confound in prior TUS-TMS work where only a flip-over sham and no active control was used. The field must critically reevaluate previous findings given the demonstrated impact of peripheral confounds. Further, rigorous experimental design via (in)active control conditions is required to make substantiated claims in future TUS studies. Only when direct effects are disentangled from those driven by peripheral confounds can TUS fully realize its potential for research and clinical applications.

neuroscience↗

bioRxiv2022

Goal-directed recruitment of Pavlovian biases through selective visual attention

Prospective outcomes bias behavior in a "Pavlovian" manner: Reward prospect invigorates action, while punishment prospect suppresses it. Theories have posited Pavlovian biases as global action "priors" in unfamiliar or uncontrollable environments. However, this account fails to explain the strength of these biases--causing frequent action slips--even in well-known environments. We propose that Pavlovian control is additionally useful if flexibly recruited by instrumental control. Specifically, instrumental action plans might shape selective attention to reward/ punishment information and thus the input to Pavlovian control. In two eye-tracking samples (N = 35/ 64), we observed that Go/ NoGo action plans influenced when and for how long participants attended to reward/ punishment information, which in turn biased their responses in a Pavlovian manner. Participants with stronger attentional effects showed higher performance. Thus, humans appear to align Pavlovian control with their instrumental action plans, extending its role beyond action defaults to a powerful tool ensuring robust action execution.

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bioRxiv2021

Biased credit assignment in motivational learning biases arises through prefrontal influences on striatal learning

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear; in particular, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and emancipation from stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dACC, PCC) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

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bioRxiv2021

Cortical dopamine reduces the impact of motivational biases governing automated behaviour

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n=35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomized, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

neuroscience↗

bioRxiv2020

Striatal BOLD and midfrontal theta power express motivation for action

Action selection is biased by the valence of anticipated outcomes. To assess mechanisms by which these motivational biases are expressed and controlled, we measured simultaneous EEG-fMRI during a motivational Go/NoGo learning task (N=36), leveraging the temporal resolution of EEG and subcortical access of fMRI. VmPFC BOLD encoded cue valence, importantly predicting trial-by-trial valence-driven response speed differences and EEG theta power around cue onset. In contrast, striatal BOLD encoded selection of active Go responses and correlated with theta power around response time. Within trials, theta power ramped in the fashion of an evidence accumulation signal for the value of making a Go response, capturing the faster responding to reward cues. Our findings reveal a dual nature of midfrontal theta power, with early components reflecting the vmPFC contribution to motivational biases, and late components reflecting their striatal translation into behavior, in line with influential recent "value of work" theories of striatal processing.

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bioRxiv2018

Catecholamine Challenge Uncovers Distinct Mechanisms For Direct Versus Indirect, But Not Social Versus Non-Social, Learning

Evidence that social and individual learning are at least partially dissociable sustains the belief that humans possess adaptive specialisations for social learning. However, in most extant paradigms, social information comprises an indirect source that can be used to supplement ones own, direct, experience. Thus, social and individual learning differ both in terms of social nature (social versus non-social) and directness (indirect versus direct). To test whether the dissociation between social and individual learning is best explained in terms of social nature or directness, we used a catecholaminergic challenge known to modulate learning. Two groups completed a decision-making task which required direct learning, from own experience, and indirect learning from an additional source. The groups differed in terms of whether the indirect source was social or non-social. The catecholamine transporter blocker, methylphenidate, affected direct learning by improving adaptation to changes in the volatility of the environment but there was no effect of methylphenidate on learning from the social or non-social indirect source. Thus, we report positive evidence for a dissociable effect of methylphenidate on direct and indirect learning, but no evidence for a distinction between social and non-social. These data fail to support the adaptive specialisation view, instead providing evidence for distinct mechanisms for direct versus indirect learning.

neuroscience↗

bioRxiv2017

A neuronal mechanism underlying decision-making deficits during hyperdopaminergic states

Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision-making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to faulty decision-making in rats. Activation of the VTA-nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTA-prefrontal cortex pathway promotes risky decision-making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision-making, providing a mechanistic understanding of the reckless behaviors seen in substance abuse, mania, and after dopamine replacement therapy in Parkinsons disease.

neuroscience↗