40 Hz Steady-State Response in Human Auditory Cortex Is Shaped by GABAergic Neuronal Inhibition.

The 40 Hz auditory steady-state response (ASSR), an oscillatory brain response to periodically modulated auditory stimuli, is a promising, non-invasive physiological biomarker for schizophrenia and related neuropsychiatric disorders. The 40 Hz ASSR might be amplified by synaptic interactions in cortical circuits, which are, in turn, disturbed in neuropsychiatric disorders. Here, we tested whether the 40 Hz ASSR in human auditory cortex depends on two key synaptic components of neuronal interactions within cortical circuits: excitation via N-methyl-aspartate glutamate (NMDA) receptors and inhibition via gamma-amino-butyric acid (GABA) receptors. We combined magnetoencephalography (MEG) recordings with placebo-controlled, low-dose pharmacological interventions in the same healthy human participants (13 males, 7 females). All participants exhibited a robust 40 Hz ASSR in auditory cortices, especially in the right hemisphere, under placebo. The GABAA receptor-agonist lorazepam increased the amplitude of the 40 Hz ASSR, while no effect was detectable under the NMDA-blocker memantine. Our findings indicate that the 40 Hz ASSR in auditory cortex involves synaptic (and likely intracortical) inhibition via the GABA-A receptor, thus highlighting its utility as a mechanistic signature of cortical circuit dysfunctions involving GABAergic inhibition.Significance statement The 40 Hz auditory steady-state response is a candidate non-invasive biomarker for schizophrenia and related neuropsychiatric disorders. Yet, the understanding of the synaptic basis of this neurophysiological signature in humans has remained incomplete. We combined magnetoencephalography (MEG) recordings with placebo-controlled pharmacological interventions in healthy human subjects to test the modulation of the 40 Hz ASSR in auditory cortex by two synaptic components that have been implicated in the generation of neuronal oscillations in cortical microcircuits: glutamate N-methyl-aspartate glutamate (NMDA) receptors and gamma-amino-butyric acid (GABA) -A receptors. Boosting GABAergic transmission, but not blocking NMDA-receptors, increased the amplitude of this ASSR. Thus, GABAergic inhibition modulates 40 Hz steady-state responses in auditory cortex.

Adaptive biasing of action-selective cortical build-up activity by stimulus history.

Decisions under uncertainty are often biased by the history of preceding sensory input, behavioral choices, or received outcomes. Behavioral studies of perceptual decisions suggest that such history-dependent biases affect the accumulation of evidence and can be adapted to the correlation structure of the sensory environment. Here, we systematically varied this correlation structure while human participants performed a canonical perceptual choice task. We tracked the trial-by-trial variations of history biases via behavioral modeling and of a neural signature of decision formation via magnetoencephalography (MEG). The history bias was flexibly adapted to the environment and exerted a selective effect on the build-up (not baseline level) of action-selective motor cortical activity during decision formation. This effect added to the impact of the current stimulus. We conclude that the build-up of action plans in human motor cortical circuits is shaped by dynamic prior expectations that result from an adaptive interaction with the environment.

Brainstem fMRI signaling of surprise across different types of deviant stimuli.

Detection of deviant stimuli is crucial to orient and adapt our behavior. Previous work shows that deviant stimuli elicit phasic activation of the locus coeruleus (LC), which releases noradrenaline and controls central arousal. However, it is unclear whether the detection of behaviorally relevant deviant stimuli selectively triggers LC responses or other neuromodulatory systems (dopamine, serotonin, and acetylcholine). We combine human functional MRI (fMRI) recordings optimized for brainstem imaging with pupillometry to perform a mapping of deviant-related responses in subcortical structures. Participants have to detect deviant items in a "local-global" paradigm that distinguishes between deviance based on the stimulus probability and the sequence structure. fMRI responses to deviant stimuli are distributed in many cortical areas. Both types of deviance elicit responses in the pupil, LC, and other neuromodulatory systems. Our results reveal that the detection of task-relevant deviant items recruits the same multiple subcortical systems across computationally different types of deviance.

An information-theoretic quantification of the content of communication between brain regions.

Quantifying the amount, content and direction of communication between brain regions is key to understanding brain function. Traditional methods to analyze brain activity based on the Wiener-Granger causality principle quantify the overall information propagated by neural activity between simultaneously recorded brain regions, but do not reveal the information flow about specific features of interest (such as sensory stimuli). Here, we develop a new information theoretic measure termed Feature-specific Information Transfer (FIT), quantifying how much information about a specific feature flows between two regions. FIT merges the Wiener-Granger causality principle with information-content specificity. We first derive FIT and prove analytically its key properties. We then illustrate and test them with simulations of neural activity, demonstrating that FIT identifies, within the total information flowing between regions, the information that is transmitted about specific features. We then analyze three neural datasets obtained with different recording methods, magneto- and electro-encephalography, and spiking activity, to demonstrate the ability of FIT to uncover the content and direction of information flow between brain regions beyond what can be discerned with traditional anaytical methods. FIT can improve our understanding of how brain regions communicate by uncovering previously hidden feature-specific information flow.

Flexible sensory-motor mapping rules manifest in correlated variability of stimulus and action codes across the brain.

Humans and non-human primates can flexibly switch between different arbitrary mappings from sensation to action to solve a cognitive task. It has remained unknown how the brain implements such flexible sensory-motor mapping rules. Here, we uncovered a dynamic reconfiguration of task-specific correlated variability between sensory and motor brain regions. Human participants switched between two rules for reporting visual orientation judgments during fMRI recordings. Rule switches were either signaled explicitly or inferred by the participants from ambiguous cues. We used behavioral modeling to reconstruct the time course of their belief about the active rule. In both contexts, the patterns of correlations between ongoing fluctuations in stimulus- and action-selective activity across visual- and action-related brain regions tracked participants' belief about the active rule. The rule-specific correlation patterns broke down around the time of behavioral errors. We conclude that internal beliefs about task state are instantiated in brain-wide, selective patterns of correlated variability.

Persistent activity in human parietal cortex mediates perceptual choice repetition bias.

Humans and other animals tend to repeat or alternate their previous choices, even when judging sensory stimuli presented in a random sequence. It is unclear if and how sensory, associative, and motor cortical circuits produce these idiosyncratic behavioral biases. Here, we combined behavioral modeling of a visual perceptual decision with magnetoencephalographic (MEG) analyses of neural dynamics, across multiple regions of the human cerebral cortex. We identified distinct history-dependent neural signals in motor and posterior parietal cortex. Gamma-band activity in parietal cortex tracked previous choices in a sustained fashion, and biased evidence accumulation toward choice repetition; sustained beta-band activity in motor cortex inversely reflected the previous motor action, and biased the accumulation starting point toward alternation. The parietal, not motor, signal mediated the impact of previous on current choice and reflected individual differences in choice repetition. In sum, parietal cortical signals seem to play a key role in shaping choice sequences.

Time estimation and arousal responses in dopa-responsive dystonia.

Dopa-responsive dystonia (DRD) is caused by an impaired dopamine biosynthesis due to a GTP-cyclohydrolase-1 (GCH1) deficiency, resulting in a combination of dystonia and parkinsonism. However, the effect of GCH1 mutations and levodopa treatment on motor control beyond simple movements, such as timing, action preparation and feedback processing, have not been investigated so far. In an active time estimation task with trial-by-trial feedback, participants indicated a target interval (1200 ms) by a motor response. We compared 12 patients tested (in fixed order) under their current levodopa medication ("ON") and after levodopa withdrawal ("OFF") to matched healthy controls (HC), measured twice to control for repetition effects. We assessed time estimation accuracy, trial-to-trial adjustment, as well as task- and feedback-related pupil-linked arousal responses. Patients showed comparable time estimation accuracy ON medication as HC but reduced performance OFF medication. Task-related pupil responses showed the reverse pattern. Trial-to-trial adjustments of response times were reduced in DRD, particularly OFF medication. Our results indicate differential alterations of time estimation accuracy and task-related arousal dynamics in DRD patients as a function of dopaminergic medication state. A medication-independent alteration of task repetition effects in DRD cannot be ruled out with certainty but is discussed as less likely.

Coupling of pupil- and neuronal population dynamics reveals diverse influences of arousal on cortical processing.

Fluctuations in arousal, controlled by subcortical neuromodulatory systems, continuously shape cortical state, with profound consequences for information processing. Yet, how arousal signals influence cortical population activity in detail has so far only been characterized for a few selected brain regions. Traditional accounts conceptualize arousal as a homogeneous modulator of neural population activity across the cerebral cortex. Recent insights, however, point to a higher specificity of arousal effects on different components of neural activity and across cortical regions. Here, we provide a comprehensive account of the relationships between fluctuations in arousal and neuronal population activity across the human brain. Exploiting the established link between pupil size and central arousal systems, we performed concurrent magnetoencephalographic (MEG) and pupillographic recordings in a large number of participants, pooled across three laboratories. We found a cascade of effects relative to the peak timing of spontaneous pupil dilations: Decreases in low-frequency (2-8 Hz) activity in temporal and lateral frontal cortex, followed by increased high-frequency (>64 Hz) activity in mid-frontal regions, followed by monotonic and inverted U relationships with intermediate frequency-range activity (8-32 Hz) in occipito-parietal regions. Pupil-linked arousal also coincided with widespread changes in the structure of the aperiodic component of cortical population activity, indicative of changes in the excitation-inhibition balance in underlying microcircuits. Our results provide a novel basis for studying the arousal modulation of cognitive computations in cortical circuits.

Functional magnetic resonance imaging responses during perceptual decision-making at 3 and 7 T in human cortex, striatum, and brainstem.

While functional magnetic resonance imaging (fMRI) at ultra-high field (7 T) promises a general increase in sensitivity compared to lower field strengths, the benefits may be most pronounced for specific applications. The current study aimed to evaluate the relative benefit of 7 over 3 T fMRI for the assessment of responses evoked in different brain regions by a well-controlled cognitive task. At 3 and 7 T, the same participants made challenging perceptual decisions about visual motion combined with monetary rewards for correct choices. Previous work on this task has extensively characterized the underlying cognitive computations and single-cell responses in cortical and subcortical structures. We quantified the evoked fMRI responses in extrastriate visual cortical areas, the striatum, and the brainstem during the decision interval and the post-feedback interval of the task. The dependence of response amplitudes on field strength during the decision interval differed between cortical, striatal, and brainstem regions, with a generally bigger 7 versus 3 T benefit in subcortical structures. We also found stronger responses during relatively easier than harder decisions at 7 T for dopaminergic midbrain nuclei, in line with reward expectation. Our results demonstrate the potential of 7 T fMRI for illuminating the contribution of small brainstem nuclei to the orchestration of cognitive computations in the human brain.

Adaptive circuit dynamics across human cortex during evidence accumulation in changing environments.

Many decisions under uncertainty entail the temporal accumulation of evidence that informs about the state of the environment. When environments are subject to hidden changes in their state, maximizing accuracy and reward requires non-linear accumulation of evidence. How this adaptive, non-linear computation is realized in the brain is unknown. We analyzed human behavior and cortical population activity (measured with magnetoencephalography) recorded during visual evidence accumulation in a changing environment. Behavior and decision-related activity in cortical regions involved in action planning exhibited hallmarks of adaptive evidence accumulation, which could also be implemented by a recurrent cortical microcircuit. Decision dynamics in action-encoding parietal and frontal regions were mirrored in a frequency-specific modulation of the state of the visual cortex that depended on pupil-linked arousal and the expected probability of change. These findings link normative decision computations to recurrent cortical circuit dynamics and highlight the adaptive nature of decision-related feedback to the sensory cortex.

Pupil Dilation and the Slow Wave ERP Reflect Surprise about Choice Outcome Resulting from Intrinsic Variability in Decision Confidence.

Central to human and animal cognition is the ability to learn from feedback in order to optimize future rewards. Such a learning signal might be encoded and broadcasted by the brain's arousal systems, including the noradrenergic locus coeruleus. Pupil responses and the positive slow wave component of event-related potentials reflect rapid changes in the arousal level of the brain. Here, we ask whether and how these variables may reflect surprise: the mismatch between one's expectation about being correct and the outcome of a decision, when expectations fluctuate due to internal factors (e.g., engagement). We show that during an elementary decision task in the face of uncertainty both physiological markers of phasic arousal reflect surprise. We further show that pupil responses and slow wave event-related potential are unrelated to each other and that prediction error computations depend on feedback awareness. These results further advance our understanding of the role of central arousal systems in decision-making under uncertainty.

Choices change the temporal weighting of decision evidence.

Many decisions result from the accumulation of decision-relevant information (evidence) over time. Even when maximizing decision accuracy requires weighting all the evidence equally, decision-makers often give stronger weight to evidence occurring early or late in the evidence stream. Here, we show changes in such temporal biases within participants as a function of intermittent judgments about parts of the evidence stream. Human participants performed a decision task that required a continuous estimation of the mean evidence at the end of the stream. The evidence was either perceptual (noisy random dot motion) or symbolic (variable sequences of numbers). Participants also reported a categorical judgment of the preceding evidence half-way through the stream in one condition or executed an evidence-independent motor response in another condition. The relative impact of early versus late evidence on the final estimation flipped between these two conditions. In particular, participants' sensitivity to late evidence after the intermittent judgment, but not the simple motor response, was decreased. Both the intermittent response as well as the final estimation reports were accompanied by nonluminance-mediated increases of pupil diameter. These pupil dilations were bigger during intermittent judgments than simple motor responses and bigger during estimation when the late evidence was consistent than inconsistent with the initial judgment. In sum, decisions activate pupil-linked arousal systems and alter the temporal weighting of decision evidence. Our results are consistent with the idea that categorical choices in the face of uncertainty induce a change in the state of the neural circuits underlying decision-making.NEW & NOTEWORTHY The psychology and neuroscience of decision-making have extensively studied the accumulation of decision-relevant information toward a categorical choice. Much fewer studies have assessed the impact of a choice on the processing of subsequent information. Here, we show that intermittent choices during a protracted stream of input reduce the sensitivity to subsequent decision information and transiently boost arousal. Choices might trigger a state change in the neural machinery for decision-making.

Dynamic expressions of confidence within an evidence accumulation framework.

Human observers can reliably report their confidence in the choices they make. An influential framework conceptualizes decision confidence as the probability of a decision being correct, given the choice made and the evidence on which it was based. This framework accounts for three diagnostic signatures of human confidence reports, including an opposite dependence of confidence on evidence strength for correct and error trials. However, the framework does not account for the temporal evolution of these signatures, because it only describes the transformation of a static representation of evidence into choice and the associated confidence. Here, we combine this framework with another influential framework: dynamic accumulation of evidence over time, and build on the notion that confidence reflects the probability of being correct, given the choice and accumulated evidence up until that point. Critically, we show that such a dynamic model predicts that the diagnostic signatures of confidence depend on time; most critically, it predicts a stronger opposite dependence of confidence on evidence strength and choice correctness as a function of time. We tested, and confirmed, these predictions in human behaviour during random dot motion discrimination, in which confidence judgments were queried at different points in time. We conclude that human confidence reports reflect the dynamics of the probability of being correct given the accumulated evidence and choice.

Large-scale dynamics of perceptual decision information across human cortex.

Perceptual decisions entail the accumulation of sensory evidence for a particular choice towards an action plan. An influential framework holds that sensory cortical areas encode the instantaneous sensory evidence and downstream, action-related regions accumulate this evidence. The large-scale distribution of this computation across the cerebral cortex has remained largely elusive. Here, we develop a regionally-specific magnetoencephalography decoding approach to exhaustively map the dynamics of stimulus- and choice-specific signals across the human cortical surface during a visual decision. Comparison with the evidence accumulation dynamics inferred from behavior disentangles stimulus-dependent and endogenous components of choice-predictive activity across the visual cortical hierarchy. We find such an endogenous component in early visual cortex (including V1), which is expressed in a low (<20 Hz) frequency band and tracks, with delay, the build-up of choice-predictive activity in (pre-) motor regions. Our results are consistent with choice- and frequency-specific cortical feedback signaling during decision formation.

Pupil-linked phasic arousal predicts a reduction of choice bias across species and decision domains.

Decisions are often made by accumulating ambiguous evidence over time. The brain's arousal systems are activated during such decisions. In previous work in humans, we found that evoked responses of arousal systems during decisions are reported by rapid dilations of the pupil and track a suppression of biases in the accumulation of decision-relevant evidence (de Gee et al., 2017). Here, we show that this arousal-related suppression in decision bias acts on both conservative and liberal biases, and generalizes from humans to mice, and from perceptual to memory-based decisions. In challenging sound-detection tasks, the impact of spontaneous or experimentally induced choice biases was reduced under high phasic arousal. Similar bias suppression occurred when evidence was drawn from memory. All of these behavioral effects were explained by reduced evidence accumulation biases. Our results point to a general principle of interplay between phasic arousal and decision-making.

Reinforcement biases subsequent perceptual decisions when confidence is low, a widespread behavioral phenomenon.

Learning from successes and failures often improves the quality of subsequent decisions. Past outcomes, however, should not influence purely perceptual decisions after task acquisition is complete since these are designed so that only sensory evidence determines the correct choice. Yet, numerous studies report that outcomes can bias perceptual decisions, causing spurious changes in choice behavior without improving accuracy. Here we show that the effects of reward on perceptual decisions are principled: past rewards bias future choices specifically when previous choice was difficult and hence decision confidence was low. We identified this phenomenon in six datasets from four laboratories, across mice, rats, and humans, and sensory modalities from olfaction and audition to vision. We show that this choice-updating strategy can be explained by reinforcement learning models incorporating statistical decision confidence into their teaching signals. Thus, reinforcement learning mechanisms are continually engaged to produce systematic adjustments of choices even in well-learned perceptual decisions in order to optimize behavior in an uncertain world.

Post-training Load-Related Changes of Auditory Working Memory - An EEG Study.

Working memory (WM) refers to the temporary retention and manipulation of information, and its capacity is highly susceptible to training. Yet, the neural mechanisms that allow for increased performance under demanding conditions are not fully understood. We expected that post-training efficiency in WM performance modulates neural processing during high load tasks. We tested this hypothesis, using electroencephalography (EEG) (N = 39), by comparing source space spectral power of healthy adults performing low and high load auditory WM tasks. Prior to the assessment, participants either underwent a modality-specific auditory WM training, or a modality-irrelevant tactile WM training, or were not trained (active control). After a modality-specific training participants showed higher behavioral performance, compared to the control. EEG data analysis revealed general effects of WM load, across all training groups, in the theta-, alpha-, and beta-frequency bands. With increased load theta-band power increased over frontal, and decreased over parietal areas. Centro-parietal alpha-band power and central beta-band power decreased with load. Interestingly, in the high load condition a tendency toward reduced beta-band power in the right medial temporal lobe was observed in the modality-specific WM training group compared to the modality-irrelevant and active control groups. Our finding that WM processing during the high load condition changed after modality-specific WM training, showing reduced beta-band activity in voice-selective regions, possibly indicates a more efficient maintenance of task-relevant stimuli. The general load effects suggest that WM performance at high load demands involves complementary mechanisms, combining a strengthening of task-relevant and a suppression of task-irrelevant processing.

Author Correction: Thalamus exhibits less sensory variability quenching than cortex.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Relationship between Trial-by-Trial Variability and Oscillations of Cortical Population Activity.

Neural activity fluctuates over time, creating considerable variability across trials. This trial-by-trial neural variability is dramatically reduced ("quenched") after the presentation of sensory stimuli. Likewise, the power of neural oscillations, primarily in the alpha-beta band, is also reduced after stimulus onset. Despite their similarity, these phenomena have so far been studied and discussed independently. We hypothesized that the two phenomena are tightly coupled in electrophysiological recordings of large cortical neural populations. To test this, we examined magnetoencephalography (MEG) recordings of healthy subjects viewing repeated presentations of a visual stimulus. The timing, amplitude, and spatial topography of variability-quenching and power-suppression were remarkably similar. Neural variability quenching was eliminated by excluding the alpha-beta band from the recordings, but not by excluding other frequency-bands. Moreover, individual magnitudes of alpha-beta band-power explained 86% of between-subject differences in variability quenching. An alternative mechanism that may generate variability quenching is increased phase alignment across trials. However, changes in inter-trial-phase-coherence (ITPC) exhibited distinct timing and no correlations with the magnitude of variability quenching in individual participants. These results reveal that neural variability quenching is tightly coupled with stimulus-induced changes in the power of alpha-beta band oscillations, associating two phenomena that have so far been studied in isolation.

Confidence predicts speed-accuracy tradeoff for subsequent decisions.

When external feedback about decision outcomes is lacking, agents need to adapt their decision policies based on an internal estimate of the correctness of their choices (i.e., decision confidence). We hypothesized that agents use confidence to continuously update the tradeoff between the speed and accuracy of their decisions: When confidence is low in one decision, the agent needs more evidence before committing to a choice in the next decision, leading to slower but more accurate decisions. We tested this hypothesis by fitting a bounded accumulation decision model to behavioral data from three different perceptual choice tasks. Decision bounds indeed depended on the reported confidence on the previous trial, independent of objective accuracy. This increase in decision bound was predicted by a centro-parietal EEG component sensitive to confidence. We conclude that internally computed neural signals of confidence predict the ongoing adjustment of decision policies.