Temporal Expectation Hastens Decision Onset But Does Not Affect Evidence Quality.

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory/motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modeling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation but had no effect on its build-up rate. Anticipatory α band power was modulated by temporal expectation and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events.SIGNIFICANCE STATEMENT Temporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We manipulated expectations about the onset of a dim visual target using a temporal cueing paradigm, and probed the locus of the expectation effect with two complementary approaches: drift diffusion modeling (DDM) of behavior, and estimation of the onset and progression of the decision process from a supramodal accumulation-to-bound signal in simultaneously measured EEG signals. Behavioral modeling and neural data provided strong, converging evidence for an account in which temporal expectations enhance perception by speeding up decision onset, without affecting evidence quality.

Amplification and Suppression of Distinct Brainwide Activity Patterns by Catecholamines.

The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogeneous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brainwide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of fMRI measurements performed in humans (19 females, 5 males) at "rest" under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α1 norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), D2-like dopamine receptors (pattern: atomoxetine > placebo), and ß norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.SIGNIFICANCE STATEMENT The catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogeneous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brainwide fMRI signals at "rest." We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.

Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations.

UNLABELLED: Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT: Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

UNLABELLED: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

Post-error slowing as a consequence of disturbed low-frequency oscillatory phase entrainment.

A common finding across many reaction time tasks is that people slow down on trials following errors, a phenomenon known as post-error slowing. In the present study, we tested a novel hypothesis about the neural mechanism underlying post-error slowing. Recent research has shown that when task-relevant stimuli occur in a rhythmic stream, neuronal oscillations entrain to the task structure, thereby enhancing reaction speed. We hypothesized that under such circumstances post-error slowing results from an error-induced disturbance of this endogenous brain rhythm. To test this hypothesis, we measured oscillatory EEG dynamics while human subjects performed a demanding discrimination task under time pressure. We found that low-frequency neuronal oscillations entrained to the stimulus presentation rhythm, and that the low-frequency phase at stimulus onset predicted the speed of responding. Importantly, we found that this entrainment was disrupted following errors, and that the degree of phase disturbance was closely related to the degree of post-error slowing on the subsequent trial. These results describe a new mechanism underlying behavioral changes following errors.

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.

Neuronal timescales are functionally dynamic and shaped by cortical microarchitecture.

Complex cognitive functions such as working memory and decision-making require information maintenance over seconds to years, from transient sensory stimuli to long-term contextual cues. While theoretical accounts predict the emergence of a corresponding hierarchy of neuronal timescales, direct electrophysiological evidence across the human cortex is lacking. Here, we infer neuronal timescales from invasive intracranial recordings. Timescales increase along the principal sensorimotor-to-association axis across the entire human cortex, and scale with single-unit timescales within macaques. Cortex-wide transcriptomic analysis shows direct alignment between timescales and expression of excitation- and inhibition-related genes, as well as genes specific to voltage-gated transmembrane ion transporters. Finally, neuronal timescales are functionally dynamic: prefrontal cortex timescales expand during working memory maintenance and predict individual performance, while cortex-wide timescales compress with aging. Thus, neuronal timescales follow cytoarchitectonic gradients across the human cortex and are relevant for cognition in both short and long terms, bridging microcircuit physiology with macroscale dynamics and behavior.

The human brain can both quickly react to a fleeting sight, like a changing traffic light, and slowly integrate complex information to form a long-term plan. To mirror these requirements, how long a neuron can be activated for ­ its 'timescale' ­ varies greatly between cells. A range of timescales has been identified in animal brains, by measuring single neurons at a few different locations. However, a comprehensive study of this property in humans has been hindered by technical and ethical concerns. Without this knowledge, it is difficult to understand the factors that may shape different timescales, and how these can change in response to environmental demands. To investigate this question, Gao et al. used a new computational method to analyse publicly available datasets and calculate neuronal timescales across the human brain. The data were produced using a technique called invasive electrocorticography, where electrodes placed directly on the brain record the total activity of many neurons. This allowed Gao et al. to examine the relationship between timescales and brain anatomy, gene expression, and cognition. The analysis revealed a continuous gradient of neuronal timescales between areas that require neurons to react quickly and those relying on long-term activity. 'Under the hood', these timescales were associated with a number of biological processes, such as the activity of genes that shape the nature of the connections between neurons and the amount of proteins that let different charged particles in and out of cells. In addition, the timescales could be flexible: they could lengthen when areas specialised in working memory were actively maintaining information, or shorten with age across many areas of the brain. Ultimately, the technique and findings reported by Gao et al. could have useful applications in the clinic, using neuronal timescale to better understand brain disorders and pinpoint their underlying causes.

Sustaining attention for a prolonged period of time increases temporal variability in cortical responses.

Our ability to stay focused is limited: prolonged performance of a task typically results in mental fatigue and decrements in performance over time. This so-called vigilance decrement has been attributed to depletion of attentional resources, though other factors such as reductions in motivation likely also play a role. In this study, we examined three electroencephalography (EEG) markers of attentional control, to elucidate which stage of attentional processing is most affected by time-on-task and motivation. To elicit the vigilance decrement, participants performed a sustained attention task for 80 min without breaks. After 60 min, participants were motivated by an unexpected monetary incentive to increase performance in the final 20 min. We found that task performance and self-reported motivation declined rapidly, reaching stable levels well before the motivation manipulation was introduced. Thereafter, motivation increased back up to the initial level, and remained there for the final 20 min. While task performance also increased, it did not return to the initial level, and fell to the lowest level overall during the final 10 min. This pattern of performance changes was mirrored by the trial-to-trial consistency of the phase of theta (3-7 Hz) oscillations, an index of the variability in timing of the neural response to the stimulus. As task performance decreased, temporal variability increased, suggesting that attentional stability is crucial for sustained attention performance. The effects of attention on our two other EEG measures-early P1/N1 event-related potentials (ERPs) and pre-stimulus alpha (9-14 Hz) power-did not change with time-on-task or motivation. In sum, these findings show that the vigilance decrement is accompanied by a decline in only some facets of attentional control, which cannot be fully brought back online by increases in motivation. The vigilance decrement might thus not occur due to a single cause, but is likely multifactorial in origin.

Catecholaminergic manipulation alters dynamic network topology across cognitive states.

The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.

Norepinephrine transporter blocker atomoxetine increases salivary alpha amylase.

It has been suggested that central norepinephrine (NE) activity may be inferred from increases in salivary alpha-amylase (SAA), but data in favor of this proposition are limited. We administered 40mg of atomoxetine, a selective NE transporter blocker that increases central NE levels, to 24 healthy adult participants in a double-blind, placebo-controlled cross-over design. Atomoxetine administration significantly increased SAA secretion and concentrations at 75-180min after treatment (more than doubling baseline levels). Consistent with evidence that elevation in central NE is a co-determinant of hypothalamic-pituitary-adrenal axis activity, salivary cortisol also approximately doubled at the same time points. Moreover, changes in salivary cortisol positively correlated with SAA (0.44

Pupil Diameter Tracks Lapses of Attention.

Our ability to sustain attention for prolonged periods of time is limited. Studies on the relationship between lapses of attention and psychophysiological markers of attentional state, such as pupil diameter, have yielded contradicting results. Here, we investigated the relationship between tonic fluctuations in pupil diameter and performance on a demanding sustained attention task. We found robust linear relationships between baseline pupil diameter and several measures of task performance, suggesting that attentional lapses tended to occur when pupil diameter was small. However, these observations were primarily driven by the joint effects of time-on-task on baseline pupil diameter and task performance. The linear relationships disappeared when we statistically controlled for time-on-task effects and were replaced by consistent inverted U-shaped relationships between baseline pupil diameter and each of the task performance measures, such that most false alarms and the longest and most variable response times occurred when pupil diameter was both relatively small and large. Finally, we observed strong linear relationships between the temporal derivative of pupil diameter and task performance measures, which were largely independent of time-on-task. Our results help to reconcile contradicting findings in the literature on pupil-linked changes in attentional state, and are consistent with the adaptive gain theory of locus coeruleus-norepinephrine function. Moreover, they suggest that the derivative of baseline pupil diameter is a potentially useful psychophysiological marker that could be used in the on-line prediction and prevention of attentional lapses.