Timing emerges from a hierarchy of computations ranging from early encoding of physical duration (time sensation) to abstract time representations (time perception) suitable for storage and decisional processes. However, the neural basis of the perceptual experience of time remains elusive. To address this, we dissociate brain activity uniquely related to lower-level sensory and higher-order perceptual timing operations, using event-related fMRI. Participants compared subsecond (500 msec) sinusoidal gratings drifting with constant velocity (standard) against two probe stimuli: (1) control gratings drifting at constant velocity or (2) accelerating gratings, which induced illusory shortening of time. We tested two probe intervals: a 500-msec duration (Short) and a longer duration required for an accelerating probe to be perceived as long as the standard (Long—individually determined). On each trial, participants classified the probe as shorter or longer than the standard. This allowed for comparison of trials with an “Objective” (physical) or “Subjective” (perceived) difference in duration, based on participant classifications. Objective duration revealed responses in bilateral early extrastriate areas, extending to higher visual areas in the fusiform gyrus (at more lenient thresholds). By contrast, Subjective duration was reflected by distributed responses in a cortical/subcortical areas. This comprised the left superior frontal gyrus and the left cerebellum, and a wider set of common timing areas including the BG, parietal cortex, and posterior cingulate cortex. These results suggest two functionally independent timing stages: early extraction of duration information in sensory cortices and Subjective experience of duration in a higher-order cortical–subcortical timing areas.

The neural dynamics underpinning binary perceptual decisions and their transformation into actions are well studied, but real-world decisions typically offer more than two response alternatives. How does decision-related evidence accumulation dynamically influence multiple action representations in humans? The heightened conservatism required in multiple compared with binary choice scenarios suggests a mechanism that compensates for increased uncertainty when multiple choices are present by suppressing baseline activity. Here, we tracked action representations using corticospinal excitability during four- and two-choice perceptual decisions and modeled them using a sequential sampling framework. We found that the predictions made by leaky competing accumulator models to accommodate multiple choices (i.e., reduced baseline activity to compensate increased uncertainty) were borne out by dynamic changes in human action representations. This suggests a direct and continuous influence of interacting evidence accumulators, each favoring a different decision alternative, on downstream corticospinal excitability during complex choice.

The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.

Humans carry out many daily tasks in a seemingly automatic fashion. However, when unexpected changes in the environment occur, we have the capacity to inhibit prepotent behavior and replace it with an alternative one. Such behavioral flexibility is a hallmark of executive functions. The neurotransmitter dopamine is known to be crucial for fast, efficient, and accurate cognitive flexibility. Despite the perceived similarities between cognitive and motor flexibility, less is known regarding the role of dopamine within the motor domain. Therefore, the aim of this study was to determine the role of dopamine in motor flexibility. In a double-blind, five-session, within-subject pharmacological experiment, human participants performed an RT task within a probabilistic context that was either predictable or unpredictable. The probabilistic nature of the predictable context resulted in prediction errors. This required participants to replace the prepotent or prepared action with an unprepared action (motor flexibility). The task was overlearned, and changes in context were explicitly instructed, thus controlling for contributions from other dopamine-related processes such as probabilistic or reversal learning and interactions with other types of uncertainty. We found that dopamine receptor blockade by high-dose haloperidol (D1/D2 dopamine receptors) impaired participants' ability to react to unexpected events occurring in a predictable context, which elicit large prediction errors and necessitate motor flexibility. This effect was not observed with selective D2 receptor blockade (sulpiride), with a general increase in tonic dopamine levels (levodopa), or during an unpredictable context, which evoked minimal prediction error. We propose that dopamine is vital in responding to low-level prediction errors about stimulus outcome that requires motor flexibility.

The pFC has a crucial role in cognitive control, executive function, and sensory processing. Functional imaging, neurophysiological, and animal studies provide evidence for a functional connectivity between the dorsolateral pFC (DLPFC) and the primary motor cortex (M1) during free choice but not instructed choice selection tasks. In this study, twin coil, neuronavigated TMS was used to examine the precise timing of the functional interaction between human left DLPFC and ipsilateral M1 during the execution of a free/specified choice selection task involving the digits of the right hand. In a thumb muscle that was not involved in the task, a conditioning pulse to the left DLPFC enhanced the excitability of the ipsilateral M1 during free selection more than specified selection 100 msec after presentation of the cue; the opposite effect was seen at 75 msec. However, the difference between free and externally specified conditions disappeared when a task-specific muscle was investigated. In this case, the influence from DLPFC was dominated by task involvement rather than mode of selection, suggesting that other processes related to movement execution were also operating. Finally, we show that the effects were spatially specific because they were absent when an adjacent area of DLPFC was stimulated. These results reveal temporally and spatially selective interactions between BA 46 and M1 that are both task and muscle specific.

We used concurrent TMS–fMRI to test directly for hemispheric differences in causal influences of the right or left fronto-parietal cortex on activity (BOLD signal) in the human occipital cortex. Clinical data and some behavioral TMS studies have been taken to suggest right-hemisphere specialization for top–down modulation of vision in humans, based on deficits such as spatial neglect or extinction in lesioned patients, or findings that TMS to right (vs. left) fronto-parietal structures can elicit stronger effects on visual performance. But prior to the recent advent of concurrent TMS and neuroimaging, it was not possible to directly examine the causal impact of one (stimulated) brain region upon others in humans. Here we stimulated the frontal or intraparietal cortex in the left or right hemisphere with TMS, inside an MR scanner, while measuring with fMRI any resulting BOLD signal changes in visual areas V1–V4 and V5/MT+. For both frontal and parietal stimulation, we found clear differences between effects of right- versus left-hemisphere TMS on activity in the visual cortex, with all differences significant in direct statistical comparisons. Frontal TMS over either hemisphere elicited similar BOLD decreases for central visual field representations in V1–V4, but only right frontal TMS led to BOLD increases for peripheral field representations in these regions. Hemispheric differences for effects of parietal TMS were even more marked: Right parietal TMS led to strong BOLD changes in V1–V4 and V5/MT+, but left parietal TMS did not. These data directly confirm that the human frontal and parietal cortex show right-hemisphere specialization for causal influences on the visual cortex.