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While many high-level cortical areas have been implicated in timing, timing activity has also been observed even in the earliest cortical stages of the visual system over the past decade. This activity has been formally modeled as one arising from a reinforcement signal, leading to testable hypotheses with recent experimental support, demonstrating the necessity and sufficiency of that reinforcement signal. As observed in other cortical areas implicated in timing, interval timing activity within the visual cortex abides by the temporal scalar property. Finally, perturbations of the visual cortex during interval timing results in lawful shifts in timing. These and related observations advance the notion that visual cortex is a substrate for learning and expressing visually-associated temporal expectations governing behaviorally-relevant actions.
An understanding of how the brain apprehends the passage of time, remembers relevant intervals, and produces those intervals to inform appropriately timed actions remains elusive despite much progress towards this goal, as reviewed within this issue, at the experimental, computational, and theoretical levels [1–4]. While it is recognized that any time varying neural process could in principle serve to mark the passage of time , one of the fundamental challenges faced by experimenters is in distinguishing between neural activity arising from any ongoing process from that which is truly used as a timing signal. Below we identify a number of qualities observable experimentally that increase the likelihood that a neural pattern of activity in visual cortex―and in cortex generally―is an expression of how the brain apprehends, remembers, and produces temporal intervals; namely, a 1) Phenomenological description of activity subtending and/or marking the expiry of the interval to be timed, 2) Dissociation between putative neural- and behavioral-timing activity, 3) Formalization of how, in principle, such neural timing may arise, 4) Manipulation of the biological instantiation of that theorized process, 5) Localization of that process to the area of interest, 6) generation of neural activity that can give rise to the Temporal Scalar Property, and 7) a causal demonstration of the Behavioral relevance of that neural activity (see Figure 1). Using reports of cued-interval timing in the visual cortex and its mechanistic investigation as a vehicle, we identify general challenges to, and potential approaches for, identifying and understanding the genesis of cortical timing signals.
Identifying candidate interval timing signals in cortex begins with phenomenological reports of neural activity that modulate predictably in time in response to a cue (such as in reporting a hazard function) or subtends/demarcates the expiry of an interval of interest (such as a delay to reward). Within visual cortical areas, examples of neural activity tracking visually-cued hazard functions have been observed in modulations of single unit spiking in monkey V4 , gamma oscillations in monkey V1 , and BOLD signaling in human V1,2&3 . With respect to reporting the expiry of an interval of interest, such as a delayed reward, is the report of “reward timing” in V1 of rodents, wherein pairing visual cues with subsequent reward leads to the emergence of cue-evoked neural responses that express the typical delay to reward [9–12]. Trials in which reward is expected but withheld can then be used to assess whether changes in neural activation at the time of expected reward is a consequence of the interval elapsing (as observed in V1), or, more trivially, as a direct response to the acquisition of reward itself. As noted, however, an abiding challenge is in distinguishing between putative timing signals and those that may arise as a consequence of actions [13–15], measured or not, that are used during the report of the expiry of the interval. Therefore, the candidacy of a timing signal can be further advanced by assessing whether it can be evoked (as in the case of reward timing  even in the absence of producing task-relevant actions (e.g. licking for reward), or otherwise dissociating those actions from neurally encoded intervals [9, 10, 15]. The identification of candidate timing signals expressing 1) a relation to the interval of interest, 2) an insensitivity to the presence/absence of outcomes, and/or 3) an insensitivity to the actions terminating the interval, then well-motivate a computational investigation into how such neural response profiles may come about.
Having characterized at the phenomenological level candidate interval timing signals, can their acquisition and expression be successfully formalized to capture key features in a parsimonious and biologically plausible way? A family of timing models propose potential solutions to how, in principle, a network could learn and express temporal intervals (see , for review). One such model describes the emergence of cued-interval timing activity observed in V1 as resulting from a process of reinforcement learning occurring within V1 itself [15, 17–20]. In it, a signal conveying behavioral outcome permits recently active synapses within V1 to be modified (or, as in , the intrinsic excitability of single cells) so as to come to encode the cue-reward delay. Having rationalized, formally, how timing signals may emerge and be expressed in the cortex, the merit of any model can then be challenged by assessing whether its minimal assumptions are satisfied within the area of interest, and, if so, by demonstrating the necessity and sufficiency of those critical elements.
Since a signal conveying behavioral outcome is an essential provision of the model regarding reward timing in V1, what input may reasonably serve to convey such a signal, and can it be disrupted to show its necessity in learning a cued-interval? And, complementary, can such a signal be activated to show its sufficiency in establishing, neurally, the cued-interval response? As neuromodulatory systems have been widely implicated in governing synaptic plasticity and responding to behaviorally relevant events [21, 22], we conjectured that one or more such systems may convey the acquisition of reward to V1, serving as the hypothesized reinforcement signal. By selectively lesioning cholinergic innervation of V1, we demonstrated that it is indeed necessary for reward timing activity to learn novel cue-reward delays . We also demonstrated that optogenetically-commandeering cholinergic basal forebrain input to V1 is sufficient to condition cued-interval timing activity in V1, mimicking that which is observed following behavioral conditioning . Together, these observations advance the case that the cholinergic system serves as a reinforcement signal governing the learning in V1 of cue-reward associations and their interceding intervals.
Manipulations as that above demonstrate how a cortical area can be implicated as generating interval timing by showing how given inputs—themselves not the source of the interval—are critical to the emergence of observing timing activity within that area of interest. That the manipulations of cholinergic innervation were localized to V1 increases the likelihood that interval timing arises from processes occurring within it, rather than simply reflecting timing which might be learned elsewhere, such as described in mPFC , LIP , medial agranular cortex , or striatum , amongst others, though this may also occur. Indeed, Makino and Komiyama recently provided evidence in support of retrosplenial cortex sourcing aversively conditioned timing information to V1 . In general, lesion and/or inactivation, has advanced the case that many cortical areas are involved in timing [28–30], typically by assessing the impact on behavioral reports of timing. Yet definitive evidence that any area expressing timing activity can do so as a consequence of its own internal processes poses a challenge, for how can such a case be made without removing all its inputs?
Rather than lesioning an area of interest and observing a deficiency, an area of interest could be assessed in isolation as to whether it, nonetheless, is capable of generating timing activity mimicking that observed in the fully intact preparation. In this extreme, the use of in vitro preparations has done much to advance our understanding of how a given region could, in principle, learn and express time. Isolated recurrent networks have been reported to produce repeatable temporally-evolving patterns [31, 32] that could embody the passage of time . Cortical networks in vitro have even been demonstrated to adapt such temporally-evolving patterns in accordance with conditioned temporal intervals . With respect to interval timing in V1, it has been demonstrated in a slice preparation of V1 that stimulus-evoked responses can be conditioned by delayed cholinergic agonist application following electrical stimulation  to produce, in response to subsequent electrical stimulation, the conditioned interval. Together, these studies address how the dynamics of local recurrent networks can represent the passage of time, and how they can be modified to produce temporal intervals experienced by the animal.
Should a neural process observed within an area serve to inform the perception or production of temporal intervals, the form that it takes must be reconcilable with the patterns and errors generated when estimating or producing reports of time behaviorally [34–37]. In regards to errors in behavioral timing is the observation that the distribution of times produced for a given target interval proportionally scales with the magnitude of the target time, the so called Temporal Scalar Property [1, 2, 38, 39] (a strong form of Weber’s law in the temporal domain which holds, more generally, that the magnitude of timing errors are directly proportional to the magnitude of the interval to be timed). This proffers the question as to whether putative cortical representations of temporal intervals similarly express a variability that scales with the interval to report (or, if not, if some read-out process of those temporal patterns observed would so scale ). Scaling of neural responses with target intervals has been observed in a number of cortical regions implicated in timing, exemplified by recordings made in monkey LIP , prefrontal cortex, motor cortex, and in rat prefrontal cortex . With regards to the visual cortex, behaviorally as well as optogenetically conditioned cue-evoked signaling of temporal intervals has been shown to exhibit a multiplicative scaling of their temporal distributions . That a scalar variabiltiy observed in neural timing accords with the variability generally observed behaviorally further advances the case that cortical regions are involved in timing, as is apparently true of even the primary visual cortex.
While any neural signature of interval timing is potentially useful as a model of the world, its biological relevance remains uncertain in the absence of ultimately relating it, phenomenologically, to some timed behavior. Further, should a brain area generate timing activity and inform timed actions, perturbations to that activity should lawfully affect the timing of those actions. For example, following the observation that neural response functions within mPFC scaled to target intervals (noted above), Xu and colleagues proceeded to demonstrate that cooling mPFC resulted in a delay in the timing of the behavior of the animal, consistent with mPFC informing upon those timed actions . Similarly, perturbations to visual cortical areas have advanced the case that they contribute to the perception and generation of temporal intervals, apart from their recognized roles in image processing. For instance, transcranial magnetic stimulation (TMS) of V5 has been demonstrated to affect discrimination of the duration of visual targets  and to shift the timing of response to intercept moving targets . Subsequent work from the Bueti laboratory demonstrated that TMS of not only V5/MT, but also of V1, affects the apprehension and memory of experienced visually-cued intervals .
With respect to reward timing activity observed in V1 in the spiking activity of single neurons, a general critique has been that its biological relevance is uncertain in the absence of relating it to timed behavior on a trial-to-trial basis, as has been demonstrated in other cortical areas [23, 41, 42]. These observations motivated us to address whether visually-evoked signals informing timed actions may also be observed within V1 when timed actions following a visual cue are required of the animal . Under these conditions, while reward timing (the reporting of the average time of expected reward) continues to be observed, another population of V1 neurons is observed to express the interval to the timed action on a per trial basis, as if informing the animal when the target interval has expired (“action timing responses”). Importantly, this correlation is present only on trials in which the animal is using the visual cues to time the response (visually-timed trials), and not on those trials in which those cues are not being used to time the response (non-visually-timed trials). To test the hypothesis that such activity may inform the animal as to when the target interval has expired, we optogenetically perturbed V1 activity for a brief period during the interval between the visual cue and the behavioral report of the interval, and assessed its effect on the timing of the behavioral report. Perturbing activity in V1 during the interceding interval consistently shifted the timing behavior of animals within an experimental session. Further, this shift was present only on visually-timed trials and not on non-visually-timed trials, even though both trial types contain the exact same visual stimulus, laser and action . Collectively, these observations indicate that V1 is a site that expresses interval timing activity that informs behavioral timing.
Predicting outcomes, evaluating options, and producing timed actions that are behavioral beneficial requires an ability to apprehend, remember, and produce temporal intervals. This collection of reviews comprehensively synthesizes current advances in the experimental, computational, and theoretical investigation of timing in the brain, focusing on those brain areas with the preponderance of evidence in support of their roles in timing. Here we advance the case that even early visual cortical areas may be involved in these temporal processes, beyond their recognized role in responding to the features of visual inputs. The observations reviewed here collectively satisfy a broad set of criteria (see figure 1) for establishing an area as expressing, as well as being a substrate for learning to express interval timing activity. Visual cortical areas exhibit 1) the phenomenology of timing signals that can be 2) disassociated from ongoing behaviors, and can be 3) formalized conceptually with models that have garnered experimental support by 4) manipulating critical components. Visual cortex is also demonstrated to possess minimal requirements for it to 5) locally generate timing signals. As with other areas implicated in timing, visual cortical areas can exhibit timing responses that accord with the 6) Temporal Scalar Property, furthering the case that such activity is of 7) behavioral relevance, as directly tested by perturbing these areas and observing effects of visually-cued timing behavior. Future goals in assessing the role of visual cortical areas in timing will be to make a reckoning of why subjective time takes the form it does , and how various sources of noise are contended with and shape those processes .
Visual cortical areas are implicated in interval timing
Timing activity within visual cortex can be formally rationalized
Necessity and sufficiency of essential components of a timing model are demonstrated
Neural reports within visual cortex abide by the temporal scalar property
Perturbations implicate visual cortex in informing timed actions
This work was funded by NIMH (R01 MH093665) to M.G.H.S.