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How the Human Brain Masters Time

Periodic Reporting for period 3 - BiT (How the Human Brain Masters Time)

Reporting period: 2019-10-01 to 2021-03-31

BiT aims to understand where, how and when the human brain represents and processes time in a range spanning from a few hundreds of milliseconds to a few seconds.
Specifically, BiT addresses the following research issues: a) BiT asks whether duration, similarly to other sensory or motor features, is represented in the brain via duration tuning and topography i.e. neural units selectively responsive to different durations and orderly mapped in contiguous portions of the cortical surface. b) BiT asks whether spatial and temporal information are processed within the same neural circuits i.e. are the duration of a visual object and its spatial position processed together? c) By inducing perceptual distortions of time, BiT investigates the mechanisms underlying duration perception and their brain correlates. d) BiT explores the functional connectivity and the temporal hierarchies within putative “time regions” i.e. which region is connected to which and which region comes first? In particular BiT is interested in investigating the relationship between visual areas (between V1 and V5/MT), between visual and associative cortices (V1-V5/MT and posterior parietal and frontal cortices) and between areas showing duration tuning (i.e. brain areas responding preferentially to a specific duration).
To address those goals, BiT uses the full palette of human neuroscience techniques: psychophysics, neuroimaging, brain stimulation techniques and the simultaneous combination of the two.
By being able to answer these questions, BiT research will have an impact on the field of temporal cognition and on human cognition in general. BiT will gain knowledge on how the perception of time is achieved in the adult brain. These findings will prompt further work to investigate brain changes underlying time perception deficits, and to develop new methods for manipulating time perception in healthy and clinical populations.
Work package (WP) 1: A principle of temporal representation in the human brain

In WP1 we ask whether duration, similarly to other sensory or motor features, is represented in the brain via duration tuning and topography i.e. neural units selectively responsive to different durations and orderly mapped in contiguous portions of the cortical surface
We were able to complete 3 out of the 4 planned functional Magnetic Resonance Imaging (fMRI) experiments. In these studies, conducted at ultra-high field (7 Tesla), we show: A) with two distinct data sets and different types of data analysis (i.e. univariate and multivariate) the existence in parietal, occipital and frontal cortices of duration tuning and in supplementary motor area (SMA) of chronotopy. B) chronomaps change according to the durations at hand i.e. they represent time in a relative rather than an absolute fashion, and they are maps of perceived rather than physical time.  C) Chronomaps in SMA are present for both visual and auditory stimuli.

In order to prove the causal engagement of SMA in engendering chronomaps, we are also running a Transcranial Magnetic Stimulation (TMS) experiment. We are starting the data collection in these days, after a behavioral pilot to optimize the design.
We are also planning an Electroencephalography (EEG) experiment to better see the time-course of duration selectivity i.e. when does the preferential response to a given duration occur? Is there an EEG signature of it (e.g. a specific topography, ERP component, oscillatory rhythm)?

WP2: Characterizing the functional properties of visual and auditory cortices in temporal computations

The aim of WP2 was specifying the functional role of visual and auditory cortices in time processing (encoding and perception). Up to now we focused mainly on visual cortices (i.e. primary visual cortex V1 and extra-striate area V5/MT) wondering whether the duration of a visual object is processed within the same circuit processing its spatial position.
We completed two TMS experiments in which we showed that time is processed within visual spatial circuits. Specifically, the extra-striate area V5/MT seems to encode duration information within an hemifield-specific frame of reference, whereas primary visual cortex (V1) in a retinotopic frame.
Two more TMS experiment are at the piloting stage. Both focus on the investigation of the role of primary visual cortex in duration perception rather than encoding. By using different experimental paradigms (with and without perceptual adaptation) and different TMS protocols (low intensity TMS and single pulse TMS), our aim is to induce duration perception biases via TMS stimulation of V1.

WP3: Disclosing the functional dynamics and the temporal hierarchies between ‘modality-specific’ and ‘modality-independent’ timing areas.

The aim of WP3 was to assess by mean of TMS, TMS-EEG, EEG and fMRI with functional connectivity analysis, the functional relationship and the temporal hierarchies between putative “time regions”.  
So far, we completed two TMS, one EEG experiment and one Dynamic Causal Modelling-DCM analysis.
With the two TMS experiments, we tried to understand the contribution of V1 and V5/MT to time encoding by looking at the engagement over time (i.e. the chronometry) of these two areas. Overall, the data of these experiments show that the chronometry of V1 and V5/MT in duration encoding is stimulus dependent: the offset is more critical for empty rather than filled durations. When filled durations are used, the TMS effects support the idea that V1 and V5/MT encode time via accumulation of sensory information.
With the EEG study, we induced duration perception distortions to find changes in brain responses correlated with changes in duration perception. Specifically, we used visual perceptual adaptation to fast moving stimuli. We performed ERP and frequency analysis. At ERP level, we found a modulation of the bias shift on the amplitude of the N200 component in occipital electrodes and of the Contingent Negative Variation (CNV) in fronto-central electrodes. Moreover, the amplitude of both components correlated significantly with the perceptual shift. Finally, the perceptual bias was associated with an increase in the beta-band frequency spectrum. These findings highlight the existence of a strong link between beta band frequency, early occipital, late frontocentral components and time perception.

To perform the DCM analysis, we used one of the fMRI data sets of WP1. Our goal here was to define the effective connectivity between the five brain areas (i.e. cerebellum, primary visual cortex, inferior parietal lobule, Supplementary Motor Area-SMA and inferior frontal cortex) displaying selective responses to stimulus duration (“duration channels”) and their “duration channels”. We tested the hypothesis that the existence of connections, their modulation by stimulus presentation as well as their input-region might be: a) stimulus-duration independent, b) only partially stimulus-duration dependent i.e. neighboring specific or c) totally stimulus-duration dependent. Bayesian Model Selection revealed that the best model is the one that has all connections between the 20 nodes. However, the connections within each region are modulated by stimulus presentation in a neighboring-specific fashion whereas the connections between-regions as well as the modulation on the input region in a duration-specific manner.

Figure 1 Legend
fMRI results, comparison between the chronotopic maps of two experiments. (A) Chronotopic maps in the left SMA in the two Experiments, group-level maps are superimposed on an inflated Dartel template computed on the T1-weighted images of the 21 subjects. White lines are the borders of the maps. The posterior border lies on the most posterior part of the pre-central gyrus. (B) For each experiment (squares is Exp.1 and circles Exp.2) and for each duration selective clusters of vertices, we estimated the centroids and then calculated their absolute distance from the posterior border.
The groundbreaking achievement of BiT comes from its most challenging and novel ideas: the existence of a network of brain areas displaying selective responses to stimulus timing and organized into topographic maps by their timing preferences.
This finding shows, for the first time in the human brain, that the adaptive representation of an abstract feature such as time, that lacks of sensory organ, can be achieved by a topographical arrangement of duration-sensitive neural populations similar to that observed in several cortical and subcortical structures for the processing of sensory and motor signals. Demonstrating the existence of chronomaps represents a significant and groundbreaking step forward our understanding of the neural representation of time since it shows a possible mechanism of temporal representation and its location in the brain (what is the mechanism and where it is). This finding will challenge current models of time perception and open up new approaches to the study of time processing and more in general to cognitive neuroscience. From generally looking at brain regions processing time (i.e. a single mechanism, a single neural circuit where all durations are processed similarly and have a similar status), we can move towards the idea of a greater specificity in the processing of different durations (where each duration has a specific status and a specific relationship with others within a map). The effect of this change of approach will have consequences that will go beyond the length of the ERC project. For example, temporal maps (either sensory or read-out) could in future become a neurophysiological marker of the efficiency of temporal mechanisms in the brain. This may be used as diagnostic tool and prompt future research to investigates temporal deficits. This is particularly important since time deficits are common in neurological and psychiatric disorders but also in aging populations, they are highly disruptive of every-day life activities but they rarely become the target of treatments.

Concerning the expected achievements by the end of the project, I expect first, to be able to publish all the results that are still unpublished. And second, to be able to carry-out what is still missing from the original plan i.e. part of the experiments of WP2, and WP3.
In particular there are 2 issues I am very keen on:
1. Conducting the experiments in which I explore the functional connectivity.
- An experiment in which I can use a new TMS protocol (called ccPAS) to stimulate two brain areas at a very short delay from each other (a few milliseconds). I can use this protocol to assess the connectivity between visual regions and between visual and parietal cortices.
- Do simultaneous EEG TMS, to first see by nocking-out a certain brain region (e.g. V1), whether we are able to suppress the visual N200 component that is associated with a duration perception bias. Second, to see whether suppressing the same area when it is resonating a specific frequency (on peak or off peak in the alpha band) causes a change in temporal judgments.
2. Going deep into the investigation of the relationship between representation of space and time in visual cortex by running a new fMRI experiment at 7Tesla to see how different durations are represented in different retinotopic positions.
Figure 1 fMRI results, comparison between the chronotopic maps of two experiments