From Automatic to Conscious Timing in the brain: a core cognitive deficit in schizophrenia? – AutoTime

Our common paradigm consists in examining to which extent a temporal information (order vs. duration, consciously perceived or not) can be used to anticipate an event. Two squares A and B are diplayed in AB or BA order, and this order is consciously perceived or not, according to the delay between squares. Each order is associated with a given information, e.g. a color, and subjects are instructed to give a response to this color. Linking order and colot allows subjects to anticipate the color and to improve their performance. This task is associated with several techniques that allow to measure brain activity, in human and in animal. This will allow us to determine the physiological mechanisms underlying order and duration coding. When applied to schizophrenia;, the task will determine the origin of the patients' difficulty to structure their mental activity in time.
In order to understand how the coding of a temporal event leads to a conscious representation of order and duration, we will record neuronal oscillations, and, in particular, the coupling between the signals emitted at different frequencies (in M/EEG, and in rats in order to explore deep brain structures and the effect of psychotomimetic drugs). We also examine the areas activated in fMRI when predicting order vs. duration. These studies are conducted both in healthy volunteers and in patients with schizophrenia. Regarding schizophrenia; we also aim at examining the impact of time ordering abilities on causality judgements. To this aim we examine how the temporal order of two visual events (a moving square stopped by another square), affects causality judgements.

- Our results suggest that when subjects are encouraged to used temporal order information, they can do it even when this information is not consciously accessible.
- We confirmed that patients with schizophrenia and minimal self disorders have difficulties to benefit from the passahe of time. (Martin et al., 2017, 2018).
- We obtained several contracts to develop therapeutic applications for schizophrenia, which derive from the AutoTime project.
- We organized a conference in Strasbourg from the 25 to 27 october 2017: the 1st internation conference of theTiming Research Forum, which was attended to by more than 270 participants.

Our results suggest complex interactions between conscious and unconscious processes, with a possible mutual influence of the subject's current goals on how his mental activity is unconsciously temporally structured, The ongoing project will allow us to better understand the nature of these reciprocal influences.
In addition, the confirmation of the link between time and self disorders in schizophrenia encourages us to develop proofs of therapeutic concept targeting temporal disorders in this pathology. Several contracts have been obtained with this objective, i.e.e aimed at checking the involvement of brain structures like the cerebellum, and at examining the possibility to target time disorders with transcranial stimulation techniques.

Two studies (1 group study and one single case) suggest that patients with schizophrenia and minimal self disorders have difficulties to benefit from the passage of time : Martin B et al (2017). Fragile temporal prediction in patients with schizophrenia is related to minimal self disorders. Scientific Reports 7 : 8278.
Martin B et al (2018) Minimal self and timing disorders in schizophrenia: a case report. Front. Hum. Neurosci. 12:132.
We developed new statistical methods to modelize the frequecy couling in temporal series, which is important for the analysis of our MEG and EEG data, in human and animal.
La Tour T. D et al (2017). Non-linear auto-regressive models for cross-frequency coupling in neural time series. PLoS Computational Biology, 13(12), e1005893.

Ordering events in time plays a pervasive role in cognitive and social functions, e.g. causality judgements, and appears to be impaired in patients with schizophrenia. However, it is unclear whether events can be ordered automatically, without cognitive effort: a succession of percepts may not be enough to derive order, and the neural mechanisms underlying temporal order perception remain elusive. The distinct paths taken by each of our 4 teams converge to a strong working hypothesis: while certain temporal properties are likely automatically encoded, e.g. the duration of an event, additional processing stages are required for duration and order to be consciously perceived. While this has been studied for duration, much less is known about temporal order and causality. However, only conscious temporal order processing correlates with clinical symptoms in patients with schizophrenia, suggesting automatic and conscious temporal processes are dissociable. The conscious perception of the temporal structure of events (i.e. their duration and order) has been suggested to be the outcome of cognitive processes in which entire sequences of events would be reconstructed a posteriori from temporal cognitive maps. Within a framework of a 2-staged cognitive model of temporal order processing (automatic extraction of temporal properties followed by construction of an internal representation of temporal structure) we will test neural hypotheses regarding underlying brain structures and neural oscillations. To do so, we will combine multidisciplinary expertise in experimental psychology, fMRI, MEEG, electrophysiology and schizophrenia, in both human and rat populations. Our single trans-methodology paradigm is innovative in contrasting temporal order with automatic duration processing. Our paradigm capitalizes on the classic variable foreperiod paradigm, which measures how duration (provided implicitly by the “hazard function” or explicitly by attentional cues) can be used to anticipate the time of onset of an impending event, thus optimizing processing of that event. The task also makes use of associative learning and conditioning, to examine the automatic vs. conscious extraction of temporal order information. In order to understand how the encoding of event timing leads to a conscious representation of order and duration we will record neural oscillatory activity and explore time-related changes in nested frequency-coupling. This will be conducted in the healthy human brain (M/EEG) and also in rats, which allows deep brain structures and the effect of psychotomimetic drugs to be explored. The paradigm will also be used in studies of patients with schizophrenia (behaviourally and with fMRI and EEG) and in their first-degree siblings. In patients and siblings, we will additionally explore the impact of temporal order on causality judgements, whose perturbation might underlie the clinical symptom of delusions. This will allow us to determine whether impairments in the automatic processing of temporal information represent a vulnerability factor for delusions.
The project will help resolve how the automatic extraction of the temporal structure of events is built into an internal representation of time. Second, uncovering underlying cognitive and neural mechanisms will help identify key processes putatively involved in the emergence of major clinical symptoms in schizophrenia. Our project will thus provide empirical tools to help characterize disorders that impact upon the temporal structure of consciousness itself. More generally, the collaboration between a team specialized in psychiatric research with three multidisciplinary teams in the basic neurosciences will help to renew the understanding of both time processing and the pathophysiology of schizophrenia.