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The role of noradrenaline in human perception: from single neuron to whole brain and behavior

Periodic Reporting for period 1 - RoleOfNEinPerception (The role of noradrenaline in human perception: from single neuron to whole brain and behavior)

Reporting period: 2015-06-01 to 2017-05-31

"An identical sensory stimulus might lead to a different chain of neuronal responses and perceptual experience, depending on the behavioral state of the organism and on cognitive factors such as vigilance, attention and intention. Perhaps the most dramatic illustration of this phenomenon is provided by sleep, where perceptual awareness is strikingly ""disconnected"" from the external world. This disconnection, which we all experience every night, remains a major puzzle since it can occur along with robust early neuronal responses to external stimuli, and while we are conscious – but in the form of dreams – that are rarely affected by external stimuli. While cortical electrophysiology and metabolism can be grossly similar across wakefulness (when we are ‘connected’ to the external world) and sleep (when we are largely ‘disconnected’), the neuromodulatory milieu is fundamentally altered. Therefore, we reasoned that neuromodulation might play a key role in determining the neural and perceptual fate of sensory events. In particular, several lines of evidence suggest that noradrenaline (NE) may play a key role in sensory processing, and that its reduced activity throughout sleep may mediate disconnection from the external environment. Thus we hypothesized that even during wakefulness, reducing NE levels will impair sensory perception, i.e. lead to a mild form of “waking sensory disconnection” and conversely, that boosting NE signaling may lead to improved sensory perception. While previous human NE studies focused on high-level cognition including memory, emotion, attention, motivation, decision-making and metacognition, studies investigating the causal role of NE in basic sensory processing are still missing. In the course of this project, we investigated this by pharmacologically and bi-directionally manipulating NE levels in healthy volunteers, while they were performing simple visual detection and discrimination tasks. We measured how reduced or enhanced NE signaling affected behavior, EEG, fMRI, pupil size, as well as peripheral and subjective measures of arousal, thereby taking advantages of the full-range of neuroscientific methods available to study human cognition and brain activity. We found that while reduced NE signaling impaired detection and discrimination abilities and lead to delayed and reduced late neural response, enhanced NE signaling lead to the opposite results. These results establish that NE indeed has a causal role in modulating sensory perception, and its reduced signaling in sleep likely plays a key role in mediating the “sensory disconnection” that we experience throughout sleep. The results have been presented in several conferences and are now summarized in a manuscript entitled “Noradrenaline causally modulates visual perception and late visually-evoked activity”, that we plan to submit within the next month."
During the two-year period of the project we ran and analyzed two experiments – an EEG experiment with 18 subjects, and an fMRI experiment with six subjects. Each subject participated in three different sessions conducted a week apart. In each session we administered Clonidine (to decrease NE signaling), Reboxetine (to boost NE signaling) or Placebo, using a double-blind within-subject design. Subjects performed visual detection and discrimination tasks before and after drug administration while behavior and neural activity (EEG or fMRI) were measured. We found that detection and discrimination abilities and subjective visibility deteriorated with reduced NE signaling and improved with enhanced NE signaling. In addition, the NE manipulation casually affected late visual responses in EEG (around 200ms) and in fMRI (in high-order visual cortex), known to correlate well with perceptual awareness. Taken together, these results establish for the first time that neuromodulation, and noradrenaline in particular, constitutes a crucial enabling factor in linking visual awareness to external world events. These results have been presented in several national and international conferences and are summarized now in a manuscript that will be submitted within the next month.
I addition we have built a setup for combining eye-tracking with human single neuron recordings in epilepsy patients, in order to investigate the relationship between endogenous fluctuations in NE levels (using an established marker of NE levels – the size of the pupil) and responses to sensory stimuli at the level of single neurons, and obtained preliminary results from one patient. We are also in the course of investigating the relationship between endogenous fluctuations in NE levels (measured by the pupil) and behavioral and neural measures during the Placebo session of the abovementioned EEG experiment, with some promising preliminary results.
Finally we also pursued a related research direction that pertains to the same question of the neuronal basis of conscious perception, but from a different angle. There we followed the activity of human medial temporal and frontal neurons during internal switches in the content of conscious perception in the absence of change in the external world. We found a medial fronto-temporal network whose activity precede the internal change in perception by almost two seconds, attesting to its involvement in the process that lead to the formation of the percept. These results are now summarized in a manuscript that was submitted for publication. Results from both projects have been presented in several conferences, workshops and outreach activities.
Noradrenaline has been implicated in high-level cognition including memory, emotion, attention, motivation, decision-making and metacognition, but its role in perception per se has not been investigated. Our results show that NE indeed plays an enabling causal role in basic sensory processing and perceptual awareness. While this is a basic science study with no immediate implications for society, it does shed new light on the mechanisms that underlie sensory awareness and sensory disconnection. As such it might pave the way for improved anesthesia techniques that will reduce cases of intraoperative awareness, and aid in the diagnosis and treatment of patients with disorders of consciousness.