Catecholamines alter the intrinsic variability of cortical population activity and perception

Abstract

The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of “scale-free” population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation–inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders.

Cerebral blood flow predicts differential neurotransmitter activity

“…With the additionally demonstrated excellent test-retest reliability of obtained CBF to receptor density profiles, these findings further strengthen the value of CBF as a promising tool for drug development and disease evaluation. Our findings and other recent research demonstrate that a combination of pharmacological modulations with neurophysiological read-outs can provide novel insight into specific mechanisms of brain function 50 , 51 . Overall, this research shows that the combination of both techniques may provide a unique cross-species translational approach for studying local and remote neurophysiological and neurometabolic effects associated with modulation of specific neurotransmitter systems.…”

Long-Range Temporal Correlations in Alpha Oscillations Stabilize Perception of Ambiguous Visual Stimuli

“…This was supported, in the same study, by pharmacological modulation showing that potentiation of the catecholaminergic system leads to increased LRTC both during eyes-open rest and during a structure-from-motion task. Surprisingly, Pfeffer et al ( 2018 ) reported an increase in the number of perceptual switches when pharmacologically increasing LRTC of alpha oscillations in occipital and parietal regions, which is unexpected in view of the negative association that we report here for the within-subject relationship between LRTC and perceptual switches. It is likely that the pharmacological manipulation in Pfeffer et al ( 2018 ) affects aspects of neuronal dynamics other than LRTC in a different manner from our study, resulting in the observed discrepancy.…”

“…Surprisingly, Pfeffer et al ( 2018 ) reported an increase in the number of perceptual switches when pharmacologically increasing LRTC of alpha oscillations in occipital and parietal regions, which is unexpected in view of the negative association that we report here for the within-subject relationship between LRTC and perceptual switches. It is likely that the pharmacological manipulation in Pfeffer et al ( 2018 ) affects aspects of neuronal dynamics other than LRTC in a different manner from our study, resulting in the observed discrepancy. It is known that activity in the locus-coeruleus norepinephrine system is related to the level of arousal (Rajkowski et al, 1994 ; Aston-Jones et al, 2007 ).…”

“…Also, atomoxetine may affect differentially the interaction between neuronal populations coding for competing percepts. Notably, while atomoxetine administration is not followed by changes in alpha power during the SFM task (Pfeffer et al, 2018 ), in our study, alpha power increases significantly between the Neutral and the Hold condition. Still, we expect that in the cortical state with LRTC elevated by means of atomoxetine, the same results as in our study should hold: subjects with higher LRTC should experience more stable percepts, and regulation of the number of switches due to task requirements should be accompanied by changes in LRTC.…”

“…Computational modeling has shown that LRTC can emerge from a balance between excitatory and inhibitory connectivity in neuronal networks producing oscillations (Poil et al, 2012 ). Recent extensions to this model have shown that neuromodulation can dynamically regulate LRTC presumably by shifting the excitation/inhibition balance (Pfeffer et al, 2018 ). This was supported, in the same study, by pharmacological modulation showing that potentiation of the catecholaminergic system leads to increased LRTC both during eyes-open rest and during a structure-from-motion task.…”