Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations

Abstract

Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N ϭ 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N ϭ 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations.Key words: catecholamine; dopamine; fMRI; norepinephrine; perception; psychopharmacology IntroductionIn vivo and in vitro cell recordings indicate that the neuromodulators norepinephrine and dopamine increase the responsivity of neurons in target brain areas to both excitatory and inhibitory inputs (Berridge and Waterhouse, 2003; Winterer and Weinberger, 2004). An influential theory of catecholamine function proposes that this property of norepinephrine and dopamine allows them to perform the key computational function of gain regulation, thus tuning neural network dynamics to optimize processing in a given context (Servan-Schreiber et al., 1990;Aston-Jones and Cohen, 2005 Significance StatementNorepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.The Journal of Neuroscience, May 25, 2016 • 36(21):5...

Midfrontal theta and pupil dilation parametrically track subjective conflict (but also surprise) during intertemporal choice

“…For example, changes in pupil responses correspond to changes in locus coeruleus firing rate (Joshi et al, 2016;Murphy et al, 2014;Varazzani et al, 2015), as well as norepinephrine concentrations (Phillips et al, 2000;Warren et al, 2016). Extending recent work (Chmielewski et al, 2017;Dippel et al, 2017;Mückschel et al, 2017), we found that midfrontal theta correlated with pupil dilation responses, suggesting that the mPFC and LC-NE might interact to resolve conflict and respond to surprising events even during choices based on personal preferences.…”

“…Further, enhanced midfrontal theta and pupil responses might reflect dynamic switching between brain networks (Cocchi et al, 2013;Uddin, 2015). For example, past work suggests that pupil responses correlate strongly with LC-NE system activity (Aston-Jones and Cohen, 2005b; Murphy et al, 2014;Rajkowski et al, 1994), and this neuromodulatory system may be involved in resetting networks and optimizing behavior (Bouret and Sara, 2005;Nieuwenhuis et al, 2005;Sara and Bouret, 2012;Urai et al, 2017;Usher et al, 1999;Warren et al, 2016).…”

Global gain modulation generates time-dependent urgency during perceptual choice in humans

“…1) performed the motion discrimination task optimized for measurement of decision-related changes in pupil diameter. We first examined the effect of speed emphasis on unbaselined pupil diameter prior to motion onset, which has previously been used as a proxy for ‘tonic' fluctuations in neural gain4548. Consistent with a static increase in gain under greater speed pressure, this metric was larger in the DL regime than in the FR regime ( t 22 =6.9, P <1 × 10 −6 ; Fig.…”

The accessory stimulus effect is mediated by phasic arousal: A pupillometry study

“…The brainstem nucleus locus coeruleus exhibits a rapid increase in activity in response to salient stimuli, including task-irrelevant intense auditory stimuli (Grant, Aston-Jones, & Redmond, 1988), and the consequent phasic increase in norepinephrine release increases neural gain. In recent research, we have found that norepinephrinemediated increases in gain enhance the precision of cortical perceptual representations (Warren et al, 2016). Several researchers have proposed that the AS effect and related phasic alerting effects are mediated by phasic norepinephrine release (Fernandez-Duque & Posner, 1997;Hackley & Valle-Incl an, 1999.…”