Janusz Rajkowski

Role of locus coeruleus in attention and behavioral flexibility

Previous findings have implicated the noradrenergic locus coeruleus (LC) system in functions along the dimension of arousal or attention. It has remained uncertain what role this system has in attention, or what mechanisms may be involved. We review our recent work examining activity of LC neurons in monkeys performing a visual discrimination task that requires focused attention. Results indicate that LC cells exhibit phasic or tonic modes of activity, that closely correspond to good or poor performance on this task, respectively. A computational model was used to simulate these results. This model predicts that alterations in electrotonic coupling among LC cells may produce the different modes of activity and corresponding differences in performance. This model also indicates that the phasic mode of LC activity may promote focused or selective attention, whereas the tonic mode may produce a state of high behavioral flexibility or scanning attentiveness. The implications of these results for clinical disorders such as attention-deficit hyperactivity disorder, stress disorders, and emotional and affective disorders are discussed.

Locus coeruleus and regulation of behavioral flexibility and attention

Publisher Summary Recent work on the locus coeruleus-norepinephrine (LC-NE) system has led us to hypothesize that it plays a central role in regulating this balance between focused vs. flexible responding, or selective vs. scanning attention. This chapter discusses previous work on the LC system relevant to understanding its role in cognitive activity and attention, and then describes the recent neurophysiology in behaving monkeys and modeling work aimed at understanding the mechanisms by which this neuromodulatory brain system operates, and how it regulates behavior. The present analysis indicates that the LC system could play a role not only in the regulation of attentional stability and responsiveness, but also in disorders of attention. The results indicate that attention deficit-hyperactivity disorder (ADHD) may result, at least in part, from an overly tonic LC mode. That is, ADHD may occur in subjects whose LC neurons exhibit the tonic mode inappropriately in many contexts, and only infrequently transition to the phasic mode.

Phasic Activation of Monkey Locus Ceruleus Neurons by Simple Decisions in a Forced-Choice Task

The noradrenergic locus ceruleus (LC) system has been implicated in several behavioral functions, most notably, response to salient sensory events. Here, we provide new evidence indicating a role in the execution of responses associated with simple decisions. We examined impulse activity of monkey LC neurons during performance of a forced-choice discrimination task. The timing of LC activity more closely tracked behavioral responses than stimulus presentation. LC neurons were phasically activated preceding behavioral responses for both correct and incorrect identifications but were not activated by stimuli that failed to elicit lever responses nor by nontask-related lever movements. We hypothesize that the LC responds to the outcome of task-related decision processes, facilitating their influence on overt behavior. This role of the LC in regulating the behavioral outcome of decisional processes contrasts with more traditional views of LC responses as primarily related to sensory processes.

The Influence of Spike Rate and Stimulus Duration on Noradrenergic Neurons

We model spiking neurons in locus coeruleus (LC), a brain nucleus involved in modulating cognitive performance, and compare with recent experimental data. Extracellular recordings from LC of monkeys performing target detection and selective attention tasks show varying responses dependent on stimuli and performance accuracy. From membrane voltage and ion channel equations, we derive a phase oscillator model for LC neurons. Average spiking probabilities of a pool of cells over many trials are then computed via a probability density formulation. These show that: (1) Post-stimulus response is elevated in populations with lower spike rates; (2) Responses decay exponentially due to noise and variable pre-stimulus spike rates; and (3) Shorter stimuli preferentially cause depressed post-activation spiking. These results allow us to propose mechanisms for the different LC responses observed across behavioral and task conditions, and to make explicit the role of baseline firing rates and the duration of task-related inputs in determining LC response.

Brain Norepinephrine: The locus coeruleus and regulation of behavioral flexibility and attention: clinical implications

It has been proposed that the locus coeruleus (LC) regulates nonspecific arousal and thereby may participate in a wide range of functions. Our work indicates that, while the LC may indeed play an important role in arousal, it has more specific effects on behavior and may regulate cortical mechanisms involved in selective attention and task performance. In one study, we recorded impulse activity of LC neurons in monkeys performing a visual discrimination task. Phasic and tonic firing characteristics of LC neurons varied in close relation to task performance. Phasically, LC neurons were selectively activated by target cues and not by other task events, including behavioral responses. The target-elicited LC responses were limited to periods of good performance, when tonic firing rates were at an intermediate level (∼ 1 to 2 spikes/s). Higher levels of tonic activity were associated with few or no phasic LC responses, and poor task performance. Direct manipulations of LC activity via local microinfusions yielded behavioral results consistent with the above recordings. A computational model was constructed to explore mechanisms that underlie these patterns of LC activity and their relationship to task performance.1 This model revealed that electrotonic coupling among LC neurons can provide a mechanism for regulating the pattern of LC activity between two modes of functioning, which may in turn regulate task performance. In one mode (high electrotonic coupling, resulting in intermediate levels of tonic LC activity and robust phasic responses to task-defined target stimuli), LC responses facilitate the processing of target stimuli while responses to distractors are reduced. In the

Simplified dynamics in a model of noradrenergic modulation of cognitive performance

Neurophysiological work in monkeys has shown that changes in tonic and stimulus-induced activity in the noradrenergic brainstem nucleus locus coeruleus (LC) are tightly correlated with fluctuations in behavioral performance in a visual discrimination task. Simulation work suggests transitions between observed modes of LC activity may be mediated by changes in the level of coherent firing among individual LC neurons. We have simplified this simulation by abstracting the LC to a simple, excitable system in two variables modeled after the FitzHugh-Nagumo relaxation oscillator. This abstracted LC simulates population-level dynamics of the nucleus relevant to its influence on behavior. Coherence within the nucleus was simulated as a single parameter which amplified external input to the abstracted LC while attenuating tonic, uncorrelated activity. Simulated results captured LC dynamics and their relationship with behavior observed in monkeys. Behavior was further simulated over a range of potential LC states not, as yet, directly observed. These results suggest a reverse sigmoidal relationship between false alarm rate and coherence, and a more complex, non-monotonic relationship between response time and coherence.

Optimal Decisions: From Neural Spikes, through Stochastic Differential Equations, to Behavior*This paper is an expanded version of a plenary lecture delivered at the International Symposium on Nonlinear Theory and its Applications (NOLTA2004), Fukuoka, Japan, Nov. 29--Dec. 3, 2004.

There is increasing evidence from in vivo recordings in monkeys trained to respond to stimuli by making left- or rightward eye movements, that firing rates in certain groups of neurons in oculo-motor areas mimic drift-diffusion processes, rising to a (fixed) threshold prior to movement initiation. This supplements earlier observations of psychologists, that human reaction-time and error-rate data can be fitted by random walk and diffusion models, and has renewed interest in optimal decision-making ideas from information theory and statistical decision theory as a clue to neural mechanisms. We review results from decision theory and stochastic ordinary differential equations, and show how they may be extended and applied to derive explicit parameter dependencies in optimal performance that may be tested on human and animal subjects. We then briefly describe a biophysically-based model of a pool of neurons in locus coeruleus, a brainstem nucleus implicated in widespread norepinephrine release. This neurotransmitter can effect transient gain changes in cortical circuits of the type that the abstract drift-diffusion analysis requires. We also describe how optimal gain schedules can be computed in the presence of time-varying noisy signals. We argue that a rational account of how neural spikes give rise to simple behaviors is beginning to emerge.

Role of the Locus Coeruleus-Norepinephrine System in Attention and Behavioral Flexibility

The ability to respond selectively to certain aspects of the environment, and filter-out others that are irrelevant to the current behavioral plan, is critical for goal-directed behavior. At the same time, behavior must be flexible and adaptive, so as to quickly adjust to new imperative, or unexpected events. Thus, successful behavior in both animals and humans requires the capacity for both selective responding in a stable environment, and rapid adaptive responding in a changing environment. Our recent work on the locus coeruleus-norepinephrine (LC-NE) system has led us to hypothesize that it plays a central role in regulating this balance between focused vs. flexible responding.