The Emerging Science of Interoception: Sensing, Integrating, Interpreting, and Regulating Signals within the Self.

Interoception refers to the representation of the internal states of an organism, and includes the processes by which it senses, interprets, integrates, and regulates signals from within itself. This review presents a unified research framework and attempts to offer definitions for key terms to describe the processes involved in interoception. We elaborate on these definitions through illustrative research findings, and provide brief overviews of central aspects of interoception, including the anatomy and function of neural and non-neural pathways, diseases and disorders, manipulations and interventions, and predictive modeling. We conclude with discussions about major research gaps and challenges.

NIH BRAIN Circuits Programs: An Experiment in Supporting Team Neuroscience.

The NIH BRAIN Initiative is aimed at revolutionizing our understanding of the human brain. Here, we present a discussion of support for team research in investigative neuroscience at different stages and on various scales.

The promise of the BRAIN initiative: NIH strategies for understanding neural circuit function.

New neurotechnologies fueled by the BRAIN Initiative now allow investigators to map, monitor and modulate complex neural circuits, enabling the pursuit of research questions previously considered unapproachable. Yet it is the convergence of molecular neuroscience with the new systems neuroscience that promises the greatest future advances. This is particularly true for our understanding of nervous system disorders, some of which have known molecular drivers or pathology but result in unknown perturbations in circuit function. NIH-supported research on "BRAIN Circuits" programs integrate experimental, analytic, and theoretical capabilities for analysis of specific neural circuits and their contributions to perceptions, motivations, and actions. In this review, we describe the BRAIN priority areas, review our strategy for balancing early feasibility with mature projects, and the balance of individual with team science for this 'BRAIN Circuits' program. We also highlight the diverse portfolio of techniques, species, and neural systems represented in these projects.

Tectal etiology for irrepressible saccades: a case study in a Rhesus monkey.

Brain circuits controlling eye movements are widely distributed and complex. The etiology of irrepressible square wave saccades is not fully understood and is likely different for different neuropathologies. In a previous study, spontaneously occurring irrepressible saccades were noted after a cerebrovascular accident that damaged the rostral superior colliculus (SC) and its commissure in a Rhesus monkey. Here, we tracked and quantified the development of similar symptoms in a Rhesus monkey caused by a lesion in the rostromedial SC and its commissure. We documented the changes in these saccadic intrusions while the monkey attempted fixation of a target on three consecutive days post-onset. On the first day, eye jerk amplitude was ~10 degrees and the direction was ~30 degrees above the left horizontal meridian. On the second day, the amplitude decreased to 6.5 degrees and the direction shifted towards vertical, ~20 degrees to the left of the vertical meridian. Size, but not direction, of the eye jerks continued to decrease until intrusions dissipated within one month. Histological examination after ~6 months from the first appearance of the intrusions revealed a lesion in the commissure of the SC. Results from this and the previous study confirm the involvement of the commissure of the SC as the common target for triggering this neuropathy. Our data suggest that commissural fibers play an important role in maintaining normal visual stability. Interrupting the commissure between the two superior colliculi causes saccadic intrusions in the form of irrepressible jerking of the eyes, probably by disrupting inhibitory signals transmitted through the commissure. Furthermore, disappearance of the symptoms suggests that inhibitory fields within the SC are plastic and can expand, possibly via inputs from inter-collicular and nigrotectal pathways.

Saccade trajectories evoked by sequential and colliding stimulation of the monkey superior colliculus.

Using microstimulation we employed an explicit experimental control of activity in the superior colliculus at two sites within the motor map. We compared saccade metrics and dynamics evoked at each site independently with those caused by sequential presentation and collisions of the two stimulation trains. Essentially, we forced controlled spatio-temporal patterns of activity into the saccade control circuit with various timing relationships from known sites within the collicular motor map, thus revealing the spatio-temporal transformation from superior colliculus to eye movement dynamics under experimentally controlled conditions. We extend prior findings about decreasing time intervals between sequential presentations of stimulations to include mid-flight combinations and dynamic modifications of trajectory. We explore how asynchronous collisions between two movements systematically engage a normalization mechanism of movement metrics, and demonstrate how dynamic patterns of activity across the SC motor map can create mid-flight curvature of movement through the post-collicular dynamics of a displacement controller. The explicit control addresses feasibility for systems control models and provides benchmark data for experimental verification of model mechanisms.

Activity of omnipause neurons during "staircase saccades" elicited by persistent microstimulation of the superior colliculus.

We have recorded the activity of omnipause neurons (OPNs) in the raphe interpositus during so-called staircase saccades produced by prolonged activation of the superior colliculus (SC) by microstimulation. By showing that OPNs cyclically pause during the periodic movements produced by the steady activation function, we reveal the functional relationship of the OPNs within the recurrent brainstem network that produces dynamic, closed-loop, and feedback control of saccades. Despite persistent, steady activation of the SC, the OPNs followed the periodic activity of the brainstem burst generator. This reveals a dominant influence of the oscillating brainstem circuit over descending control from the SC.

Irrepressible saccades from a tectal lesion in a Rhesus monkey.

We present a case of spontaneously occurring irrepressible saccades in an experimental Rhesus monkey. Though eye jerks are sometimes associated with cerebellar disease, central demyelination or brainstem lesions, there is little consensus on their neurological mechanisms. From neurological and anatomical investigation we report that these irrepressible saccades were caused by a discrete cerebrovascular accident that involved the rostral superior colliculus along with its commissure, and with minor invasion of periaqueductal gray and adjacent mesencephalic reticular formation. Other suspected structures, like the raphe interpositus, substantia nigra and the cerebellum, were unaffected.

Spectral cancellation of microstimulation artifact for simultaneous neural recording in situ.

A fundamental technical hurdle in systems neurophysiology has been to record the activity of individual neurons in situ while using microstimulation to activate inputs or outputs. Stimulation artifact at the recording electrode has largely limited the usefulness of combined stimulating and recording to using single stimulation pulses (e.g., orthodromic and antidromic activation) or to presenting brief trains of pulses to look for transient responses (e.g., paired-pulse stimulation). Using an adaptive filter, we have developed an on-line method that allows continuous extracellular isolation of individual neuron spikes during sustained experimental microstimulation. We show that the technique accurately and robustly recovers neural spikes from stimulation-corrupted records. Moreover, we demonstrate that the method should generalize to any recording situation where a stereotyped, triggered transient might obscure a neural event.

Reliable real-time spike discrimination during microstimulation.

A fundamental technical hurdle in systems neurophysiology has been to record the activity of individual neurons in situ while using microstimulation to activate inputs or outputs. Stimulation artifact at the recording electrode has largely limited the usefulness of combined stimulating and recording to using single stimulation pulses or to presenting brief trains of pulses to look for transient responses. We have developed an adaptive filter that in real time allows continuous extracellular isolation of individual neural spikes during sustained experimental microstimulation. Using signal detection analysis we now quantifiably demonstrate the reliability of spike recovery from stimulus-corrupted records. Recordings were made from the regular firing of action potentials from the oculomotor or trochlear nuclei of two macaque monkeys while stimulating at a variety of locations. We found that the adaptive filter technique gave a projected error rate of <1 in 10(4) and the detection index, d', was significantly better than two other methods tested: a 4-parameter 'window discriminator' technique and the sample-and-hold technique. This adaptive technique should generalize to any recording situation where a stereotyped, triggered transient might obscure a neural event and will significantly advance our knowledge in areas of electrophysiology where the experimental design requires prolonged microstimulation.

Single-unit recording in the lateral geniculate nucleus of the awake behaving monkey.

In recent years, recording neuronal activity in the awake, behaving primate brain has become established as one of the major tools available to study the neuronal specificity of the initiation and control of various behaviors. Primates have traditionally been used in these studies because of their ability to perform more complex behaviors closely akin to those of humans, a desirable prerequisite since our ultimate aim is to elucidate the neuronal correlates of human behaviors. A wealth of knowledge has accumulated on the sensory and motor systems such as vision, audition, and eye movements. For more demanding behaviors where the main focus has been on attention, recordings in awake primates have begun to yield valuable data on the centers of the brain that are reactive to different attributes of this behavior. As a result, various hypotheses of the origin and distribution of attentional effects have evolved. For instance, visual attentional effects have been described not only in the higher cortical area (V4) but also in areas earlier in the visual pathway which presumably involve a feedback mechanism in the latter region. Here we outline the ways in which we have successfully used these methods to make single-cell recordings in awake macaques to show how certain behavioral paradigms affect neurons of the thalamus (with emphasis on the lateral geniculate nucleus). As we have done with established techniques these methods can be readily adapted to incorporate most behaviors needed to be tested and allow recordings to be made in virtually any part of the brain.