Sensation and expectation are embedded in mouse motor cortical activity.

During behavior, the motor cortex sends copies of motor-related signals to sensory cortices. Here, we combine closed-loop behavior with large-scale physiology, projection-pattern-specific recordings, and circuit perturbations to show that neurons in mouse secondary motor cortex (M2) encode sensation and are influenced by expectation. When a movement unexpectedly produces a sound, M2 becomes dominated by sound-evoked activity. Sound responses in M2 are inherited partially from the auditory cortex and are routed back to the auditory cortex, providing a path for the reciprocal exchange of sensory-motor information during behavior. When the acoustic consequences of a movement become predictable, M2 responses to self-generated sounds are selectively gated off. These changes in single-cell responses are reflected in population dynamics, which are influenced by both sensation and expectation. Together, these findings reveal the embedding of sensory and expectation signals in motor cortical activity.

Developmentally Unique Cerebellar Processing Prioritizes Self- over Other-Generated Movements.

Animals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self-generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) 8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses with twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.

Pre-saccadic shifts of attention in individuals diagnosed with schizophrenia.

INTRODUCTION: Pathophysiological theories of schizophrenia (SZ) symptoms posit an abnormality in using predictions to guide behavior. One such prediction is based on imminent movements, via corollary discharge signals (CD) that relay information about planned movement kinematics to sensory brain regions. Empirical evidence suggests a reduced influence of sensorimotor predictions in individuals with SZ within multiple sensory systems, including in the visual system. One function of CD in the visual system is to selectively enhance visual sensitivity at the location of planned eye movements (pre-saccadic attention), thus enabling a prediction of the to-be-foveated stimulus. We expected pre-saccadic attention shifts to be less pronounced in individuals with SZ than in healthy controls (HC), resulting in unexpected sensory consequences of eye movements, which may relate to symptoms than can be explained in the context of altered allocation of attention. METHODS: We examined this question by testing 30 SZ and 30 HC on a pre-saccadic attention task. On each trial participants made a saccade to a cued location in an array of four stimuli. A discrimination target that was either congruent or incongruent with the cued location was briefly presented after the cue, during saccade preparation. Pre-saccadic attention was quantified by comparing accuracy on congruent trials to incongruent trials within the interval preceding the saccade. RESULTS: Although SZs were less accurate overall, the magnitude of the pre-saccadic attention effect generally did not differ across groups nor show a convincing relationship with symptom severity. We did, however, observe that SZ had reduced pre-saccadic attention effects when the discrimination target (probe) was presented at early stages of saccade planning, when pre-saccadic attention effects first emerged in HC. CONCLUSION: These findings suggest generally intact pre-saccadic shifts of attention in SZ, albeit slightly delayed. Results contribute to our understanding of altered sensory predictions in people with schizophrenia.

Organization of an ascending circuit that conveys flight motor state in Drosophila.

Natural behaviors are a coordinated symphony of motor acts that drive reafferent (self-induced) sensory activation. Individual sensors cannot disambiguate exafferent (externally induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to carry out adaptive behaviors through corollary discharge circuits (CDCs), which provide predictive motor signals from motor pathways to sensory processing and other motor pathways. Yet, how CDCs comprehensively integrate into the nervous system remains unexplored. Here, we use connectomics, neuroanatomical, physiological, and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs) in Drosophila, which function as a predictive CDC in other insects. Both AHN pairs receive input primarily from a partially overlapping population of descending neurons, especially from DNg02, which controls wing motor output. Using Ca2+ imaging and behavioral recordings, we show that AHN activation is correlated to flight behavior and precedes wing motion. Optogenetic activation of DNg02 is sufficient to activate AHNs, indicating that AHNs are activated by descending commands in advance of behavior and not as a consequence of sensory input. Downstream, each AHN pair targets predominantly non-overlapping networks, including those that process visual, auditory, and mechanosensory information, as well as networks controlling wing, haltere, and leg sensorimotor control. These results support the conclusion that the AHNs provide a predictive motor signal about wing motor state to mostly non-overlapping sensory and motor networks. Future work will determine how AHN signaling is driven by other descending neurons and interpreted by AHN downstream targets to maintain adaptive sensorimotor performance.

Presynaptic inhibition selectively suppresses leg proprioception in behaving Drosophila.

The sense of proprioception is mediated by internal mechanosensory neurons that detect joint position and movement. To support a diverse range of functions, from stabilizing posture to coordinating movements, proprioceptive feedback to limb motor control circuits must be tuned in a context-dependent manner. How proprioceptive feedback signals are tuned to match behavioral demands remains poorly understood. Using calcium imaging in behaving Drosophila, we find that the axons of position-encoding leg proprioceptors are active across behaviors, whereas the axons of movement-encoding leg proprioceptors are suppressed during walking and grooming. Using connectomics, we identify a specific class of interneurons that provide GABAergic presynaptic inhibition to the axons of movement-encoding proprioceptors. These interneurons are active during self-generated but not passive leg movements and receive input from descending neurons, suggesting they are driven by predictions of leg movement originating in the brain. Predictively suppressing expected proprioceptive feedback provides a mechanism to attenuate reflexes that would otherwise interfere with voluntary movement.

Bridging phenomenology and neural mechanisms of inner speech: ALE meta-analysis on egocentricity and spontaneity in a dual-mechanistic framework.

The neural mechanisms of inner speech remain unclear despite its importance in a variety of cognitive processes and its implication in aberrant perceptions such as auditory verbal hallucinations. Previous research has proposed a corollary discharge model in which inner speech is a truncated form of overt speech, relying on speech production-related regions (e.g. left inferior frontal gyrus). This model does not fully capture the diverse phenomenology of inner speech and recent research suggesting alternative perception-related mechanisms of generation. Therefore, we present and test a framework in which inner speech can be generated by two separate mechanisms, depending on its phenomenological qualities: a corollary discharge mechanism relying on speech production regions and a perceptual simulation mechanism within speech perceptual regions. The results of the activation likelihood estimation meta-analysis examining inner speech studies support the idea that varieties of inner speech recruit different neural mechanisms.

The perceptual consequences and neurophysiology of eye blinks.

A hand passing in front of a camera produces a large and obvious disruption of a video. Yet the closure of the eyelid during a blink, which lasts for hundreds of milliseconds and occurs thousands of times per day, typically goes unnoticed. What are the neural mechanisms that mediate our uninterrupted visual experience despite frequent occlusion of the eyes? Here, we review the existing literature on the neurophysiology, perceptual consequences, and behavioral dynamics of blinks. We begin by detailing the kinematics of the eyelid that define a blink. We next discuss the ways in which blinks alter visual function by occluding the pupil, decreasing visual sensitivity, and moving the eyes. Then, to anchor our understanding, we review the similarities between blinks and other actions that lead to reductions in visual sensitivity, such as saccadic eye movements. The similarity between these two actions has led to suggestions that they share a common neural substrate. We consider the extent of overlap in their neural circuits and go on to explain how recent findings regarding saccade suppression cast doubt on the strong version of the shared mechanism hypothesis. We also evaluate alternative explanations of how blink-related processes modulate neural activity to maintain visual stability: a reverberating corticothalamic loop to maintain information in the face of lid closure; and a suppression of visual transients related to lid closure. Next, we survey the many areas throughout the brain that contribute to the execution of, regulation of, or response to blinks. Regardless of the underlying mechanisms, blinks drastically attenuate our visual abilities, yet these perturbations fail to reach awareness. We conclude by outlining opportunities for future work to better understand how the brain maintains visual perception in the face of eye blinks. Future work will likely benefit from incorporating theories of perceptual stability, neurophysiology, and novel behavior paradigms to address issues central to our understanding of natural visual behavior and for the clinical rehabilitation of active vision.

Internal models of self-motion: neural computations by the vestibular cerebellum.

The vestibular cerebellum plays an essential role in maintaining our balance and ensuring perceptual stability during activities of daily living. Here I examine three key regions of the vestibular cerebellum: the floccular lobe, anterior vermis (lobules I-V), and nodulus and ventral uvula (lobules X-IX of the posterior vermis). These cerebellar regions encode vestibular information and combine it with extravestibular signals to create internal models of eye, head, and body movements, as well as their spatial orientation with respect to gravity. To account for changes in the external environment and/or biomechanics during self-motion, the neural mechanisms underlying these computations are continually updated to ensure accurate motor behavior. To date, studies on the vestibular cerebellum have predominately focused on passive vestibular stimulation, whereas in actuality most stimulation is the result of voluntary movement. Accordingly, I also consider recent research exploring these computations during active self-motion and emerging evidence establishing the cerebellum's role in building predictive models of self-generated movement.

Vestibular motor control.

The vestibular system is an essential sensory system that generates motor reflexes that are crucial for our daily activities, including stabilizing the visual axis of gaze and maintaining head and body posture. In addition, the vestibular system provides us with our sense of movement and orientation relative to space and serves a vital role in ensuring accurate voluntary behaviors. Neurophysiological studies have provided fundamental insights into the functional circuitry of vestibular motor pathways. A unique feature of the vestibular system compared to other sensory systems is that the same central neurons that receive direct input from the afferents of the vestibular component of the 8th nerve can also directly project to motor centers that control vital vestibular motor reflexes. In turn, these reflexes ensure stabilize gaze and the maintenance of posture during everyday activities. For instance, a direct three-neuron pathway mediates the vestibulo-ocular reflex (VOR) pathway to provide stable gaze. Furthermore, recent studies have advanced our understanding of the computations performed by the cerebellum and cortex required for motor learning, compensation, and voluntary movement and navigation. Together, these findings have provided new insights into how the brain ensures accurate self-movement during our everyday activities and have also advanced our knowledge of the neurobiological mechanisms underlying disorders of vestibular processing.

Bayesian and Discriminative Models for Active Visual Perception across Saccades.

The brain interprets sensory inputs to guide behavior, but behavior itself disrupts sensory inputs. Perceiving a coherent world while acting in it constitutes active perception. For example, saccadic eye movements displace visual images on the retina and yet the brain perceives visual stability. Because this percept of visual stability has been shown to be influenced by prior expectations, we tested the hypothesis that it is Bayesian. The key prediction was that priors would be used more as sensory uncertainty increases. Humans and rhesus macaques reported whether an image moved during saccades. We manipulated both prior expectations and levels of sensory uncertainty. All psychophysical data were compared with the predictions of Bayesian ideal observer models. We found that humans were Bayesian for continuous judgments. For categorical judgments, however, they were anti-Bayesian: they used their priors less with greater uncertainty. We studied this categorical result further in macaques. The animals' judgments were similarly anti-Bayesian for sensory uncertainty caused by external, image noise, but Bayesian for uncertainty due to internal, motor-driven noise. A discriminative learning model explained the anti-Bayesian effects. We conclude that active vision uses both Bayesian and discriminative models depending on task requirements (continuous vs categorical) and the source of uncertainty (image noise vs motor-driven noise). In the context of previous knowledge about the saccadic system, our results provide an example of how the comparative analysis of Bayesian versus non-Bayesian models of perception offers novel insights into underlying neural organization.

Hormonal coordination of motor output and internal prediction of sensory consequences in an electric fish.

Steroid hormones remodel neural networks to induce seasonal or developmental changes in behavior. Hormonal changes in behavior likely require coordinated changes in sensorimotor integration. Here, we investigate hormonal effects on a predictive motor signal, termed corollary discharge, that modulates sensory processing in weakly electric mormyrid fish. In the electrosensory pathway mediating communication behavior, inhibition activated by a corollary discharge blocks sensory responses to self-generated electric pulses, allowing the downstream circuit to selectively analyze communication signals from nearby fish. These pulses are elongated by increasing testosterone levels in males during the breeding season. We induced electric-pulse elongation using testosterone treatment and found that the timing of electroreceptor responses to self-generated pulses was delayed as electric-pulse duration increased. Simultaneous recordings from an electrosensory nucleus and electromotor neurons revealed that the timing of corollary discharge inhibition was delayed and elongated by testosterone. Furthermore, this shift in the timing of corollary discharge inhibition was precisely matched to the shift in timing of receptor responses to self-generated pulses. We then asked whether the shift in inhibition timing was caused by direct action of testosterone on the corollary discharge circuit or by plasticity acting on the circuit in response to altered sensory feedback. We surgically silenced the electric organ of fish and found similar hormonal modulation of corollary discharge timing between intact and silent fish, suggesting that sensory feedback was not required for this shift. Our findings demonstrate that testosterone directly regulates motor output and internal prediction of the resulting sensory consequences in a coordinated manner.

Organization of an Ascending Circuit that Conveys Flight Motor State.

Natural behaviors are a coordinated symphony of motor acts which drive self-induced or reafferent sensory activation. Single sensors only signal presence and magnitude of a sensory cue; they cannot disambiguate exafferent (externally-induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to make appropriate decisions and initiate adaptive behavioral outcomes. This is mediated by predictive motor signaling mechanisms, which emanate from motor control pathways to sensory processing pathways, but how predictive motor signaling circuits function at the cellular and synaptic level is poorly understood. We use a variety of techniques, including connectomics from both male and female electron microscopy volumes, transcriptomics, neuroanatomical, physiological and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs), which putatively provide predictive motor signals to several sensory and motor neuropil. Both AHN pairs receive input primarily from an overlapping population of descending neurons, many of which drive wing motor output. The two AHN pairs target almost exclusively non-overlapping downstream neural networks including those that process visual, auditory and mechanosensory information as well as networks coordinating wing, haltere, and leg motor output. These results support the conclusion that the AHN pairs multi-task, integrating a large amount of common input, then tile their output in the brain, providing predictive motor signals to non-overlapping sensory networks affecting motor control both directly and indirectly.

An internal model for canceling self-generated sensory input in freely behaving electric fish.

Internal models that predict the sensory consequences of motor actions are vital for sensory, motor, and cognitive functions. However, the relationship between motor action and sensory input is complex, often varying from one moment to another depending on the state of the animal and the environment. The neural mechanisms for generating predictions under such challenging, real-world conditions remain largely unknown. Using novel methods for underwater neural recording, a quantitative analysis of unconstrained behavior, and computational modeling, we provide evidence for an unexpectedly sophisticated internal model at the first stage of active electrosensory processing in mormyrid fish. Closed-loop manipulations reveal that electrosensory lobe neurons are capable of simultaneously learning and storing multiple predictions of the sensory consequences of motor commands specific to different sensory states. These results provide mechanistic insights into how internal motor signals and information about the sensory environment are combined within a cerebellum-like circuitry to predict the sensory consequences of natural behavior.

Moving without sensory feedback: online TMS over the dorsal premotor cortex impairs motor performance during ischemic nerve block.

The study investigates the role of dorsal premotor cortex (PMd) in generating predicted sensory consequences of movements, i.e. corollary discharges. In 2 different sessions, we disrupted PMd and parietal hand's multisensory integration site (control area) with transcranial magnetic stimulation (TMS) during a finger-sequence-tapping motor task. In this TMS sham-controlled design, the task was performed with normal sensory feedback and during upper-limb ischemic nerve block (INB), in a time-window where participants moved without somatosensation. Errors and movement timing (objective measures) and ratings about movement perception (subjective measures) were collected. We found that INB overall worsens objective and subjective measures, but crucially in the PMd session, the absence of somatosensation together with TMS disruption induced more errors, less synchronized movements, and increased subjective difficulty ratings as compared with the parietal control session (despite a carryover effect between real and sham stimulation to be addressed in future studies). Contrarily, after parietal area interference session, when sensory information is already missing due to INB, motor performance was not aggravated. Altogether these findings suggest that the loss of actual (through INB) and predicted (through PMd disruption) somatosensory feedback degraded motor performance and perception, highlighting the crucial role of PMd in generating corollary discharge.

Neurodevelopmental Antecedents and Sensory Phenomena in Obsessive Compulsive Disorder: A Systematic Review Supporting a Phenomenological-Developmental Model.

BACKGROUND: The majority of models on obsessive compulsive disorder (OCD) endorse a top-down perspective on the cognitive mechanisms underlying OCD functioning and maintenance, whereas a bottom-up perspective is rarely pursued. OBJECTIVES: The aim of the study was to review the empirical literature on sensory phenomena (SP) and neurodevelopmental antecedents of OCD, which could support the conceptualization of an alternative, bottom-up perspective integrating neurodevelopmental and phenomenological levels of analysis on OCD. METHODS: A systematic review according to PRISMA guidelines was performed in PubMed/MEDLINE, PsycInfo, the Cochrane Library, and Excerpta Medica Database (EMBASE) and focused on SP and "neurodevelopmental antecedents" (operationalized in early risk factors, neuroimaging signs, neurological soft signs, and sensory responsivity). The time interval was from inception up to March 31, 2022. RESULTS: From the search in electronic databases, 48 studies were retained and reviewed. SP are highly prevalent in OCD patients and overrepresented in comparison with healthy controls. Similarly, OCD patients also present a higher prevalence of early environmental adversities and sensorimotor alterations in terms of neurological soft signs and sensory over-responsivity in the tactile and acoustic domains; additional findings included hypogyrification signs at neuroimaging. Both sensorimotor alterations and SP are associated with tic-related manifestations and poorer insight in OCD patients. CONCLUSIONS: On the ground of established common subjective experience of SP and premorbid neurodevelopmental features, we hypothesized an explanatory model for OCD, which considers the possible pathophysiological role for altered corollary discharge and enhanced error detection in the neurodevelopment of SP and obsessions. SP may represent the subjective experiential resonance of an individual history of persistently inaccurate sensory predictions, whereas accompanying manifestations, such as the obsessive need for order and symmetry, may represent a compensatory attempt to mitigate SP. This neurodevelopmental-phenomenological bottom-up model, describing a dimensional gradient of sensorimotor alterations and related subjective experiences, may contribute to explain the dimensional affinity between OCD and schizophrenia spectrum disorders. Furthermore, this model could be useful for the early detection of subjects at higher risk of OCD.

Series en disnea. Parte 3. Mecanismos, copia eferente o descarga corolaria / Series on Dyspnea. Part 3. Mechanisms, efferent copy or corollary discharge

Todas las teorías sobre los mecanismos de generación de disnea tuvieron defensores y detractores e, interesantemente, con el desarrollo de sofisticadas técnicas neurofisiológicas y de imágenes funcionales ha sido posible jerarquizar cada uno de ellos. Todas han sobrevivido al paso del tiempo y ninguna puede explicar por sí sola la disnea en todas las situaciones clínicas, lo cual habla de la naturaleza compleja y multifactorial del fenómeno. El concepto de inadecuación tensión y longitud halló en las últimas décadas un sustento con nuevas evidencias a su favor. En particular, con el hallazgo de las vías involucradas y con la aplicación de conocimientos neurofisiológicos, la teoría de la inadecuación tensión y longitud se vería refinada con la descarga corolaria o copia eferente. Esta descarga corolaria o copia eferente es un atributo básico del sistema nervioso, que se encuentra en el reino animal, desde los invertebrados a los primates y en la especie humana. Este artículo está dedicado a la historia de la copia eferente y su incorporación como hipótesis para explicar la disnea, la más aceptada en la actualidad.

All the theories about the mechanisms of generation of dyspnea had defenders and detractors and, interestingly, with the development of sophisticated neurophysiological techniques and functional imaging, it has been possible to rank each one of them. All have survived the passage of time and none can singularly explain dyspnea in all clini cal situations, showing the complex and multifactorial nature of the phenomenon. The concept of length-tension inappropriateness has found support in recent decades with new evidence in its favor. Specially with the discovery of the pathways involved and with the application of neurophysiological knowledge, the length-tension inappropriate ness theory would be refined with the corollary discharge or efferent copy. This corol lary discharge or efferent copy is a basic attribute of the nervous system found in the animal kingdom, from invertebrates to primates and in the human species. This article is dedicated to the history of the efferent copy and its incorporation as a hypothesis to explain dyspnea, which is currently the most accepted one.

Approach to impaired corollary discharge in patients with schizophrenia: An analysis of self-induced somatosensory evoked potentials and fields.

Background: Difficulty in distinguishing between self-generated actions and those generated by others is a core feature of schizophrenia. This is thought to be underpinned by the failure of corollary discharge. However, few studies have investigated these events using somatosensory evoked potentials (SEPs) and somatosensory evoked magnetic fields (SEFs). Methods: The study included 15 right-handed patients with schizophrenia and 16 healthy controls. SEP and SEF were elicited by electrical stimuli to the left median nerve at intervals of 1-3 s. In the external condition, stimuli were externally induced by a machine. In the self-condition, stimuli were induced by tapping the participants' own right index finger. Peak amplitude at C4' in SEP and root mean square in 10 channels on the right primary somatosensory area in SEF were analyzed. Results: Although there was a significant main effect of condition at N20m, and a significant main effect of condition and group at P30m, no significant interactions of condition and group were found in either N20m or P30m. The post-hoc Wilcoxon signed-rank test revealed that the peak value of P30m in the external condition was significantly higher than that in the self-condition in the healthy control group only. In addition, there was a significant positive correlation between the peak value of P30m in the self-condition and a positive symptom score. Conclusion: In the current study, we did not find abnormalities of corollary discharge in primary sensory areas in patients with schizophrenia. Further investigations with more cases may reveal the possibility of corollary discharge disturbance in the primary sensory cortex.

Consider the pons: bridging the gap on sensory prediction abnormalities in schizophrenia.

A shared mechanism across species heralds the arrival of self-generated sensations, helping the brain to anticipate, and therefore distinguish, self-generated from externally generated sensations. In mammals, this sensory prediction mechanism is supported by communication within a cortico-ponto-cerebellar-thalamo-cortical loop. Schizophrenia is associated with impaired sensory prediction as well as abnormal structural and functional connections between nodes in this circuit. Despite the pons' principal role in relaying and processing sensory information passed from the cortex to cerebellum, few studies have examined pons connectivity in schizophrenia. Here, we first briefly describe how the pons contributes to sensory prediction. We then summarize schizophrenia-related abnormalities in the cortico-ponto-cerebellar-thalamo-cortical loop, emphasizing the dearth of research on the pons relative to thalamic and cerebellar connections. We conclude with recommendations for advancing our understanding of how the pons relates to sensory prediction failures in schizophrenia.

A corollary discharge mediates saccade-related inhibition of single units in mnemonic structures of the human brain.

Despite the critical link between visual exploration and memory, little is known about how neuronal activity in the human mesial temporal lobe (MTL) is modulated by saccades. Here, we characterize saccade-associated neuronal modulations, unit-by-unit, and contrast them to image onset and to occipital lobe neurons. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies saccades, inhibiting/exciting a unique population of broad-/narrow-spiking units, respectively, before and during saccades and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking neuronal activity to event-related potentials (ERPs), which are directionally modulated following saccades, we recontextualize the ERP associated with saccades as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded saccade-related ERP in the human brain.