Neural mechanisms of sequential dependence in time perception: the impact of prior task and memory processing.

Our perception and decision-making are susceptible to prior context. Such sequential dependence has been extensively studied in the visual domain, but less is known about its impact on time perception. Moreover, there are ongoing debates about whether these sequential biases occur at the perceptual stage or during subsequent post-perceptual processing. Using functional magnetic resonance imaging, we investigated neural mechanisms underlying temporal sequential dependence and the role of action in time judgments across trials. Participants performed a timing task where they had to remember the duration of green coherent motion and were cued to either actively reproduce its duration or simply view it passively. We found that sequential biases in time perception were only evident when the preceding task involved active duration reproduction. Merely encoding a prior duration without reproduction failed to induce such biases. Neurally, we observed activation in networks associated with timing, such as striato-thalamo-cortical circuits, and performance monitoring networks, particularly when a "Response" trial was anticipated. Importantly, the hippocampus showed sensitivity to these sequential biases, and its activation negatively correlated with the individual's sequential bias following active reproduction trials. These findings highlight the significant role of memory networks in shaping time-related sequential biases at the post-perceptual stages.

Post-COVID breathlessness: a mathematical model of respiratory processing in the brain.

Breathlessness is among the most common post-COVID symptoms. In a considerable number of patients, severe breathlessness cannot be explained by peripheral organ impairment. Recent concepts have described how such persistent breathlessness could arise from dysfunctional processing of respiratory information in the brain. In this paper, we present a first quantitative and testable mathematical model of how processing of respiratory-related signals could lead to breathlessness perception. The model is based on recent theories that the brain holds an adaptive and dynamic internal representation of a respiratory state that is based on previous experiences and comprises gas exchange between environment, lung and tissue cells. Perceived breathlessness reflects the brain's estimate of this respiratory state signaling a potentially hazardous disequilibrium in gas exchange. The internal respiratory state evolves from the respiratory state of the last breath, is updated by a sensory measurement of CO2 concentration, and is dependent on the current activity context. To evaluate our model and thus test the assumed mechanism, we used data from an ongoing rebreathing experiment investigating breathlessness in patients with post-COVID without peripheral organ dysfunction (N = 5) and healthy control participants without complaints after COVID-19 (N = 5). Although the observed breathlessness patterns varied extensively between individual participants in the rebreathing experiment, our model shows good performance in replicating these individual, heterogeneous time courses. The model assumes the same underlying processes in the central nervous system in all individuals, i.e., also between patients and healthy control participants, and we hypothesize that differences in breathlessness are explained by different weighting and thus influence of these processes on the final percept. Our model could thus be applied in future studies to provide insight into where in the processing cascade of respiratory signals a deficit is located that leads to (post-COVID) breathlessness. A potential clinical application could be, e.g., the monitoring of effects of pulmonary rehabilitation on respiratory processing in the brain to improve the therapeutic strategies.

The precuneus as a central node in declarative memory retrieval.

Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.

Individual differences do matter.

The integrative experiment design proposal currently only relates to group results, but downplays individual differences between participants, which may nevertheless be substantial enough to constitute a relevant dimension in the design space. Excluding the individual participant in the integrative design will not solve all problems mentioned in the target article, because averaging results may obscure the underlying mechanisms.

Synchronization between instructor and observer when learning a complex bimanual skill.

While learning from an instructor by watching a 'how-to' video has become common practice, we know surprisingly little about the relation between brain activities in instructor and observers. In this fMRI study we investigated the temporal synchronization between instructor and observers using intersubject correlation in the naturalistic setting of learning to fold origami. Brain activity of the blindfolded instructor during action production was compared to the observers while they viewed the instructor's video-taped actions. We demonstrate for the first time that the BOLD activity in the instructor's and observer's brain are synchronized while observing and learning a manual complex task with the goal of reproducing it. We can rule out that this synchrony originates from visual feedback. Observers exhibiting higher synchrony with the instructor in the ventral premotor cortex, while viewing the video for the first time, were more successful in reproducing the origami afterwards. Furthermore, changes in instructor-observer synchrony across observational learning sessions occur in cerebellar areas, as well as differences in instructor-observer synchrony between learning and the counting folds, our non-learning control. Not only known cerebellar motor production areas show synchrony, shedding new light on the involvement of the cerebellum in action observation and learning.

Short-term synaptic depression can increase the rate of information transfer at a release site.

The release of neurotransmitters from synapses obeys complex and stochastic dynamics. Depending on the recent history of synaptic activation, many synapses depress the probability of releasing more neurotransmitter, which is known as synaptic depression. Our understanding of how synaptic depression affects the information efficacy, however, is limited. Here we propose a mathematically tractable model of both synchronous spike-evoked release and asynchronous release that permits us to quantify the information conveyed by a synapse. The model transits between discrete states of a communication channel, with the present state depending on many past time steps, emulating the gradual depression and exponential recovery of the synapse. Asynchronous and spontaneous releases play a critical role in shaping the information efficacy of the synapse. We prove that depression can enhance both the information rate and the information rate per unit energy expended, provided that synchronous spike-evoked release depresses less (or recovers faster) than asynchronous release. Furthermore, we explore the theoretical implications of short-term synaptic depression adapting on longer time scales, as part of the phenomenon of metaplasticity. In particular, we show that a synapse can adjust its energy expenditure by changing the dynamics of short-term synaptic depression without affecting the net information conveyed by each successful release. Moreover, the optimal input spike rate is independent of the amplitude or time constant of synaptic depression. We analyze the information efficacy of three types of synapses for which the short-term dynamics of both synchronous and asynchronous release have been experimentally measured. In hippocampal autaptic synapses, the persistence of asynchronous release during depression cannot compensate for the reduction of synchronous release, so that the rate of information transmission declines with synaptic depression. In the calyx of Held, the information rate per release remains constant despite large variations in the measured asynchronous release rate. Lastly, we show that dopamine, by controlling asynchronous release in corticostriatal synapses, increases the synaptic information efficacy in nucleus accumbens.

Characteristics and mechanism of apogeotropic central positional nystagmus.

Here we characterize persistent apogeotropic type of central positional nystagmus, and compare it with the apogeotropic nystagmus of benign paroxysmal positional vertigo involving the lateral canal. Nystagmus was recorded in 27 patients with apogeotropic type of central positional nystagmus (22 with unilateral and five with diffuse cerebellar lesions) and 20 patients with apogeotropic nystagmus of benign paroxysmal positional vertigo. They were tested while sitting, while supine with the head straight back, and in the right and left ear-down positions. The intensity of spontaneous nystagmus was similar while sitting and supine in apogeotropic type of central positional nystagmus, but greater when supine in apogeotropic nystagmus of benign paroxysmal positional vertigo. In central positional nystagmus, when due to a focal pathology, the lesions mostly overlapped in the vestibulocerebellum (nodulus, uvula, and tonsil). We suggest a mechanism for apogeotropic type of central positional nystagmus based on the location of lesions and a model that uses the velocity-storage mechanism. During both tilt and translation, the otolith organs can relay the same gravito-inertial acceleration signal. This inherent ambiguity can be resolved by a 'tilt-estimator circuit' in which information from the semicircular canals about head rotation is combined with otolith information about linear acceleration through the velocity-storage mechanism. An example of how this mechanism works in normal subjects is the sustained horizontal nystagmus that is produced when a normal subject is rotated at a constant speed around an axis that is tilted away from the true vertical (off-vertical axis rotation). We propose that when the tilt-estimator circuit malfunctions, for example, with lesions in the vestibulocerebellum, the estimate of the direction of gravity is erroneously biased away from true vertical. If the bias is toward the nose, when the head is turned to the side while supine, there will be sustained, unwanted, horizontal positional nystagmus (apogeotropic type of central positional nystagmus) because of an inappropriate feedback signal indicating that the head is rotating when it is not.

Rapid and independent memory formation in the parietal cortex.

Previous evidence indicates that the brain stores memory in two complementary systems, allowing both rapid plasticity and stable representations at different sites. For memory to be established in a long-lasting neocortical store, many learning repetitions are considered necessary after initial encoding into hippocampal circuits. To elucidate the dynamics of hippocampal and neocortical contributions to the early phases of memory formation, we closely followed changes in human functional brain activity while volunteers navigated through two different, initially unknown virtual environments. In one condition, they were able to encode new information continuously about the spatial layout of the maze. In the control condition, no information could be learned because the layout changed constantly. Our results show that the posterior parietal cortex (PPC) encodes memories for spatial locations rapidly, beginning already with the first visit to a location and steadily increasing activity with each additional encounter. Hippocampal activity and connectivity between the PPC and hippocampus, on the other hand, are strongest during initial encoding, and both decline with additional encounters. Importantly, stronger PPC activity related to higher memory-based performance. Compared with the nonlearnable control condition, PPC activity in the learned environment remained elevated after a 24-h interval, indicating a stable change. Our findings reflect the rapid creation of a memory representation in the PPC, which belongs to a recently proposed parietal memory network. The emerging parietal representation is specific for individual episodes of experience, predicts behavior, and remains stable over offline periods, and must therefore hold a mnemonic function.

Synaptic Information Transmission in a Two-State Model of Short-Term Facilitation.

Action potentials (spikes) can trigger the release of a neurotransmitter at chemical synapses between neurons. Such release is uncertain, as it occurs only with a certain probability. Moreover, synaptic release can occur independently of an action potential (asynchronous release) and depends on the history of synaptic activity. We focus here on short-term synaptic facilitation, in which a sequence of action potentials can temporarily increase the release probability of the synapse. In contrast to the phenomenon of short-term depression, quantifying the information transmission in facilitating synapses remains to be done. We find rigorous lower and upper bounds for the rate of information transmission in a model of synaptic facilitation. We treat the synapse as a two-state binary asymmetric channel, in which the arrival of an action potential shifts the synapse to a facilitated state, while in the absence of a spike, the synapse returns to its baseline state. The information bounds are functions of both the asynchronous and synchronous release parameters. If synchronous release facilitates more than asynchronous release, the mutual information rate increases. In contrast, short-term facilitation degrades information transmission when the synchronous release probability is intrinsically high. As synaptic release is energetically expensive, we exploit the information bounds to determine the energy-information trade-off in facilitating synapses. We show that unlike information rate, the energy-normalized information rate is robust with respect to variations in the strength of facilitation.

Functional Organization of Vestibulo-Ocular Responses in Abducens Motoneurons.

Vestibulo-ocular reflexes (VORs) are the dominating contributors to gaze stabilization in all vertebrates. During horizontal head movements, abducens motoneurons form the final element of the reflex arc that integrates visuovestibular inputs into temporally precise motor commands for the lateral rectus eye muscle. Here, we studied a possible differentiation of abducens motoneurons into subtypes by evaluating their morphology, discharge properties, and synaptic pharmacology in semi-intact in vitro preparations of larval Xenopus laevis Extracellular nerve recordings during sinusoidal head motion revealed a continuum of resting rates and activation thresholds during vestibular stimulation. Differences in the sensitivity to changing stimulus frequencies and velocities allowed subdividing abducens motoneurons into two subgroups, one encoding the frequency and velocity of head motion (Group I), and the other precisely encoding angular velocity independent of stimulus frequency (Group II). Computational modeling indicated that Group II motoneurons are the major contributor to actual eye movements over the tested stimulus range. The segregation into two functional subgroups coincides with a differential activation of glutamate receptor subtypes. Vestibular excitatory inputs in Group I motoneurons are mediated predominantly by NMDA receptors and to a lesser extent by AMPA receptors, whereas an AMPA receptor-mediated excitation prevails in Group II motoneurons. Furthermore, glycinergic ipsilateral vestibular inhibitory inputs are activated during the horizontal VOR, whereas the tonic GABAergic inhibition is presumably of extravestibular origin. These findings support the presence of physiologically and pharmacologically distinct functional subgroups of extraocular motoneurons that act in concert to mediate the large dynamic range of extraocular motor commands during gaze stabilization.SIGNIFICANCE STATEMENT Outward-directed gaze-stabilizing eye movements are commanded by abducens motoneurons that combine different sensory inputs including signals from the vestibular system about ongoing head movements (vestibulo-ocular reflex). Using an amphibian model, this study investigates whether different types of abducens motoneurons exist that become active during different types of eye movements. The outcome of this study demonstrates the presence of specific motoneuronal populations with pharmacological profiles that match their response dynamics. The evolutionary conservation of the vestibulo-ocular circuitry makes it likely that a similar motoneuronal organization is also implemented in other vertebrates. Accordingly, the physiological and pharmacological understanding of specific motoneuronal contributions to eye movements might help in designing drug therapies for human eye movement dysfunctions such as abducens nerve palsy.

Fronto-parietal coding of goal-directed actions performed by artificial agents.

With advances in technology, artificial agents such as humanoid robots will soon become a part of our daily lives. For safe and intuitive collaboration, it is important to understand the goals behind their motor actions. In humans, this process is mediated by changes in activity in fronto-parietal brain areas. The extent to which these areas are activated when observing artificial agents indicates the naturalness and easiness of interaction. Previous studies indicated that fronto-parietal activity does not depend on whether the agent is human or artificial. However, it is unknown whether this activity is modulated by observing grasping (self-related action) and pointing actions (other-related action) performed by an artificial agent depending on the action goal. Therefore, we designed an experiment in which subjects observed human and artificial agents perform pointing and grasping actions aimed at two different object categories suggesting different goals. We found a signal increase in the bilateral inferior parietal lobule and the premotor cortex when tool versus food items were pointed to or grasped by both agents, probably reflecting the association of hand actions with the functional use of tools. Our results show that goal attribution engages the fronto-parietal network not only for observing a human but also a robotic agent for both self-related and social actions. The debriefing after the experiment has shown that actions of human-like artificial agents can be perceived as being goal-directed. Therefore, humans will be able to interact with service robots intuitively in various domains such as education, healthcare, public service, and entertainment.

3-D spatial memory and navigation: functions and disorders.

PURPOSE OF REVIEW: The aim of this review is to report on the specialized neuronal systems mediating spatial orientation and navigation discovered in animal experiments. These findings have important implications for the clinical management of patients with vestibular disorders or dementia and for translational research in these fields. RECENT FINDINGS: The following anatomically and functionally separate, but nevertheless cooperative cell types have been characterized: angular head velocity cells and head direction cells, which depend on vestibular input and interact with place cells and grid cells, which represent position and distance. The entire system is thought to encode internal cognitive maps whose spatial data can be utilized for navigation and orientation. Flying and swimming species use spatial orientation and navigation isotropically, i.e., in the earth-horizontal and vertical directions, whereas ground-based species, including humans, perform better in the earth-horizontal plane (anisotropically). Examples of clinical disorders with deficits of spatial orientation and navigation are bilateral peripheral vestibulopathy, mild cognitive impairment, and dementia. SUMMARY: Testing spatial orientation and navigation should become an integral part of routine neurological examinations, especially in the elderly. Also desirable are the further development and standardization of simple and reliable smart phone-based bedside tests to measure these functions in patients.

Information Rate Analysis of a Synaptic Release Site Using a Two-State Model of Short-Term Depression.

Synapses are the communication channels for information transfer between neurons; these are the points at which pulse-like signals are converted into the stochastic release of quantized amounts of chemical neurotransmitter. At many synapses, prior neuronal activity depletes synaptic resources, depressing subsequent responses of both spontaneous and spike-evoked releases. We analytically compute the information transmission rate of a synaptic release site, which we model as a binary asymmetric channel. Short-term depression is incorporated by assigning the channel a memory of depth one. A successful release, whether spike evoked or spontaneous, decreases the probability of a subsequent release; if no release occurs on the following time step, the release probabilities recover back to their default values. We prove that synaptic depression can increase the release site's information rate if spontaneous release is more strongly depressed than spike-evoked release. When depression affects spontaneous and evoked release equally, the information rate must invariably decrease, even when the rate is normalized by the resources used for synaptic transmission. For identical depression levels, we analytically disprove the hypothesis, at least in this simplified model, that synaptic depression serves energy- and information-efficient encoding.

It's not all black and white: visual scene parameters influence optokinetic reflex performance in Xenopus laevis tadpoles.

The maintenance of visual acuity during active and passive body motion is ensured by gaze-stabilizing reflexes that aim at minimizing retinal image slip. For the optokinetic reflex (OKR), large-field visual motion of the surround forms the essential stimulus that activates eye movements. Properties of the moving visual world influence cognitive motion perception and the estimation of visual image velocity. Therefore, the performance of brainstem-mediated visuo-motor behaviors might also depend on image scene characteristics. Employing semi-intact preparations of mid-larval stages of Xenopus laevis tadpoles, we studied the influence of contrast polarity, intensity, contour shape and different motion stimulus patterns on the performance of the OKR and multi-unit optic nerve discharge during motion of a large-field visual scene. At high contrast intensities, the OKR amplitude was significantly larger for visual scenes with a positive contrast (bright dots on a dark background) compared with those with a negative contrast. This effect persisted for luminance-matched pairs of stimuli, and was independent of contour shape. The relative biases of OKR performance along with the independence of the responses from contour shape were closely matched by the optic nerve discharge evoked by the same visual stimuli. However, the multi-unit activity of retinal ganglion cells in response to a small single moving vertical edge was strongly influenced by the light intensity in the vertical neighborhood. This suggests that the underlying mechanism of OKR biases related to contrast polarity directly derives from visual motion-processing properties of the retinal circuitry.

Magnetic vestibular stimulation modulates default mode network fluctuations.

Strong magnetic fields (>1 Tesla) can cause dizziness and it was recently shown that healthy subjects (resting in total darkness) developed a persistent nystagmus even when remaining completely motionless within a MR tomograph. Consequently, it was speculated that this magnetic vestibular stimulation (MVS) might influence fMRI results, as nystagmus is indicative of an imbalance in the vestibular system, potentially influencing other systems via multisensory vestibular interactions. The objective of our study was to investigate whether MVS does indeed modulate BOLD signal fluctuations. We recorded eye movements, as well as, resting-state fMRI of 30 volunteers in darkness at 1.5 T and 3.0 T to answer the question whether MVS modulated parts of the default mode resting-state network (DMN) in accordance with the Lorentz-force model for MVS, while distinguishing this from the known signal increase due to field strength related imaging effects. Our results showed that modulation of the default mode network occurred mainly in areas associated with vestibular and ocular motor function, and was in accordance with the Lorentz-force model, i.e., double than the expected signal scaling due to field strength alone. We discuss the implications of our findings for the interpretation of studies using resting-state fMRI, especially those concerning vestibular research. We conclude that MVS needs to be considered in vestibular research to avoid biased results, but it might also offer the possibility of manipulating network dynamics and may thus help in studying the brain as a dynamical system.

Eye Velocity Gain Fields in MSTd During Optokinetic Stimulation.

Lesion studies argue for an involvement of cortical area dorsal medial superior temporal area (MSTd) in the control of optokinetic response (OKR) eye movements to planar visual stimulation. Neural recordings during OKR suggested that MSTd neurons directly encode stimulus velocity. On the other hand, studies using radial visual flow together with voluntary smooth pursuit eye movements showed that visual motion responses were modulated by eye movement-related signals. Here, we investigated neural responses in MSTd during continuous optokinetic stimulation using an information-theoretic approach for characterizing neural tuning with high resolution. We show that the majority of MSTd neurons exhibit gain-field-like tuning functions rather than directly encoding one variable. Neural responses showed a large diversity of tuning to combinations of retinal and extraretinal input. Eye velocity-related activity was observed prior to the actual eye movements, reflecting an efference copy. The observed tuning functions resembled those emerging in a network model trained to perform summation of 2 population-coded signals. Together, our findings support the hypothesis that MSTd implements the visuomotor transformation from retinal to head-centered stimulus velocity signals for the control of OKR.

Vestibular and cerebellar contribution to gaze optimality.

Patients with chronic bilateral vestibular loss have large gaze variability and experience disturbing oscillopsia, which impacts physical and social functioning, and quality of life. Gaze variability and oscillopsia in these patients are attributed to a deficient vestibulo-ocular reflex, i.e. impaired online feedback motor control. Here, we assessed whether the lack of vestibular input also affects feed-forward motor learning, i.e. the ability to choose optimal movement parameters that minimize variability during active movements such as combined eye-head gaze shifts. A failure to learn from practice and reshape feed-forward motor commands in response to sensory error signals to achieve appropriate movements has been proposed to explain dysmetric gaze shifts in patients with cerebellar ataxia. We, therefore, assessed the differential roles of both sensory vestibular information and the cerebellum in choosing optimal movement kinematics. We have previously shown that, in the course of several gaze shifts, healthy subjects adjust the motor command to minimize endpoint variability also when movements are experimentally altered by an increase in the head moment of inertia. Here, we increased the head inertia in five patients with chronic complete bilateral vestibular loss (aged 45.4±7.1 years, mean±standard deviation), nine patients with cerebellar ataxia (aged 56.7±12.6 years), and 10 healthy control subjects (aged 39.7±6.3 years) while they performed large (75° and 80°) horizontal gaze shifts towards briefly flashed targets in darkness and, using our previous optimal control model, compared their gaze shift parameters to the expected optimal movements with increased head inertia. Patients with chronic bilateral vestibular loss failed to update any of the gaze shift parameters to the new optimum with increased head inertia. Consequently, they displayed highly variable, suboptimal gaze shifts. Patients with cerebellar ataxia updated some movement parameters to serve the minimum variance optimality principle but inaccurately undershot the target leading to an average gaze error of 11.4±2.0°. Thus, vestibulopathy leads to gaze variability not only as a result of deficient online gaze control but also a failure in motor learning because of missing error signals. Patients with cerebellar ataxia in our setting can learn from practice-similar to recent findings in reaching movements-and reshape feed-forward motor commands to decrease variability. However, they compromise optimality with inaccurately short movements. The importance of vestibular information for motor learning implies that patients with incomplete bilateral vestibulopathy, and patients with cerebellar ataxia, should be advised to actively move their head whenever appropriate. This way, sensory error signals can be used to shape the motor command and optimize gaze shifts trial-by-trial.

Downbeat nystagmus: evidence for enhancement of utriculo-ocular pathways by ocular vestibular evoked myogenic potentials?

Downbeat nystagmus (DBN) is caused by an impairment of Purkinje cells in the flocculus. The decreased cerebellar inhibitory input affects otolith pathways. Since ocular and cervical vestibular evoked myogenic potentials (o-/cVEMP) test the otoliths, the VEMP were measured in DBN patients and in controls. Sixteen patients with DBN, 14 cerebellar oculomotor disorder patients without DBN (COMD), and 16 healthy controls were examined with o-/cVEMP. Computational modeling was used to predict VEMP differences between groups. DBN patients had significantly higher oVEMP peak-to-peak (PP) amplitudes than COMD patients without DBN and controls. Cervical VEMP did not differ. The computational model of DBN predicted a twofold oVEMP increase for DBN patients. These findings suggest an enhancement of the utriculo-ocular response. The unchanged cVEMP indicate no effect on the otolith-cervical reflex in DBN. Computational modeling suggests that the utriculo-ocular enhancement is caused by an impaired vertical neural integrator resulting in the increased influence of utricular signals. This also explains the gravitational dependence of DBN.