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Downbeat nystagmus (DBN) is a neuro-otological finding frequently encountered by clinicians dealing with patients with vertigo. Since DBN is a finding that should be understood because of central vestibular dysfunction, it is necessary to know how to frame it promptly to suggest the correct diagnostic-therapeutic pathway to the patient. As knowledge of its pathophysiology has progressed, the importance of this clinical sign has been increasingly understood. At the same time, clinical diagnostic knowledge has increased, and it has been recognized that this sign may occur sporadically or in association with others within defined clinical syndromes. Thus, in many cases, different therapeutic solutions have become possible. In our work, we have attempted to systematize current knowledge about the origin of this finding, the clinical presentation and current treatment options, to provide an overview that can be used at different levels, from the general practitioner to the specialist neurologist or neurotologist. [ABSTRACT FROM AUTHOR]

Myoelectric prostheses have recently shown significant promise for restoring hand function in individuals with upper limb loss or deficiencies, driven by advances in machine learning and increasingly accessible bioelectrical signal acquisition devices. Here, we first introduce and validate a novel experimental paradigm using a virtual reality headset equipped with hand-tracking capabilities to facilitate the recordings of synchronized EMG signals and hand pose estimation. Using both the phasic and tonic EMG components of data acquired through the proposed paradigm, we compare hand gesture classification pipelines based on standard signal processing features, convolutional neural networks, and covariance matrices with Riemannian geometry computed from raw or xDAWN-filtered EMG signals. We demonstrate the performance of the latter for gesture classification using EMG signals. We further hypothesize that introducing physiological knowledge in machine learning models will enhance their performances, leading to better myoelectric prosthesis control. We demonstrate the potential of this approach by using the neurophysiological integration of the "move command" to better separate the phasic and tonic components of the EMG signals, significantly improving the performance of sustained posture recognition. These results pave the way for the development of new cutting-edge machine learning techniques, likely refined by neurophysiology, that will further improve the decoding of real-time natural gestures and, ultimately, the control of myoelectric prostheses. [ABSTRACT FROM AUTHOR]

During foraging behavior, action values are persistently encoded in neural activity and updated depending on the history of choice outcomes. What is the neural mechanism for action value maintenance and updating? Here, we explore two contrasting network models: synaptic learning of action value versus neural integration. We show that both models can reproduce extant experimental data, but they yield distinct predictions about the underlying biological neural circuits. In particular, the neural integrator model but not the synaptic model requires that reward signals are mediated by neural pools selective for action alternatives and their projections are aligned with linear attractor axes in the valuation system. We demonstrate experimentally observable neural dynamical signatures and feasible perturbations to differentiate the two contrasting scenarios, suggesting that the synaptic model is a more robust candidate mechanism. Overall, this work provides a modeling framework to guide future experimental research on probabilistic foraging. [ABSTRACT FROM AUTHOR]

Downbeat nystagmus (DBN) is a neuro-otological finding frequently encountered by clinicians dealing with patients with vertigo. Since DBN is a finding that should be understood because of central vestibular dysfunction, it is necessary to know how to frame it promptly to suggest the correct diagnostic-therapeutic pathway to the patient. As knowledge of its pathophysiology has progressed, the importance of this clinical sign has been increasingly understood. At the same time, clinical diagnostic knowledge has increased, and it has been recognized that this sign may occur sporadically or in association with others within defined clinical syndromes. Thus, in many cases, different therapeutic solutions have become possible. In our work, we have attempted to systematize current knowledge about the origin of this finding, the clinical presentation and current treatment options, to provide an overview that can be used at different levels, from the general practitioner to the specialist neurologist or neurotologist.

Myoelectric prostheses have recently shown significant promise for restoring hand function in individuals with upper limb loss or deficiencies, driven by advances in machine learning and increasingly accessible bioelectrical signal acquisition devices. Here, we first introduce and validate a novel experimental paradigm using a virtual reality headset equipped with hand-tracking capabilities to facilitate the recordings of synchronized EMG signals and hand pose estimation. Using both the phasic and tonic EMG components of data acquired through the proposed paradigm, we compare hand gesture classification pipelines based on standard signal processing features, convolutional neural networks, and covariance matrices with Riemannian geometry computed from raw or xDAWN-filtered EMG signals. We demonstrate the performance of the latter for gesture classification using EMG signals. We further hypothesize that introducing physiological knowledge in machine learning models will enhance their performances, leading to better myoelectric prosthesis control. We demonstrate the potential of this approach by using the neurophysiological integration of the “move command" to better separate the phasic and tonic components of the EMG signals, significantly improving the performance of sustained posture recognition. These results pave the way for the development of new cutting-edge machine learning techniques, likely refined by neurophysiology, that will further improve the decoding of real-time natural gestures and, ultimately, the control of myoelectric prostheses.

Abstract Background The oculomotor integrator (OI) in the vertebrate hindbrain transforms eye velocity input into persistent position coding output, which plays a crucial role in retinal image stability. For a mechanistic understanding of the integrator function and eye position control, knowledge about the tuning of the OI and other oculomotor nuclei is needed. Zebrafish are increasingly used to study integrator function and sensorimotor circuits, yet the precise neuronal tuning to motor variables remains uncharacterized. Results Here, we recorded cellular calcium signals while evoking monocular and binocular optokinetic eye movements at different slow-phase eye velocities. Our analysis reveals the anatomical distributions of motoneurons and internuclear neurons in the nucleus abducens as well as those of oculomotor neurons in caudally adjacent hindbrain volumes. Each neuron is tuned to eye position and/or velocity to variable extents and is only activated after surpassing particular eye position and velocity thresholds. While the abducens (rhombomeres 5/6) mainly codes for eye position, in rhombomeres 7/8, a velocity-to-position coding gradient exists along the rostro-caudal axis, which likely corresponds to the oculomotor structures storing velocity and position, and is in agreement with a feedforward mechanism of persistent activity generation. Position encoding neurons are recruited at eye position thresholds distributed across the behaviourally relevant dynamic range, while velocity-encoding neurons have more centred firing thresholds for velocity. In the abducens, neurons coding exclusively for one eye intermingle with neurons coding for both eyes. Many of these binocular neurons are preferentially active during conjugate eye movements and less active during monocular eye movements. This differential recruitment during monocular versus conjugate tasks represents a functional diversification in the final common motor pathway. Conclusions We localized and functionally characterized the repertoire of oculomotor neurons in the zebrafish hindbrain. Our findings provide evidence for a mixed but task-specific binocular code and suggest that generation of persistent activity is organized along the rostro-caudal axis in the hindbrain.

In this brief, a recurrent network was derived for a neural integrator (NI) described by an ordinary differential equation (ODE) that can be solved with fewer computational resources. Subsequently, based on the reduced ODE model, a hardware-oriented recurrent network model was proposed for a NI consisting of asynchronous cellular automaton (CA) neurons. The proposed model, reduced ODE model, and the previously proposed NI model were implemented on a field-programmable gate array. Analysis results suggest that the proposed model consumes fewer hardware resources and lower power than those of the reduced ODE model and the previously proposed NI model. [ABSTRACT FROM AUTHOR]

Cerebellar functions are modulated by cholinergic inputs, the density of which varies among cerebellar regions. Although the prepositus hypoglossi nucleus (PHN), a brainstem structure involved in controlling gaze holding, is known as one of the major sources of these cholinergic inputs, the proportions of cholinergic neurons in PHN projections to distinct cerebellar regions have not been quantitatively analyzed. In this study, we identified PHN neurons projecting to the cerebellum by applying retrograde labeling with dextran‐conjugated Alexa 488 in choline acetyltransferase (ChAT)‐tdTomato transgenic rats and compared the proportion of cholinergic PHN neurons in the PHN projections to four different regions of the cerebellum, namely the flocculus (FL), the uvula and nodulus (UN), lobules III‐V in the vermis (VM), and the hemispheric paramedian lobule and crus 2 (PC). In the PHN, the percentage of cholinergic PHN neurons was lower in the projection to the FL than in the projection to the UN, VM or PC. Preposito‐cerebellar neurons, except for preposito‐FL neurons, included different proportions of cholinergic neurons at different rostrocaudal positions in the PHN. These results suggest that cholinergic PHN neurons project to not only the vestibulocerebellum but also the anterior vermis and posterior hemisphere and that the proportion of cholinergic neurons among projection neurons from the PHN differs depending on cerebellar target areas and the rostro‐caudal regions of the PHN. This study provides insights regarding the involvement of cerebellar cholinergic networks in gaze holding. [ABSTRACT FROM AUTHOR]

Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator – the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits – drifts followed by rapid corrective movements – a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning.

Modern manufacturing and assembly environments are characterized by a high variability in the built process which challenges human–robot cooperation. To reduce the cognitive workload of the operator, the robot should not only be able to learn from experience but also to plan and decide autonomously. Here, we present an approach based on Dynamic Neural Fields that apply brain-like computations to endow a robot with these cognitive functions. A neural integrator is used to model the gradual accumulation of sensory and other evidence as time-varying persistent activity of neural populations. The decision to act is modeled by a competitive dynamics between neural populations linked to different motor behaviors. They receive the persistent activation pattern of the integrators as input. In the first experiment, a robot learns rapidly by observation the sequential order of object transfers between an assistant and an operator to subsequently substitute the assistant in the joint task. The results show that the robot is able to proactively plan the series of handovers in the correct order. In the second experiment, a mobile robot searches at two different workbenches for a specific object to deliver it to an operator. The object may appear at the two locations in a certain time period with independent probabilities unknown to the robot. The trial-by-trial decision under uncertainty is biased by the accumulated evidence of past successes and choices. The choice behavior over a longer period reveals that the robot achieves a high search efficiency in stationary as well as dynamic environments. [ABSTRACT FROM AUTHOR]

Feldman AG, Zhang L. Eye and head movements and vestibulo-ocular reflex in the context of indirect, referent control of motor actions. J Neurophysiol 124: 115-133, 2020. First published June 3, 2020; doi:10.1152/jn.00076.2020.--Conventional explanations of the vestibulo-ocular reflex (VOR) and eye and head movements are revisited by considering two alternative frameworks addressing the question of how the brain controls motor actions. Traditionally, biomechanical and/or computational frameworks reflect the views of several prominent scholars of the past, including Helmholtz and von Holst, who assumed that the brain directly specifies the desired motor outcome and uses efference copy to influence perception. However, empirical studies resulting in the theory of referent control of action and perception (an extension of the equilibrium-point hypothesis) revealed that direct specification of motor outcome is inconsistent with nonlinear properties of motoneurons and with the physical principle that the brain can control motor actions only indirectly, by changing or maintaining the values of neurophysiological parameters that influence, but can remain independent of, biomechanical variables. Some parameters are used to shift the origin (referent) points of spatial frames of reference (FRs) or system of coordinates in which motor actions emerge without being predetermined. Parameters are adjusted until the emergent motor actions meet the task demands. Several physiological parameters and spatial FRs have been identified, supporting the notion of indirect, referent control of movements. Instead of integration of velocity-dependent signals, position-dimensional referent signals underlying head motion can likely be transmitted to motoneurons of extraocular muscles. This would produce compensatory eye movement preventing shifts in gaze during head rotation, even after bilateral destruction of the labyrinths. The referent control framework symbolizes a shift in the paradigm for the understanding of VOR and eye and head movement production. [ABSTRACT FROM AUTHOR]

Background: The oculomotor integrator (OI) in the vertebrate hindbrain transforms eye velocity input into persistent position coding output, which plays a crucial role in retinal image stability. For a mechanistic understanding of the integrator function and eye position control, knowledge about the tuning of the OI and other oculomotor nuclei is needed. Zebrafish are increasingly used to study integrator function and sensorimotor circuits, yet the precise neuronal tuning to motor variables remains uncharacterized. Results: Here, we recorded cellular calcium signals while evoking monocular and binocular optokinetic eye movements at different slow-phase eye velocities. Our analysis reveals the anatomical distributions of motoneurons and internuclear neurons in the nucleus abducens as well as those of oculomotor neurons in caudally adjacent hindbrain volumes. Each neuron is tuned to eye position and/or velocity to variable extents and is only activated after surpassing particular eye position and velocity thresholds. While the abducens (rhombomeres 5/6) mainly codes for eye position, in rhombomeres 7/8, a velocity-to-position coding gradient exists along the rostro-caudal axis, which likely corresponds to the oculomotor structures storing velocity and position, and is in agreement with a feedforward mechanism of persistent activity generation. Position encoding neurons are recruited at eye position thresholds distributed across the behaviourally relevant dynamic range, while velocity-encoding neurons have more centred firing thresholds for velocity. In the abducens, neurons coding exclusively for one eye intermingle with neurons coding for both eyes. Many of these binocular neurons are preferentially active during conjugate eye movements and less active during monocular eye movements. This differential recruitment during monocular versus conjugate tasks represents a functional diversification in the final common motor pathway. Conclusions: We localized and functionally characterized the repertoire of oculomotor neurons in the zebrafish hindbrain. Our findings provide evidence for a mixed but task-specific binocular code and suggest that generation of persistent activity is organized along the rostro-caudal axis in the hindbrain. [ABSTRACT FROM AUTHOR]

Abstract Dystonia is the third most common movement disorder affecting three million people worldwide. Cervical dystonia is the most common form of dystonia. Despite common prevalence the pathophysiology of cervical dystonia is unclear. Traditional view is that basal ganglia is involved in pathophysiology of cervical dystonia, while contemporary theories suggested the role of cerebellum and proprioception in the pathophysiology of cervical dystonia. It was recently proposed that the cervical dystonia is due to malfunctioning of the head neural integrator – the neuron network that normally converts head velocity to position. Most importantly the neural integrator model was inclusive of traditional proposal emphasizing the role of basal ganglia while also accommodating the contemporary view suggesting the involvement of cerebellum and proprioception. It was hypothesized that the head neural integrator malfunction is the result of impairment in cerebellar, basal ganglia, or proprioceptive feedback that converge onto the integrator. The concept of converging input from the basal ganglia, cerebellum, and proprioception to the network participating in head neural integrator explains that abnormality originating anywhere in the network can lead to the identical motor deficits – drifts followed by rapid corrective movements – a signature of neural integrator dysfunction. We tested this hypothesis in an experiment examining simultaneously recorded globus pallidal single-unit activity, synchronized neural activity (local field potential), and electromyography (EMG) measured from the neck muscles during the standard-of-care deep brain stimulation surgery in 12 cervical dystonia patients (24 hemispheres). Physiological data were collected spontaneously or during voluntary shoulder shrug activating the contralateral trapezius muscle. The activity of pallidal neurons during shoulder shrug exponentially decayed with time constants that were comparable to one measured from the pretectal neural integrator and the trapezius electromyography. These results show that evidence of abnormal neural integration is also seen in globus pallidum, and that latter is connected with the neural integrator. Pretectal single neuron responses consistently preceded the muscle activity; while the globus pallidum internus response always lagged behind the muscle activity. Globus pallidum externa had equal proportion of lag and lead neurons. These results suggest globus pallidum receive feedback from the muscles or the efference copy from the integrator or the other source of the feedback. There was bi-hemispheric asymmetry in the pallidal single-unit activity and local field potentials. The asymmetry correlated with degree of lateral head turning in cervical dystonia patients. These results suggest that bihemispheric asymmetry in the feedback leads to asymmetric dysfunction in the neural integrator causing head turning. Highlights • Integrative network of brainstem, cerebellum, and basal ganglia can cause dystonia. • Integration is changing dynamic signal to steady-state discharge. • Discharge property of the basal ganglia output reflect abnormal neural integration. • Basal ganglia abnormality is secondary, due to impaired network feedback. [ABSTRACT FROM AUTHOR]

The ability to interact with our environment requires the brain to transform spatially represented sensory signals into temporally encoded motor commands for appropriate control of the relevant effectors. For visually guided eye movements, or saccades, the superior colliculus (SC) is assumed to be the final stage of spatial representation, and instantaneous control of the movement is achieved through a rate code representation in the lower brain stem. We investigated whether SC activity in nonhuman primates (Macaca mulatta, 2 male and 1 female) also uses a dynamic rate code, in addition to the spatial representation. Noting that the kinematics of amplitude-matched movements exhibit trial-to-trial variability, we regressed instantaneous SC activity with instantaneous eye velocity and found a robust correlation throughout saccade duration. Peak correlation was tightly linked to time of peak velocity, the optimal efferent delay between SC activity and eye velocity was constant at ~12 ms both at onset and during the saccade, and SC neurons with higher firing rates exhibited stronger correlations. Moreover, the strong correlative relationship and constant efferent delay observation were preserved when eye movement profiles were substantially altered by a blink-induced perturbation. These results indicate that the rate code of individual SC neurons can control instantaneous eye velocity and argue against a serial process of spatial-to-temporal transformation. They also motivated us to consider a new framework of saccade control that does not incorporate traditionally accepted elements, such as the comparator and resettable integrator, whose neural correlates have remained elusive. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To evaluate the role of neural integrators (NI) in the oculomotor system. Methods: A literature search was carried out using several electronic databases during the months of June 2014 to March 2015. The following keywords were used to generate focused results: ‘neural integrators’, ‘gaze‐holding’, ‘oculomotor integration’, ‘impaired gaze‐holding’, ‘gaze evoked nystagmus’ and ‘gaze dysfunction’. Further materials were found through searching relevant articles within reference lists. Seventy‐one articles were sourced for this review which analysed animal and human subjects and network models; 45 were studies of humans, 16 studies of primates, three studies of felines and one study from rats and network models. The remaining articles were literature reviews. Results: The horizontal and vertical, including torsional, NI are located logically in the brainstem, nearby their appropriate target extraocular motoneuron nuclei for stable eye position in eccentric position. The nucleus prepositus hypoglossi (NPH) and medial vestibular nuclei (MVN) are closely linked at the caudal pons and dorsal rostral medulla, integrating horizontal conjugate eye movement. The interstitial nucleus of Cajal (INC) integrates vertical and torsional eye movement at the upper midbrain. The integrator time constant is averaged to 25 seconds in human horizontal and animal vertical NI to perform its function. Case reports revealed that dysfunction of horizontal NI also resulted in vertical ocular deviations, indicating some overlap of horizontal and vertical gaze control. Furthermore, pharmacological inactivation of NI exposed a population of inhibitory neurotransmitters that permits its mechanism of action; allowing for smooth conjugate movement. Conclusions: Neural integrators operate to integrate eye velocity and eye position information to provide signals to extraocular motoneurons to attain and maintain a new position. Therefore, NI allow image stabilization during horizontal and vertical eye movements at eccentric positions for comfortable single vision. [ABSTRACT FROM AUTHOR]

Neurons in the prepositus hypoglossi nucleus (PHN), which is involved in controlling horizontal gaze, show distinct firing patterns in response to depolarizing current pulses. Although the firing patterns are commonly used to classify neuron types, whether the classified PHN neurons show differences in voltage response properties when stimulated with various types of current inputs remains unclear. In this study, we investigated the response properties of PHN neurons to various current stimuli using whole-cell recordings in rat brainstem slices. In response to pulse currents, neurons that exhibited oscillatory firing (OSC type) showed greater gain than other types, and neurons with a low firing rate (LFR type) showed strong overshooting firing responses to ramp currents. In response to triangular ramp currents, the late-spiking type and the LFR type showed a marked hysteretic frequency-current relationship. In response to sinusoidal currents, the gain was larger in the OSC type than in the other types, although the gain and phase of all types of neurons were similarly modulated by an increase in the input frequency. These findings suggest that distinct neuron types show distinct response properties, depending on the type of stimulus. These neuron types may represent the functionally different populations in the PHN. [ABSTRACT FROM AUTHOR]

Control of standing posture requires fusion of multiple inputs including visual, vestibular, somatosensory, and other sensors, each having distinct dynamics. The semicircular canals, for example, have a unique high-pass filter response to angular velocity, quickly sensing a step change in head rotational velocity followed by a decay. To stabilize gaze direction despite this decay, the central nervous system supplies a neural "velocity storage" integrator, a filter that extends the angular velocity signal. Similar filtering might contribute temporal dynamics to posture control, as suggested by some state estimation models. However, such filtering has not been tested explicitly. We propose that posture control indeed entails a neural integrator for sensory inputs, and we test its behavior with classic sensory perturbations: a rotating optokinetic stimulus to the visual system and a galvanic vestibular stimulus to the vestibular system. A simple model illustrates how these two inputs and body tilt sensors might produce a postural tilt response in the frontal plane. The model integrates these signals through a direct weighted sum of inputs, with or without an indirect pathway containing a neural integrator. Comparison with experimental data from healthy adult subjects (N = 16) reveals that the direct weighting model alone is insufficient to explain resulting postural transients, as measured by lateral tilt of the trunk. In contrast, the neural integrator, shared by sensory signals, produces the dynamics of both optokinetic and galvanic vestibular responses. These results suggest that posture control may involve both direct and indirect pathways, which filter sensory signals and make them compatible for sensory fusion. NEW & NOTEWORTHY Control of standing posture requires fusion of multiple inputs including visual, vestibular, somatosensory, and other sensors, each having distinct dynamics. We propose that postural control also entails a shared neural integrator. To test this theory, we perturbed standing subjects with classic sensory stimuli (optokinetic and galvanic vestibular stimulation) and found that our proposed shared filter reproduces the dynamics of subjects' postural responses. [ABSTRACT FROM AUTHOR]

Caloric vestibular stimulation (CVS) and galvanic vestibular stimulation (GVS) act primarily on the peripheral vestibular system. Although the electrical current applied during GVS is thought to flow through peripheral vestibular organs, some current may spread into areas within the central nervous system, particularly when the bilateral galvanic vestibular stimulation (bGVS) method is used. According to Alexander's law, the magnitude of nystagmus increases with eccentric gaze movement, due to the function of the neural integrator (NI); thus, if the information for vestibular stimulation corresponds to Alexander's law, the peripheral vestibular organ is stimulated. Therefore, it would appear that if CVS results comply with Alexander's law, and bGVS results do not, the sites stimulated by bGVS are not perfectly located in the peripheral vestibular area. In our experiments on normal human subjects, the magnitude of nystagmus under CVS increased with rising gaze eccentricity in the direction that the magnitude of the nystagmus increases, and this change was found to follow Alexander's law. However, in the case of nystagmus under bGVS, results did not follow Alexander's law. In addition, study of the influences of bGVS at different current intensities on nystagmus magnitude showed that bGVS at 5 mA distorted nystagmus magnitude more than at 3 mA, which suggests bGVS acts not only on the peripheral vestibular nerves, but also on some areas of the central nervous system, particularly the NI. According to our experiments, bGVS directly affects neural integrator function. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nystagmus is a commonly encountered clinical finding both in children and adults. Despite its complexities, a fundamental understanding of the basic etiology and underlying pathophysiology of nystagmus is critical to manage these patients appropriately. Patients and Method: The subset of ocular motility disorders that constitutes true nystagmus is identified and delineated from saccadic intrusions. Once defined, we explore the causes of commonly encountered forms of nystagmus and their clinical features. Results: Three separate mechanisms work to integrate sensory input and calibrate ocular movements: the afferent visual pathway, the neural integrator, and the vestibular system. Specific neuroanatomical pathways and corresponding pathologic changes are reviewed. Conclusion: A basic understanding of the underlying pathophysiology of nystagmus is essential to clinical practice. Three main mechanisms utilize multifactorial sensory input to produce a normally functioning ocular motor system. Both congenital and acquired forms of nystagmus result from pathology within these systems causing insufficient or asymmetric input to the central nervous system. [ABSTRACT FROM AUTHOR]

Visual scan paths exhibit complex, stochastic dynamics. Even during visual fixation, the eye is in constant motion. Fixational drift and tremor are thought to reflect fluctuations in the persistent neural activity of neural integrators in the oculomotor brainstem, which integrate sequences of transient saccadic velocity signals into a short term memory of eye position. Despite intensive research and much progress, the precise mechanisms by which oculomotor posture is maintained remain elusive. Drift exhibits a stochastic statistical profile which has been modelled using random walk formalisms. Tremor is widely dismissed as noise. Here we focus on the dynamical profile of fixational tremor, and argue that tremor may be a signal which usefully reflects the workings of the oculomotor postural control. We identify signatures reminiscent of a certain flavour of transient neurodynamics; toric travelling waves which rotate around a central phase singularity. Spiral waves play an organisational role in dynamical systems at many scales throughout nature, though their potential functional role in brain activity remains a matter of educated speculation. Spiral waves have a repertoire of functionally interesting dynamical properties, including persistence, which suggest that they could in theory contribute to persistent neural activity in the oculomotor postural control system. Whilst speculative, the singularity hypothesis of oculomotor postural control implies testable predictions, and could provide the beginnings of an integrated dynamical framework for eye movements across scales.

Many neural systems can store short-term information in persistently firing neurons. Such persistent activity is believed to be maintained by recurrent feedback among neurons. This hypothesis has been fleshed out in detail for the oculomotor integrator (OI) for which the so-called line attractor network model can explain a large set of observations. Here we show that there is a plethora of such models, distinguished by the relative strength of recurrent excitation and inhibition. In each model, the firing rates of the neurons relax towards the persistent activity states. The dynamics of relaxation can be quite different, however, and depend on the levels of recurrent excitation and inhibition. To identify the correct model, we directly measure these relaxation dynamics by performing optogenetic perturbations in the OI of zebrafish expressing halorhodopsin or channelrhodopsin. We show that instantaneous, inhibitory stimulations of the OI lead to persistent, centripetal eye position changes ipsilateral to the stimulation. Excitatory stimulations similarly cause centripetal eye position changes, yet only contralateral to the stimulation. These results show that the dynamics of the OI are organized around a central attractor state---the null position of the eyes---which stabilizes the system against random perturbations. Our results pose new constraints on the circuit connectivity of the system and provide new insights into the mechanisms underlying persistent activity.

Selection of a model organism creates tension between competing constraints. The recent explosion of modern molecular techniques has revolutionized the analysis of neural systems in organisms that are amenable to genetic techniques. Yet, the non-human primate remains the gold-standard for the analysis of the neural basis of behavior, and as a bridge to the operation of the human brain. The challenge is to generalize across species in a way that exposes the operation of circuits as well as the relationship of circuits to behavior. Eye movements provide an opportunity to cross the bridge from mechanism to behavior through research on diverse species. Here, we review experiments and computational studies on a circuit function called “neural integration” that occurs in the brainstems of larval zebrafish, primates, and species “in between”. We show that analysis of circuit structure using modern molecular and imaging approaches in zebrafish has remarkable explanatory power for details of the responses of integrator neurons in the monkey. The combination of research from the two species has led to a much stronger hypothesis for the implementation of the neural integrator than could have been achieved using either species alone. [ABSTRACT FROM AUTHOR]

The accumulation and storage of information over time, temporal integration, is key to numerous behaviors. Many oculomotor tasks depend on integration of eye-velocity signals to eye-position commands, a transformation achieved by a hindbrain cell group termed the velocity-to-position neural integrator (VPNI). Although the VPNI's coding properties have been well characterized, its mechanism of function remains poorly understood because few links exist between neuronal activity, structure, and genotypic identity. To fill this gap, we used calcium imaging and single-cell electroporation during oculomotor behaviors to map VPNI neural activity in zebrafish onto a hindbrain scaffold consisting of alternating excitatory and inhibitory parasagittal stripes. Three distinct classes of VPNI cells were identified. One glutamatergic class was medially located along a stripe associated with the alx transcription factor; these cells had ipsilateral projections terminating near abducens motoneurons and collateralized extensively within the ipsilateral VPNI in a manner consistent with integration through recurrent excitation. A second glutamatergic class was more laterally located along a stripe associated with transcription factor dbxlb; these glutamatergic cells had contralateral projections collateralizing near abducens motoneurons, consistent with a role in disconjugate eye movements. A third class, immunohistochemically suggested to be GABAergic, was located primarily in the dbxlb stripe and also had contralateral projections terminating near abducens motoneurons; these cells collateralized extensively in the dendritic field of contralateral VPNI neurons, consistent with a role in coordinating activity between functionally opposing populations. This mapping between VPNI activity, structure, and genotype may provide a blueprint for understanding the mechanisms governing temporal integration. [ABSTRACT FROM AUTHOR]

Cervical dystonia is characterized by abnormal posturing of the head, often combined with tremor-like oscillatory head movements. The nature and source of these oscillatory head movements is controversial, so they were quantified to delineate their characteristics and develop a hypothetical model for their genesis. A magnetic search coil system was used to measure head movements in 14 subjects with cervical dystonia. Two distinct types of oscillatory head movements were detected for most subjects, even when they were not clinically evident. One type had a relatively large amplitude and jerky irregular pattern, and the other had smaller amplitude with a more regular and sinusoidal pattern. The kinematic properties of these two types of oscillatory head movements were distinct, although both were often combined in the same subject. Both had features suggestive of a defect in a central neural integrator. The combination of different types of oscillatory head movements in cervical dystonia helps to clarify some of the current debates regarding whether they should be considered as manifestations of dystonia or tremor and provides novel insights into their potential pathogenesis. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Head direction (HD) cells in the rat limbic system fire according to the animal's orientation independently of the animal's environmental location or behavior. These HD cells receive strong inputs from the vestibular system, among other areas, as evidenced by disruption of their directional firing after lesions or inactivation of vestibular inputs. Two brainstem nuclei, the supragenual nucleus (SGN) and nucleus prepositus hypoglossi (NPH), are known to project to the HD network and are thought to be possible relays of vestibular information. Previous work has shown that lesioning the SGN leads to a loss of spatial tuning in downstream HD cells, but the NPH has historically been defined as an oculomotor nuclei and therefore its role in contributing to the HD signal is less clear. Here, we investigated this role by recording HD cells in the anterior thalamus after either neurotoxic or electrolytic lesions of the NPH. There was a total loss of direction-specific firing in anterodorsal thalamus cells in animals with complete NPH lesions. However, many cells were identified that fired in bursts unrelated to the animals' directional heading and were similar to cells seen in previous studies that damaged vestibular associated areas. Some animals with significant but incomplete lesions of the NPH had HD cells that were stable under normal conditions, but were unstable under conditions designed to minimize the use of external cues. These results support the hypothesis that the NPH, beyond its traditional oculomotor function, plays a critical role in conveying vestibular-related information to the HD circuit. [ABSTRACT FROM AUTHOR]

Eye position-sensitive neurons are found in parietooccipital and anterior-inferior temporal cortex. Putative role of these neurons is to facilitate transformation of reference frame from the retina-fixed to world-fixed coordinates and assure precise action. We assessed the nature of ocular motor disorder in a subject who had selective resection of the right anterior-inferior temporal cortex for the treatment of intractable epilepsy from cortical dysplasia. The gaze was stable when the subject was viewing straight-ahead, but centrally directed drifts in the eye position were seen during eccentric horizontal gaze holding. Eye-in-orbit position determined drift velocity and its direction. Conjugate and sinusoidal vertical oscillations were also present. Horizontal drifts and vertical oscillations became prominent and disconjugate in the absence of visual cue. The gaze-holding deficit was consistent with impairment in neural integration, but in the absence of cerebellar and visual deficits. We speculate that brainstem neural integrator might receive cortical feedback regarding world-fixed coordinates. Visual system might calibrate this process. Hence the lesion of the anterior-inferior temporal lobe leads to impairment in the function of neural integrator. Vision might be used to calibrate such feedback, hence the lack of visual cue further impairs the function of the neural integrator leading to worsening of gaze-holding deficits. [ABSTRACT FROM AUTHOR]

Abstract: Saccadic eye movements rapidly shift gaze to the target of interest. Once the eyes reach a given target, the brainstem ocular motor integrator utilizes feedback from various sources to assure steady gaze. One of such sources is cerebellum whose lesion can impair neural integration leading to gaze-evoked nystagmus. The gaze evoked nystagmus is characterized by drifts moving the eyes away from the target and a null position where the drifts are absent. The extent of impairment in the neural integration for two opposite eccentricities might determine the location of the null position. Eye in the orbit position might also determine the location of the null. We report this phenomenon in a patient with Arnold Chiari type 1 malformation who had intermittent esotropia and horizontal gaze-evoked nystagmus with a shift in the null position. During binocular viewing, the null was shifted to the right. During monocular viewing, when the eye under cover drifted nasally (secondary to the esotropia), the null of the gaze-evoked nystagmus reorganized toward the center. We speculate that the output of the neural integrator is altered from the bilateral conflicting eye in the orbit position secondary to the strabismus. This could possibly explain the reorganization of the location of the null position. [Copyright &y& Elsevier]

Visual scan paths exhibit complex, stochastic dynamics. Even during visual fixation, the eye is in constant motion. Fixational drift and tremor are thought to reflect fluctuations in the persistent neural activity of neural integrators in the oculomotor brainstem, which integrate sequences of transient saccadic velocity signals into a short term memory of eye position. Despite intensive research and much progress, the precise mechanisms by which oculomotor posture is maintained remain elusive. Drift exhibits a stochastic statistical profile which has been modeled using random walk formalisms. Tremor is widely dismissed as noise. Here we focus on the dynamical profile of fixational tremor, and argue that tremor may be a signal which usefully reflects the workings of oculomotor postural control. We identify signatures reminiscent of a certain flavor of transient neurodynamics; toric traveling waves which rotate around a central phase singularity. Spiral waves play an organizational role in dynamical systems at many scales throughout nature, though their potential functional role in brain activity remains a matter of educated speculation. Spiral waves have a repertoire of functionally interesting dynamical properties, including persistence, which suggest that they could in theory contribute to persistent neural activity in the oculomotor postural control system. Whilst speculative, the singularity hypothesis of oculomotor postural control implies testable predictions, and could provide the beginnings of an integrated dynamical framework for eye movements across scales. [ABSTRACT FROM AUTHOR]

Many neural systems can store short-term information in persistently firing neurons. Such persistent activity is believed to be maintained by recurrent feedback among neurons. This hypothesis has been fleshed out in detail for the oculomotor integrator (OI) for which the so-called "line attractor" network model can explain a large set of observations. Here we show that there is a plethora of such models, distinguished by the relative strength of recurrent excitation and inhibition. In each model, the firing rates of the neurons relax toward the persistent activity states. The dynamics of relaxation can be quite different, however, and depend on the levels of recurrent excitation and inhibition. To identify the correct model, we directly measure these relaxation dynamics by performing optogenetic perturbations in the OI of zebrafish expressing halorhodopsin or channelrhodopsin. We show that instantaneous, inhibitory stimulations of the OI lead to persistent, centripetal eye position changes ipsilateral to the stimulation. Excitatory stimulations similarly cause centripetal eye position changes, yet only contralateral to the stimulation. These results show that the dynamics of the OI are organized around a central attractor state-the null position of the eyes-which stabilizes the system against random perturbations. Our results pose new constraints on the circuit connectivity of the system and provide new insights into the mechanisms underlying persistent activity. [ABSTRACT FROM AUTHOR]

Subjects performing simple reaction-time tasks can improve reaction times by learning the expected timing of action-imperative stimuli and preparing movements in advance. Success or failure on the previous trial is often an important factor for determining whether a subject will attempt to time the stimulus or wait for it to occur before initiating action. The medial prefrontal cortex (mPFC) has been implicated in enabling the top-down control of action depending on the outcome of the previous trial. Analysis of spike activity from the rat mPFC suggests that neural integration is a key mechanism for adaptive control in precisely timed tasks. We show through simulation that a spiking neural network consisting of coupled neural integrators captures the neural dynamics of the experimentally recorded mPFC. Errors lead to deviations in the normal dynamics of the system, a process that could enable learning from past mistakes. We expand on this coupled integrator network to construct a spiking neural network that performs a reaction-time task by following either a cue-response or timing strategy, and show that it performs the task with similar reaction times as experimental subjects while main-taining the same spiking dynamics as the experimentally recorded mPFC. [ABSTRACT FROM AUTHOR]

Abstract: The paramedian tract (PMT) neurons, a group of neurons associated with eye movement that project into the cerebellar flocculus, are present in or near the medial longitudinal fasciculus (MLF) in the paramedian region of the lower brainstem. A 66-year-old man with multiple sclerosis in whom downbeat nystagmus appeared along with right MLF syndrome due to a unilateral pontomedullary lesion is described. In light of these findings, a possible schema for the vestibular balance control mechanism circuit of the PMT neurons via the flocculus is presented. Damage to the PMT neurons impaired the elective inhibitory control mechanism of the anterior semicircular canal neural pathway by the flocculus. This resulted in the appearance of anterior semicircular canal-dominant vestibular imbalance and the formation of downbeat nystagmus. From the pathogenesis of this vertical vestibular nystagmus, the action of the PMT neurons in the vestibular eye movement neuronal pathway to maintain vestibular balance was conjectured to be as follows. PMT neurons transmit vestibular information from the anterior semicircular canals to the cerebellum, forming a cerebellum/brainstem feedback loop. Vestibular information from that loop is integrated in the cerebellum, inhibiting only the anterior semicircular canal neuronal pathway via the flocculus and controlling vestibular balance. [Copyright &y& Elsevier]

Abstract: Impairment of gaze holding mechanism and gaze-evoked nystagmus (GEN) in the vertical plane due to a focal brain lesion is usually caused by a failure of the vertical neural integrator, which is known to be localized in the interstitial nucleus of the Cajal in the upper midbrain. We report a patient with hemorrhagic stroke involving the paramedian pontine tegmentum who presented with vertical GEN due to a failure of vertical gaze holding mechanism and unilateral internuclear ophthalmoplegia. The possible structure taking a role as a vertical neural integrator in this patient might be the paramedian tract (PMT) neuron. [Copyright &y& Elsevier]

Abstract: In our previous study on the prepositus hypoglossi nucleus (PHN), we found a neuronal subtype exhibiting a specific firing pattern in which the first interspike interval (ISI) was longer than that of the second, designated FIL (first interspike interval long) neurons. In the present study, we explored the ionic mechanisms underlying this firing pattern using whole-cell recordings of rat brainstem slice preparations. In addition to a longer first ISI, FIL neurons showed properties such as increased slow afterhyperpolarization (AHP) of the first spike relative to the second spike. The application of 4-aminopyridine (4-AP) shortened the longer first ISI and reduced the larger AHP of the first spike, but α-dendrotoxin affected neither the ISI nor the AHP. A voltage clamp study revealed that FIL neurons express transient outward currents with slow decay kinetics. When T-type Ca2+ currents alone or T-type Ca2+ plus persistent Na+ currents were blocked, the FIL firing pattern changed to one with transient hyperpolarization and delayed spike generation characteristic of late-spiking neurons. These findings indicate that A-type K+ currents showing slow decay, T-type Ca2+ currents, and persistent Na+ currents all contribute to the specific firing pattern of FIL neurons. [Copyright &y& Elsevier]

Disturbance of vertical saccades is a cardinal feature of progressive supranuclear palsy (PSP). We investigated whether the amplitude and peak velocity (PV) of saccades are affected by the orbital position from which movements start in PSP patients and age-matched control subjects. Subjects made vertical saccades in response to ±5° vertical target jumps with their heads in one of three positions: head 'center,' head pitched forward ∼15°, and head pitched back ∼15°. All patients showed some effect of starting eye position, whether beginning in the upward or downward field of gaze, on saccade amplitude, PV, and net range of movement. Generally, reduction of amplitude and PV were commensurate and bidirectional in the affected hemifield of gaze. Such findings are unlikely to be because of orbital factors and could be explained by varying degrees of involvement of rostral midbrain nuclei in the pathological process. [ABSTRACT FROM AUTHOR]

Abstract: Experimental data indicate that simple motor decisions in vertebrates are preceded by integration of evidence in certain cortical areas, and that the competition between them is resolved in the basal ganglia. While the occurrence of cortical integration is well established, it is not yet clear exactly how the integration occurs. Several models have been proposed, including the race model, the feed forward inhibition (FFI) model and the leaky competing accumulator (LCA) model. In this paper we establish qualitative and quantitative differences between the above mentioned models, with respect to how they are able to initiate the integration process without integrating noise prior to stimulus onset, as well as the models’ ability to terminate the integration after a decision has been made, to ensure the possibility of subsequent decisions. Our results show that the LCA model has advantages over the race model and the FFI model in both respects, leading to shorter decision times and an effective termination process. [Copyright &y& Elsevier]

A neural integrator (NI) is presumed to exist in the oculomotor system to assist in numerous tasks such as maintaining gaze on imaginary targets in the dark. It is shared by all ocular reflexes including the vestibuloocular reflex (VOR). It has been widely accepted that the NI acts as a ldquoperfectrdquo integrator even in the dark with time constants as large as 1950s. However, the NI time constant is often less than ideal and its value can also be dependent on context [W. W. P. Chan and H. L. Galiana, ldquoIntegrator function in the oculomotor system is dependent on sensory context,rdquo J. Neurophysiol., vol. 93, pp. 3709--3717, Feb. 2005.]. In this paper, a nonlinear feedback model is postulated to model the context-dependent properties of the NI. Algorithms are first developed and validated to fit both linear and nonlinear NI models to experimental data in the presence of ocular nystagmus. Preliminary results indicate that even normal subjects can have a nonlinear VOR and NI. [ABSTRACT FROM PUBLISHER]

The prepositus hypoglossi nucleus (PHN) is thought to be a neural structure involved in transforming eye or head velocity signals into eye position signals for horizontal eye movements. In this study, we investigated the relationship between electrophysiological membrane properties and expression patterns of cellular markers for excitatory and inhibitory neurons by whole-cell patch clamp recordings followed by reverse transcription polymerase chain reaction (RT-PCR) analysis in rat brainstem slices. Three types of voltage response properties, namely afterhyperpolarization (AHP), firing pattern, and response to hyperpolarizing current pulses, were characterized in each neuron. Following RT-PCR analysis, we identified PHN neurons as either glutamatergic ( n = 22) or GABAergic ( n = 43), although a small number of cholinergic ( n = 2) and glycinergic neurons ( n = 1) were also identified. Both glutamatergic and GABAergic neurons showed a wide variety of membrane properties; however, we found several characteristic relationships between neuronal type and membrane properties. Most neurons exhibiting (i) AHP without a slow component, (ii) a firing pattern with a delay in the generation of the first spike, (iii) a firing pattern with a transient burst and (iv) a firing pattern with a prolonged initial interspike interval were GABAergic. On the other hand, glutamatergic neurons were primarily characterized by a low firing rate. These results indicate that there is a close relationship between specific electrophysiological membrane properties and expression of chemical markers in some types of glutamatergic and GABAergic PHN neurons. [ABSTRACT FROM AUTHOR]

Alexander’s law (AL) states that the slow-phase velocity of spontaneous nystagmus of peripheral vestibular origin is dependent on horizontal gaze position, with greater velocity when gaze is directed in the fast-phase direction. AL is thought to be a compensatory reaction resulting from adaptive changes in the horizontal ocular motor neural integrator. Until now, only horizontal eye movements have been investigated with respect to AL. Because spontaneous nystagmus usually includes vertical and torsional components, we asked whether horizontal gaze changes would have an effect on the 3D drift of spontaneous nystagmus and, thus, on the vertical/torsional neural integrator. We hypothesized that AL reduces all nystagmus components proportionally. Moreover, we questioned the classical theory of a single bilaterally organized horizontal integrator and searched for nonlinearities of AL implying a network of multiple integrators. Using dual scleral search coils, we measured AL in 17 patients with spontaneous nystagmus. Patients followed a pulsed laser dot at eye level jumping in 5° steps along the horizontal meridian between 25° right and left in otherwise complete darkness. AL was observed in 15 of 17 patients. Whereas individual patients typically showed a change of 3D-drift direction at different horizontal eye positions, the average change in direction was not different from zero. The strength of AL (= rate of change of total velocity with gaze position) correlated with nystagmus slow-phase velocity (Spearman’s rho = 0.5; p < 0.05) and, on average, did not change the 3D nystagmus drift direction. In general, eye velocity did not vary linearly with eye position. Rather, there was a stronger dependence of velocity on horizontal position when subjects looked in the slow-phase direction compared to the fast-phase direction. We conclude that the theory of a simple leak of a single horizontal neural integrator is not sufficient to explain all aspects of AL. [ABSTRACT FROM AUTHOR]

Abstract: Background: A sustained gaze-evoked nystagmus (GEN) is an important ocular finding that may indicate serious neurologic pathology. It is also a finding that can be missed easily during routine extraocular muscle (EOM) testing. This report presents a case that should familiarize the reader with GEN and presents a novel approach to testing EOM function. Case report: The mother of an otherwise healthy 4-year-old girl noted that her daughter’s eyes crossed occasionally, the right lid drooped on one occasion, and she had been having strange headaches. An asymmetric, sustained, gaze-evoked nystagmus was detected using a different approach to EOM testing. Magnetic resonance imaging found a large, brainstem astrocytoma in the cerebellar-pontine angle. Conclusion: EOM function often is overlooked or underperformed but is an important part of the battery of clinical tests to rule out neurologic problems. Most forms of EOM testing will check for muscle palsies but little else. If the time is taken to extend the patient’s gaze to the extreme ends, to attempt to hold the gaze in all 9 positions, and to maintain an accurate speed, the clinician can stand to gain much more information regarding the neurologic system. [Copyright &y& Elsevier]

Albinism effects a surprising manipulation of the visual pathway in which some of the normally uncrossed axons of the temporal retina instead cross at the chiasm. An expected consequence of this misrouting is that subjects with albinism will have difficulty in specifying the targets of saccades. Usually albinos have nystagmus so the stability of their saccadic eye movements is not readily accessible, but some albinos do not have nystagmus. In these subjects it was found that they had frequent saccadic intrusions, the sizes of which were correlated with velocities of steady drifts in fixations ( r = 0.802, P < 0.05). An explanation for the correlation between the amplitudes of the intrusions and the velocities of the drifts is that it is due to a common failure in the development of a saccadic system which is responsible for converting a given retinal displacement into a matching eye movement, with the extent of the failure reflecting the severity of the misrouting. [ABSTRACT FROM AUTHOR]

Abstract: Animals or humans often encounter such situations in which they must choose their behavioral responses to be made in the near or distant future. Such a decision is made through continuous and bidirectional interactions between the environment surrounding the brain and its internal state or dynamical processes. Therefore, decision making may provide a unique field of researches for studying information processing by the brain, a biological system open to information exchanges with the external world. To make a decision, the brain must analyze pieces of information given externally, past experiences in a similar situation, possible behavioral responses, and predicted outcomes of the individual responses. In this article, we review results of recent experimental and theoretical studies of neuronal substrates and computational algorithms for decision processes. [Copyright &y& Elsevier]