Dysfunctional mode switching between fixation and saccades: collaborative insights into two unusual clinical disorders.

Voluntary rapid eye movements (saccades) redirect the fovea toward objects of visual interest. The saccadic system can be considered as a dual-mode system: in one mode the eye is fixating, in the other it is making a saccade. In this review, we consider two examples of dysfunctional saccades, interrupted saccades in late-onset Tay-Sachs disease and gaze-position dependent opsoclonus after concussion, which fail to properly shift between fixation and saccade modes. Insights and benefits gained from bi-directional collaborative exchange between clinical and basic scientists are emphasized. In the case of interrupted saccades, existing mathematical models were sufficiently detailed to provide support for the cause of interrupted saccades. In the case of gaze-position dependent opsoclonus, existing models could not explain the behavior, but further development provided a reasonable hypothesis for the mechanism underlying the behavior. Collaboration between clinical and basic science is a rich source of progress for developing biologically plausible models and understanding neurological disease. Approaching a clinical problem with a specific hypothesis (model) in mind often prompts new experimental tests and provides insights into basic mechanisms.

Evidence From Parkinson's Disease That the Superior Colliculus Couples Action and Perception.

BACKGROUND: Action and perception should be coordinated for good visual-motor performance. The mechanism coupling action and perception may be a prominence map in the intermediate layer of the superior colliculus that modulates motor and attentional/perceptual processes. This coordination comes with a cost: the misperception that briefly overlapping stimuli are separated in time. Our model predicts that abnormal intermediate layer of the superior colliculus inhibition, such as that arising from increased basal ganglia output, would affect the action and perception coupling, and it would worsen the misperception. OBJECTIVE: To test the prominence map model by measuring reaction times and perceptions in human intermediate layer of the superior colliculus dysfunction. METHODS: We measured the saccadic and perceptual reaction time changes and the percept for different temporal asynchronies between fixation point offset and peripheral target onset in Parkinson's disease (PD). RESULTS: We found that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus prominence map disrupted the normal coupling of action and perception. With increasing temporal asynchronies, the PD perceptual reaction times increased approximately 3 times more than the increase of the saccadic reaction times. Also, PD subjects misperceive small overlaps as gaps for temporal asynchronies up to 3 times longer than controls. The results can be reproduced by an intermediate layer of the superior colliculus rostral-caudal gradient of inhibition. CONCLUSION: These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus couples action and perception through modulation of attention. A dysfunction of this network quantifies abnormal basal ganglia output and could underlie visual deficits, including common, yet poorly understood, misperceptions and visual-motor deficits of PD. © 2019 International Parkinson and Movement Disorder Society.

Suppression and Contrast Normalization in Motion Processing.

Sensory neurons are activated by a range of stimuli to which they are said to be tuned. Usually, they are also suppressed by another set of stimuli that have little effect when presented in isolation. The interactions between preferred and suppressive stimuli are often quite complex and vary across neurons, even within a single area, making it difficult to infer their collective effect on behavioral responses mediated by activity across populations of neurons. Here, we investigated this issue by measuring, in human subjects (three males), the suppressive effect of static masks on the ocular following responses induced by moving stimuli. We found a wide range of effects, which depend in a nonlinear and nonseparable manner on the spatial frequency, contrast, and spatial location of both stimulus and mask. Under some conditions, the presence of the mask can be seen as scaling the contrast of the driving stimulus. Under other conditions, the effect is more complex, involving also a direct scaling of the behavioral response. All of this complexity at the behavioral level can be captured by a simple model in which stimulus and mask interact nonlinearly at two stages, one monocular and one binocular. The nature of the interactions is compatible with those observed at the level of single neurons in primates, usually broadly described as divisive normalization, without having to invoke any scaling mechanism.SIGNIFICANCE STATEMENT The response of sensory neurons to their preferred stimulus is often modulated by stimuli that are not effective when presented alone. Individual neurons can exhibit multiple modulatory effects, with considerable variability across neurons even in a single area. Such diversity has made it difficult to infer the impact of these modulatory mechanisms on behavioral responses. Here, we report the effects of a stationary mask on the reflexive eye movements induced by a moving stimulus. A model with two stages, each incorporating a divisive modulatory mechanism, reproduces our experimental results and suggests that qualitative variability of masking effects in cortical neurons might arise from differences in the extent to which such effects are inherited from earlier stages.

Binocular summation for reflexive eye movements.

Psychophysical studies and our own subjective experience suggest that, in natural viewing conditions (i.e., at medium to high contrasts), monocularly and binocularly viewed scenes appear very similar, with the exception of the improved depth perception provided by stereopsis. This phenomenon is usually described as a lack of binocular summation. We show here that there is an exception to this rule: Ocular following eye movements induced by the sudden motion of a large stimulus, which we recorded from three human subjects, are much larger when both eyes see the moving stimulus, than when only one eye does. We further discovered that this binocular advantage is a function of the interocular correlation between the two monocular images: It is maximal when they are identical, and reduced when the two eyes are presented with different images. This is possible only if the neurons that underlie ocular following are sensitive to binocular disparity.

A Motion-from-Form Mechanism Contributes to Extracting Pattern Motion from Plaids.

Since the discovery of neurons selective for pattern motion direction in primate middle temporal area MT (Albright, 1984; Movshon et al., 1985), the neural computation of this signal has been the subject of intense study. The bulk of this work has explored responses to plaids obtained by summing two drifting sinusoidal gratings. Unfortunately, with these stimuli, many different mechanisms are similarly effective at extracting pattern motion. We devised a new set of stimuli, obtained by summing two random line stimuli with different orientations. This allowed several novel manipulations, including generating plaids that do not contain rigid 2D motion. Importantly, these stimuli do not engage most of the previously proposed mechanisms. We then recorded the ocular following responses that such stimuli induce in human subjects. We found that pattern motion is computed even with stimuli that do not cohere perceptually, including those without rigid motion, and even when the two gratings are presented separately to the two eyes. Moderate temporal and/or spatial separation of the gratings impairs the computation. We show that, of the models proposed so far, only those based on the intersection-of-constraints rule, embedding a motion-from-form mechanism (in which orientation signals are used in the computation of motion direction signals), can account for our results. At least for the eye movements reported here, a motion-from-form mechanism is thus involved in one of the most basic functions of the visual motion system: extracting motion direction from complex scenes. SIGNIFICANCE STATEMENT: Anatomical considerations led to the proposal that visual function is organized in separate processing streams: one (ventral) devoted to form and one (dorsal) devoted to motion. Several experimental results have challenged this view, arguing in favor of a more integrated view of visual processing. Here we add to this body of work, supporting a role for form information even in a function--extracting pattern motion direction from complex scenes--for which decisive evidence for the involvement of form signals has been lacking.

The role of dentate nuclei in human oculomotor control: insights from cerebrotendinous xanthomatosis.

KEY POINTS: A cerebellar dentate nuclei (DN) contribution to volitional oculomotor control has recently been hypothesized but not fully understood. Cerebrotendinous xanthomatosis (CTX) is a rare neurometabolic disease typically characterized by DN damage. In this study, we compared the ocular movement characteristics of two sets of CTX patients, with and without brain MRI evidence of DN involvement, with a set of healthy subjects. Our results suggest that DN participate in voluntary behaviour, such as the execution of antisaccades, and moreover are involved in controlling the precision of the ocular movement. The saccadic abnormalities related to DN involvement were independent of global and regional brain atrophy. Our study confirms the relevant role of DN in voluntary aspects of oculomotion and delineates specific saccadic abnormalities that could be used to detect the involvement of DN in other cerebellar disorders. ABSTRACT: It is well known that the medial cerebellum controls saccadic speed and accuracy. In contrast, the role of the lateral cerebellum (cerebellar hemispheres and dentate nuclei, DN) is less well understood. Cerebrotendinous xanthomatosis (CTX) is a lipid storage disorder due to mutations in CYP27A1, typically characterized by DN damage. CTX thus provides a unique opportunity to study DN in human oculomotor control. We analysed horizontal and vertical visually guided saccades and horizontal antisaccades of 19 CTX patients. Results were related to the presence/absence of DN involvement and compared with those of healthy subjects. To evaluate the contribution of other areas, abnormal saccadic parameters were compared with global and regional brain volumes. CTX patients executed normally accurate saccades with normal main sequence relationships, indicating that the brainstem and medial cerebellar structures were functionally spared. Patients with CTX executed more frequent multistep saccades and directional errors during the antisaccade task than controls. CTX patients with DN damage showed less precise saccades with longer latencies, and more frequent directional errors, usually not followed by corrections, than either controls or patients without DN involvement. These saccadic abnormalities related to DN involvement but were independent of global and regional brain atrophy. We hypothesize that two different cerebellar networks contribute to the metrics of a movement: the medial cerebellar structures determine accuracy, whereas the lateral cerebellar structures control precision. The lateral cerebellum (hemispheres and DN) also participates in modulating goal directed gaze behaviour, by prioritizing volitional over reflexive movements.

Impaired Motor Learning in a Disorder of the Inferior Olive: Is the Cerebellum Confused?

An attractive hypothesis about how the brain learns to keep its motor commands accurate is centered on the idea that the cerebellar cortex associates error signals carried by climbing fibers with simultaneous activity in parallel fibers. Motor learning can be impaired if the error signals are not transmitted, are incorrect, or are misinterpreted by the cerebellar cortex. Learning might also be impaired if the brain is overwhelmed with a sustained barrage of meaningless information unrelated to simultaneously appearing error signals about incorrect performance. We test this concept in subjects with syndrome of oculopalatal tremor (OPT), a rare disease with spontaneous, irregular, roughly pendular oscillations of the eyes thought to reflect an abnormal, synchronous, spontaneous discharge to the cerebellum from the degenerating neurons in the inferior olive. We examined motor learning during a short-term, saccade adaptation paradigm in patients with OPT and found a unique pattern of disturbed adaptation, quite different from the abnormal adaption when the cerebellum is involved directly. Both fast (seconds) and slow (minutes) timescales of learning were impaired. We suggest that the spontaneous, continuous, synchronous output from the inferior olive prevents the cerebellum from receiving the error signals it needs for appropriate motor learning. The important message from this study is that impaired motor adaptation and resultant dysmetria is not the exclusive feature of cerebellar disorders, but it also highlights disorders of the inferior olive and its connections to the cerebellum.

Combining 1-D components to extract pattern information: It is about more than component similarity.

At least under some conditions, plaid stimuli are processed by combining information first extracted in orientation and scale-selective channels. The rules that govern this combination across channels are only partially understood. Although the available data suggests that only components having similar spatial frequency and contrast are combined, the extent to which this holds has not been firmly established. To address this question, we measured, in human subjects, the short-latency reflexive vergence eye movements induced by stereo plaids in which spatial frequency and contrast of the components are independently varied. We found that, although similarity in component spatial frequency and contrast matter, they interact in a nonseparable way. One way in which this relationship might arise is if the internal estimate of contrast is not a faithful representation of stimulus contrast but is instead spatial frequency-dependent (with higher spatial frequencies being boosted). We propose that such weighting might have been put in place by a mechanism that, in an effort of achieve contrast constancy and/or coding efficiency, regulates the gain of detectors in early visual cortex to equalize their long-term average response to natural images.

Vestibulo-ocular reflex suppression during head-fixed saccades reveals gaze feedback control.

Previous experiments have shown that the vestibulo-ocular reflex (VOR) is partially suppressed during large head-free gaze (gaze = eye-in-head + head-in-space) shifts when both the eyes and head are moving actively, on a fixed body, or when the eyes are moving actively and the head passively on a fixed body. We tested, in human subjects, the hypothesis that the VOR is also suppressed during gaze saccades made with en bloc, head and body together, rotations. Subjects made saccades by following a target light. During some trials, the chair rotated so as to move the entire body passively before, during, or after a saccade. The modulation of the VOR was a function of both saccade amplitude and the time of the head perturbation relative to saccade onset. Despite the perturbation, gaze remained accurate. Thus, VOR modulation is similar when gaze changes are programmed for the eyes alone or for the eyes and head moving together. We propose that the brain always programs a change in gaze using feedback based on gaze and head signals, rather than on separate eye and head trajectories.

Action and perception are temporally coupled by a common mechanism that leads to a timing misperception.

We move our eyes to explore the world, but visual areas determining where to look next (action) are different from those determining what we are seeing (perception). Whether, or how, action and perception are temporally coordinated is not known. The preparation time course of an action (e.g., a saccade) has been widely studied with the gap/overlap paradigm with temporal asynchronies (TA) between peripheral target onset and fixation point offset (gap, synchronous, or overlap). However, whether the subjects perceive the gap or overlap, and when they perceive it, has not been studied. We adapted the gap/overlap paradigm to study the temporal coupling of action and perception. Human subjects made saccades to targets with different TAs with respect to fixation point offset and reported whether they perceived the stimuli as separated by a gap or overlapped in time. Both saccadic and perceptual report reaction times changed in the same way as a function of TA. The TA dependencies of the time change for action and perception were very similar, suggesting a common neural substrate. Unexpectedly, in the perceptual task, subjects misperceived lights overlapping by less than ∼100 ms as separated in time (overlap seen as gap). We present an attention-perception model with a map of prominence in the superior colliculus that modulates the stimulus signal's effectiveness in the action and perception pathways. This common source of modulation determines how competition between stimuli is resolved, causes the TA dependence of action and perception to be the same, and causes the misperception.

Terminator disparity contributes to stereo matching for eye movements and perception.

In the context of motion detection, the endings (or terminators) of 1-D features can be detected as 2-D features, affecting the perceived direction of motion of the 1-D features (the barber-pole illusion) and the direction of tracking eye movements. In the realm of binocular disparity processing, an equivalent role for the disparity of terminators has not been established. Here we explore the stereo analogy of the barber-pole stimulus, applying disparity to a 1-D noise stimulus seen through an elongated, zero-disparity, aperture. We found that, in human subjects, these stimuli induce robust short-latency reflexive vergence eye movements, initially in the direction orthogonal to the 1-D features, but shortly thereafter in the direction predicted by the disparity of the terminators. In addition, these same stimuli induce vivid depth percepts, which can only be attributed to the disparity of line terminators. When the 1-D noise patterns are given opposite contrast in the two eyes (anticorrelation), both components of the vergence response reverse sign. Finally, terminators drive vergence even when the aperture is defined by a texture (as opposed to a contrast) boundary. These findings prove that terminators contribute to stereo matching, and constrain the type of neuronal mechanisms that might be responsible for the detection of terminator disparity.

Temporal evolution of pattern disparity processing in humans.

Stereo matching, i.e., the matching by the visual system of corresponding parts of the images seen by the two eyes, is inherently a 2D problem. To gain insights into how this operation is carried out by the visual system, we measured, in human subjects, the reflexive vergence eye movements elicited by the sudden presentation of stereo plaids. We found compelling evidence that the 2D pattern disparity is computed by combining disparities first extracted within orientation selective channels. This neural computation takes 10-15 ms, and is carried out even when subjects perceive not a single plaid but rather two gratings in different depth planes (transparency). However, we found that 1D disparities are not always effectively combined: when spatial frequency and contrast of the gratings are sufficiently different pattern disparity is not computed, a result that cannot be simply attributed to the transparency of such stimuli. Based on our results, we propose that a narrow-band implementation of the IOC (Intersection of Constraints) rule (Fennema and Thompson, 1979; Adelson and Movshon, 1982), preceded by cross-orientation suppression, underlies the extraction of pattern disparity.

Hierarchical control of two-dimensional gaze saccades.

Coordinating the movements of different body parts is a challenging process for the central nervous system because of several problems. Four of these main difficulties are: first, moving one part can move others; second, the parts can have different dynamics; third, some parts can have different motor goals; and fourth, some parts may be perturbed by outside forces. Here, we propose a novel approach for the control of linked systems with feedback loops for each part. The proximal parts have separate goals, but critically the most distal part has only the common goal. We apply this new control policy to eye-head coordination in two-dimensions, specifically head-unrestrained gaze saccades. Paradoxically, the hierarchical structure has controllers for the gaze and the head, but not for the eye (the most distal part). Our simulations demonstrate that the proposed control structure reproduces much of the published empirical data about gaze movements, e.g., it compensates for perturbations, accurately reaches goals for gaze and head from arbitrary initial positions, simulates the nine relationships of the head-unrestrained main sequence, and reproduces observations from lesion and single-unit recording experiments. We conclude by showing how our model can be easily extended to control structures with more linked segments, such as the control of coordinated eye on head on trunk movements.

Neuromimetic model of saccades for localizing deficits in an atypical eye-movement pathology.

BACKGROUND: When patients with ocular motor deficits come to the clinic, in numerous situations it is hard to relate their behavior to one or several deficient neural structures. We sought to demonstrate that neuromimetic models of the ocular motor brainstem could be used to test assumptions of the neural deficits linked to a patient's behavior. METHODS: Eye movements of a patient with unexplained neurological pathology were recorded. We analyzed the patient's behavior in terms of a neuromimetic saccadic model of the ocular motor brainstem to formulate a pathophysiological hypothesis. RESULTS: Our patient exhibited unusual ocular motor disorders including increased saccadic peak velocities (up to ≈1000 deg/s), dynamic saccadic overshoot, left-right asymmetrical post-saccadic drift and saccadic oscillations. We show that our model accurately reproduced the observed disorders allowing us to hypothesize that those disorders originated from a deficit in the cerebellum. CONCLUSION: Our study suggests that neuromimetic models could be a good complement to traditional clinical tools. Our behavioral analyses combined with the model simulations localized four different features of abnormal eye movements to cerebellar dysfunction. Importantly, this assumption is consistent with clinical symptoms.

Role of cerebellum in motion perception and vestibulo-ocular reflex-similarities and disparities.

Vestibular velocity storage enhances the efficacy of the angular vestibulo-ocular reflex (VOR) during relatively low-frequency head rotations. This function is modulated by GABA-mediated inhibitory cerebellar projections. Velocity storage also exists in perceptual pathway and has similar functional principles as VOR. However, it is not known whether the neural substrate for perception and VOR overlap. We propose two possibilities. First, there is the same velocity storage for both VOR and perception; second, there are nonoverlapping neural networks: one might be involved in perception and the other for the VOR. We investigated these possibilities by measuring VOR and perceptual responses in healthy human subjects during whole-body, constant-velocity rotation steps about all three dimensions (yaw, pitch, and roll) before and after 10 mg of 4-aminopyridine (4-AP). 4-AP, a selective blocker of inward rectifier potassium conductance, can lead to increased synchronization and precision of Purkinje neuron discharge and possibly enhance the GABAergic action. Hence 4-AP could reduce the decay time constant of the perceived angular velocity and VOR. We found that 4-AP reduced the decay time constant, but the amount of reduction in the two processes, perception and VOR, was not the same, suggesting the possibility of nonoverlapping or partially overlapping neural substrates for VOR and perception. We also noted that, unlike the VOR, the perceived angular velocity gradually built up and plateau prior to decay. Hence, the perception pathway may have additional mechanism that changes the dynamics of perceived angular velocity beyond the velocity storage. 4-AP had no effects on the duration of build-up of perceived angular velocity, suggesting that the higher order processing of perception, beyond the velocity storage, might not occur under the influence of mechanism that could be influenced by 4-AP.

Ocular following in humans: spatial properties.

Ocular following responses (OFRs) are tracking eye movements elicited at ultrashort latency by the sudden movement of a textured pattern. Here we report the results of our study of their dependency on the spatial arrangement of the motion stimulus. Unlike previous studies that looked at the effect of stimulus size, we investigated the impact of stimulus location and how two distinct stimuli, presented together, collectively determine the OFR. We used as stimuli vertical gratings that moved in the horizontal direction and that were confined to either one or two 0.58° high strips, spanning the width of the screen. We found that the response to individual strips varied as a function of the location and spatial frequency (SF) of the stimulus. The response decreased as the stimulus eccentricity increased, but this relationship was more accentuated at high than at low spatial frequencies. We also found that when pairs of stimuli were presented, nearby stimuli interacted strongly, so that the response to the pair was barely larger than the response to a single strip in the pair. This suppressive effect faded away as the separation between the strips increased. The variation of the suppressive interaction with strip separation, paired with the dependency on eccentricity of the responses to single strips, caused the peak response for strip pairs to be achieved at a specific separation, which varied as a function of SF.

Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity.

The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model's synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation's amplitude until they stop (at approximately 20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum.

Eye movement sequence generation in humans: Motor or goal updating?

Saccadic eye movements are often grouped in pre-programmed sequences. The mechanism underlying the generation of each saccade in a sequence is currently poorly understood. Broadly speaking, two alternative schemes are possible: first, after each saccade the retinotopic location of the next target could be estimated, and an appropriate saccade could be generated. We call this the goal updating hypothesis. Alternatively, multiple motor plans could be pre-computed, and they could then be updated after each movement. We call this the motor updating hypothesis. We used McLaughlin's intra-saccadic step paradigm to artificially create a condition under which these two hypotheses make discriminable predictions. We found that in human subjects, when sequences of two saccades are planned, the motor updating hypothesis predicts the landing position of the second saccade in two-saccade sequences much better than the goal updating hypothesis. This finding suggests that the human saccadic system is capable of executing sequences of saccades to multiple targets by planning multiple motor commands, which are then updated by serial subtraction of ongoing motor output.

Short-term memory trace in rapidly adapting synapses of inferior temporal cortex.

Visual short-term memory tasks depend upon both the inferior temporal cortex (ITC) and the prefrontal cortex (PFC). Activity in some neurons persists after the first (sample) stimulus is shown. This delay-period activity has been proposed as an important mechanism for working memory. In ITC neurons, intervening (nonmatching) stimuli wipe out the delay-period activity; hence, the role of ITC in memory must depend upon a different mechanism. Here, we look for a possible mechanism by contrasting memory effects in two architectonically different parts of ITC: area TE and the perirhinal cortex. We found that a large proportion (80%) of stimulus-selective neurons in area TE of macaque ITCs exhibit a memory effect during the stimulus interval. During a sequential delayed matching-to-sample task (DMS), the noise in the neuronal response to the test image was correlated with the noise in the neuronal response to the sample image. Neurons in perirhinal cortex did not show this correlation. These results led us to hypothesize that area TE contributes to short-term memory by acting as a matched filter. When the sample image appears, each TE neuron captures a static copy of its inputs by rapidly adjusting its synaptic weights to match the strength of their individual inputs. Input signals from subsequent images are multiplied by those synaptic weights, thereby computing a measure of the correlation between the past and present inputs. The total activity in area TE is sufficient to quantify the similarity between the two images. This matched filter theory provides an explanation of what is remembered, where the trace is stored, and how comparison is done across time, all without requiring delay period activity. Simulations of a matched filter model match the experimental results, suggesting that area TE neurons store a synaptic memory trace during short-term visual memory.

Mathematical models and human disease.

Mathematical models of brain function are built from data covering anatomy, physiology, biophysics and behavior. In almost all cases, many possible models could fit the available data. Theoreticians make assumptions that allow them to constrain the number of possible model structures. However, a model that was more useful clinically would result if the constraints came from lesion studies in animals or clinical disorders. Here, we show a few examples of how clinical disorders have led to improvements in models. We also show a few examples of how models could lead to neural prostheses for patients. The best outcomes result when clinicians, basic scientists and theoreticians work together to understand brain function.