A Model for the Origin of Motion Direction Selectivity in Visual Cortex.

Motion perception is a vital part of our sensory repertoire in that it contributes to navigation, awareness of moving objects, and communication. Motion sense in carnivores and primates originates with primary visual cortical neurons selective for motion direction. More than 60 years after the discovery of these neurons, there is still no consensus on the mechanism underlying direction selectivity. This paper describes a model of the cat's visual system in which direction selectivity results from the well-documented orientation selectivity of inhibitory neurons: inhomogeneities in the orientation preference map for inhibitory neurons leads to spatially asymmetric inhibition, and thus to direction selectivity. Stimulation of the model with a drifting grating shows that direction selectivity results from the relative timing of excitatory and inhibitory inputs to a neuron. Using a stationary contrast-reversing grating reveals that the inhibitory input is spatially displaced in the preferred direction relative to the excitatory input, and that this asymmetry leads to the timing difference. More generally, the model yields physiologically realistic estimates of the direction selectivity index, and it reproduces the critical finding with contrast-reversing gratings that response phase advances with grating spatial phase. It is concluded that a model based on intracortical inhibition can account well for the known properties of direction selectivity in carnivores and primates.SIGNIFICANCE STATEMENT Motion perception is vital for navigation, communication, and the awareness of moving objects. Motion sense depends on cortical neurons that are selective for motion direction, and this paper describes a model for the physiological mechanism underlying cortical direction selectivity. The essence of the model is that intracortical inhibition of a direction-selective cell is spatially inhomogeneous and therefore depends on whether a stimulus generates inhibition before or after reaching the cell's receptive field: the response is weaker in the former than in the latter case. If the model is correct, it will contribute to the understanding of motion processing in carnivores and primates.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

BACKGROUND: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

A model for the origin and development of visual orientation selectivity.

Orientation selectivity is a key property of primary visual cortex that contributes, downstream, to object recognition. The origin of orientation selectivity, however, has been debated for decades. It is known that on- and off-centre subcortical pathways converge onto single neurons in primary visual cortex, and that the spatial offset between these pathways gives rise to orientation selectivity. On- and off-centre pathways are intermingled, however, so it is unclear how their inputs to cortex come to be spatially segregated. We here describe a model in which the segregation occurs through Hebbian strengthening and weakening of geniculocortical synapses during the development of the visual system. Our findings include the following. 1. Neighbouring on- and off-inputs to cortex largely cancelled each other at the start of development. At each receptive field location, the Hebbian process increased the strength of one input sign at the expense of the other sign, producing a spatial segregation of on- and off-inputs. 2. The resulting orientation selectivity was precise in that the bandwidths of the orientation tuning functions fell within empirical estimates. 3. The model produced maps of preferred orientation-complete with iso-orientation domains and pinwheels-similar to those found in real cortex. 4. These maps did not originate in cortical processes, but from clustering of off-centre subcortical pathways and the relative location of neighbouring on-centre clusters. We conclude that a model with intermingled on- and off-pathways shaped by Hebbian synaptic plasticity can explain both the origin and development of orientation selectivity.

Orientation discrimination requires coactivation of on- and off-dominated visual channels.

Orientation sensitivity depends on the cortical convergence of on- and off-center subcortical neurons. Off-center inputs are faster and stronger than their on-center counterparts: How does this asymmetry affect orientation discrimination? We tackled this question psychophysically with grating stimuli that either increased or decreased luminance. The gratings were of low contrast in order to avoid the complicating influences of nonlinearities such as response saturation, masking, and aftereffects. Gratings were presented in either of two locations, and subjects indicated the perceived location. Stimuli were randomly timed, and response correctness and reaction time were recorded. We found the following: (a) Contrast sensitivity was insignificant for a range of contrasts around zero. (b) Outside this range, contrast sensitivity for contrast decrements exceeded that for increments by an average of 15%. (c) Reaction times for contrast decrements were up to 45 ms less than for increments. (d) These findings are reproduced by a signal-detection model which incorporates recent physiological findings: Neurons in primary visual cortex are hyperpolarized at rest; these neurons respond more to darks than to lights; and off-dominated cortical neurons have shorter latencies than their on-dominated neighbors. (e) We tested orientation discrimination by splitting a grating into two components, one containing the light bars and the other the dark, and presenting the two components asynchronously. Discrimination was optimal when light bars preceded dark bars, consistent with coactivation of on- and off-center cortical inputs. We conclude that the ability to discriminate between orientations is intimately connected with the properties of subcortical channels.

Chronic and acute biases in perceptual stabilization.

When perceptually ambiguous stimuli are presented intermittently, the percept on one presentation tends to be the same as that on the previous presentation. The role of short-term, acute biases in the production of this perceptual stability is relatively well understood. In addition, however, long-lasting, chronic bias may also contribute to stability. In this paper we develop indices for both biases and for stability, and show that stability can be expressed as a sum of contributions from the two types of bias. We then apply this analytical procedure to binocular rivalry, showing that adjustment of the monocular contrasts can alter the relative contributions of the two biases. Stability is mainly determined by chronic bias when the contrasts are equal, but acute bias dominates stability when right-eye contrast is set lower than left-eye contrast. Finally, we show that the right-eye bias persists in continuous binocular rivalry. Our findings reveal a previously unappreciated contribution of chronic bias to stable perception.

Measuring perception without introspection.

Binocular rivalry, the perceptual alternation between incompatible monocular stimuli, is conventionally measured by asking the subject which percept is currently visible. This is problematic because the response is unverifiable, open to response bias, and falsely assumes that the perceptual experience is binary. We overcame these limitations in a new approach that does not require subjective reporting of perceptual state. A brief test stimulus was added to one eye's inducing stimulus at random times and contrasts. The test was presented at one of two spatial locations, the subject indicated which alternative had been shown, and the correctness of the response was recorded as a function of test contrast. Given the random timing of the test stimulus, it was sometimes delivered when the tested eye was dominant and, at other times, suppressed. Accordingly, the psychometric function recorded during rivalry should be a mixture of the dominance and suppression forms of the function. This was indeed the case: The probability of a correct response during rivalry was significantly less than that obtained with a binocularly congruent stimulus. The psychometric function during rivalry was well modeled as a weighted sum of the congruence curve with an assumed suppression curve. Optimal fitting provided estimates of both suppression depth and percept predominance that corresponded closely with estimates obtained with the conventional method. We have therefore characterized rivalry without the uncertainties introduced by the subject's perceptual report. This provides a model that may be applicable to the broader field of perceptual ambiguity.

Thyroid disease in cervical dystonia.

There are many possible etiologies for cervical dystonia (CD), but a cause cannot be identified in most cases. Most recent attention has focused on genetic causes, although a few prior studies have highlighted autoimmune mechanisms instead. Because autoimmune disorders frequently co-exist, the current study evaluated the hypothesis that autoimmune disorders might be more common in CD than neurological controls. The frequency of 32 common autoimmune disorders was evaluated using a systematic survey comparing 300 subjects with CD with 391 neurological controls. The frequency of thyroid disease was significantly higher in CD (20%) compared with controls (6%). Regression analyses that accounted for age and sex revealed an odds ratio of 4.5 (95% CI 2.5-8.1, p < 0.001). All other autoimmune disorders occurred with similar frequencies in CD and controls. Although these studies do not establish a mechanistic link between CD and autoimmune disease, they suggest the need for further attention to a potential relationship, and more specifically with thyroid disease.

Daytime alertness in Parkinson's disease: potentially dose-dependent, divergent effects by drug class.

Many patients with idiopathic Parkinson's disease experience difficulties maintaining daytime alertness. Controversy exists regarding whether this reflects effects of antiparkinsonian medications, the disease itself, or other factors such as nocturnal sleep disturbances. In this study we examined the phenomenon by evaluating medicated and unmedicated Parkinson's patients with objective polysomnographic measurements of nocturnal sleep and daytime alertness. Patients (n = 63) underwent a 48-hour laboratory-based study incorporating 2 consecutive nights of overnight polysomnography and 2 days of Maintenance of Wakefulness Testing. We examined correlates of individual differences in alertness, including demographics, clinical features, nocturnal sleep variables, and class and dosage of anti-Parkinson's medications. Results indicated that, first, relative to unmediated patients, all classes of dopaminergic medications were associated with reduced daytime alertness, and this effect was not mediated by disease duration or disease severity. Second, the results showed that increasing dosages of dopamine agonists were associated with less daytime alertness, whereas higher levels of levodopa were associated with higher levels of alertness. Variables unrelated to the Maintenance of Wakefulness Test defined daytime alertness including age, sex, years with diagnosis, motor impairment score, and most nocturnal sleep variables. Deficits in objectively assessed daytime alertness in Parkinson's disease appear to be a function of both the disease and the medications and their doses used. The apparent divergent dose-dependent effects of drug class in Parkinson's disease are anticipated by basic science studies of the sleep/wake cycle under different pharmacological agents.

A model for the development of binocular congruence in primary visual cortex.

Neurons in primary visual cortex are selective for stimulus orientation, and a neuron's preferred orientation changes little when the stimulus is switched from one eye to the other. It has recently been shown that monocular orientation preferences are uncorrelated before eye opening; how, then, do they become aligned during visual experience? We aimed to provide a model for this acquired congruence. Our model, which simulates the cat's visual system, comprises multiple on-centre and off-centre channels from both eyes converging onto neurons in primary visual cortex; development proceeds in two phases via Hebbian plasticity in the geniculocortical synapse. First, cortical drive comes from waves of activity drifting across each retina. The result is orientation tuning that differs between the two eyes. The second phase begins with eye opening: at each visual field location, on-centre cortical inputs from one eye can cancel off-centre inputs from the other eye. Synaptic plasticity reduces the destructive interference by up-regulating inputs from one eye at the expense of its fellow, resulting in binocular congruence of orientation tuning. We also show that orthogonal orientation preferences at the end of the first phase result in ocular dominance, suggesting that ocular dominance is a by-product of binocular congruence.

Rapid serial visual presentation of motion: short-term facilitation and long-term suppression.

The visual system can detect coherent motion in the midst of motion noise. This is accomplished with motion-sensitive channels, each of which is tuned to a limited range of motion directions. Our aim was to show how a single channel is affected by motions both within and outside its tuning range. We used a psychophysical reverse-correlation procedure. An array of dots moved coherently with a new, randomly chosen, direction every 14 or 28 ms. Human subjects pressed a key whenever they saw upwards movement. The results were analyzed by finding two motion directions before each key-press: the first preceded the key-press by the reaction time, and the second preceded the first by a variable interval. There were two main findings. First, the subject was significantly more likely to press the key when the vector average of the two motions was in the target direction. This effect was short-lived: it was only seen for inter-stimulus intervals of several tens of milliseconds. Second, motion detection was reduced when the target direction was preceded by a motion of similar direction 100-200 ms earlier. The results support the idea that a motion-sensitive channel sums sub-optimal inputs, and is suppressed by similar motion in the long term.

A metabolomic study of cervical dystonia.

INTRODUCTION: Cervical dystonia is the most common of the adult-onset focal dystonias. Most cases are idiopathic. The current view is that cervical dystonia may be caused by some combination of genetic and environmental factors. Genetic contributions have been studied extensively, but there are few studies of other factors. We conducted an exploratory metabolomics analysis of cervical dystonia to identify potentially abnormal metabolites or altered biological pathways. METHODS: Plasma samples from 100 cases with idiopathic cervical dystonia and 100 controls were compared using liquid chromatography coupled with mass spectrometry-based metabolomics. RESULTS: A total of 7346 metabolic features remained after quality control, and up to 289 demonstrated significant differences between cases and controls, depending on statistical criteria chosen. Pathway analysis revealed 9 biological processes to be significantly associated at p < 0.05, 5 pathways were related to carbohydrate metabolism, 3 pathways were related to lipid metabolism. CONCLUSION: This is the first large scale metabolomics study for any type of dystonia. The results may provide potential novel insights into the biology of cervical dystonia.

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

OBJECTIVE: To assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia. METHODS: Clinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition. RESULTS: Methodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics. CONCLUSION: The large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

Lengthy suppression from similar stimuli during rapid serial visual presentation.

The stimulus at any point in the visual field is rarely static during normal viewing: observer and object movement conspire to produce a continually changing series of stimuli. Our aim was to study both the short- and long-term interactions between responses to a series of stimuli presented at a single visual location. We used rapid serial visual presentation (RSVP) in which the stimuli were randomly oriented gratings delivered at the rate of 30 per second. Human subjects pressed a key whenever they saw a target orientation, for example horizontal. The results were analyzed by finding two orientations before each key-press. The first preceded the key-press by the reaction time, and the second preceded the first by an interval of variable duration. There were two main findings. First, the subject was more likely to press the key when the target was immediately preceded by a grating of similar orientation. This facilitation presumably results from the summation of sub-threshold inputs. Second, a key-press was reduced in probability when a target orientation was preceded by a similar orientation with an interstimulus interval of 100-400 ms. The time course of this suppression is similar to that seen in attentional blink experiments.

An open-label, sequential dose-escalation, safety, and tolerability study of rimabotulinumtoxinb in subjects with cervical dystonia.

OBJECTIVES: Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. METHODS: This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). RESULTS: 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). CONCLUSION: BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.

Opponent motion interactions in the perception of structure from motion.

Motion provides important cues for the perception of depth and object structure. The kinetic depth effect illustrates this phenomenon: dots moving in a two-dimensional plane can produce a vivid perception of a rotating three-dimensional object. We studied the origin of this depth percept in a psychophysical study employing inducing and test stimuli. The inducing stimulus, containing dots moving with simple harmonic motion in the fixation plane, was perceived as a rotating cylinder. The test stimulus had binocular disparity that placed it close to either the near or far surface of the cylinder. We found that sensitivity to the test was lower when it moved in the opposite direction to the adjacent surface of the inducing stimulus than when the two stimuli moved in the same direction. We also simplified the inducing stimulus by using two uniform arrays of dots translating in opposite directions. Subjects saw one array as being closer than the other, and test sensitivity was again reduced when the test was close to a surface moving in the opposite direction. These results support the idea that there are suppressive interactions between opposing motions at the same depth, leading to a single perceived direction of motion at each depth.

A founding LRRK2 haplotype shared by Tunisian, US, European and Middle Eastern families with Parkinson's disease.

The Leucine-rich repeat kinase 2 (LRRK2) gene has been identified as a disease susceptibility gene for Parkinson's disease (PD), with G2019 (6055G>A) being the most frequent mutation. This mutation was present in 42% (38/91) of Tunisian families and 2% (1/39) of US families we have studied. A founding haplotype was identified in our data and it is shared by families from Tunisia, US, European and Middle Eastern countries. The most recent common founder of the mutation was dated to 2600 (95% CI: 1950-3850) years ago although additional studies are warranted to ensure an accurate age estimate for this mutation.

Cross-orientation interactions in human vision.

Humans can discriminate one visual contour from another on the basis of small differences in orientation. This capability depends on cortical detectors that are selective for a small range of orientations. We have measured this orientation bandwidth and the suppression that helps to shape it, with a reverse correlation technique. Human subjects were presented with a stream of randomly oriented gratings at a rate of 30 per second. Their task was to press a key whenever they saw an orientation nominated as the target. We analyzed the data by finding the probability density of two orientations: One preceded the key-press by the reaction time, and the second preceded the first by up to 100 ms. The results were as follows: (1) One grating facilitated the following one in producing a key-press when the gratings differed little in orientation. The estimate of orientation bandwidth resulting from this facilitation was 38 degrees . (2) A large angle between the two orientations reduced the probability of a key-press. This finding was best modelled as a suppression that did not vary with orientation, consistent with the idea that cross-orientation suppression is non-oriented. (3) Analysis of non-consecutive grating pairs showed that cross-orientation interactions lasted no longer than 67 ms.

Motion changes response balance between ON and OFF visual pathways.

Humans are faster at detecting dark than light stationary stimuli, a temporal difference that originates early in the visual pathway. Here we show that this difference reverses when stimuli move, making detection faster for moving lights than darks. Human subjects judged the direction of moving edges and bars, and made faster and more accurate responses for light than for dark stimuli. This light/dark asymmetry is greatest at low speeds and disappears at high speeds. In parallel experiments, we recorded responses in the cat visual cortex for moving bars and again find that responses are faster for light bars than for dark bars moving at low speeds. We show that differences in the luminance-response function between ON and OFF pathways can reproduce these findings, and may explain why ON pathways are used for slow-motion image stabilization in many species.

Pilot Single-Blind Trial of AbobotulinumtoxinA in Oromandibular Dystonia.

Oromandibular dystonia (OMD) causes involuntary movements of masticatory and lingual muscles impairing eating, speaking, and swallowing. Treatment options are limited. The objective of this study was to determine the safety and efficacy of abobotulinumtoxinA (aboBoNTA) in OMD. A dose-finding study (phase 1) followed by a single session, prospective, single-blind trial (phase 2) was carried out. OMD subjects were evaluated at baseline, 6 and 12 weeks. Muscles injected were tailored to individual symptoms using EMG guidance, but the aboBoNTA dose for each muscle was pre-specified based on phase 1 results. Evaluations were Global Dystonia Rating Scale (GDS), Unified Dystonia Rating Scale (UDRS), Clinical Global Impression (CGI) improvement and severity, and quality of life (OMDQ-25). Adverse events were monitored. The lowest dosage in phase 1 resulted in adverse effects in two of three patients and thus was used in phase 2. In phase 2, adverse effects were observed in 50% of subjects including dysphagia, voice change, and soft palate weakness. Most were mild. Significant improvement was seen in quality of life (OMDQ-25), speech (BFMq21), and change in GDS, UDRS, CGI severity assessed by the unblinded investigator, but not in blinded video ratings. We conclude that aboBoNTA therapy in this study was associated with improved quality of life and was generally well tolerated in OMD, but occurrence of dysphagia dictated the importance of using low genioglossus dosing. Face to face assessment appears to be more sensitive than video assessment for change in OMD severity. Consideration of the disability in OMD places constraints on traditional placebo-control trial design. Development of novel trial designs is warranted.

Affective Correlates of Psychosis in Parkinson's Disease.

OBJECTIVE: To examine the nature of the association between affective disorders and psychosis in Parkinson's disease (PD). BACKGROUND: In PD, psychosis and affective disorders are common and independently impact quality of life and mortality. Both depression and psychosis are correlated with the occurrence of cognitive dysfunction, suggesting that they may share neurobiological substrates. Anxiety has not been examined as a correlate of psychosis. METHODS: 144 PD subjects were evaluated with the Schedule for Assessment of Positive Symptoms to assess psychotic features, while depression and anxiety were examined by the Structured Clinical Interview for DSM-IV-TR (SCID) and self-assessment scales Beck Depression Inventory II (BDI-II) and Beck Anxiety Inventory (BAI). Correlational analyses assessed associations between hallucinations and delusions with depression and anxiety. RESULTS: A diagnosis of anxiety (SCID) was significantly (p=.015) associated with hallucinations (OR=4.81, CI=1.36-16.99). Severity of anxiety (BAI) significantly predicted (p=.03) the presence of hallucinations (OR=1.08, CI=1.01-1.15) and delusions (OR=1.09, CR=1.01-1.17). Current depression (SCID) was significantly (p=.001) associated with the presence of hallucinations (OR=6.12, CI=2.04-18.39) and delusions (OR=7.14, CI=2.23-22.93). Multiple linear regressions revealed that severity of anxiety remained an independent predictor (p<.05) of both the number of types of hallucinations (t=3.06, p=.003) and delusions (t=2.87, p=.005). Severity of depression was a significant predictor of the total number of delusions (t=2.28, p=.024). CONCLUSIONS: This study demonstrates an association between depression and psychosis and, for the first time, an association between anxiety and psychosis. These associations may have implications on pathophysiology and treatment of psychosis in PD.