Eyelid Conditioning Research Articles

Using a million cell simulation of the cerebellum: Network scaling and task generality

Several factors combine to make it feasible to build computer simulations of the cerebellum and to test them in biologically realistic ways. These simulations can be used to help understand the computational contributions of various cerebellar components, including the relevance of the enormous number of neurons in the granule cell layer. In previous work we have used a simulation containing 12000 granule cells to develop new predictions and to account for various aspects of eyelid conditioning, a form of motor learning mediated by the cerebellum. Here we demonstrate the feasibility of scaling up this simulation to over one million granule cells using parallel graphics processing unit (GPU) technology. We observe that this increase in number of granule cells requires only twice the execution time of the smaller simulation on the GPU. We demonstrate that this simulation, like its smaller predecessor, can emulate certain basic features of conditioned eyelid responses, with a slight improvement in performance in one measure. We also use this simulation to examine the generality of the computation properties that we have derived from studying eyelid conditioning. We demonstrate that this scaled up simulation can learn a high level of performance in a classic machine learning task, the cart–pole balancing task. These results suggest that this parallel GPU technology can be used to build very large-scale simulations whose connectivity ratios match those of the real cerebellum and that these simulations can be used guide future studies on cerebellar mediated tasks and on machine learning problems.

Prolonging the postcomplex spike pause speeds eyeblink conditioning

Climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. However, it is not understood how this neural pathway coordinates changes in cerebellar circuitry during learning. Here, we use pharmacological manipulations to prolong the postcomplex spike pause, a component of the climbing fiber signal in Purkinje neurons, and show that these manipulations enhance the rate of learning in classical eyelid conditioning. Our findings elucidate an unappreciated aspect of the climbing fiber teaching signal, and are consistent with a model in which convergent postcomplex spike pauses drive learning-related plasticity in the deep cerebellar nucleus. They also suggest a physiological mechanism that could modulate motor learning rates.

Eyelid problems in general practice

General practitioners are often confronted with complaints regarding the eyelids. The author presents a number of clinical cases that illustrate common eyelid problems, and provides a discussion of each case to highlight the important features of the condition. Appropriate treatment for each condition is also covered. Many eyelid conditions are amenable to treatment from general practitioners, but those conditions requiring specialist management need to be identified, and referred appropriately.

Abord homéopathique des infections des paupières

The two localisations of microbial and viral infections of the eye, which non specialist homeopathic doctors may treat as part of their daily practice, are mainly those affecting the eyelids and the anterior segment of the eye (conjunctiva). We will firstly consider eyelid conditions; those relating to the conjunctiva will be studied in a future article.

Serotonin, presynaptic 5-HT3receptors and synaptic plasticity in the developing cerebellum

The cerebellum was initially viewed as having a primary role in motor programming, largely in feedback and feedforward control evident in decerebrate animals walking on a treadmill and the clinical condition of spinocerebellar ataxia. Comparative input from the disynaptic parallel fibre pathway and the climbing fibre pathway on Purkinje cells (PCs) was postulated to serve as an ‘error-correction’ circuit (Fig. 1). From elegant lesion studies, it became clear early on that the cerebellum was also involved in motor learning using, for example, the associative eyelid conditioning task (McCormick et al. 1985). Hebbian modulation resulting from the parallel fibre and climbing fibre inputs onto the Purkinje cells had been postulated on the basis of their apparent anatomical interaction, and correspondingly, both long-term potentiation (LTP) and long-term depression (LTD) were later demonstrated to occur along these input pathways. This synaptic plasticity provides substrates for motor learning.

Persistent activity in a cortical-to-subcortical circuit: bridging the temporal gap in trace eyelid conditioning

We have addressed the source and nature of the persistent neural activity that bridges the stimulus-free gap between the conditioned stimulus (CS) and unconditioned stimulus (US) during trace eyelid conditioning. Previous work has demonstrated that this persistent activity is necessary for trace eyelid conditioning: CS-elicited activity in mossy fiber inputs to the cerebellum does not extend into the stimulus-free trace interval, which precludes the cerebellar learning that mediates conditioned response expression. In behaving rabbits we used in vivo recordings from a region of medial prefrontal cortex (mPFC) that is necessary for trace eyelid conditioning to test the hypothesis that neurons there generate activity that persists beyond CS offset. These recordings revealed two patterns of activity during the trace interval that would enable cerebellar learning. Activity in some cells began during the tone CS and persisted to overlap with the US, whereas in other cells, activity began during the stimulus-free trace interval. Injection of anterograde tracers into this same region of mPFC revealed dense labeling in the pontine nuclei, where recordings also revealed tone-evoked persistent activity during trace conditioning. These data suggest a corticopontine pathway that provides an input to the cerebellum during trace conditioning trials that bridges the temporal gap between the CS and US to engage cerebellar learning. As such, trace eyelid conditioning represents a well-characterized and experimentally tractable system that can facilitate mechanistic analyses of cortical persistent activity and how it is used by downstream brain structures to influence behavior.

Multiple sites of extinction for a single learned response

Most learned responses can be diminished by extinction, a process that can be engaged when a conditioned stimulus (CS) is presented but not reinforced. We present evidence that plasticity in at least two brain regions can mediate extinction of responses produced by trace eyelid conditioning, where the CS and the reinforcing stimulus are separated by a stimulus-free interval. We observed individual differences in the effects of blocking extinction mechanisms in the cerebellum, the structure that, along with several forebrain structures, mediates acquisition of trace eyelid responses; in some rabbits extinction was prevented, whereas in others it was largely unaffected. We also show that cerebellar mechanisms can mediate extinction when noncerebellar mechanisms are bypassed. Together, these observations indicate that trace eyelid responses can be extinguished via processes operating at more than one site, one in the cerebellum and one upstream in forebrain. The relative contributions of these sites may vary from animal to animal and situation to situation.

Characteristics of timing learning in delayed eyelid conditioning tested with an amplitude-modulated tone as a conditioned stimulus

Characteristics of timing learning in delayed eyelid conditioning tested with an amplitude-modulated tone as a conditioned stimulus

Involutional Lower Eyelid Entropion: Combined Wheeler’s and Wedge Resection of Tarsal Plate

Involutional entropion, a common eyelid condition, has different methods of surgical correction and attendant variable recurrence rates, depending to a large degree on the method used. To describe and evaluate a modified technique of entropion repair where the Wheeler's method is combined with wedge resection of the tarsal plate. This was a chart review study of 49 patients who had the modified technique carried out to correct their involutional entropion. The technique essentially involves dissecting and separating the lower lid pre-tarsal orbicularis muscle from the tarsal plate, resecting a down-base triangular wedge of the tarsus followed by shortening the orbicularis and anchoring it to the tarsal plate superiorly. Over the three and a half-year review period, 54 eyelids of 49 patients underwent the procedure to correct their lower eyelid entropion. Of these, 28(57%) were females and 21(43%) males with a mean age of 73.5 years. The mean follow up period was 30.3 months. One (1.9%) recurrence was recorded in all the cases during the follow-up period. Complications were minimal. The combined Wheeler and wedge resection of the tarsal plate produces very good post-operative results and can be used in primary involutional entropion or as the procedure of choice if an initial different surgical technique used fails.

Adaptive Timing of Motor Output in the Mouse: The Role of Movement Oscillations in Eyelid Conditioning

To survive, animals must learn to control their movements with millisecond-level precision, and adjust the kinematics if conditions, or task requirements, change. Here, we examine adaptive timing of motor output in mice, using a simple eyelid conditioning task. Mice were trained to blink in response to a light stimulus that was always followed by a corneal air-puff at a constant time interval. Different mice were trained with different intervals of time separating the onset of the light and the air-puff. As in previous work in other animal species, mice learned to control the speed of the blink, such that the time of maximum eyelid closure matched the interval used during training. However, we found that the time of maximum eyelid speed was always in the first 100 ms after movement onset and did not scale with the training interval, indicating that adaptive timing is not accomplished by slowing down (or speeding up) the eyelid movement uniformly throughout the duration of the blink. A new analysis, specifically designed to examine the kinematics of blinks in single trials, revealed that the underlying control signal responsible for the eyelid movement is made up of oscillatory bursts that are time-locked to the light stimulus at the beginning of the blink, becoming desynchronized later on. Furthermore, mice learn to blink at different speeds and time the movement appropriately by adjusting the amplitude, but not the frequency of the bursts in the eyelid oscillation.

Learned Timing of Motor Behavior in the Smooth Eye Movement Region of the Frontal Eye Fields

Proper timing is a critical aspect of motor learning. We report a relationship between a representation of time and an expression of learned timing in neurons in the smooth eye movement region of the frontal eye fields (FEF(SEM)). During prelearning pursuit of target motion at a constant velocity, each FEF(SEM) neuron is most active at a distinct time relative to the onset of pursuit tracking. In response to an instructive change in target direction, a neuron expresses the most learning when the instruction occurs near the time of its maximal participation in prelearning pursuit. Different neurons are most active, and undergo the most learning, at distinct times during pursuit. We suggest that the representation of time in the FEF(SEM) drives learning that is temporally linked to an instructive change in target motion, and that this may be a general function of motor areas of the cortex.

A Decrementing Form of Plasticity Apparent in Cerebellar Learning

Long-term synaptic plasticity is believed to underlie the capacity for learning and memory. In the cerebellum, for example, long-term plasticity contributes to eyelid conditioning and to learning in eye movement systems. We report evidence for a decrementing form of cerebellar plasticity as revealed by the behavioral properties of eyelid conditioning in the rabbit. We find that conditioned eyelid responses exhibit within-session changes that recover by the next day. These changes, which increase with the interstimulus interval, involve decreases in conditioned response magnitude and likelihood as well as increases in latency to onset. Within-subject comparisons show that these changes differ in magnitude depending on the type of training, arguing against motor fatigue or changes in motor pathways downstream of the cerebellum. These phenomena are also observed when stimulation of mossy fibers substitutes for the conditioned stimulus, suggesting that changes take place within the cerebellum or in downstream efferent pathways. Together, these observations suggest a plasticity mechanism in the cerebellum that is induced during training sessions and fades within 23 h. To formalize this hypothesis more specifically, we show that incorporating a short-lasting potentiation at the granule cell to Purkinje cell synapses in a computer simulation of the cerebellum reproduces these behavioral effects. We propose the working hypothesis that the presynaptic form of long-term potentiation observed at these synapses is reversed by time rather than by a corresponding long-term depression. These results demonstrate the utility of eyelid conditioning as a means to identify and characterize the rules that govern input to output transformations in the cerebellum.

Case report: Chalazion and its features visualized by ultrahigh resolution optical coherence tomography

The purpose of this case report is to highlight the clinical characteristics of a recurrent chalazion through the use of digital photography and ultra-high resolution optical coherence tomography (UHROCT). A single case is presented, along with digital biomicroscopic photographs and UHROCT images. A review of the literature describing the histopathological and associations of chalazia and other disorders, suggest it may be possible to differentiate different eyelid conditions based on their clinical manifestations and appearance on UHROCT tomograms. Based on the images presented here, it appears that this case is typical of a post-menopausal incidence of chalazion and risk for acne rosacea.

Eyelid conditioning to a target amplitude: adding how much to whether and when.

Conceptual and practical advantages of pavlovian eyelid conditioning facilitate analysis of cerebellar computation and learning. Even so, eyelid conditioning procedures are unrealistic in an important way. The error signal to the olivocerebellar system does not decrease as learning adapts response amplitude or gain. This inherently limits the utility of eyelid conditioning for studies investigating how cerebellar learning mechanisms acquire and store an adaptive response amplitude. We report the development and characterization of a training procedure in which conditioned response amplitude is brought under experimental control with contingencies that more closely parallel natural conditions. In this procedure, the delivery of the unconditioned stimulus (US) is made contingent on conditioned response amplitude: the US is delivered for responses that fail to reach a specified target amplitude and is omitted for responses that meet or exceed the target. We find that rabbits trained with either a tone or with mossy fiber stimulation as the conditioned stimulus learn responses that approach target amplitudes ranging from 2 to 5 mm. Inactivating the interpositus nucleus with muscimol infusions abolished these conditioned responses, indicating that cerebellar involvement in eyelid conditioning is not tied explicitly to the use of pavlovian procedures. Together with previous studies, these data suggest that response amplitude is learned and encoded in the cerebellum during eyelid conditioning. As such, these results provide a foundation for systematic and controlled investigations of the cerebellar mechanisms that learn and encode the proper amplitude of adaptive movements.

P68 The prevalence of eye disease in Norfolk and Waveney

IntroductionVisual impairment is an important preventable cause of disability in the UK. Cataract, glaucoma, diabetic retinopathy and age related macular degeneration are the common causes of visual impairment in the...

Temporal patterns of inputs to cerebellum necessary and sufficient for trace eyelid conditioning.

Trace eyelid conditioning is a form of associative learning that requires several forebrain structures and cerebellum. Previous work suggests that at least two conditioned stimulus (CS)-driven signals are available to the cerebellum via mossy fiber inputs during trace conditioning: one driven by and terminating with the tone and a second driven by medial prefrontal cortex (mPFC) that persists through the stimulus-free trace interval to overlap in time with the unconditioned stimulus (US). We used electric stimulation of mossy fibers to determine whether this pattern of dual inputs is necessary and sufficient for cerebellar learning to express normal trace eyelid responses. We find that presenting the cerebellum with one input that mimics persistent activity observed in mPFC and the lateral pontine nuclei during trace eyelid conditioning and another that mimics tone-elicited mossy fiber activity is sufficient to produce responses whose properties quantitatively match trace eyelid responses using a tone. Probe trials with each input delivered separately provide evidence that the cerebellum learns to respond to the mPFC-like input (that overlaps with the US) and learns to suppress responding to the tone-like input (that does not). This contributes to precisely timed responses and the well-documented influence of tone offset on the timing of trace responses. Computer simulations suggest that the underlying cerebellar mechanisms involve activation of different subsets of granule cells during the tone and during the stimulus-free trace interval. These results indicate that tone-driven and mPFC-like inputs are necessary and sufficient for the cerebellum to learn well-timed trace conditioned responses.

Newborn infants learn during sleep

Newborn infants must rapidly adjust their physiology and behavior to the specific demands of the novel postnatal environment. This adaptation depends, at least in part, on the infant's ability to learn from experiences. We report here that infants exhibit learning even while asleep. Bioelectrical activity from face and scalp electrodes was recorded from neonates during an eye movement conditioning procedure in which a tone was followed by a puff of air to the eye. Sleeping newborns rapidly learned the predictive relationship between the tone and the puff. Additionally, in the latter part of training, these infants exhibited a frontally maximum positive EEG slow wave possibly reflecting memory updating. As newborns spend most of their time sleeping, the ability to learn about external stimuli in the postnatal environment during nonawake states may be crucial for rapid adaptation and infant survival. Furthermore, because eyelid conditioning reflects functional cerebellar circuitry, this method potentially offers a unique approach for early identification of infants at risk for a range of developmental disorders including autism and dyslexia.

Deactivation of L-type Ca Current by Inhibition Controls LTP at Excitatory Synapses in the Cerebellar Nuclei

Long-term potentiation (LTP) of mossy fiber EPSCs in the cerebellar nuclei is controlled by synaptic inhibition from Purkinje neurons. EPSCs are potentiated by a sequence of excitation, inhibition, and disinhibition, raising the question of how these stimuli interact to induce plasticity. Here, we find that synaptic excitation, inhibition, and disinhibition couple to different calcium-dependent signaling pathways. In LTP induction protocols, constitutively active calcineurin can replace synaptic excitation, and constitutively active alpha-CaMKII can replace calcium influx associated with resumption of spiking upon disinhibition. Additionally, nimodipine can replace hyperpolarization, indicating that inhibition of firing decreases Ca influx through L-type Ca channels, providing a necessary signal for LTP. Together, these data suggest that potentiation develops after a calcineurin priming signal combines with an alpha-CaMKII triggering signal if and only if L-type Ca current is reduced. Thus, hyperpolarization induced by synaptic inhibition actively controls excitatory synaptic plasticity in the cerebellar nuclei.

Floppy Eyelid Syndrome as a Subset of Lax Eyelid Conditions: Relationships and Clinical Relevance (an ASOPRS Thesis)

To better define the wide spectrum of lax eyelid conditions, especially the subtype referred to as floppy eyelid syndrome, and to clarify its relationship with associated ophthalmic findings. A case-based retrospective review of all patients seen at UNC Department of Ophthalmology with a diagnosis of floppy eyelid syndrome or lax upper eyelid was performed. The period of review was from March 2002 to March 2007. A literature review was also performed using the term "floppy eyelid syndrome" and "lax eyelid syndrome" as the keywords in a PubMed search. Charts and cases were reviewed for the following information: age, sex, presence or absence of obesity, presence or absence of upper eyelid laxity, presence or absence of lower eyelid laxity, symmetry or asymmetry of eyelid laxity, sleeping position preference, diagnosis of obstructive sleep apnea (OSA), history of eye rubbing, diagnosis of keratoconus (KCN), lash ptosis, history of spontaneous eyelid eversion, papillary conjunctivitis, systemic hyperlaxity, diagnosis of meibomianitis, signs of anterior segment inflammation, and smoking or excessive sun exposure history. From our UNC case review, 14 patients involving 17 eyelids were identified. From the literature review, 72 articles were recovered and evaluated to yield a total of 324 reported cases through February 2007. From the combined data (n = 338), the overall minimum prevalence of sleep apnea in patients with lax eyelid condition was 16% compared with an estimated 9% to 24% in the general population. Of patients with lax eyelid syndrome, those identified with OSA had significantly more individuals with obesity (76% vs. 20%) and male gender (89% vs. 61%) than the group without OSA. The prevalence of KCN in patients with lax eyelid syndrome was a minimum of 6.8%, which is considerably higher than the estimated prevalence in the general population of 0.6%. However, KCN appears to show a significant association with the patient's side of sleeping preference. Eyelid laxity can result from a number of involutional, local, and systemic diseases but is frequently of unknown etiology. When it is consistently associated with papillary conjunctivitis and dry eyes it can be referred to as lax eyelid syndrome (LES). A number of specific subsets of LES can be identified. One such subset, occurring primarily though not exclusively in males and associated with obesity, has been defined as the floppy eyelid syndrome (FES). OSA has been associated with FES where it occurs with greater frequency than in the general population, but no greater than seen in obese males without FES, and therefore appears to represent an epiphonomenom only. However, given the demographics of FES, this condition offers some predictive value for OSA and should alert the physician to evaluate the sleep habits of all such patients. Keratoconus also shows some association with FES and with LES. However, data suggest that the causative factors are sleep preference for the involved side and nocturnal eyelid eversion, rather than any underlying physiologic or anatomic relationship.

Cerebellar Cortex Contributions to the Expression and Timing of Conditioned Eyelid Responses

We used micro-infusions during eyelid conditioning in rabbits to investigate the relative contributions of cerebellar cortex and the underlying deep nuclei (DCN) to the expression of cerebellar learning. These tests were conducted using two forms of cerebellum-dependent eyelid conditioning for which the relative roles of cerebellar cortex and DCN are controversial: delay conditioning, which is largely unaffected by forebrain lesions, and trace conditioning, which involves interactions between forebrain and cerebellum. For rabbits trained with delay conditioning, silencing cerebellar cortex by micro-infusions of the local anesthetic lidocaine unmasked stereotyped short-latency responses. This was also the case after extinction as observed previously with reversible blockade of cerebellar cortex output. Conversely, increasing cerebellar cortex activity by micro-infusions of the GABA(A) antagonist picrotoxin reversibly abolished conditioned responses. Effective cannula placements were clustered around the primary fissure and deeper in lobules hemispheric lobule IV (HIV) and hemispheric lobule V (HV) of anterior lobe. In well-trained trace conditioned rabbits, silencing this same area of cerebellar cortex or reversibly blocking cerebellar cortex output also unmasked short-latency responses. Because Purkinje cells are the sole output of cerebellar cortex, these results provide evidence that the expression of well-timed conditioned responses requires a well-timed decrease in the activity of Purkinje cells in anterior lobe. The parallels between results from delay and trace conditioning suggest similar contributions of plasticity in cerebellar cortex and DCN in both instances.