Association between angiotensin-converting enzyme (ACE) gene I/D polymorphism with the risk of knee OA: A systematic review, meta-analysis, and meta-regression.

Background: Previous studies have linked genetics to knee osteoarthritis. Angiotensin-converting enzyme (ACE) gene I/D polymorphism may cause OA. However, evidence remains inconsistent. This study examines knee OA risk and ACE gene I/D polymorphism. Methods: We explored Europe PMC, Medline, Scopus, and Cochrane Library using keywords. Three assessment bias factors were assessed using the Newcastle-Ottawa Scale (NOS). Criteria for inclusion: (1) Split the study population into knee OA patients and healthy controls; (2) Analysed the ACE gene I/D polymorphism; (3) Case-control or cross-sectional surveys. Studies with non-knee OA, incomplete data, and no full-text were excluded. The odds ratio (OR) and 95% confidence intervals (95% CI) were calculated using random-effect models. Results: A total of 6 case-control studies consist of 1,226 patients with knee OA and 1,145 healthy subjects as controls were included. Our pooled analysis revealed that a significant association between ACE gene I/D polymorphism and risk of knee OA was only seen in the dominant (DD + ID vs. II) [OR 1.69 (95% CI 1.14 - 2.50), p = 0.009, I2 = 72%], and ID vs. II [OR 1.37 (95% CI 1.01- 1.86), p = 0.04, I2 = 43%] genotype models. Other genotype models, including recessive (DD vs. ID + II), alleles (D vs. I), DD vs. ID, and DD vs. II models did not show a significant association with knee OA risk. Further regression analysis revealed that ethnicity and sex may influence those relationships in several genotype models. Conclusions: Dominant and ID vs. II ACE gene I/D polymorphism models increased knee OA risk significantly. More research with larger samples and different ethnic groups is needed to confirm our findings. After ethnicity subgroup analysis, some genetic models in our study showed significant heterogeneities, and most studies are from Asian countries with Asian populations, with little evidence on Arabs.

Dynamic interaction of obesity, age, MCP-1 Level, and ACE-1 gene with the severity of knee osteoarthritis: a cross-sectional study.

The risk factors most strongly associated with knee osteoarthritis (OA) are old age and obesity. However, few studies have evaluated the interaction between aging and obesity in conjunction with inflammatory markers and knee OA severity as part of a complete assessment of knee OA management. Therefore, this study aims to evaluate the interaction between obesity, age, inflammation [including the I/D polymorphism of angiotensin converting enzyme-1 (ACE-1)], and the severity of knee OA. Methods: A total of 80 knee OA patients were included in this cross-sectional study. The severity of knee OA was determined based on the Kellgren-Lawrence system. All patients underwent physical and radiological examination; monocyte chemoattractant protein 1 (MCP-1) markers were measured. The parameters of the ACE-1 gene were examined with sequencing DNA. Results: There was a significant relationship between age and severity of knee OA (P=0.007), with subjects aged greater than or equal to 65 having a 3.56-fold higher risk of developing moderate to severe OA than subjects aged less than 65. There was a significant difference between body weight and knee OA severity (P=0.026), in which subjects weighing greater than or equal to 60 kg had 3.14 times the risk of experiencing severe knee OA. Multivariate regression analysis indicated that age was the strongest independent variable for knee OA severity compared with body weight. MCP-1 levels were significantly higher in mild knee OA than in moderate to severe knee OA. The DD genotype of the ACE-1 gene increases the risk of severe knee OA by four times in subjects aged greater than or equal to 65 compared to subjects aged less than 65. However, the DD genotype of the ACE-1 gene does not increase the risk of severe knee OA in subjects weighing greater than or equal to 60 kg. Conclusion: While obesity and age were found to be associated with the severity of knee OA, age emerged as the independent risk factor for knee OA severity. Furthermore, MCP-1 levels were significantly higher in cases of mild knee OA compared to severe knee OA. It was observed that the DD genotype of the ACE-1 gene increases the risk of severe knee OA in individuals aged 65 years or older.

Congenital talipes equinovarus: A literature review.

Congenital talipes equinovarus (CTEV) is a congenital disability characterized by leg deformities in the cavus, adducts, varus, and equinus. The etiology of CTEV is poorly understood, despite its incidence ranging from 0.76 to 3.49 cases per 1000 live births in Indonesia. CTEV involves the fixation of the foot in the adducts, varus, and equinus with concurrent soft tissue anomalies. Despite advances in treatment, disability often persists. Theoretical models have been proposed for neurological, vascular, connective tissue, bone, and muscular causes; however, the currently available data suggests that mild cases are associated with intrauterine position. CTEV's etiology appears to involve a hereditary component, as its prevalence varies by ethnic group. Genetic factors have been identified in 24-50% of cases, depending on the community studied. Based on a complex segregation analysis, the most plausible inheritance pattern is a single large-effect gene interacting with a polygenic background.

Hypothyroidism in Bangladesh: Is Autoimmunity the Next Big Threat?

In many low and middle-income countries, iodine-deficient hypothyroidism leads to complex public health consequences. However, increasing evidence from population-based studies has linked thyroid autoimmunity with excess iodine intake. The iodine supplementation program in Bangladesh was a success story. This cross-sectional study aims to assess the pattern and predictors of autoimmunity among Bangladeshi hypothyroid patients. In this study, 154 consecutive, newly detected, biochemically-confirmed patients with primary hypothyroidism were recruited from the Endocrinology outpatient department of Bangabandhu Sheikh Mujib Medical University and tested for anti-thyroid peroxidase and anti-thyroglobulin antibody levels from October 2015 and November 2016. Patterns of thyroid autoimmunity were assessed via descriptive statistics. Predictors of autoimmunity were assessed with multivariable mixed-effect logistic regression. The mean age of participants was 36.1±11.0 years, and 70.1% were female. The frequency of thyroid autoimmunity in the study subjects was very high, 89.0% were positive for either anti-TPO or anti-Tg antibodies and 48.7% were positive for both. More participants were positive for anti-TPO antibodies (82.5%) than anti-Tg antibodies (55.2%). The risk of autoimmunity was associated with the thyroid's structural abnormalities but not with functional status. Weight gain and hypertension were associated with autoimmunity, whereas diabetes was protective against autoimmunity.

Antithyroid Antibody Status in Non-Pregnant Adult Bangladeshi Patients with Subclinical Hypothyroidism.

Sub clinical hypothyroidism (SCH) is common in clinical practice. Autoimmunity is thought to be the most important cause of SCH. In this cross-sectional study, we investigated 120 SCH patients and 100 healthy controls attending the Endocrinology Outpatient Department of Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from June 2014 to April 2015 for anti-thyroid antibodies (anti-TPO and anti-Tg). Measurement of serum TSH, FT4, anti-TPO, and anti-Tg antibodies were done by using the chemiluminescent sequential immunometric assay. SCH patients had a higher mean age; the frequencies of female subjects, those having family history of thyroid disease or other autoimmune diseases, and goiter were higher in SCH group than in the control group. Forty-five percent (45%) of SCH patients were positive for anti-thyroid antibodies (23.3% for both anti-TPO and anti-Tg, 16.7% for only anti-TPO, and 5% positive for only anti-Tg) in comparison to only 10% anti-thyroid antibody positive controls (none for both antibodies, 8% for only anti-TPO, and 2% positive for only anti-Tg). The SCH subjects in the lower age group, females and with a TSH >10µIU/mL had the higher frequency of thyroid autoimmunity. Female gender, high socioeconomic condition, the presence of other autoimmune diseases, the presence of goiter and TSH >10µIU/mL were associated with higher odds of anti-thyroid antibody positivity in the SCH group, though none were statistically significant. The frequency of anti-thyroid antibody was higher in SCH and was more prevalent among the females, younger patients and those having a goiter, other autoimmune diseases, and TSH >10µIU/mL.

Orexin-A inputs onto visuomotor cell groups in the monkey brainstem.

Orexin-A, synthesized by neurons of the lateral hypothalamus helps to maintain wakefulness through excitatory projections to nuclei involved in arousal. Obvious changes in eye movements, eyelid position and pupil reactions seen in the transition to sleep led to the investigation of orexin-A projections to visuomotor cell groups to determine whether direct pathways exist that may modify visuomotor behaviors during the sleep-wake cycle. Histological markers were used to define these specific visuomotor cell groups in monkey brainstem sections and combined with orexin-A immunostaining. The dense supply by orexin-A boutons around adjacent neurons in the dorsal raphe nucleus served as a control standard for a strong orexin-A input. The quantitative analysis assessing various functional cell groups of the oculomotor system revealed that almost no input from orexin-A terminals reached motoneurons supplying the singly-innervated muscle fibers of the extraocular muscles in the oculomotor nucleus, the omnipause neurons in the nucleus raphe interpositus and the premotor neurons in the rostral interstitial nucleus of the medial longitudinal fasciculus. In contrast, the motoneurons supplying the multiply-innervated muscle fibers of the extraocular muscles, the motoneurons of the levator palpebrae muscle in the central caudal nucleus, and especially the preganglionic neurons supplying the ciliary ganglion received a strong orexin input. We interpret these results as evidence that orexin-A does modulate pupil size, lid position, and possibly convergence and eye alignment via the motoneurons of multiply-innervated muscle fibres. However orexin-A does not directly modulate premotor pathways for saccades or the singly-innervated muscle fibre motoneurons.

MSTd neurons during ocular following and smooth pursuit perturbation.

MSTd neurons in the behaving monkey were investigated during step-ramp smooth pursuit eye movements (SPEM), short perturbations of the small visual target during ongoing pursuit, and large-field visual stimulation inducing ocular following responses (OFR). Neurons responded with short latencies to visual motion during OFR. In contrast the non-retinal responses during SPEM and perturbations followed the eye movements by 100-150 ms and were in the opposite direction to the OFR response. Often neurons were not modulated by the perturbation. Although, both the OFR and the perturbation response are involuntary eye movements due to visual motion, it seems very unlikely that these MSTd neurons with non-retinal responses are involved in their direct control. Based on these responses, we suggest that our MSTd neurons may code for gaze direction in space based on visual estimates of self-motion and extraretinal estimates of eye-in-head motion.

Enhanced motion sensitivity follows saccadic suppression in the superior temporal sulcus of the macaque cortex.

The responses of neurons in the middle temporal and medial superior temporal areas of macaque cortex are suppressed during saccades compared with saccade-like stimulus movements. We utilized the short-latency ocular following paradigm to show that this saccadic suppression is followed by postsaccadic enhancement of motion responses. The level of enhancement decays with a time constant of 100 ms from saccade end. The speed of ocular following is also enhanced after saccades and decays over a similar time course, suggesting a link between the neural and behavioral effects. There is some evidence that maximum postsaccadic enhancement occurs when cells are stimulated at their optimum speeds. Latencies of motion responses are saccade dependent: 37 ms for saccade-generated motion, 45 ms for motion in the half-second after saccades, and 70 ms with no prior saccades. The finding that saccades alter response latencies may partially explain perceptual time compression during saccades and time dilation after saccades.

Comparing acceleration and speed tuning in macaque MT: physiology and modeling.

Studies of individual neurons in area MT have traditionally investigated their sensitivity to constant speeds. We investigated acceleration sensitivity in MT neurons by comparing their responses to constant steps and linear ramps in stimulus speed. Speed ramps constituted constant accelerations and decelerations between 0 and 240 degrees /s. Our results suggest that MT neurons do not have explicit acceleration sensitivity, although speed changes affected their responses in three main ways. First, accelerations typically evoked higher responses than the corresponding deceleration rate at all rates tested. We show that this can be explained by adaptation mechanisms rather than differential processing of positive and negative speed gradients. Second, we inferred a cell's preferred speed from the responses to speed ramps by finding the stimulus speed at the latency-adjusted time when response amplitude peaked. In most cells, the preferred speeds inferred from deceleration were higher than those for accelerations of the same rate or from steps in stimulus speed. Third, neuron responses to speed ramps were not well predicted by the transient or sustained responses to steps in stimulus speed. Based on these findings, we developed a model incorporating adaptation and a neuron's speed tuning that predicted the higher inferred speeds and lower spike rates for deceleration responses compared with acceleration responses. This model did not predict acceleration-specific responses, in accordance with the lack of acceleration sensitivity in the neurons. The outputs of this single-cell model were passed to a population-vector-based model used to estimate stimulus speed and acceleration. We show that such a model can accurately estimate relative speed and acceleration using information from the population of neurons in area MT.

Rapid processing of retinal slip during saccades in macaque area MT.

The primate middle temporal area (MT) is involved in the analysis and perception of visual motion, which is generated actively by eye and body movements and passively when objects move. We studied the responses of single cells in area MT of awake macaques, comparing the direction tuning and latencies of responses evoked by wide-field texture motion during fixation (passive viewing) and during rewarded, target-directed saccades and non-rewarded, spontaneous saccades over the same stationary texture (active viewing). We found that MT neurons have similar motion sensitivity and direction-selectivity for retinal slip associated with active and passive motion. No cells showed reversals in direction tuning between the active and passive viewing conditions. However, mean latencies were significantly different for saccade-evoked responses (30 ms) and stimulus-evoked responses (67 ms). Our results demonstrate that neurons in area MT retain their direction-selectivity and display reduced processing times during saccades. This rapid, accurate processing of peri-saccadic motion may facilitate post-saccadic ocular following reflexes or corrective saccades.

Torsional eye movements during psychophysical testing with rotating patterns.

Torsional eye movements were measured while subjects viewed a large, high contrast windmill pattern rotating at 53 degrees /s or a small (5 degrees diameter) dot pattern rotating at 115 degrees /s. Both stimuli generated rotational eye movements consisting of torsional optokinetic nystagmus (tOKN) superimposed on a slow torsional drift in the direction of pattern rotation. With the wide-field windmill stimulus, torsional drifts of up to 7 degrees over 20 s were found. The dot pattern produced drifts of up to 2 degrees over 5-20 s. In both cases, the slow-phase speeds during tOKN were low (0.5-1 degrees /s). We conclude that reductions in slip speed are minimal with rotating stimuli, so torsional eye speeds will have a minimal effect on investigations of rotational motion aftereffect strength and perceived speed. While the slow-phase tOKN gain is low, the slow drift in torsional eye position will have significant effects on psychophysical results when the tests rely on keeping selected regions of the stimulus confined to specific areas of the retina, as is the case for phantom or remote motion aftereffects.

Information processing by parafoveal cells in the primate nucleus of the optic tract.

We recorded from single units in the pretectal nucleus of the optic tract (NOT) of the nonhuman primate. Specifically, we examined units that are modulated during smooth tracking of a small laser spot against a dark background. We used a nonlinear optimization procedure to determine whether the unit responses of these parafoveal cells are better described by a model that incorporates retinal error motion parameters or by a model that incorporates eye motion parameters. Our main finding was that all the cells in our sample group were better fit with a three-component model that incorporated retinal error motion parameters of position, velocity and acceleration (average coefficient of determination = 0.84) than a model that used position, velocity and acceleration components of eye motion (average coefficient of determination = 0.68). Other analyses involved comparison of goodness of fit between the three-component retinal error model and two-component retinal error models that excluded position or acceleration related terms. We found that there was a statistically significant degradation in the fit when position and acceleration related terms were dropped from the retinal error based model (P<0.05). Unit data from experiments in which the laser spot was extinguished for a brief period of time during tracking showed that the unit response was decreased following the target blink. We conclude on the basis of this and previous experimental data and our dynamic modeling approach that the parafoveal cells in the NOT primarily encode retinal error motion. Further they encode position, velocity and acceleration components of retinal error that could be used by other downstream structures for synthesis of a smooth-pursuit eye movement.

Gaze-stabilizing deficits and latent nystagmus in monkeys with brief, early-onset visual deprivation: eye movement recordings.

The normal development and the capacity to calibrate gaze-stabilizing systems may depend on normal vision during infancy. At the end of 1 yr of dark rearing, cats have gaze-stabilizing deficits similar to that of the newborn human infant including decreased monocular optokinetic nystagmus (OKN) in the nasal to temporal (N-T) direction and decreased velocity storage in the vestibuloocular reflex (VOR). The purpose of this study is to determine to what extent restricted vision during the first 2 mo of life in monkeys affects the development of gaze-stabilizing systems. The eyelids of both eyes were sutured closed in three rhesus monkeys (Macaca mulatta) at birth. Eyelids were opened at 25 days in one monkey and 40 and 55 days in the other two animals. Eye movements were recorded from each eye using scleral search coils. The VOR, OKN, and fixation were examined at 6 and 12 mo of age. We also examined ocular alignment, refraction, and visual acuity in these animals. At 1 yr of age, visual acuity ranged from 0.3 to 0.6 LogMAR (20/40-20/80). All animals showed a defect in monocular OKN in the N-T direction. The velocity-storage component of OKN (i.e., OKAN) was the most impaired. All animals had a mild reduction in VOR gain but had a normal time constant. The animals deprived for 40 and 55 days had a persistent strabismus. All animals showed a nystagmus similar to latent nystagmus (LN) in human subjects. The amount of LN and OKN defect correlated positively with the duration of deprivation. In addition, the animal deprived for 55 days demonstrated a pattern of nystagmus similar to congenital nystagmus in human subjects. We found that restricted visual input during the first 2 mo of life impairs certain gaze-stabilizing systems and causes LN in primates.

Gaze-stabilizing deficits and latent nystagmus in monkeys with early-onset visual deprivation: role of the pretectal not.

We studied the role of the pretectal nucleus of the optic tract (NOT) in the development of monocular optokinetic nystagmus (OKN) asymmetries and latent nystagmus (LN) in two monkeys reared with binocular deprivation (BD) caused by binocular eyelid suture for either the first 25 or 55 days of life. Single-unit recordings were performed in the right and left NOT of both monkeys at 2-3 yr of age and compared with similar unit recordings in normally reared monkeys. We also examined ocular motor behavior during electrical stimulation of the NOT and during pharmacological inactivation and activation using GABA(A) agonists and antagonists. In BD animals a large proportion of NOT units was dominated by the contralateral eye, in striking contrast to normal animals where 100% of NOT units were sensitive to stimuli delivered to either eye. In the 55-day BD animal no binocularly sensitive neurons were found, while in the 25-day BD animal 60% of NOT units retained at least some binocular sensitivity. Differences in direction sensitivity were also observed in BD animals. We found that 56% of units in the 55-day BD monkey and 10% of units in the 25-day BD monkey responded preferentially to contraversive visual motion. In contrast, only 5% of the NOT units encountered in normally reared monkeys respond preferentially during contraversive visual motion, the rest were most sensitive to ipsiversive visual motion. NOT neurons of BD monkeys showed a wide range of speed sensitivities similar to that of normal monkeys. Unilateral electrical stimulation of the NOT in BD animals induced a conjugate nystagmus with slow phases directed toward the side of stimulation. When we blocked the activity of NOT units with muscimol, a potent GABA(A) agonist, LN was abolished. In contrast, LN was increased when spontaneous activity of the NOT was enhanced with bicuculline, a GABA(A) antagonist. Our results indicate that the NOT in BD monkeys plays an important role in the OKN deficits and LN generation during monocular viewing. We hypothesize that the large proportion of units dominated by the contralateral eye contribute to the development of monocular OKN asymmetries and LN.

The anatomical organization of the macaque pregeniculate complex.

Saccade-related activity recorded in the primate pregeniculate nucleus, and its anatomical connections with the pretectal nucleus of the optic tract (NOT) and superior colliculus (SC), suggest that it plays a role in visual-ocular motor integration. To study this role, a clearer understanding of pregeniculate organization is required. Based on its connectivity and neurotransmitter immunocytochemistry, we demonstrate that this nucleus is composed of several subnuclei, suggesting the term, pregeniculate complex (PrGC). The PrGC includes a weakly developed dorsal lamina, rostrally, and a well-developed ventral lamina. The ventral lamina includes the retinorecipient and superior sublayers, rostrally, and the medial division, caudally. A thin lamina of cells lateral to the dorsal lateral geniculate nucleus is contiguous with the PrGC; we term this the lateral division. The PrGC and the lateral division each project to the SC/NOT; the superior sublayer and medial division of the PrGC are connected reciprocally to the SC/NOT. Immunocytochemistry for gamma-aminobutyric acid (GABA) and substance P (SP) further delineate the PrGC subnuclei. The retinorecipient sublayer stains most intensely for GABA and SP. The superior sublayer and medial division also stain strongly for GABA and SP. Essentially all neurons in the lateral division are GABA-positive. The combination of tract tracing and immunocytochemistry demonstrate differences in the connectivity of the PrGC subnuclei and the lateral division with the SC/NOT. This, combined with the differential localization of GABA in the PrGC, provides a basis for further study of its functional role.

Role of the pretectal nucleus of the optic tract in short-latency ocular following responses in monkeys.

When a large-field image is suddenly moved in front of an observer, an ocular following response (OFR) with short latency (<60 ms in monkey and <85 ms in human) is observed. Previous studies have shown that neurons in the pretectal nucleus of the optic tract (NOT) of the monkey respond to movements of large-field visual stimuli. To understand the potential role of the NOT in the OFR, we first recorded single-unit activity in the NOT of four monkeys (Macaca fuscata). Sixty-six NOT neurons preferred large-field ipsiversive visual motion. In 86% (49/57) of the neurons, optimal directions were distributed over +/-30 degrees from ipsilateral. NOT units were sensitive to the speed of the visual motion; 54% (27/50) preferred slow (< or =20 degrees/s), 22% (11/50) preferred fast (> or =80 degrees/s) and the remainder intermediate speeds. Their response latencies to the moving visual scene were very short (approximately 51 ms), and 44% of them led the onset of the OFR by 10 ms or more. To characterize the response properties of these neurons, we reconstructed the temporal firing patterns of 17 NOT neurons, using the acceleration, velocity, position and bias components of retinal image slip or eye movements during the OFR by a least squares error method. For each stimulus speed fitting condition, using either retinal slip or eye movements, their firing patterns were matched to some extent although the goodness of fit was better using retinal slip than when eye movements were used. Neither of these models could be applied independently of stimulus speed, suggesting that the firing pattern of the NOT neurons represented information associated with retinal slip or eye movements during the OFR, over a limited range. To provide further evidence that the NOT is involved in generating the OFR, we placed unilateral microinjections of muscimol into the NOT. Following the muscimol injection, we observed a approximately 50% decrease in eye velocity of the OFR toward the side of injection regardless of stimulus speed, while only a weak effect was observed in the OFR during contraversive or vertical image motion. These results suggest that the NOT may play a role in the initiation and support of the short-latency ocular following response.

Asymmetric responses in cortical visually evoked potentials to motion are not derived from eye movements.

PURPOSE: Normal neonates and many adults after abnormal visual development have directional preferences for visual stimulus motions; i.e., they give better responses for optokinetic nystagmus (OKN) and visually evoked potentials (VEPs) in one direction than to those in the opposite direction. The authors tested whether the VEP responses were asymmetrical because of abnormal eye movements. METHODS: VEPs were recorded from the visual cortices of five macaque monkeys: one normal, one neonate, and three reared with alternating monocular occlusion (AMO). They were lightly anesthetized, followed by paralysis to prevent eye movements. They then had "jittered" vertical grating patterns presented in their visual fields. The steady state VEPs were analyzed with discrete Fourier transforms to obtain the amplitudes and phases of the asymmetries. RESULTS: The normal, control monkey had small, insignificant amplitudes of its asymmetrical Fourier component and random phases that were not 180 degrees out of phase across the left and right eyes. The neonatal monkey and the AMO monkeys all had large, significant asymmetries that were approximately 180 degrees out of phase between the left and right eyes. CONCLUSIONS: The neonate and abnormally reared monkeys continued to have asymmetrical responses even after their eyes were paralyzed. Therefore, eye movements cannot be the source of the asymmetrical amplitudes of the VEPs, and the visual cortex is at least one source responsible for asymmetries observed in neonates and adults reared under abnormal visual inputs.

Response properties of pretectal omnidirectional pause neurons in the behaving primate.

We have identified a region in the pretectum of rhesus monkeys (Macaca mulatta) that contains units that evince a complete cessation in firing immediately after saccades. The pause occurs for saccades to target steps and catch up saccades during smooth pursuit, spontaneously in complete darkness or after quick phases of nystagmus. Because the pause in unit firing always follows saccade onset, we call these neurons following omnidirectional pause neurons (FOPNs). Because the pause also occurs with saccades in the dark, it is related to the saccade per se and is not a visually contingent response. The duration of the pause in firing exceeded the duration of all saccades up to 40 deg. For targeting saccades, the start of the pause was locked rather tightly to the beginning of the saccade but began an average of 51 ms after the saccade did. The end of the pause was linked only loosely to either the beginning or end of the saccade. About half (54%) of our 59 FOPNs also discharged a distinct burst of firing that preceded the pause. In different units, the burst preceded saccade onset by from 0 to 20 ms with an average of 11 ms and therefore could signal the occurrence of an impending saccade. The presaccadic burst was not correlated with any parameter of the saccade. Most FOPNs were found 278 microns, on average, dorsal to the direction-selective units characteristic of the pretectal nucleus of the optic tract (NOT) and occasionally slightly beyond the anterior-posterior and medial-lateral borders of the NOT. The FOPN region does not coincide with any known anatomically or functionally delineated pretectal nucleus. Because the characteristics of the FOPN pause are not reflected in the characteristics of the saccade and the FOPN pause occurs well after the saccade is over, it is unlikely that the pause in pretectal FOPNs is involved with saccade generation. On the other hand, the leading burst exhibited by the majority of FOPNs reliably signals that a saccade is occurring but neither its size nor direction. Perhaps this signal indicating the occurrence of all saccades is routed to visual relay neurons to effect saccadic modification of visual pathways. The substantial efferent connections of the FOPN/NOT region to the pregeniculate nucleus and the saccadic discharge or pregeniculate cells are discussed in the context of this suggestion.

Transneuronal pathways to the vestibulocerebellum.

The alpha-herpes virus (pseudorabies, PRV) was used to observe central nervous system (CNS) pathways associated with the vestibulocerebellar system. Retrograde transneuronal migration of alpha-herpes virions from specific lobules of the gerbil and rat vestibulo-cerebellar cortex was detected immunohistochemically. Using a time series analysis, progression of infection along polyneuronal cerebellar afferent pathways was examined. Pressure injections of > 20 nanoliters of a 10(8) plaque forming units (pfu) per ml solution of virus were sufficient to initiate an infectious locus which resulted in labeled neurons in the inferior olivary subnuclei, vestibular nuclei, and their afferent cell groups in a progressive temporal fashion and in growing complexity with increasing incubation time. We show that climbing fibers and some other cerebellar afferent fibers transported the virus retrogradely from the cerebellum within 24 hours. One to three days after cerebellar infection discrete cell groups were labeled and appropriate laterality within crossed projections was preserved. Subsequent nuclei labeled with PRV after infection of the flocculus/paraflocculus, or nodulus/uvula, included the following: vestibular (e.g., z) and inferior olivary nuclei (e.g., dorsal cap), accessory oculomotor (e.g., Darkschewitsch n.) and accessory optic related nuclei, (e.g., the nucleus of the optic tract, and the medial terminal nucleus); noradrenergic, raphe, and reticular cell groups (e.g., locus coeruleus, dorsal raphe, raphe pontis, and the lateral reticular tract); other vestibulocerebellum sites, the periaqueductal gray, substantia nigra, hippocampus, thalamus and hypothalamus, amygdala, septal nuclei, and the frontal, cingulate, entorhinal, perirhinal, and insular cortices. However, there were differences in the resulting labeling between infection in either region. Double-labeling experiments revealed that vestibular efferent neurons are located adjacent to, but are not included among, flocculus-projecting supragenual neurons. PRV transport from the vestibular labyrinth and cervical muscles also resulted in CNS infections. Virus propagation in situ provides specific connectivity information based on the functional transport across synapses. The findings support and extend anatomical data regarding vestibulo-olivo-cerebellar pathways.