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Background: Lymph node (LN) involvement is a poor prognostic factor for malignant pleural mesothelioma (MPM). However, to our knowledge, postresection outcomes of node-negative (cN0/pN0), occult pathologic nodal disease (cN0/pN+), and clinical node-positive disease (cN+) have not been compared to date., Patients and Methods: The National Cancer Data Base was queried for newly diagnosed, resected MPM with known clinical/pathologic LN information. Three cohorts were compared: cN0/pN0, cN+, and cN0/pN+. Multivariable logistic regression examined predictors of pathologic nodal upstaging. Kaplan-Meier analysis with propensity matching assessed overall survival (OS); multivariate Cox proportional hazards modeling examined predictors thereof., Results: Of 1369 patients, 687 (50%) had cN0/pN0, 457 (33%) cN+, and 225 (16%) cN0/pN+ disease. Median follow-up was 29 months. In patients with cN0 disease, factors associated with pathologic nodal upstaging were younger age, greater number of examined LNs, and nonsarcomatoid histology (P < .05 for all). Relative to pN0 cases, occult LN involvement (65% being pN2) was associated with 51% higher hazard of mortality on multivariate analysis (P = .005). Following propensity matching, the OS of cN0/pN+ was similar to cN+ cases (P = .281). On multivariate analysis, the number of involved LNs (continuous variable, P = .013), but not nodal tumor, node, metastasis (TNM) classification or LN ratio (P > .05 for both), was associated with OS., Conclusion: Detecting occult nodal disease during resection for cN0 MPM is associated with poorer prognosis, with similar survival as cN+ cases, underscoring the importance of routine preoperative pathologic nodal assessment for potentially resectable MPM. The number of involved LNs (rather than current location-based classification) may provide more robust prognostic stratification for future TNM staging., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The organization of extraocular muscles (EOMs) and their motor nuclei was investigated in the mouse due to the increased importance of this model for oculomotor research. Mice showed a standard EOM organization pattern, although their eyes are set at the side of the head. They do have more prominent oblique muscles, whose insertion points differ from those of frontal-eyed species. Retrograde tracers revealed that the motoneuron layout aligns with the general vertebrate plan with respect to nuclei and laterality. The mouse departed in some significant respects from previously studied species. First, more overlap between the distributions of muscle-specific motoneuronal pools was present in the oculomotor nucleus (III). Furthermore, motoneuron dendrites for each pool filled the entire III and extended beyond the edge of the abducens nucleus (VI). This suggests mouse extraocular motoneuron afferents must target specific pools based on features other than dendritic distribution and nuclear borders. Second, abducens internuclear neurons are located outside the VI. We concluded this because no unlabeled abducens internuclear neurons were observed following lateral rectus muscle injections and because retrograde tracer injections into the III labeled cells immediately ventral and ventrolateral to the VI, not within it. This may provide an anatomical substrate for differential input to motoneurons and internuclear neurons that allows rodents to move their eyes more independently. Finally, while soma size measurements suggested motoneuron subpopulations supplying multiply and singly innervated muscle fibers are present, markers for neurofilaments and perineuronal nets indicated overlap in the size distributions of the two populations. Anat Rec, 302:1865-1885, 2019. © 2019 American Association for Anatomy., (© 2019 American Association for Anatomy.)

Background: Conventional radiation therapy (RT) has produced unprecedented cure rates in patients with Hodgkin's lymphoma (HL) but exposed large volumes of nontargeted tissue to radiation (integral dose)., Objective: Our goal was to report the effects of integral radiation dose on health outcomes in patients with at least 20 years of potential follow-up time., Methods and Materials: We reviewed the medical records of 365 patients who were treated with RT for HL between 1965 and 1995. All patients were confirmed to have received primary RT with curative intent at our institution for de novo HL. Serious adverse events were classified as HL progression or death, grade ≥3 treatment- or staging-related acute or late effects, second malignancies, or cardiovascular events., Results: The minimum potential follow-up time was 20 years, and the actual median follow-up time 22 years (range, <1-49 years) for all patients and 27 years (range, 5-49 years) for surviving patients. The overall survival rates at 5, 10, 20, 30, and 40 years were 86%, 76%, 64%, 44%, and 27%, respectively. The observed-to-expected ratio for second malignancy was 3.6 (95% confidence interval, 2.9-4.4). Grade ≥3 cardiovascular events occurred in 31% of all patients (n = 112). At the time of the most recent follow up, serious adverse events occurred in 70% of the entire cohort (n = 256) and 58% (n = 103), 77% (n = 103), and 93% (n = 50) among those with a potential 20, 30, and 40 years of follow up, respectively., Conclusions: With increased survivorship, the long-term impact of the integral radiation dose may result in clinically significant adverse events, which suggests the importance of surveillance and affirms advances in both chemotherapy and RT that minimize the integral dose in future patients with HL., (© 2019 The Authors.)

Background: Vaginal dilators (VD) are recommended following vaginal or pelvic radiotherapy for patients with endometrial carcinoma (EC) to prevent vaginal stenosis (VS). The time course of VS is not fully understood and the optimal duration of VD use is unknown., Methods: We reviewed 243 stage IA-II EC patients who received adjuvant brachytherapy (BT) at an academic tertiary referral center. Patients were instructed to use their VD three times per week for at least 1-year duration. The primary outcome was development of grade ≥ 1 VS using CTCAEv4 criteria during the follow-up period. The log-rank test and multivariable Cox proportional hazards modeling were used to evaluate the effect of VD use (noncompliance vs. standard compliance [up to 1 year] vs. extended compliance [over 1 year]) on VS., Results: The median follow-up was 15.2 months over the 5-year study period. At 15 months, the incidence of VS was 38.8% for noncompliant patients, 33.5% for those with standard compliance, and 21.4% for those with extended compliance (median time to grade ≥ 1 VS was 17.5 months, 26.7 months, and not yet reached for these groups, respectively). On multivariable Cox regression analysis, extended compliance remained a significant predictor of reduced VS risk when compared to both noncompliance (HR 0.38, 95% CI 0.18-0.80, p = 0.012) and standard compliance (HR 0.43, 95% CI 0.20-0.89, p = 0.023)., Conclusions: The risk of VS persists beyond 1 year after BT. Extended VD compliance beyond 1 year may mitigate this risk.

Purpose: We assessed the cost-effectiveness of adjuvant intravaginal brachytherapy (IVBT) vs. observation after total hysterectomy and bilateral salpingo-oophorectomy (TH/BSO) for high-intermediate risk (HIR) endometrial carcinoma., Methods and Materials: A Markov model was used to assess the cost-effectiveness of IVBT by comparing average cumulative costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) between patients allocated to (1) 'observation' or (2) 'IVBT' after TH/BSO. We used a prototype Post-Operative Radiation Therapy in Endometrial Carcinoma (PORTEC)-defined HIR patient in the base case analysis. We calibrated the model to match the outcomes reported in the PORTEC-1 and PORTEC-2 trials. Utilities were obtained from published estimates, and costs were calculated based on Medicare reimbursement ($5445 for IVBT). The societal willingness-to-pay threshold was set at $100,000 per QALY. The time horizon was 5 years., Results: IVBT was associated with a net increase of 0.094 QALYs (4.512 vs. 4.418) as well as an increase in mean cost ($17,453 vs. $15,620) relative to observation. The ICER for IVBT was $19,500 per QALY. On one-way sensitivity analysis, IVBT remained cost-effective when its cost was less than $12,937. If the probability of vaginal recurrence in the observation arm was increased or decreased by 25%, the ICER became $1335 per QALY and $87,925 per QALY, respectively. Probabilistic sensitivity analysis revealed that IVBT was the preferred management option in 86% of simulations., Conclusions: IVBT is cost-effective compared with observation after TH/BSO for HIR endometrial carcinoma by commonly accepted willingness-to-pay thresholds., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Purpose: For inoperable stage I (T1-T2N0) small cell lung cancer (SCLC), national guidelines recommend chemotherapy with or without conventionally fractionated radiation therapy. The present multi-institutional cohort study investigated the role of stereotactic ablative radiation therapy (SABR) for this population., Methods and Materials: The clinical and treatment characteristics, toxicities, outcomes, and patterns of failure were assessed in patients with histologically confirmed stage T1-T2N0M0 SCLC. Kaplan-Meier analysis was used to evaluate the survival outcomes. Univariate and multivariate analyses identified predictors of outcomes., Results: From 24 institutions, 76 lesions were treated in 74 patients (median follow-up 18 months). The median age and tumor size was 72 years and 2.5 cm, respectively. Chemotherapy and prophylactic cranial irradiation were delivered in 56% and 23% of cases, respectively. The median SABR dose and fractionation was 50 Gy and 5 fractions. The 1- and 3-year local control rate was 97.4% and 96.1%, respectively. The median disease-free survival (DFS) duration was 49.7 months. The DFS rate was 58.3% and 53.2% at 1 and 3 years, respectively. The median, 1-year, and 3-year disease-specific survival was 52.3 months, 84.5%, and 64.4%, respectively. The median, 1-year, and 3-year overall survival (OS) was 17.8 months, 69.9%, and 34.0% respectively. Patients receiving chemotherapy experienced an increased median DFS (61.3 vs 9.0 months; P=.02) and OS (31.4 vs 14.3 months; P=.02). The receipt of chemotherapy independently predicted better outcomes for DFS/OS on multivariate analysis (P=.01). Toxicities were uncommon; 5.2% experienced grade ≥2 pneumonitis. Post-treatment failure was most commonly distant (45.8% of recurrence), followed by nodal (25.0%) and "elsewhere lung" (20.8%). The median time to each was 5 to 7 months., Conclusions: From the findings of the largest report of SABR for stage T1-T2N0 SCLC to date, SABR (≥50 Gy) with chemotherapy should be considered a standard option., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: To determine the effect of biologically effective dose (BED 10 ) and radiation treatment schedule on overall survival (OS) in patients with early-stage non-small cell lung cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT)., Methods and Materials: Using data from 65 treatment centers in the United States, we retrospectively reviewed the records of T1-2 N0 NSCLC patients undergoing SBRT alone from 2006 to 2014. Biologically relevant covariates, including dose per fraction, number of fractions, and time between fractions, were used to quantify BED 10 and radiation treatment schedule. The linear-quadratic equation was used to calculate BED 10 and to generate a dichotomous dose variable of <105 Gy versus ≥105 Gy BED 10 . The primary outcome was OS. We used the Kaplan-Meier method, the log-rank test, and Cox proportional hazards regression with propensity score matching to determine whether prescription BED 10 was associated with OS., Results: We identified 747 patients who met inclusion criteria. The median BED 10 was 132 Gy, and 59 (7.7%) had consecutive-day fractions. Median follow-up was 41 months, and 452 patients (60.5%) had died by the conclusion of the study. The 581 patients receiving ≥105 Gy BED 10 had a median survival of 28 months, whereas the 166 patients receiving <105 Gy BED 10 had a median survival of 22 months (log-rank, P=.01). Radiation treatment schedule was not a significant predictor of OS on univariable analysis. After adjusting for T stage, sex, tumor histology, and Eastern Cooperative Oncology Group performance status, BED 10 ≥105 Gy versus <105 Gy remained significantly associated with improved OS (hazard ratio 0.78, 95% confidence interval 0.62-0.98, P=.03). Propensity score matching on imbalanced variables within high- and low-dose cohorts confirmed a survival benefit with higher prescription dose., Conclusions: We found that dose escalation to 105 Gy BED 10 and beyond may improve survival in NSCLC patients treated with SBRT., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This paper considers the utility of several alternative energy measures to reduce the energy required by a stimulation current source to charge a neuron membrane capacitance to a prescribed value in the case of a single sodium channel. For a simple case, minimizing the energy of the nonlinear channel conductance provides improved efficiency in terms of stimulator energy as compared to minimizing a squared-integral measure of the stimulation current. This work lays the foundation for expanding this investigation to a full conductance-based Hodgkin-Huxley model.

Purpose: The purpose of this study was to examine the impact of robotic-assisted laparoscopic hysterectomy (RALH) compared with total abdominal hysterectomy by laparotomy (TAH) on vaginal cuff healing in early-stage endometrial carcinoma patients receiving adjuvant intravaginal brachytherapy (IVBT)., Methods and Materials: We included 137 consecutive patients who underwent adjuvant IVBT without external beam radiation therapy or chemotherapy for stage I-II endometrial carcinoma. All patients underwent either RALH or TAH. Vaginal cuff healing status as assessed by inspection and palpation at initial evaluation by radiation oncology (VC1) was the primary outcome, with secondary outcomes including vaginal cuff healing status at first scheduled IVBT (VC2), time interval from hysterectomy to initiation of IVBT, and local recurrence., Results: Among 137 patients, 74 (54.0%) underwent RALH and 63 (46.0%) underwent TAH. There was no significant difference in mean time from hysterectomy to initial radiation oncology evaluation between RALH and TAH patients (approximately 30 days in both groups). RALH was the only covariate associated with protracted vaginal cuff healing time at both VC1 (P = .003) and VC2 (P = .038). There was a significantly increased mean interval between hysterectomy and start of IVBT for patients undergoing RALH from 47.7 to 55.0 days (P < .001). Vaginal cuff healing was more likely to contribute to delay in delivery of IVBT in RALH patients, whereas abdominal or other nonvaginal wound healing was more likely to contribute to delay in TAH patients. There were no vaginal cuff recurrences detected after 16 months median follow-up., Conclusions: RALH for early-stage endometrial carcinoma was associated with longer vaginal cuff healing time and a mean increase in interval from hysterectomy to IVBT of 1 week compared with TAH., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Numerous studies have reported the ability of mobile phones to distract users and thereby degrade performance of concurrent tasks. Less is known about whether the phone-holding posture can itself influence concurrent motor activities. Horizontal eye movements are often coordinated with head movements, particularly when the amplitude of the gaze shift is large. Holding a phone to one ear has been shown to restrict the range of spontaneously generated head movements. In order to determine whether the phone-holding posture also influences gaze, we recorded eye and head movements as volunteers looked about themselves spontaneously. Holding the phone to the ear narrowed the range of gaze, principally in subjects who exhibit a strong propensity to move the head with the eyes. We argue that visual exploration may be influenced by the balance between costs and benefits of turning the head, with the phone-holding posture increasing the costs. The effects on gaze would be seen most clearly in subjects who have a higher predilection for coupling eye and head movements. Conversely, this effect would be minimal if tested in tasks that rarely elicit head movements in the specific subjects being tested. The results emphasize the close coordination between eye and head movements, and have implications for the design of ergonomic studies comparing the effects of handheld vs. hands-free mobile phones on performance of specific tasks, such as driving., (Published by Elsevier B.V.)

Humans exhibit considerable individuality in their propensity to make head movements during horizontal saccades. These variations originate in multiple quantifiable characteristics, including individuals' preferred ranges of gaze, eye-in-head, and head-on-neck eccentricity. Such "eye-head tendencies" have been uniformly assessed in seated subjects. It is unknown whether they continue to influence behavior when subjects are in motion. Previous studies of eye-head coordination in subjects ambulating in laboratories would predict that wholly different eye-head tendencies become ascendant when subjects ambulate. We tested this prediction by recording eye and head positions in normal subjects in an outdoor environment as they spontaneously regarded their surroundings while seated, passively riding in a wheelchair, and ambulating. Individuals exhibited the usual subject-to-subject variations in the preferred ranges of eye, head, and gaze position, but their own behavior was similar across the different conditions. While ambulation did affect some of the measured eye-head tendencies, passively riding had similar effects, indicating that these effects relate more to motion through the environment than to the act of walking. In a surprising departure from studies of eye-head coordination in subjects ambulating in laboratory environments, neither head nor gaze was particularly strongly aligned with the direction of travel. Thus, the neural mechanisms of walking do not demand that specific gaze or head orientations be maintained continuously, at least not in the common situation of a non-challenging path that can be negotiated without much attention. In such situations eye and head control is flexible, and the eye-head tendencies manifesting when stationary can emerge.

Humans with cerebellar degeneration commonly exhibit downbeat nystagmus (DBN). DBN has gravity-independent and -dependent components, and the latter has been proposed to reflect hyperactive tilt maculo-ocular reflexes (tilt-MOR). Mice with genetically determined cerebellar ataxia do not exhibit DBN, but they do exhibit tonic hyperdeviation of the eyes, which we have proposed to be the DBN equivalent. As such, the tilt-MOR might be predicted to be hyperactive in these mutant mice. We measured the tilt-MOR in 10 normal C57BL/6 mice and in 6 tottering, a mutant exhibiting ataxia and ocular motor abnormalities due to mutation of the P/Q calcium channel. Awake mice were placed in body orientations spanning 360 degrees about the pitch axis. The absolute, equilibrium vertical angular deviations of one eye were measured using infrared videooculography. In both strains, eye elevation varied quasi-sinusoidally with tilt angle in the range of 90 degrees nose-up to 90 degrees nose-down. Beyond this range the eye returned to a neutral position. Deviation over +/-30 degrees of tilt was an approximately linear function of the projection of the gravity vector into the animal's horizontal plane, and can thus be summarized by its slope (sensitivity). Sensitivity measured 14.9 degrees/g for C57BL/6 and 20.3 degrees/g for tottering, a statistically significant difference. Thus the pitch otolithic reflex of the ataxic mutants is hyperactive relative to controls and could explain tonic hyperdeviation of the eyes, consistent with the idea that the tonic hyperdeviation is analogous to DBN.

Purpose: The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy., Methods: ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined., Results: Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphorylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function., Conclusions: The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.

The ability to dissociate eye movements from head movements is essential to animals with foveas and fovea-like retinal specializations, as these species shift the eyes constantly, and moving the head with each gaze shift would be impractical and energetically wasteful. The processes by which the dissociation is effected remain unclear. We hypothesized that the dissociation is accomplished by means of a neural gate, which prevents a common gaze-shift command from reaching the neck circuitry when eye-only saccades are desired. We further hypothesized that such a gate would require a finite period to reset following opening to allow a combined eye-head saccade, and thus the probability of generating a head movement during a saccade would be augmented when a new visual target (the 'test' target) appeared during, or soon after, a combined eye-head saccade made to an earlier, 'conditioning' target. We tested human subjects using three different combinations of targets-a horizontal conditioning target followed by a horizontal test target (H/H condition), horizontal conditioning followed by vertical test (H/V), and vertical conditioning followed by horizontal test (V/H). We varied the delay between the onset of the conditioning head movement and the presentation of the test target, and determined the probability of generating a head movement to the test target as a function of target delay. As predicted, head movement probability was elevated significantly at the shortest target delays and declined thereafter. The half-life of the increase in probability averaged 740, 490, and 320 ms for the H/H, H/V, and V/H conditions, respectively. For the H/H condition, the augmentation appeared to outlast the duration of the conditioning head movement. Because the augmentation could outlast the conditioning head movement and did not depend on the head movements to the conditioning and test targets lying in the same directions, we could largely exclude the possibility that the augmentation arises from mechanical effects. These results support the existence of the hypothetical eye-head gate, and suggest ways that its constituent neurons might be identified using neurophysiological methods.

The deaf-circling Ames waltzer (av) mouse harbors a mutation in the protocadherin 15 (Pcdh15) gene and is a model for inner ear defects associated with Usher syndrome type 1F. Earlier studies showed altered cochlear hair cell morphology in young av mice. In contrast, no structural abnormality consistent with significant vestibular dysfunction in young av mice was observed. Light and scanning electron microscopic studies showed that vestibular hair cells from presumptive null alleles Pcdh15(av-Tg) and Pcdh15(av-3J) are morphologically similar to vestibular sensory cells from control littermates, suggesting that the observed phenotype in these alleles might be a result of a central, rather than peripheral, defect. In the present study, a combination of physiologic and anatomic methods was used to more thoroughly investigate the source of vestibular dysfunction in Ames waltzer mice. Analysis of vestibular evoked potentials and angular vestibulo-ocular reflexes revealed a lack of physiologic response to linear and angular acceleratory stimuli in Pcdh15 mutant mice. Optokinetic reflex function was diminished but still present in the mutant animals, suggesting that the defect is primarily peripheral in nature. These findings indicate that the mutation in Pcdh15 results in either a functional abnormality in the vestibular receptor organs or that the defects are limited to the vestibular nerve. AM1-43 dye uptake has been shown to correlate with normal transduction function in hair cells. Dye uptake was found to be dramatically reduced in Pcdh15 mutants compared to control littermates, suggesting that the mutation affects hair cell function, although structural abnormalities consistent with significant vestibular dysfunction are not apparent by light and scanning electron microscopy in the vestibular neuroepithelia of young animals.

Time constants of gaze holding are shortened in rocker and tottering mice, two strains whose cerebellar dysfunction stems from genetic alterations of the P/Q calcium channel. The finding suggests that in mice as in primates, the cerebellum contributes to the function of the neural integrator. Studying CACNA1A mutants may elucidate how cerebellar signals support gaze holding.

We conducted a two-year follow-up study of 40 patients with MS in whom we had reported that abnormal eye movements (AEM) were associated with greater general disability. AEM patients (17/40) remained significantly (p < .001) more disabled (median EDSS of 7.0) than those with normal eye movements (median EDSS of 5.0). AEM and great disability were associated with abnormal MRI signals in brainstem or cerebellum, where disease may involve control circuits for eye movements as well as descending motor pathways.

Two patients sharing a novel mutation of the CACNA1A gene for P/Q calcium channels showed significant slowing of adducting saccades compared with normal subjects or patients with cerebellar disease. Internuclear ophthalmoparesis (INO) was clinically evident in one. While these findings might be specific to this mutation, INO in our patients with episodic ataxia type 2 suggested involvement outside the cerebellum, either in the brain-stem internuclear pathway or at the neuromuscular junction.

Examining eye movements is an important part of the neurological evaluation of humans; the distribution of the neural circuits that control these movements is such that they are disrupted--often in highly characteristic fashions--by many disease processes. Technical advances have made it possible to measure accurately the eye movements of mice, so it is now possible to use the detective power of eye movement recording to characterize neurological dysfunction in genetically altered strains. Here we introduce analytical tools used in ocular motor research and demonstrate their ability to reveal disorders of the visual pathways, inner ear, and cerebellum.

Thanks to technical advances in eye movement recording, the mouse is destined to become increasingly important in ocular motor research. An advantage of this species is the wide range of existing mutant strains and techniques to generate new mutations affecting specific cell types. Mutations of ion channels may be used to modulate the intrinsic properties of neurons, and this approach may generate insight into the degree to which neuronal computations depend upon those intrinsic properties as opposed to the properties of circuits of neurons. Dendritic calcium currents carried by P-type voltage-activated calcium channels have been widely postulated to perform important computational functions in cerebellar Purkinje cells. Mutations of this channel lead to human diseases, and several ataxic strains of mice are now known to harbor mutations of this calcium channel. Murine P-channel mutants such as rocker are ataxic, but have normal or near-normal numbers of cerebellar Purkinje cells and thus offer the opportunity to study the effects of biophysical perturbations as opposed to outright cell destruction or inactivation. Initial studies of rocker mice reveal an array of ocular motor abnormalities, including static hyperdeviation of the eyes and an attenuation of vestibulo-ocular reflex gains at high stimulus frequencies. The pattern of gain and phase abnormalities is entirely different in lurcher, an ataxic mutant in which Purkinje cells degenerate. The ocular motor abnormalities of rocker progress with animal age, underscoring the importance of careful attention to animal age when performing ocular motor studies in this short-lived species.