Route sequence knowledge supports the formation of cognitive maps.

In this study, we examined the extent to which knowledge about the sequence of places encountered during route learning supports the formation of a metric cognitive map. In a between subjects design, participants learned a route until they could navigate it independently without error whilst also learning information about either the identity of places along the route (Recognition Learning condition) or the sequence of places along the route (Sequence Learning condition). In a follow-up Reconstruction of Order Task, we confirmed that participants in the Sequence Learning condition had more accurate route sequence knowledge than those in the Recognition Learning condition, despite requiring the same overall number of trials to learn the route. Participants then completed a Pointing Task to assess the quality of their cognitive map of the environment. Both groups performed above chance level, showing incidental encoding of metric information, but the Sequence Learning group produced significantly lower pointing errors than the Recognition Learning group. Further, we found that route distance between pairs of places was a strong predictor of pointing error in both groups, whilst Euclidean distance between places was a significant, but weak, predictor only for the Sequence Learning condition. The results of this study demonstrate that discrete route sequence knowledge directly supports the formation of metric cognitive maps. We consider how the results are best explained by interactions between striatal route representations and hippocampal metric representations, centered around the sequence of places acting as a scaffold for the encoding of metric information.

From repeating routes to planning novel routes: the impact of landmarks and ageing on route integration and cognitive mapping.

The integration of intersecting routes is an important process for the formation of cognitive maps and thus successful navigation. Here we present a novel task to study route integration and the effects that landmark information and cognitive ageing have on this process. We created two virtual environments, each comprising five places and one central intersection but with different landmark settings: in the Identical Landmark environment, the intersection contained visually monotonic features whereas the intersection contained visually distinctive features in the Different Landmarks environment. In both environments young and older participants were presented with two short routes that both traversed through the shared intersection. To test route integration, participants were asked to either repeat the learning routes, to navigate the routes from the destination to the starting place or to plan novel routes. As expected, results demonstrate better performance when repeating or retracing routes than when planning novel routes. Performance was better in younger than older participants and in the Different Landmark environment which does not require detailed knowledge of the spatial configuration of all places in the environment. A subgroup of the older participants who performed lower on a screening test for cognitive impairments could not successfully complete the experiment or did not reach the required performance criterion. These results demonstrate that strategically placed landmarks support the integration of route knowledge into spatial representations that allow for goal-dependent flexible navigation behaviour and that earliest signs of atypical cognitive ageing affect this process of route integration.

Bilateral Vestibular Schwannomas in a Patient with Ring Chromosome 22: Case Report and Review of the Literature.

INTRODUCTION: Ring chromosome 22 (r[22]) can lead to the development of intracranial tumors such as meningiomas, neurofibromas, and schwannomas similar to neurofibromatosis 2 (NF2). CASE PRESENTATION: An 18-year-old female with r(22) and a history of global development delay and cognitive impairment presented with sudden hearing loss. MRI revealed bilateral vestibular schwannomas. Given documented audiologic decline in the patient's hearing, the larger tumor was treated with CyberKnife fractionated stereotactic radiosurgery, and the smaller tumor is being monitored. CONCLUSION: This case provides further evidence that patients with r(22) can develop clinical features of NF2, including the development of bilateral vestibular schwannomas, and should be monitored for hearing disturbances starting in puberty as a warning sign for these tumors.

Are age-related deficits in route learning related to control of visual attention?

Typically aged adults show reduced ability to learn a route compared to younger adults. In this experiment, we investigate the role of visual attention through eye-tracking and engagement of attentional resources in age-related route learning deficits. Participants were shown a route through a realistic virtual environment before being tested on their route knowledge. Younger and older adults were compared on their gaze behaviour during route learning and on their reaction time to a secondary probe task as a measure of attentional engagement. Behavioural results show a performance deficit in route knowledge for older adults compared to younger adults, which is consistent with previous research. We replicated previous findings showing that reaction times to the secondary probe task were longer at decision points than non-decision points, indicating stronger attentional engagement at navigationally relevant locations. However, we found no differences in attentional engagement and no differences for a range of gaze measures between age groups. We conclude that age-related changes in route learning ability are not reflected in changes in control of visual attention or regulation of attentional engagement.

Evidence for age-related deficits in object-location binding during place recognition.

Deciding whether a place is the same or different than places encountered previously is a common task in daily navigation which requires to develop knowledge about the locations of objects (object-location binding) and to recognize places from different perspectives. These abilities rely on hippocampal functioning which is susceptible to increasing age. Thus, the question of the present study is how they both together impact on place recognition in aging. Forty people aged 20-29, 44 aged 60-69, and 32 aged 70-79 were presented with places consisting of four different objects during the encoding phase. In the test phase, they were then presented with a second place and had to decide whether it was the same or different. Test places were presented from different perspectives (0°, 30°, 60°) and with different object conditions (same, a swap of two objects, a substitution with a novel object). The sensitivity for detecting changes (d') decreased from 20-29 to 60-69 and to 70-79 years old, and with increasing perspective shifts. Importantly, older adults were less sensitive to object swapping than to object substitution, while young participants did not show any difference. Overall, these results suggest specific age-related difficulties in object-location binding in the context of place recognition.

Fixation-related potentials during mobile map assisted navigation in the real world: The effect of landmark visualization style.

An often-proposed enhancement for mobile maps to aid assisted navigation is the presentation of landmark information, yet understanding of the manner in which they should be displayed is limited. In this study, we investigated whether the visualization of landmarks as 3D map symbols with either an abstract or realistic style influenced the subsequent processing of those landmarks during route navigation. We utilized a real-world mobile electroencephalography approach to this question by combining several tools developed to overcome the challenges typically encountered in real-world neuroscience research. We coregistered eye-movement and EEG recordings from 45 participants as they navigated through a real-world environment using a mobile map. Analyses of fixation event-related potentials revealed that the amplitude of the parietal P200 component was enhanced when participants fixated landmarks in the real world that were visualized on the mobile map in a realistic style, and that frontal P200 latencies were prolonged for landmarks depicted in either a realistic or abstract style compared with features of the environment that were not presented on the map, but only for the male participants. In contrast, we did not observe any significant effects of landmark visualization style on visual P1-N1 peaks or the parietal late positive component. Overall, the findings indicate that the cognitive matching process between landmarks seen in the environment and those previously seen on a map is facilitated by more realistic map display, while low-level perceptual processing of landmarks and recall of associated information are unaffected by map visualization style.

Complication from hearing aid mold material: a case report and review of legal matters.

Ear mold impression middle ear foreign bodies are a rare complication of hearing aid fitting. Only a small number of cases have been reported; however, the actual incidence is unknown and likely much higher than expected. We present the case of a 77-year-old man with a history of preexisting tympanic membrane perforations who presented with an ear mold impression middle ear foreign body that required surgical removal. We explore the state and federal laws that guide the interaction between patients, hearing aid sellers and otolaryngologists. We highlight steps that can be taken to reduce the incidence of this complication.

Landmark Sequence Learning from Real-World Route Navigation and the Impact of Navigation Aid Visualisation Style.

Primacy and recency features of serial memory are a hallmark of typical memory functions that have been observed for a wide array of tasks. Recently, the ubiquity of this serial position effect has been supported for objects learned during navigation, with canonical serial position functions observed for sequence memory of landmarks that were encountered along a route during a highly controlled virtual navigation task. In the present study, we extended those findings to a real-world navigation task in which participants actively walked a route through a city whilst using a navigation aid featuring either realistic or abstract landmark visualisation styles. Analyses of serial position functions (i.e., absolute sequence knowledge) and sequence lags (i.e., relative sequence knowledge) yielded similar profiles to those observed in a lab based virtual navigation task from previous work and non-spatial list learning studies. There were strong primacy effects for serial position memory in both conditions; recency effects only in the realistic visualisation condition; a non-uniform distribution of item-lags peaking at lag +1; and an overall bias towards positive lags for both visualisation conditions. The findings demonstrate that benchmark serial position memory effects can be observed in uncontrolled, real-world behaviour. In a navigation context, the results support the notion that general memory mechanisms are involved in spatial learning, and that landmark sequence knowledge is a feature of spatial knowledge which is affected by navigation aids.

Virtual Reality for Spatial Navigation.

Immersive virtual reality (VR) allows its users to experience physical space in a non-physical world. It has developed into a powerful research tool to investigate the neural basis of human spatial navigation as an embodied experience. The task of wayfinding can be carried out by using a wide range of strategies, leading to the recruitment of various sensory modalities and brain areas in real-life scenarios. While traditional desktop-based VR setups primarily focus on vision-based navigation, immersive VR setups, especially mobile variants, can efficiently account for motor processes that constitute locomotion in the physical world, such as head-turning and walking. When used in combination with mobile neuroimaging methods, immersive VR affords a natural mode of locomotion and high immersion in experimental settings, designing an embodied spatial experience. This in turn facilitates ecologically valid investigation of the neural underpinnings of spatial navigation.

Serial memory for landmarks encountered during route navigation.

The present study demonstrates similarities between route learning and classical tests of serial order memory. Here, we investigated serial memory for landmarks in a route learning task, in younger and older adults. We analysed data from a route learning task with 12 landmarks. Participants (88 younger and 77 older) learned a route using either a Fixed Learning (3 exposures to the route) or Flexible Learning (repeated exposures until successful navigation was achieved) procedure. Following route learning, participants completed Immediate Free Recall (IFR) and Free Reconstruction of Order (Free RoO) of the landmarks. We show clear acquisition of sequence memory for landmarks for both age groups, with Free RoO producing a bowed serial position curve. IFR produced recency effects but no primacy effects in fixed learning, with recency reduced following flexible learning for both age groups. Younger adults displayed a primacy bias for the first item recalled in both learning conditions, as did the older adults in the flexible learning condition. In contrast, older adults displayed a recency bias in the fixed learning condition. Evidence of contiguity in IFR was present only for younger adults in the flexible learning condition. Findings are broadly consistent with results from typical short-term list learning procedures and support the universality of sequence learning effects, which we demonstrate are generalisable to a navigation context.

The impact of cognitive aging on route learning rate and the acquisition of landmark knowledge.

Aging is accompanied by changes in general cognitive functioning which may impact the learning rate of older adults; however, this is often not controlled for in cognitive aging studies. We investigated the contribution of differences in learning rates to age-related differences in landmark knowledge acquired from route learning. In Experiment 1 we used a standard learning procedure in which participants received a fixed amount of exposure to a route. Consistent with previous research, we found age-related deficits in associative cue and landmark sequence knowledge. Experiment 2 controlled for differences in learning rates by using a flexible exposure learning procedure. Specifically, participants were trained to a performance criterion during route learning before being tested on the content of their route knowledge. While older adults took longer to learn the route than younger adults, the age-related differences in associative cue knowledge were abolished. The deficit in landmark sequence knowledge, however, remained. Experiment 3 replicated these results and introduced a test situation in which a deficit in landmark sequence knowledge yielded an increased likelihood of disorientation in older adults. The findings of this study suggest that age-related deficits in landmark associative cue knowledge are attenuated by controlling for learning rates. In contrast, landmark sequence knowledge deficits persist and are best explained by changes in the learning strategy of older adults to acquire task essential associative cue knowledge at the expense of supplementary sequence knowledge.

Seipin is a discrete homooligomer.

Seipin is a transmembrane protein that resides in the endoplasmic reticulum and concentrates at junctions between the ER and cytosolic lipid droplets. Mutations in the human seipin gene, including the missense mutation A212P, lead to congenital generalized lipodystrophy (CGL), characterized by the lack of normal adipose tissue and accumulation of fat in liver and muscles. In both yeast and CGL patient fibroblasts, seipin is required for normal lipid droplet morphology; in its absence droplets appear to bud abnormally from the ER. Here we report the first purification and physical characterization of seipin. Yeast seipin is in a large discrete protein complex. Affinity purification demonstrated that seipin is the main if not exclusive protein in the complex. Detergent sucrose gradients in H(2)O, and D(2)O and gel filtration were used to determine the size of the seipin complex and account for detergent binding. Both seipin-myc13 (seipin fused to 13 tandem copies of the myc epitope) expressed from the endogenous promoter and overexpressed seipin-mCherry form ∼500 kDa proteins consisting of about 9 copies of seipin. The yeast orthologue of the human A212P allele forms only smaller complexes and is unstable; we hypothesize that this accounts for its null phenotype in humans. Seipin appears as a toroid by negative staining electron microscopy. We speculate that seipin plays at least a structural role in organizing droplets or in communication between droplets and ER.

Differences in Encoding Strategy as a Potential Explanation for Age-Related Decline in Place Recognition Ability.

The ability to recognise places is known to deteriorate with advancing age. In this study, we investigated the contribution of age-related changes in spatial encoding strategies to declining place recognition ability. We recorded eye movements while younger and older adults completed a place recognition task first described by Muffato et al. (2019). Participants first learned places, which were defined by an array of four objects, and then decided whether the next place they were shown was the same or different to the one they learned. Places could be shown from the same spatial perspective as during learning or from a shifted perspective (30° or 60°). Places that were different to those during learning were changed either by substituting an object in the place with a novel object or by swapping the locations of two objects. We replicated the findings of Muffato et al. (2019) showing that sensitivity to detect changes in a place declined with advancing age and declined when the spatial perspective was shifted. Additionally, older adults were particularly impaired on trials in which object locations were swapped; however, they were not differentially affected by perspective changes compared to younger adults. During place encoding, older adults produced more fixations and saccades, shorter fixation durations, and spent less time looking at objects compared to younger adults. Further, we present an analysis of gaze chaining, designed to capture spatio-temporal aspects of gaze behaviour. The chaining measure was a significant predictor of place recognition performance. We found significant differences between age groups on the chaining measure and argue that these differences in gaze behaviour are indicative of differences in encoding strategy between age groups. In summary, we report a direct replication of Muffato et al. (2019) and provide evidence for age-related differences in spatial encoding strategies, which are related to place recognition performance.

Balloon Dilation of the Eustachian Tube: 12-Month Follow-up of the Randomized Controlled Trial Treatment Group.

OBJECTIVE: Obstructive eustachian tube dysfunction (OETD) affects up to 5% of adults; however, available treatment strategies have limitations. It was previously reported that balloon dilation of the eustachian tube (BDET) with the eustachian tube balloon catheter + medical management (MM) results in a significantly higher proportion of subjects with normalized tympanograms versus MM alone at 6- and 24-week follow-up. The current analysis extends these initial findings by investigating the durability of BDET + MM treatment outcomes through 52 weeks. STUDY DESIGN: Prospective cohort follow-up study from the treatment group in a previously reported multicenter randomized controlled trial. SETTING: Twenty-one investigational sites across the United States. SUBJECTS AND METHODS: Here we report on secondary and exploratory endpoints for patients with OETD who previously failed MM and were randomized to the BDET + MM cohort. Analyses of tympanogram outcomes are reported by ear, unless specified otherwise, as a more accurate measure of durability of the procedure over time. RESULTS: Among subjects randomized to BDET + MM, the overall number with normalized tympanograms and ETDQ-7 scores (Eustachian Tube Dysfunction Questionnaire-7) remained comparable to those reported at 6- versus 52-week follow-up: tympanograms, 73 of 143 (51.0%) versus 71 of 128 (55.5%); ETDQ-7, 79 of 142 (55.6%) versus 71 of 124 (57.3%). The overall number of ears with normalized tympanograms also remained comparable, with 117 of 204 (57%) versus 119 of 187 (63.6%). CONCLUSIONS: The present study suggests that the beneficial effects of BDET + MM on tympanogram normalization and symptoms of subjects with refractory OETD demonstrate significant durability that is clinically relevant through 52 weeks.

Balloon dilation of the eustachian tube for dilatory dysfunction: A randomized controlled trial.

OBJECTIVES/HYPOTHESIS: To assess balloon dilation of the Eustachian tube with Eustachian tube balloon catheter in conjunction with medical management as treatment for Eustachian tube dilatory dysfunction. STUDY DESIGN: In this prospective, multicenter, randomized, controlled trial, we assigned, in a 2:1 ratio, patients age 22 years and older with Eustachian tube dilatory dysfunction refractory to medical therapy to undergo balloon dilation of the Eustachian tube with balloon catheter in conjunction with medical management or medical management alone. METHODS: The primary endpoint was normalization of tympanogram at 6 weeks. Additional endpoints were normalization of Eustachian Tube Dysfunction Questionaire-7 symptom scores, positive Valsalva maneuver, mucosal inflammation, and safety. RESULTS: Primary efficacy results demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone. Tympanogram normalization at 6-week follow-up was observed in 51.8% (72/139) of investigational patients versus 13.9% (10/72) of controls (P < .0001). Tympanogram normalization in the treatment group was 62.2% after 24 weeks. Normalization of Eustachian Tube Dysfunction Questionaire-7 Symptom scores at 6-week follow-up was observed in 56.2% (77/137) of investigational patients versus 8.5% (6/71) controls (P < .001). The investigational group also demonstrated substantial improvement in both mucosal inflammation and Valsalva maneuver at 6-week follow-up compared to controls. No device- or procedure-related serious adverse events were reported for those who underwent balloon dilation of the Eustachian tube. CONCLUSIONS: This study demonstrated superiority of balloon dilation of the Eustachian tube with balloon catheter + medical management compared to medical management alone to treat Eustachian tube dilatory dysfunction in adults. LEVEL OF EVIDENCE: 1b. Laryngoscope, 128:1200-1206, 2018.

Compensation voltage (CV) peak shapes using a domed FAIMS with the inner electrode translated to various longitudinal positions.

High-field asymmetric waveform ion mobility spectrometry (FAIMS) separates ions at atmospheric pressure based on the difference in the mobility of an ion in a strong electric field and in a weak electric field. This field-dependent mobility of an ion is reflected in the compensation voltage (CV) at which the ion is transmitted through FAIMS at an applied asymmetric waveform dispersion voltage (DV). In this report, we show that experimental CV peak shapes using dome tipped inner electrode FAIMS prototypes with inner/outer electrode radii of: (1) 0.2/0.4 cm and (2) 0.4/0.6 cm are a function of the longitudinal position of the inner electrode. Varying the longitudinal position of the inner electrode modifies the electric fields between the surfaces of the hemispherical shaped inner electrode and the outer electrode in the vicinity of the ion outlet. In this region the position-dependent electric field strength (E/N) effectively forms a second tandem FAIMS analyzer region having differing ion separation properties. The final tandem FAIMS separation is the intersection of the CV windows of these two differing FAIMS separations and, therefore, the peak width in the CV scan is dependent on the longitudinal tip displacement (LTD) of the inner electrode. CV scans are shown for a LTD range of 0.14 to 0.4 cm. These scans illustrate that it is possible to control the FAIMS resolution (CV/peak width) from about 1 for the 0.2/0.4 cm electrode set at intermediate longitudinal position to over 10 at the narrowest distance between the inner electrode and the ion outlet.

Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology.

Seipin is necessary for both adipogenesis and lipid droplet (LD) organization in nonadipose tissues; however, its molecular function is incompletely understood. Phenotypes in the seipin-null mutant of Saccharomyces cerevisiae include aberrant droplet morphology (endoplasmic reticulum-droplet clusters and size heterogeneity) and sensitivity of droplet size to changes in phospholipid synthesis. It has not been clear, however, whether seipin acts in initiation of droplet synthesis or at a later step. Here we utilize a system of de novo droplet formation to show that the absence of seipin results in a delay in droplet appearance with concomitant accumulation of neutral lipid in membranes. We also demonstrate that seipin is required for vectorial budding of droplets toward the cytoplasm. Furthermore, we find that the normal rate of droplet initiation depends on 14 amino acids at the amino terminus of seipin, deletion of which results in fewer, larger droplets that are consistent with a delay in initiation but are otherwise normal in morphology. Importantly, other functions of seipin, namely vectorial budding and resistance to inositol, are retained in this mutant. We conclude that seipin has dissectible roles in both promoting early LD initiation and in regulating LD morphology, supporting its importance in LD biogenesis.

Interleukin-8 production in response to tumor necrosis factor-alpha by cholesteatoma keratinocytes in cell culture.

OBJECTIVES/HYPOTHESIS: Keratinocytes harvested from acquired cholesteatoma and grown in cell culture will demonstrate increased interleukin-8 (IL-8) production in response to tumor necrosis factor (TNF)-alpha as compared with a control keratinocyte cell line. Immunohistochemical studies have identified IL-8 and TNF-alpha, mediators of bony destruction, in tissue samples of cholesteatoma. TNF-alpha stimulates IL-8 production in healthy epidermal keratinocyte cell lines. It is not known whether TNF-alpha stimulates IL-8 production in cultured cholesteatoma keratinocytes. STUDY DESIGN: Prospective controlled tissue culture experiment. METHODS: Tissue from an acquired cholesteatoma was dissociated and grown in keratinocyte serum-free media for 8 weeks. Cholesteatoma keratinocytes and a control cell line of skin epidermal keratinocytes were treated with TNF-alpha. Conditioned media were harvested; production of IL-8 was measured by enzyme-linked immunosorbent assay, and cell counts were performed. RESULTS: At a zero concentration of TNF-alpha, mean production of IL-8 by cholesteatoma keratinocytes was 39,809 pg/mL/24hr/1 × 10(6) cells versus 1,907 pg/mL/24hr/1 × 10(6) cells from skin epidermal keratinocytes, a statistically significant difference (P < .05). The cholesteatoma keratinocytes showed a 2.1-fold increase in response to 2 pg/mL of TNF-alpha and a 2.44-fold increase in response to 20 pg/mL of TNF-alpha. The skin epidermal keratinocyte cell line demonstrated a 1.07- and 1.13-fold increase to respective concentrations of TNF-alpha. CONCLUSIONS: Cholesteatoma keratinocytes appear to retain cell signaling characteristics in vitro that distinguish them from skin epidermal keratinocytes. This finding may indicate that cholesteatoma keratinocytes undergo a change in behavior in vivo that is preserved after the cells are removed from the inflammatory environment of the middle ear.

Late failure rate of hearing preservation after middle fossa approach for resection of vestibular schwannoma.

OBJECTIVE: To explore the long-term hearing results after a middle fossa approach for resection of vestibular schwannoma. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: All patients undergoing a middle fossa approach for resection of vestibular schwannoma at a single institution with intent to preserve hearing between December 1989 and December 2009 were included in the study population. INTERVENTIONS: Standard middle fossa approach for resection of vestibular schwannoma, magnetic resonance imaging (MRI), and audiogram. MAIN OUTCOME MEASURES: Recurrence of tumor as evaluated by MRI and hearing results as measured by serial audiograms. RESULTS: Seventy-eight patients were identified who met study criteria. Fifty-one (65%) of the 78 patients had usable hearing (American Academy of Otolaryngology-Head and Neck Surgery [AAO-HNS] class A or B) postoperatively. Forty-four patients with successful hearing preservation had follow-up beyond their initial postoperative visit. Five (11%) of the 44 patients showed late degradation to nonserviceable hearing (AAO-HNS class C or D) over a mean follow-up of 4.0 years. Kaplan-Meier estimate of preservation of class A or B hearing at 10 years was 72%. Of the five patients with late degradation in hearing, 2 were found to have recurrences of their original tumor on MRI. There were 5 confirmed recurrences in the total study population. CONCLUSION: Late degradation of hearing was an infrequent occurrence after initially successful hearing preservation. When hearing degradation did occur, there seemed to be a correlation with tumor recurrence.