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1.  Estimating Location without External Cues 
PLoS Computational Biology  2014;10(10):e1003927.
The ability to determine one's location is fundamental to spatial navigation. Here, it is shown that localization is theoretically possible without the use of external cues, and without knowledge of initial position or orientation. With only error-prone self-motion estimates as input, a fully disoriented agent can, in principle, determine its location in familiar spaces with 1-fold rotational symmetry. Surprisingly, localization does not require the sensing of any external cue, including the boundary. The combination of self-motion estimates and an internal map of the arena provide enough information for localization. This stands in conflict with the supposition that 2D arenas are analogous to open fields. Using a rodent error model, it is shown that the localization performance which can be achieved is enough to initiate and maintain stable firing patterns like those of grid cells, starting from full disorientation. Successful localization was achieved when the rotational asymmetry was due to the external boundary, an interior barrier or a void space within an arena. Optimal localization performance was found to depend on arena shape, arena size, local and global rotational asymmetry, and the structure of the path taken during localization. Since allothetic cues including visual and boundary contact cues were not present, localization necessarily relied on the fusion of idiothetic self-motion cues and memory of the boundary. Implications for spatial navigation mechanisms are discussed, including possible relationships with place field overdispersion and hippocampal reverse replay. Based on these results, experiments are suggested to identify if and where information fusion occurs in the mammalian spatial memory system.
Author Summary
Spatial navigation is one of the most important functions of animal brains. Multiple regions and cell types encode the current location in mammalian brains, but the underlying interactions between sensory and memory information remain unclear. Recent experimental and theoretical evidence have been found to suggest that the presence of a boundary fundamentally alters the task of navigation. In this paper, evidence is provided that it is possible to determine the location inside any familiar arena with 1-fold rotational symmetry, while completely ignoring sensory cues from the outside world. Surprisingly, the results show that the mere knowledge of the boundary's existence is enough, without requiring direct physical contact. Localization is robust despite the presence of noise modelled from the rodent head direction system, and even inaccuracies in the navigation system's memory of the boundary or internal models of noise. In circular arenas, rotational asymmetry can arise from interior structures such as barriers or voids, also without contact information. This theoretical evidence highlights the need to distinguish arena-based navigation common to most experimental studies, from open field navigation. These findings also point to novel ways to study information fusion in mammalian brains.
doi:10.1371/journal.pcbi.1003927
PMCID: PMC4214594  PMID: 25356642
2.  Geometric cues influence head direction cells only weakly in non-disoriented rats 
The influential hypothesis that environmental geometry is critical for spatial orientation has been extensively tested behaviorally, and yet findings have been conflicting. Head direction (HD) cells, the neural correlate of the “sense of direction”, offer a window into the processes underlying directional orientation, and may help clarify the issue. In the present study, HD cells were recorded as rats foraged in enclosures of varying geometry, with or without simultaneous manipulation of landmarks and self-motion cues (path integration). All geometric enclosures had single-order rotational symmetry and thus completely polarized the environment. They also had unique features, such as corners, which could, in principle, act like landmarks. Despite these strongly polarizing geometric cues, HD cells in non-disoriented rats never rotated with these shapes. By contrast, when a cue card (white or grey) was added to one wall, HD cells readily rotated with the enclosure. When path integration was disrupted by disorienting the rat, HD cells now did rotate with the enclosure even without the landmark. Collectively these findings indicate that geometry exerts little or no influence on heading computations in non-disoriented rats, but it can do so in disoriented rats. We suggest that geometric processing is only a weak influence, providing a backup system for heading calculations and being recruited only under conditions of disorientation.
doi:10.1523/JNEUROSCI.2257-11.2011
PMCID: PMC3242014  PMID: 22049411
geometry; head direction cells; navigation; orientation; path integration; landmarks
3.  Spatial Memory During Progressive Disorientation 
Human spatial representations of object locations in a room-sized environment were probed for evidence that the object locations were encoded relative not just to the observer (egocentrically) but also to each other (allocentrically). Participants learned the locations of 4 objects and then were blindfolded and either (a) underwent a succession of 70° and 200° whole-body rotations or (b) were fully disoriented and then underwent a similar sequence of 70° and 200° rotations. After each rotation, participants pointed to the objects without vision. Analyses of the pointing errors suggest that as participants lost orientation, represented object directions generally “drifted” off of their true directions as an ensemble, not in random, unrelated directions. This is interpreted as evidence that object-to-object (allocentric) relationships play a large part in the human spatial updating system. However, there was also some evidence that represented object directions occasionally drifted off of their true directions independently of one another, suggesting a lack of allocentric influence. Implications regarding the interplay of egocentric and allocentric information are considered.
doi:10.1037/0278-7393.34.3.602
PMCID: PMC2883724  PMID: 18444759
spatial representation; egocentric–allocentric frames of reference; spatial updating
4.  Retrieving Enduring Spatial Representations after Disorientation 
Cognition  2012;124(2):143-155.
Four experiments tested whether there are enduring spatial representations of objects’ locations in memory. Previous studies have shown that under certain conditions the internal consistency of pointing to objects using memory is disrupted by disorientation. This disorientation effect has been attributed to an absence of or to imprecise enduring spatial representations of objects’ locations. Experiment 1 replicated the standard disorientation effect. Participants learned locations of objects in an irregular layout and then pointed to objects after physically turning to face an object and after disorientation. The expected disorientation was observed. In Experiment 2, after disorientation, participants were asked to imagine they were facing the original learning direction and then physically turned to adopt the test orientation. In Experiment 3, after disorientation, participants turned to adopt the test orientation and then were informed of the original viewing direction by the experimenter. A disorientation effect was not observed in Experiment 2 or 3. In Experiment 4, after disorientation, participants turned to face the test orientation but were not told the original learning orientation. As in Experiment 1, a disorientation effect was observed. These results suggest that there are enduring spatial representations of objects’ locations specified in terms of a spatial reference direction parallel to the learning view, and that the disorientation effect is caused by uncertainty in recovering the spatial reference direction relative to the testing orientation following disorientation.
doi:10.1016/j.cognition.2012.05.006
PMCID: PMC3395066  PMID: 22682765
5.  Use of Self-to-object and Object-to-object Spatial Relations in Locomotion 
Eight experiments examined the use of representations of self-to-object or object-to-object spatial relations during locomotion. Participants learned geometrically regular or irregular layouts of objects while standing at the edge or in the middle, and then pointed to objects while blindfolded in three conditions: before turning (baseline), after rotating 240 degrees (updating), and after disorientation (disorientation). The internal consistency of pointing in the disorientation condition was equivalent to that in the updating condition when participants learned the regular layout. The internal consistency of pointing was disrupted by disorientation when participants learned the irregular layout. However when participants who learned the regular layout were instructed to use self-to-object spatial relations, the effect of disorientation on pointing consistency appeared. When participants who learned the irregular layout at the periphery of the layout were instructed to use object-to-object spatial relations, the effect of disorientation disappeared. These results suggest that people represent both self-to-object and object-to-object spatial relations, and primarily use object-to-object spatial representation in a regular layout and self-to-object spatial representation in an irregular layout.
doi:10.1037/a0016273
PMCID: PMC2774707  PMID: 19686010
self-to-object spatial relations; object-to-object spatial relations; spatial updating; disorientation
6.  The Effect of Hearing Aid Microphone Mode on Performance in an Auditory Orienting Task 
Ear and Hearing  2014;35(5):e204-e212.
Objectives:
Although directional microphones on a hearing aid provide a signal-to-noise ratio benefit in a noisy background, the amount of benefit is dependent on how close the signal of interest is to the front of the user. It is assumed that when the signal of interest is off-axis, users can reorient themselves to the signal to make use of the directional microphones to improve signal-to-noise ratio. The present study tested this assumption by measuring the head-orienting behavior of bilaterally fit hearing-impaired individuals with their microphones set to omnidirectional and directional modes. The authors hypothesized that listeners using directional microphones would have greater difficulty in rapidly and accurately orienting to off-axis signals than they would when using omnidirectional microphones.
Design:
The authors instructed hearing-impaired individuals to turn and face a female talker in simultaneous surrounding male-talker babble. Participants pressed a button when they felt they were accurately oriented in the direction of the female talker. Participants completed three blocks of trials with their hearing aids in omnidirectional mode and three blocks in directional mode, with mode order randomized. Using a Vicon motion tracking system, the authors measured head position and computed fixation error, fixation latency, trajectory complexity, and proportion of misorientations.
Results:
Results showed that for larger off-axis target angles, listeners using directional microphones took longer to reach their targets than they did when using omnidirectional microphones, although they were just as accurate. They also used more complex movements and frequently made initial turns in the wrong direction. For smaller off-axis target angles, this pattern was reversed, and listeners using directional microphones oriented more quickly and smoothly to the targets than when using omnidirectional microphones.
Conclusions:
The authors argue that an increase in movement complexity indicates a switch from a simple orienting movement to a search behavior. For the most off-axis target angles, listeners using directional microphones appear to not know which direction to turn, so they pick a direction at random and simply rotate their heads until the signal becomes more audible. The changes in fixation latency and head orientation trajectories suggest that the decrease in off-axis audibility is a primary concern in the use of directional microphones, and listeners could experience a loss of initial target speech while turning toward a new signal of interest. If hearing-aid users are to receive maximum directional benefit in noisy environments, both adaptive directionality in hearing aids and clinical advice on using directional microphones should take head movement and orientation behavior into account.
doi:10.1097/AUD.0000000000000053
PMCID: PMC4232295  PMID: 25148290
Hearing aids; Directional microphones; Head movement; Sound localization
7.  Temporoparietal encoding of space and time during vestibular-guided orientation 
Brain  2015;139(2):392-403.
The cardinal features of vestibular dysfunction are illusory self-motion (vertigo) and spatial disorientation. Testing 18 acute focal cortical lesion patients, Kaski et al. show that temporoparietal junction lesions impair vestibular-guided spatial orientation but not self-motion perception. Distinct cortical substrates thus mediate the vestibular percepts of spatial orientation and self-motion.
The cardinal features of vestibular dysfunction are illusory self-motion (vertigo) and spatial disorientation. Testing 18 acute focal cortical lesion patients, Kaski et al. show that temporoparietal junction lesions impair vestibular-guided spatial orientation but not self-motion perception. Distinct cortical substrates thus mediate the vestibular percepts of spatial orientation and self-motion.
When we walk in our environment, we readily determine our travelled distance and location using visual cues. In the dark, estimating travelled distance uses a combination of somatosensory and vestibular (i.e. inertial) cues. The observed inability of patients with complete peripheral vestibular failure to update their angular travelled distance during active or passive turns in the dark implies a privileged role for vestibular cues during human angular orientation. As vestibular signals only provide inertial cues of self-motion (e.g. velocity, °/s), the brain must convert motion information to distance information (a process called ‘path integration’) to maintain our spatial orientation during self-motion in the dark. It is unknown, however, what brain areas are involved in converting vestibular-motion signals to those that enable such vestibular-spatial orientation. Hence, using voxel-based lesion–symptom mapping techniques, we explored the effect of acute right hemisphere lesions in 18 patients on perceived angular position, velocity and motion duration during whole-body angular rotations in the dark. First, compared to healthy controls’ spatial orientation performance, we found that of the 18 acute stroke patients tested, only the four patients with damage to the temporoparietal junction showed impaired spatial orientation performance for leftward (contralesional) compared to rightward (ipsilesional) rotations. Second, only patients with temporoparietal junction damage showed a congruent underestimation in both their travelled distance (perceived as shorter) and motion duration (perceived as briefer) for leftward compared to rightward rotations. All 18 lesion patients tested showed normal self-motion perception. These data suggest that the cerebral cortical regions mediating vestibular-motion (‘am I moving?’) and vestibular-spatial perception (‘where am I?’) are distinct. Furthermore, the congruent contralesional deficit in time (motion duration) and position perception, seen only in temporoparietal junction patients, may reflect a common neural substrate in the temporoparietal junction that mediates the encoding of motion duration and travelled distance during vestibular-guided navigation. Alternatively, the deficits in timing and spatial orientation with temporoparietal junction lesions could be functionally linked, implying that the temporoparietal junction may act as a cortical temporal integrator, combining estimates of self-motion velocity over time to derive an estimate of travelled distance. This intriguing possibility predicts that timing abnormalities could lead to spatial disorientation.
doi:10.1093/brain/awv370
PMCID: PMC4805090  PMID: 26719385
vestibular perception; spatial orientation; time perception; path-integration; temporo-parietal junction
8.  Pituitary apoplexy can mimic acute meningoencephalitis or subarachnoid haemorrhage 
Pituitary apoplexy is an uncommon but life-threatening condition that is often overlooked and underdiagnosed. We report a 45-year-old man who presented to our emergency department with a sudden onset headache, acute confusion, signs of meningeal irritation and ophthalmoplegia. An initial diagnosis of acute meningoencephalitis was made, which was amended to pituitary apoplexy following thorough investigation within the emergency department.
A 45-year-old man was brought to our emergency department by ambulance with a history of sudden onset of frontal headache and acute confusion. His wife provided the history. There was no significant past medical history of diabetes, hypertension, recent travel abroad, exposure to sick contacts, involvement in outdoor pursuits such as hiking/cave diving, or trauma. He worked in a bank and had been well until 24 h prior to the onset of sudden headache, which was gradually worsening in nature and associated with increasing confusion. The patient's wife reported that he had neither experienced any fevers, night sweats, or coryzal symptoms nor received any recent vaccinations. He was not on any regular medications. He was a non-smoker and occasionally consumed alcohol. There was no significant family history. On examination in the ED, his temperature was 37.6°C, his pulse was 110/min, and he was normotensive and normoglycaemic. A macular blanching rash was noted over the patient's trunk. The patient was disoriented to time and place. Neurological examination revealed reduced GCS (11/15-E3, M6, V2), marked neck stiffness, a positive Kernig's sign and a right sixth nerve palsy.
A provisional diagnosis of acute meningoencephalitis was made and the patient was started on a course of intravenous antibiotics with benzyl penicillin 1.2 g, cefotaxime 2 g and acyclovir 750 mg. Baseline blood investigations revealed hyponatraemia (122 mmol/l), a white-cell count of 11 × 109/l and a C-reactive protein > 250. Due to the sudden onset of the symptoms and lack of prodrome, an urgent CT head scan was performed to rule out a cerebrovascular event. The scan demonstrated an enlarged pituitary gland (3 cm in diameter) with impingement of the optic chiasm. The centre of the enlarged pituitary gland was noted to be hypodense in comparison to its periphery, which was consistent with a diagnosis of pituitary apoplexy. A subsequent MRI confirmed the diagnosis (Figure 1) of an enlarged sella containing abnormal soft tissue with increased signal intensity suggestive of haemorrhage (Figure 1A).
Post-MRI a lumbar puncture was performed revealing glucose 3.4 mmol/l, protein 1.0 g/l, red cells of 53/mm3 and white cells of 174/mm3 with predominant neutrophilia. No organisms were seen, and CSF cultures and HSV DNA tests were found to be negative. Endocrinological investigations demonstrated low concentrations of thyroid hormones [TSH: 0.14 mIu/l (0.35-5.5 mlU/l), FT3: 1.1 nmol/l (1.2-3.0 nmol/l), FT4: 9.6 pmol/l (8-22 pmol/l)], gonadal hormones (LH: < 1 u/l) and prolactin: 16 u/l (<450 u/l). Serum FSH was 2.9 u/l (0.8-11.5 u/L) and cortisol 575 nmol/l (450-700 nmol/l). The patient was treated for hypopituitarism based on clinical and radiological findings with intravenous fluids, hydrocortisone (100 mg) and thyroxine (50 μg) as loading doses in the ED.
Within 24 h of commencement of therapy the patient's GCS rose to 15, and within 48 h there was marked improvement in the right sixth cranial nerve palsy. Formal visual field assessment demonstrated temporal visual field loss in the left eye. The patient was discharged to his usual residence a week later and follow-up was organised with both the endocrinologists and ophthalmologists. Follow-up MRI demonstrated that there was no significant change in either size or signal characteristics of the pituitary fossa mass (Figure 1B).
doi:10.1186/1865-1380-4-63
PMCID: PMC3205010  PMID: 21975129
9.  Precision and accuracy of the subjective haptic vertical in the roll plane 
BMC Neuroscience  2010;11:83.
Background
When roll-tilted, the subjective visual vertical (SVV) deviates up to 40° from earth-vertical and trial-to-trial variability increases with head roll. Imperfections in the central processing of visual information were postulated to explain these roll-angle dependent errors. For experimental conditions devoid of visual input, e.g. adjustments of body posture or of an object along vertical in darkness, significantly smaller errors were noted. Whereas the accuracy of verticality adjustments seems to depend strongly on the paradigm, we hypothesize that the precision, i.e. the inverse of trial-to-trial variability, is less influenced by the experimental setup and mainly reflects properties of the otoliths. Here we measured the subjective haptic vertical (SHV) and compared findings with previously reported SVV data. Twelve healthy right-handed human subjects (handedness assessed based on subjects' verbal report) adjusted a rod with the right hand along perceived earth-vertical during static head roll-tilts (0-360°, steps of 20°).
Results
SHV adjustments showed a tendency for clockwise rod rotations to deviate counter-clockwise and for counter-clockwise rod rotations to deviate clockwise, indicating hysteresis. Clockwise rod rotations resulted in counter-clockwise shifts of perceived earth-vertical up to -11.7° and an average counter-clockwise SHV shift over all roll angles of -3.3° (± 11.0°; ± 1 StdDev). Counter-clockwise rod rotations yielded peak SHV deviations in clockwise direction of 8.9° and an average clockwise SHV shift over all roll angles of 1.8° (± 11.1°). Trial-to-trial variability was minimal in upright position, increased with increasing roll (peaking around 120-140°) and decreased to intermediate values in upside-down orientation. Compared to SVV, SHV variability near upright and upside-down was non-significantly (p > 0.05) larger; both showed an m-shaped pattern of variability as a function of roll position.
Conclusions
The reduction of adjustment errors by eliminating visual input supports the notion that deviations between perceived and actual earth-vertical in roll-tilted positions arise from central processing of visual information. The shared roll-tilt dependent modulation of trial-to-trial variability for both SVV and SHV, on the other hand, indicates that the perception of earth-verticality is dominated by the same sensory signal, i.e. the otolith signal, independent of whether the line/rod setting is under visual or tactile control.
doi:10.1186/1471-2202-11-83
PMCID: PMC2912915  PMID: 20630097
10.  More than a cool illusion? Functional significance of self-motion illusion (circular vection) for perspective switches 
Frontiers in Psychology  2015;6:1174.
Self-motion can facilitate perspective switches and “automatic spatial updating” and help reduce disorientation in applications like virtual reality (VR). However, providing physical motion through moving-base motion simulators or free-space walking areas comes with high cost and technical complexity. This study provides first evidence that merely experiencing an embodied illusion of self-motion (“circular vection”) can provide similar behavioral benefits as actual self-motion: Blindfolded participants were asked to imagine facing new perspectives in a well-learned room, and point to previously learned objects. Merely imagining perspective switches while stationary yielded worst performance. When perceiving illusory self-rotation to the novel perspective, however, performance improved significantly and yielded performance similar to actual rotation. Circular vection was induced by combining rotating sound fields (“auditory vection”) and biomechanical vection from stepping along a carrousel-like rotating floor platter. In sum, illusory self-motion indeed facilitated perspective switches and thus spatial orientation, similar to actual self-motion, thus providing first compelling evidence of the functional significance and behavioral relevance of vection. This could ultimately enable us to complement the prevailing introspective vection measures with behavioral indicators, and guide the design for more affordable yet effective VR simulators that intelligently employ multi-modal self-motion illusions to reduce the need for costly physical observer motion.
doi:10.3389/fpsyg.2015.01174
PMCID: PMC4531211  PMID: 26321989
spatial updating; self-motion illusion; vection; virtual reality; perspective taking; functional significance of vection; auditory vection; biomechanical vection
11.  Meperidine-induced reversible retrograde amnesia 
Introduction: Meperidine is a synthetic opioid analog that is frequently prescribed for acute pain management. Normeperidine, the only active metabolite of meperidine, is neurotoxic and can cause significant central nervous system adverse events.
Case summary: A 29-year-old woman (height, 170 cm; weight, 85 kg) presented to Marmara University Hospital Emergency Department, Istanbul, Turkey, complaining of low back pain she described as “stabbing.” Physical examination revealed impaired lower-extremity mobility and normal vital-sign findings. There was no evidence of foot drop, head or other trauma, and systemic physical examination was unremarkable. Other common causes (eg, pyelonephritis, nephrolithiasis, pancreatitis, trauma) of lower back pain were excluded. To achieve analgesia, meperidine 80 mg was administered intravenously in 100 mL of isotonic saline solution for 20 minutes. Within 20 minutes,analgesia was achieved,but the patient developed retrograde amnesia, becoming disoriented to time, location, and persons. Her speech slowed and perceptional changes developed. After the onset of amnesia, a complete physical examination was conducted.It failed to reveal focal neurologic deficit,and laboratory (sodium, potassium, magnesium, phosphorus, serum creatinine, blood urea nitrogen, albumin, bilirubin, hemoglobin,and platelet count) and subsequent vital-sign findings (blood pressure, 150/100 mm Hg; heart rate, 100 beats per minute; respiratory rate, 18 breaths per minute; body temperature, 37 ଌ and pulse oximetry,99%) were within the normal range. Noncontrast computed tomography did not reveal any abnormality. Initially, the patient's condition was attributed to medication error due to incorrect dosage or infusion rate. Despite a review of medication logs, equipment, and the vital-sign record, the etiology for the phenomenon could not be identified. Meperidine was discontinued and oxygen and intravenous isotonic saline solution were initiated as supportive treatment. Three hours after meperidine administration was discontinued, the amnesia and disorientation spontaneously resolved.
Conclusion: Meperidine was probably associated with reversible amnesia in this healthy patient after a single therapeutic dose.
doi:10.1016/j.curtheres.2008.04.006
PMCID: PMC3969970  PMID: 24692795
meperidine; amnesia; opioid analgesic; central nervous system toxicity
12.  Effect of head pitch and roll orientations on magnetically induced vertigo 
The Journal of Physiology  2015;594(4):1051-1067.
Key points
Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole‐body rotation.The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.The hypothesis predicts that the perception of whole‐body rotation will depend on head orientation in the field.Results showed that the direction and magnitude of apparent whole‐body rotation while stationary in a 7 T magnetic field is influenced by head orientation.The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head‐referenced vestibular signals to Earth‐referenced body motion.
Abstract
High strength static magnetic fields are known to induce vertigo, believed to be via stimulation of the vestibular system. The leading hypothesis (Lorentz forces) predicts that the induced vertigo should depend on the orientation of the magnetic field relative to the head. In this study we examined the effect of static head pitch (−80 to +40 deg; 12 participants) and roll (−40 to +40 deg; 11 participants) on qualitative and quantitative aspects of vertigo experienced in the dark by healthy humans when exposed to the static uniform magnetic field inside a 7 T MRI scanner. Three participants were additionally examined at 180 deg pitch and roll orientations. The effect of roll orientation on horizontal and vertical nystagmus was also measured and was found to affect only the vertical component. Vertigo was most discomforting when head pitch was around 60 deg extension and was mildest when it was around 20 deg flexion. Quantitative analysis of vertigo focused on the induced perception of horizontal‐plane rotation reported online with the aid of hand‐held switches. Head orientation had effects on both the magnitude and the direction of this perceived rotation. The data suggest sinusoidal relationships between head orientation and perception with spatial periods of 180 deg for pitch and 360 deg for roll, which we explain is consistent with the Lorentz force hypothesis. The effects of head pitch on vertigo and previously reported nystagmus are consistent with both effects being driven by a common vestibular signal. To explain all the observed effects, this common signal requires contributions from multiple semicircular canals.
Key points
Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole‐body rotation.The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.The hypothesis predicts that the perception of whole‐body rotation will depend on head orientation in the field.Results showed that the direction and magnitude of apparent whole‐body rotation while stationary in a 7 T magnetic field is influenced by head orientation.The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head‐referenced vestibular signals to Earth‐referenced body motion.
doi:10.1113/JP271513
PMCID: PMC4753258  PMID: 26614577
13.  Effect of head pitch and roll orientations on magnetically induced vertigo 
The Journal of Physiology  2015;594(4):1051-1067.
Key points
Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole‐body rotation.The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.The hypothesis predicts that the perception of whole‐body rotation will depend on head orientation in the field.Results showed that the direction and magnitude of apparent whole‐body rotation while stationary in a 7 T magnetic field is influenced by head orientation.The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head‐referenced vestibular signals to Earth‐referenced body motion.
Abstract
High strength static magnetic fields are known to induce vertigo, believed to be via stimulation of the vestibular system. The leading hypothesis (Lorentz forces) predicts that the induced vertigo should depend on the orientation of the magnetic field relative to the head. In this study we examined the effect of static head pitch (−80 to +40 deg; 12 participants) and roll (−40 to +40 deg; 11 participants) on qualitative and quantitative aspects of vertigo experienced in the dark by healthy humans when exposed to the static uniform magnetic field inside a 7 T MRI scanner. Three participants were additionally examined at 180 deg pitch and roll orientations. The effect of roll orientation on horizontal and vertical nystagmus was also measured and was found to affect only the vertical component. Vertigo was most discomforting when head pitch was around 60 deg extension and was mildest when it was around 20 deg flexion. Quantitative analysis of vertigo focused on the induced perception of horizontal‐plane rotation reported online with the aid of hand‐held switches. Head orientation had effects on both the magnitude and the direction of this perceived rotation. The data suggest sinusoidal relationships between head orientation and perception with spatial periods of 180 deg for pitch and 360 deg for roll, which we explain is consistent with the Lorentz force hypothesis. The effects of head pitch on vertigo and previously reported nystagmus are consistent with both effects being driven by a common vestibular signal. To explain all the observed effects, this common signal requires contributions from multiple semicircular canals.
Key points
Lying supine in a strong magnetic field, such as in magnetic resonance imaging scanners, can induce a perception of whole‐body rotation.The leading hypothesis to explain this invokes a Lorentz force mechanism acting on vestibular endolymph that acts to stimulate semicircular canals.The hypothesis predicts that the perception of whole‐body rotation will depend on head orientation in the field.Results showed that the direction and magnitude of apparent whole‐body rotation while stationary in a 7 T magnetic field is influenced by head orientation.The data are compatible with the Lorentz force hypothesis of magnetic vestibular stimulation and furthermore demonstrate the operation of a spatial transformation process from head‐referenced vestibular signals to Earth‐referenced body motion.
doi:10.1113/JP271513
PMCID: PMC4753258  PMID: 26614577
14.  Tracking pigeons in a magnetic anomaly and in magnetically “quiet” terrain 
Die Naturwissenschaften  2011;98(7):575-581.
Pigeons were released at two sites of equal distance from the loft, one within a magnetic anomaly, the other in magnetically quiet terrain, and their tracks were recorded with the help of GPS receivers. A comparison of the beginning of the tracks revealed striking differences: within the anomaly, the initial phase lasted longer, and the distance flown was longer, with the pigeons' headings considerably farther from the home direction. During the following departure phase, the birds were well homeward oriented at the magnetically quiet site, whereas they continued to be disoriented within the anomaly. Comparing the tracks in the anomaly with the underlying magnetic contours shows considerable differences between individuals, without a common pattern emerging. The differences in magnetic intensity along the pigeons' path do not differ from a random distribution of intensity differences around the release site, indicating that the magnetic contours do not directly affect the pigeons' routes. Within the anomaly, pigeons take longer until their flights are oriented, but 5 km from the release point, the birds, still within the anomaly, are also significantly oriented in the home direction. These findings support the assumption that magnetically anomalous conditions initially interfere with the pigeons' navigational processes, with birds showing rather individual responses in their attempts to overcome these problems.
Electronic supplementary material
The online version of this article (doi:10.1007/s00114-011-0802-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00114-011-0802-3
PMCID: PMC3128737  PMID: 21691766
Magnetic anomaly; Pigeon navigation; Homing; GPS tracking; Magnetic “map” factors; Point of Decision
15.  Directional responding of C57BL/6J mice in the Morris water maze is influenced by visual and vestibular cues and is dependent upon the anterior thalamic nuclei 
Recent findings indicate that rats navigate in spatial tasks such as the Morris water maze (MWM) using a local cue-based reference frame rather than a distal cue-based reference frame. Specifically, rats swim in a particular direction to a location relative to pool-based cues, rather than to an absolute location defined by room-based cues. Neural mechanisms supporting this bias in rodents for relative responding in spatial tasks are not yet understood. Anterior thalamic neurons discharge according to the current directional heading of the animal. The contribution of head direction (HD) cell activity to navigation has been difficult to elucidate. We found that male C57BL/6J mice trained for 4 or 7 days in the MWM exhibited an overwhelming preference for swimming in a direction relative to pool-based cues over absolute responding during a platform-less probe test. Rotation of extra-maze cues caused a corresponding rotation of the direction mice swam during probe test, suggesting that both pool- and room-based reference frames guide platform search. However, disorienting the mice before the probe test disturbed relative responding. Therefore, relative responding is guided by both internal and external cue sources. Selective inactivation of anterior thalamic nuclei (ATN) by microinfusion of muscimol or fluorophore-conjugated muscimol caused a near complete shift in preference from relative to absolute responding. Interestingly, inactivation of the dorsal CA1 region of the hippocampus did not affect relative responding. These data suggest that ATN, and HD cells therein, may guide relative responding in the MWM, a task considered by most to reflect hippocampal processing.
doi:10.1523/JNEUROSCI.4868-11.2012
PMCID: PMC3477624  PMID: 22836256
spatial navigation; directional heading; anterior thalamus; hippocampus; head direction cell; vestibular; distal cues
16.  A Chasm Between Injury and Care: Experiences of Black Male Victims of Violence 
The Journal of trauma  2010;69(6):1372-1378.
Background
Despite higher rates of stabbing and shooting violence among black men, healthcare systems have not demonstrated an efficacious response to these patients. This study describes challenges and promotive factors for engaging black male violence victims of violence with medical and mental healthcare.
Methods
Black male victims of stabbings and shootings were recruited through fliers and word of mouth, and were interviewed individually (n = 12) or in pairs (n = 4) using a semistructured guide. A racially diverse multidisciplinary team analyzed the data using Grounded Theory methods.
Results
Challenges to engagement with healthcare included the following: (1) Disconnect in the aftermath; e.g. participants reported not realizing they were seriously injured (“just a scratch” “poke”), were disoriented (“did not know where I was”), or were consumed with anger. (2) Institutional mistrust: blurred lines between healthcare and police, money-motivated care. (3) Foreshortened future: expectations they would die young. (4) Self-reliance: fix mental and substance abuse issues on their own. (5) Logistical issues: postinjury mental health symptoms, disability, and safety concerns created structural barriers to recovery and engagement with healthcare. Promotive factors included the following: (1) desire professionalism, open personality, and shared experience from clinicians; (2) turning points: injury or birth of a child serve as a “wake up call”; and (3) positive people, future-oriented friends and family.
Conclusions
For black male violence victims, medical treatment did not address circumstances of and reactions to injury. Policies delineating boundaries between medical care and law enforcement and addressing postinjury mental health symptoms, disability, and safety concerns may improve the recovery process.
doi:10.1097/TA.0b013e3181e74fcf
PMCID: PMC3005415  PMID: 20838259
Black male; Community violence; Qualitative research
17.  The influence of vision on sound localization abilities in both the horizontal and vertical planes 
Numerous recent reports have suggested that individuals deprived of vision are able to develop heightened auditory spatial abilities. However, most such studies have compared the blind to blindfolded sighted individuals, a procedure that might introduce a strong performance bias. Indeed, while blind individuals have had their whole lives to adapt to this condition, sighted individuals might be put at a severe disadvantage when having to localize sounds without visual input. To address this unknown, we compared the sound localization ability of eight sighted individuals with and without a blindfold in a hemi-anechoic chamber. Sound stimuli were broadband noise delivered via two speaker arrays: a horizontal array with 25 loudspeakers (ranging from −90° to +90°; 7.5°) and a vertical array with 16 loudspeakers (ranging from −45° to +67.5°). A factorial design was used, where we compared two vision conditions (blindfold vs. non-blindfold), two sound planes (horizontal vs. vertical) and two pointing methods (hand vs. head). Results show that all three factors significantly interact with one another with regards to the average absolute deviation error. Although blindfolding significantly affected all conditions, it did more so for head-pointing in the horizontal plane. Moreover, blindfolding was found to increase the tendency to undershoot more eccentric spatial positions for head-pointing, but not hand-pointing. Overall, these findings suggest that while proprioceptive cues appear to be sufficient for accurate hand pointing in the absence of visual feedback, head pointing relies more heavily on visual cues in order to provide a precise response. It also strongly argues against the use of head pointing methodologies with blindfolded sighted individuals, particularly in the horizontal plane, as it likely introduces a bias when comparing them to blind individuals.
doi:10.3389/fpsyg.2013.00932
PMCID: PMC3860057  PMID: 24376430
sound localization; vision; pointing methods; spatial hearing; blindness
18.  Vestibular prosthesis tested in rhesus monkeys 
We are studying the effectiveness of a semicircular canal prosthesis to improve postural control, perception of spatial orientation, and the VOR in rhesus monkeys with bilateral vestibular hypofunction. Balance is examined by measuring spontaneous sway of the body during quiet stance and postural responses evoked by head turns and rotation of the support surface; perception is measured with a task derived from the subjective visual vertical (SVV) test during static and dynamic rotation in the roll plane; and the angular VOR is measured during rotation about the roll, pitch, and yaw axes. After the normal responses are characterized, bilateral vestibular loss is induced with intratympanic gentamicin, and then multisite stimulating electrodes are chronically implanted into the ampullae of all three canals in one ear. The postural, perceptual, and VOR responses are then characterized in the ablated state, and then bilateral, chronic electrical stimulation is applied to the ampullary nerves using a prosthesis that senses angular head velocity in three-dimensions and uses this information to modulate the rate of current pulses provided by the implanted electrodes. We are currently characterizing two normal monkeys with these paradigms, and vestibular ablation and electrode implantation are planned for the near future. In one prior rhesus monkey tested with this approach, we found that a one-dimensional (posterior canal) prosthesis improved balance during head turns, perceived head orientation during roll tilts, and the VOR in the plane of the instrumented canal. We therefore predict that the more complete information provided by a three-dimensional prosthesis that modulates activity in bilaterally-paired canals will exceed the benefits provided by the one-dimensional, unilateral approach used in our preliminary studies.
doi:10.1109/IEMBS.2011.6090573
PMCID: PMC3594774  PMID: 22254795
19.  The effect of traumatic brain injury on the health of homeless people 
Background
We sought to determine the lifetime prevalence of traumatic brain injury and its association with current health conditions in a representative sample of homeless people in Toronto, Ontario.
Methods
We surveyed 601 men and 303 women at homeless shelters and meal programs in 2004–2005 (response rate 76%). We defined traumatic brain injury as any self-reported head injury that left the person dazed, confused, disoriented or unconscious. Injuries resulting in unconsciousness lasting 30 minutes or longer were defined as moderate or severe. We assessed mental health, alcohol and drug problems in the past 30 days using the Addiction Severity Index. Physical and mental health status was assessed using the SF-12 health survey. We examined associations between traumatic brain injury and health conditions.
Results
The lifetime prevalence among homeless participants was 53% for any traumatic brain injury and 12% for moderate or severe traumatic brain injury. For 70% of respondents, their first traumatic brain injury occurred before the onset of homelessness. After adjustment for demographic characteristics and lifetime duration of homelessness, a history of moderate or severe traumatic brain injury was associated with significantly increased likelihood of seizures (odds ratio [OR] 3.2, 95% confidence interval [CI] 1.8 to 5.6), mental health problems (OR 2.5, 95% CI 1.5 to 4.1), drug problems (OR 1.6, 95% CI 1.1 to 2.5), poorer physical health status (–8.3 points, 95% CI –11.1 to –5.5) and poorer mental health status (–6.0 points, 95% CI –8.3 to –3.7).
Interpretation
Prior traumatic brain injury is very common among homeless people and is associated with poorer health.
doi:10.1503/cmaj.080341
PMCID: PMC2553875  PMID: 18838453
20.  Misperception of exocentric directions in auditory space 
Acta psychologica  2008;129(1):72-82.
Previous studies have demonstrated large errors (over 30°) in visually perceived exocentric directions (the direction between two objects that are both displaced from the observer’s location; e.g., Philbeck et al., in press). Here, we investigated whether a similar pattern occurs in auditory space. Blindfolded participants either attempted to aim a pointer at auditory targets (an exocentric task) or gave a verbal estimate of the egocentric target azimuth. Targets were located at 20° to 160° azimuth in the right hemispace. For comparison, we also collected pointing and verbal judgments for visual targets. We found that exocentric pointing responses exhibited sizeable undershooting errors, for both auditory and visual targets, that tended to become more strongly negative as azimuth increased (up to −19° for visual targets at 160°). Verbal estimates of the auditory and visual target azimuths, however, showed a dramatically different pattern, with relatively small overestimations of azimuths in the rear hemispace. At least some of the differences between verbal and pointing responses appear to be due to the frames of reference underlying the responses; when participants used the pointer to reproduce the egocentric target azimuth rather than the exocentric target direction relative to the pointer, the pattern of pointing errors more closely resembled that seen in verbal reports. These results show that there are similar distortions in perceiving exocentric directions in visual and auditory space.
doi:10.1016/j.actpsy.2008.04.008
PMCID: PMC2614239  PMID: 18555205
manual pointing; auditory space perception; perception / action; perceived direction; spatial cognition
21.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
22.  Multiple Motor Learning Strategies in Visuomotor Rotation 
PLoS ONE  2010;5(2):e9399.
Background
When exposed to a continuous directional discrepancy between movements of a visible hand cursor and the actual hand (visuomotor rotation), subjects adapt their reaching movements so that the cursor is brought to the target. Abrupt removal of the discrepancy after training induces reaching error in the direction opposite to the original discrepancy, which is called an aftereffect. Previous studies have shown that training with gradually increasing visuomotor rotation results in a larger aftereffect than with a suddenly increasing one. Although the aftereffect difference implies a difference in the learning process, it is still unclear whether the learned visuomotor transformations are qualitatively different between the training conditions.
Methodology/Principal Findings
We examined the qualitative changes in the visuomotor transformation after the learning of the sudden and gradual visuomotor rotations. The learning of the sudden rotation led to a significant increase of the reaction time for arm movement initiation and then the reaching error decreased, indicating that the learning is associated with an increase of computational load in motor preparation (planning). In contrast, the learning of the gradual rotation did not change the reaction time but resulted in an increase of the gain of feedback control, suggesting that the online adjustment of the reaching contributes to the learning of the gradual rotation. When the online cursor feedback was eliminated during the learning of the gradual rotation, the reaction time increased, indicating that additional computations are involved in the learning of the gradual rotation.
Conclusions/Significance
The results suggest that the change in the motor planning and online feedback adjustment of the movement are involved in the learning of the visuomotor rotation. The contributions of those computations to the learning are flexibly modulated according to the visual environment. Such multiple learning strategies would be required for reaching adaptation within a short training period.
doi:10.1371/journal.pone.0009399
PMCID: PMC2827554  PMID: 20195373
23.  Egocentric Representation Acquired from Offline Map Learning 
PLoS ONE  2013;8(3):e60194.
It is widely accepted that people establish allocentric spatial representation after learning a map. However, it is unknown whether people can directly acquire egocentric representation after map learning. In two experiments, the participants learned a distal environment through a map and then performed the egocentric pointing tasks in that environment under three conditions: with the heading aligned with the learning perspective (baseline), after 240° rotation from the baseline (updating), and after disorientation (disorientation). Disorientation disrupted the internal consistency of pointing among objects when the participants learned the sequentially displayed map, on which only one object name was displayed at a time while the location of “self” remained on the screen all the time. However, disorientation did not affect the internal consistency of pointing among objects when the participants learned the simultaneously displayed map. These results suggest that the egocentric representation can be acquired from a sequentially presented map.
doi:10.1371/journal.pone.0060194
PMCID: PMC3610764  PMID: 23555922
24.  Unaddressed participants’ gaze in multi-person interaction: optimizing recipiency 
One of the most intriguing aspects of human communication is its turn-taking system. It requires the ability to process on-going turns at talk while planning the next, and to launch this next turn without considerable overlap or delay. Recent research has investigated the eye movements of observers of dialogs to gain insight into how we process turns at talk. More specifically, this research has focused on the extent to which we are able to anticipate the end of current and the beginning of next turns. At the same time, there has been a call for shifting experimental paradigms exploring social-cognitive processes away from passive observation toward on-line processing. Here, we present research that responds to this call by situating state-of-the-art technology for tracking interlocutors’ eye movements within spontaneous, face-to-face conversation. Each conversation involved three native speakers of English. The analysis focused on question–response sequences involving just two of those participants, thus rendering the third momentarily unaddressed. Temporal analyses of the unaddressed participants’ gaze shifts from current to next speaker revealed that unaddressed participants are able to anticipate next turns, and moreover, that they often shift their gaze toward the next speaker before the current turn ends. However, an analysis of the complex structure of turns at talk revealed that the planning of these gaze shifts virtually coincides with the points at which the turns first become recognizable as possibly complete. We argue that the timing of these eye movements is governed by an organizational principle whereby unaddressed participants shift their gaze at a point that appears interactionally most optimal: It provides unaddressed participants with access to much of the visual, bodily behavior that accompanies both the current speaker’s and the next speaker’s turn, and it allows them to display recipiency with regard to both speakers’ turns.
doi:10.3389/fpsyg.2015.00098
PMCID: PMC4321333  PMID: 25709592
turn-taking; turn projection; eye gaze; eye-tracking; unaddressed participants
25.  Dancing Bees Improve Colony Foraging Success as Long-Term Benefits Outweigh Short-Term Costs 
PLoS ONE  2014;9(8):e104660.
Waggle dancing bees provide nestmates with spatial information about high quality resources. Surprisingly, attempts to quantify the benefits of this encoded spatial information have failed to find positive effects on colony foraging success under many ecological circumstances. Experimental designs have often involved measuring the foraging success of colonies that were repeatedly switched between oriented dances versus disoriented dances (i.e. communicating vectors versus not communicating vectors). However, if recruited bees continue to visit profitable food sources for more than one day, this procedure would lead to confounded results because of the long-term effects of successful recruitment events. Using agent-based simulations, we found that spatial information was beneficial in almost all ecological situations. Contrary to common belief, the benefits of recruitment increased with environmental stability because benefits can accumulate over time to outweigh the short-term costs of recruitment. Furthermore, we found that in simulations mimicking previous experiments, the benefits of communication were considerably underestimated (at low food density) or not detected at all (at medium and high densities). Our results suggest that the benefits of waggle dance communication are currently underestimated and that different experimental designs, which account for potential long-term benefits, are needed to measure empirically how spatial information affects colony foraging success.
doi:10.1371/journal.pone.0104660
PMCID: PMC4139316  PMID: 25141306

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