Eye movement function captured via an electronic tablet informs on cognition and disease severity in Parkinson's disease.

Studying the oculomotor system provides a unique window to assess brain health and function in various clinical populations. Although the use of detailed oculomotor parameters in clinical research has been limited due to the scalability of the required equipment, the development of novel tablet-based technologies has created opportunities for fast, easy, cost-effective, and reliable eye tracking. Oculomotor measures captured via a mobile tablet-based technology have previously been shown to reliably discriminate between Parkinson's Disease (PD) patients and healthy controls. Here we further investigate the use of oculomotor measures from tablet-based eye-tracking to inform on various cognitive abilities and disease severity in PD patients. When combined using partial least square regression, the extracted oculomotor parameters can explain up to 71% of the variance in cognitive test scores (e.g. Trail Making Test). Moreover, using a receiver operating characteristics (ROC) analysis we show that eye-tracking parameters can be used in a support vector classifier to discriminate between individuals with mild PD from those with moderate PD (based on UPDRS cut-off scores) with an accuracy of 90%. Taken together, our findings highlight the potential usefulness of mobile tablet-based technology to rapidly scale eye-tracking use and usefulness in both research and clinical settings by informing on disease stage and cognitive outcomes.

Oculomotor analysis to assess brain health: preliminary findings from a longitudinal study of multiple sclerosis using novel tablet-based eye-tracking software.

A growing body of evidence supports the link between eye movement anomalies and brain health. Indeed, the oculomotor system is composed of a diverse network of cortical and subcortical structures and circuits that are susceptible to a variety of degenerative processes. Here we show preliminary findings from the baseline measurements of an ongoing longitudinal cohort study in MS participants, designed to determine if disease and cognitive status can be estimated and tracked with high accuracy based on eye movement parameters alone. Using a novel gaze-tracking technology that can reliably and accurately track eye movements with good precision without the need for infrared cameras, using only an iPad Pro embedded camera, we show in this cross-sectional study that several eye movement parameters significantly correlated with clinical outcome measures of interest. Eye movement parameters were extracted from fixation, pro-saccade, anti-saccade, and smooth pursuit visual tasks, whereas the clinical outcome measures were the scores of several disease assessment tools and standard cognitive tests such as the Expanded Disability Status Scale (EDSS), Brief International Cognitive Assessment for MS (BICAMS), the Multiple Sclerosis Functional Composite (MSFC) and the Symbol Digit Modalities Test (SDMT). Furthermore, partial least squares regression analyses show that a small set of oculomotor parameters can explain up to 84% of the variance of the clinical outcome measures. Taken together, these findings not only replicate previously known associations between eye movement parameters and clinical scores, this time using a novel mobile-based technology, but also the notion that interrogating the oculomotor system with a novel eye-tracking technology can inform us of disease severity, as well as the cognitive status of MS participants.

A novel tablet-based software for the acquisition and analysis of gaze and eye movement parameters: a preliminary validation study in Parkinson's disease.

The idea that eye movements can reflect certain aspects of brain function and inform on the presence of neurodegeneration is not a new one. Indeed, a growing body of research has shown that several neurodegenerative disorders, such as Alzheimer's and Parkinson's Disease, present characteristic eye movement anomalies and that specific gaze and eye movement parameters correlate with disease severity. The use of detailed eye movement recordings in research and clinical settings, however, has been limited due to the expensive nature and limited scalability of the required equipment. Here we test a novel technology that can track and measure eye movement parameters using the embedded camera of a mobile tablet. We show that using this technology can replicate several well-known findings regarding oculomotor anomalies in Parkinson's disease (PD), and furthermore show that several parameters significantly correlate with disease severity as assessed with the MDS-UPDRS motor subscale. A logistic regression classifier was able to accurately distinguish PD patients from healthy controls on the basis of six eye movement parameters with a sensitivity of 0.93 and specificity of 0.86. This tablet-based tool has the potential to accelerate eye movement research via affordable and scalable eye-tracking and aid with the identification of disease status and monitoring of disease progression in clinical settings.

Mapping the human auditory cortex using spectrotemporal receptive fields generated with magnetoencephalography.

We present a novel method to map the functional organization of the human auditory cortex noninvasively using magnetoencephalography (MEG). More specifically, this method estimates via reverse correlation the spectrotemporal receptive fields (STRF) in response to a temporally dense pure tone stimulus, from which important spectrotemporal characteristics of neuronal processing can be extracted and mapped back onto the cortex surface. We show that several neuronal populations can be found examining the spectrotemporal characteristics of their STRFs, and demonstrate how these can be used to generate tonotopic gradient maps. In doing so, we show that the spatial resolution of MEG is sufficient to reliably extract important information about the spatial organization of the auditory cortex, while enabling the analysis of complex temporal dynamics of auditory processing such as best temporal modulation rate and response latency given its excellent temporal resolution. Furthermore, because spectrotemporally dense auditory stimuli can be used with MEG, the time required to acquire the necessary data to generate tonotopic maps is significantly less for MEG than for other neuroimaging tools that acquire BOLD-like signals.

Critical periods of brain development.

Brain plasticity is maximal at specific time windows during early development known as critical periods (CPs), during which sensory experience is necessary to establish optimal cortical representations of the surrounding environment. After CP closure, a range of functional and structural elements prevent passive experience from eliciting significant plastic changes in the brain. The transition from a plastic to a more fixed state is advantageous as it allows for the sequential consolidation and retention of new and more complex perceptual, motor, and cognitive functions. However, the formation of stable neural representations may pose limitations on future revisions to the circuitry. If sensory experience is abnormal or absent during this time, it can have profound effects on sensory representations in adulthood, resulting in quasi-permanent adaptations that can make it nearly impossible to learn certain skills or process certain stimulus properties later on in life. This chapter begins with a brief introduction to experience-dependent plasticity throughout the lifespan (Section Introduction). Next, we define what constitutes a CP (Section What Are Critical Periods?) and review some of the key CPs in the visual and auditory systems (Section Key Critical Periods of Sensory Systems). We then discuss the mechanisms whereby cortical plasticity is regulated both locally and through neuromodulatory systems (Section How Are Critical Periods Regulated?). Finally, we highlight studies showing that CPs can be extended beyond their normal epochs, closed prematurely, or reopened during adult life by merely altering sensory inputs (Section Timing of Critical Periods: Can CP Plasticity Be Extended, Limited, or Reactivated?).

Reversible external auditory canal ligation (REACL): A novel surgical technique to induce transient and reversible hearing loss in developing rats.

BACKGROUND: Cases of sensory loss provide an excellent model to study the plastic nature of cortical sensory systems. Models of reversible sensory loss are particularly useful for establishing the timeline of various critical periods for cortical plasticity. However, there currently is an absence of adequate methods to produce reversible hearing loss in neonatal and developing rodents. NEW METHOD: We propose a novel and reversible adaptation of an existing surgical technique-external auditory canal ligation (EACL)-that produces a reliable and moderate hearing loss. RESULTS: Auditory brainstem responses (ABRs) were used to measure both the magnitude of the hearing loss induced by EACL and the auditory thresholds following hearing restoration. The EACL and reopening procedures, as assessed by visual inspection, had success rates of 81% and 78%, respectively. The average hearing thresholds, as assessed with ABRs, increased by nearly 40 decibels across all tested frequencies. Hearing thresholds returned to normal levels following the reopening procedure. COMPARISON WITH EXISTING METHODS: Our procedure yields similar benefits to other methods, such as producing a reliable and moderate hearing loss that is entirely reversible. Furthermore, to our knowledge, it is the first that can be performed in neonatal rodents, thus allowing researchers the opportunity to assess the effects of sensory loss on behavior and cortical neurophysiology during developmental critical periods. CONCLUSION: Our modified technique of reversible external auditory canal ligation offers an easy, and reliable method to induce a transient state of hearing loss that mimics naturally occurring congenital conductive hearing loss.

Brain (re)organization following visual loss.

The study of the neural consequences of sensory loss provides a unique window into the brain's functional and organizational principles. Although the blind visual cortex has been implicated in the cross-modal processing of nonvisual inputs for quite some time, recent research has shown that certain cortical organizational principles are preserved even in the case of complete sensory loss. Furthermore, a growing body of work has shown that markers of neuroplasticity extend to neuroanatomical metrics that include cortical thickness and myelinization. Although our understanding of the mechanisms that underlie sensory deprivation-driven cross-modal plasticity is improving, several critical questions remain unanswered. The specific pathways that underlie the rerouting of nonvisual information, for instance, have not been fully elucidated. The fact that important cross-modal recruitment occurs following transient deprivation in sighted individuals suggests that significant rewiring following blindness may not be required. Furthermore, there are marked individual differences regarding the magnitude and functional relevance of the cross-modal reorganization. It is also not clear to what extent precise environmental factors may play a role in establishing the degree of reorganization across individuals, as opposed to factors that might specifically relate to the cause or the nature of the visual loss. In sum, although many unresolved questions remain, sensory deprivation continues to be an excellent model for studying the plastic nature of the brain. This article is categorized under: Psychology > Brain Function and Dysfunction Psychology > Perception and Psychophysics Neuroscience > Plasticity.

Dysregulation of auditory neuroplasticity in schizophrenia.

Schizophrenia is a complex brain syndrome characterized by an array of positive symptoms (delusions, hallucinations, disorganized speech), negative symptoms (alogia, apathy, avolition) and cognitive impairments (memory, executive functions). Although investigations of the cognitive deficits in schizophrenia have primarily concentrated on disturbances affecting higher-order cognitive processes, there is an increasing realization that schizophrenia also affects early sensory processing, which might, in fact, play a significant role in the development of higher-order cognitive impairments. Recent evidence suggests that many of these early sensory processing impairments possibly arise from a dysregulation of plasticity regulators in schizophrenia, resulting in either reduced plasticity or excessive unregulated plasticity. The purpose of the present manuscript is to provide a concise overview of how the dysregulation of cortical plasticity mechanisms contributes to schizophrenia symptoms with an emphasis on auditory dysplasticity and to discuss its relevance for treatment outcomes. The idea that plasticity mechanisms are not constrained only within sensitive periods suggests that many functional properties of sensory neurons can be altered throughout the lifetime.

PET Imaging of Perceptual Learning-Induced Changes in the Aged Rodent Cholinergic System.

The cholinergic system enhances attention and gates plasticity, making it a major regulator of adult learning. With aging, however, progressive degeneration of the cholinergic system impairs both the acquisition of new skills and functional recovery following neurological injury. Although cognitive training and perceptual learning have been shown to enhance auditory cortical processing, their specific impact on the cholinergic system remains unknown. Here we used [18F]FEOBV, a positron emission tomography (PET) radioligand that selectively binds to the vesicular acetylcholine transporter (VAChT), as a proxy to assess whether training on a perceptual task results in increased cholinergic neurotransmission. We show for the first time that perceptual learning is associated with region-specific changes in cholinergic neurotransmission, as detected by [18F]FEOBV PET imaging and corroborated with immunohistochemistry.

Dynamic Brains and the Changing Rules of Neuroplasticity: Implications for Learning and Recovery.

A growing number of research publications have illustrated the remarkable ability of the brain to reorganize itself in response to various sensory experiences. A traditional view of this plastic nature of the brain is that it is predominantly limited to short epochs during early development. Although examples showing that neuroplasticity exists outside of these finite time-windows have existed for some time, it is only recently that we have started to develop a fuller understanding of the different regulators that modulate and underlie plasticity. In this article, we will provide several lines of evidence indicating that mechanisms of neuroplasticity are extremely variable across individuals and throughout the lifetime. This variability is attributable to several factors including inhibitory network function, neuromodulator systems, age, sex, brain disease, and psychological traits. We will also provide evidence of how neuroplasticity can be manipulated in both the healthy and diseased brain, including recent data in both young and aged rats demonstrating how plasticity within auditory cortex can be manipulated pharmacologically and by varying the quality of sensory inputs. We propose that a better understanding of the individual differences that exist within the various mechanisms that govern experience-dependent neuroplasticity will improve our ability to harness brain plasticity for the development of personalized translational strategies for learning and recovery following brain injury or disease.

Sex and gender considerations in Canadian clinical practice guidelines: a systematic review.

BACKGROUND: The importance of sex and gender in the diagnosis and management of health conditions is well established, but the extent to which this evidence is integrated into clinical practice guidelines remains unknown. We aimed to determine the proportion of Canadian clinical practice guidelines that integrate evidence on sex and gender considerations. METHODS: We searched the Canadian Medical Association's CPG Infobase, PubMed, all provincial/territorial websites and websites of professional organizations for English- and French-language Canadian clinical practice guidelines published between January 2013 and June 2015 on selected conditions identified as priorities by policy-makers and practitioners. Citations and text were searched electronically using keyword terms related to sex and gender. Three investigators independently analyzed and categorized the content of text-positive clinical practice guidelines based on clinical relevance for practitioners. RESULTS: Of the 118 clinical practice guidelines that met the inclusion criteria, 79 (66.9%) were text-positive for sex and/or gender keywords; 8 (10%) of the 79 used the keywords only in relation to pregnancy. Of the remaining 71 guidelines, 25 (35%) contained sex-related diagnostic or management recommendations. An additional 5 (7%) contained recommendations for sex-specific laboratory reference values, 29 (41%) referred to differences in epidemiologic features or risk factors only, and 12 (17%) contained nonrelevant mentions of search keywords. Twenty-five (35%) of the text-positive guidelines used the terms "sex" and/or "gender" correctly. INTERPRETATION: Recommendations related to sex and gender are inconsistently reported in Canadian clinical practice guidelines. Guidelines such as the Sex and Gender Equity in Research guidelines may help inform the meaningful inclusion of sex and gender evidence in the development of clinical practice guidelines.

Crossmodal Processing of Haptic Inputs in Sighted and Blind Individuals.

In a previous behavioral study, it was shown that early blind individuals were superior to sighted ones in discriminating two-dimensional (2D) tactile angle stimuli. The present study was designed to assess the neural substrate associated with a haptic 2D angle discrimination task in both sighted and blind individuals. Subjects performed tactile angle size discriminations in order to investigate whether the pattern of crossmodal occipital recruitment was lateralized as a function of the stimulated hand. Task-elicited activations were also compared across different difficulty levels to ascertain the potential modulatory role of task difficulty on crossmodal processing within occipital areas. We show that blind subjects had more widespread activation within the right lateral and superior occipital gyri when performing the haptic discrimination task. In contrast, the sighted activated the left cuneus and lingual gyrus more so than the blind when performing the task. Furthermore, activity within visual areas was shown to be predictive of tactile discrimination thresholds in the blind, but not in the sighted. Activity within parietal and occipital areas was modulated by task difficulty, where the easier angle comparison elicited more focal occipital activity along with bilateral posterior parietal activity, whereas the more difficult comparison produced more widespread occipital activity combined with reduced parietal activation. Finally, we show that crossmodal reorganization within the occipital cortex of blind individuals was primarily right lateralized, regardless of the stimulated hand, supporting previous evidence for a right-sided hemispheric specialization of the occipital cortex of blind individuals for the processing of tactile and haptic inputs.

Pairing Cholinergic Enhancement with Perceptual Training Promotes Recovery of Age-Related Changes in Rat Primary Auditory Cortex.

We used the rat primary auditory cortex (A1) as a model to probe the effects of cholinergic enhancement on perceptual learning and auditory processing mechanisms in both young and old animals. Rats learned to perform a two-tone frequency discrimination task over the course of two weeks, combined with either the administration of a cholinesterase inhibitor or saline. We found that while both age groups learned the task more quickly through cholinergic enhancement, the young did so by improving target detection, whereas the old did so by inhibiting erroneous responses to nontarget stimuli. We also found that cholinergic enhancement led to marked functional and structural changes within A1 in both young and old rats. Importantly, we found that several functional changes observed in the old rats, particularly those relating to the processing and inhibition of nontargets, produced cortical processing features that resembled those of young untrained rats more so than those of older adult rats. Overall, these findings demonstrate that combining auditory training with neuromodulation of the cholinergic system can restore many of the auditory cortical functional deficits observed as a result of normal aging and add to the growing body of evidence demonstrating that many age-related perceptual and neuroplastic changes are reversible.

Auditory Spatial Perception without Vision.

Valuable insights into the role played by visual experience in shaping spatial representations can be gained by studying the effects of visual deprivation on the remaining sensory modalities. For instance, it has long been debated how spatial hearing evolves in the absence of visual input. While several anecdotal accounts tend to associate complete blindness with exceptional hearing abilities, experimental evidence supporting such claims is, however, matched by nearly equal amounts of evidence documenting spatial hearing deficits. The purpose of this review is to summarize the key findings which support either enhancements or deficits in spatial hearing observed following visual loss and to provide a conceptual framework that isolates the specific conditions under which they occur. Available evidence will be examined in terms of spatial dimensions (horizontal, vertical, and depth perception) and in terms of frames of reference (egocentric and allocentric). Evidence suggests that while early blind individuals show superior spatial hearing in the horizontal plane, they also show significant deficits in the vertical plane. Potential explanations underlying these contrasting findings will be discussed. Early blind individuals also show spatial hearing impairments when performing tasks that require the use of an allocentric frame of reference. Results obtained with late-onset blind individuals suggest that early visual experience plays a key role in the development of both spatial hearing enhancements and deficits.

Trade-off in the sound localization abilities of early blind individuals between the horizontal and vertical planes.

There is substantial evidence that sensory deprivation leads to important cross-modal brain reorganization that is paralleled by enhanced perceptual abilities. However, it remains unclear how widespread these enhancements are, and whether they are intercorrelated or arise at the expense of other perceptual abilities. One specific area where such a trade-off might arise is that of spatial hearing, where blind individuals have been shown to possess superior monaural localization abilities in the horizontal plane, but inferior localization abilities in the vertical plane. While both of these tasks likely involve the use of monaural cues due to the absence of any relevant binaural signal, there is currently no proper explanation for this discrepancy, nor has any study investigated both sets of abilities in the same sample of blind individuals. Here, we assess whether the enhancements observed in the horizontal plane are related to the deficits observed in the vertical plane by testing sound localization in both planes in groups of blind and sighted persons. Our results show that the blind individuals who displayed the highest accuracy at localizing sounds monaurally in the horizontal plane are also the ones who exhibited the greater deficit when localizing in the vertical plane. These findings appear to argue against the idea of generalized perceptual enhancements in the early blind, and instead suggest the possibility of a trade-off in the localization proficiency between the two auditory spatial planes, such that learning to use monaural cues for the horizontal plane comes at the expense of using those cues to localize in the vertical plane.

Early visual deprivation changes cortical anatomical covariance in dorsal-stream structures.

Early blind individuals possess thicker occipital cortex compared to sighted ones. Occipital cortical thickness is also predictive of performance on several auditory discrimination tasks in the blind, which suggests that it can serve as a neuroanatomical marker of auditory behavioural abilities. In light of this atypical relationship between occipital thickness and auditory function, we sought to investigate here the covariation of occipital cortical morphology in occipital areas with that of all other areas across the cortical surface, to assess whether the anatomical covariance with the occipital cortex differs between early blind and sighted individuals. We observed a reduction in anatomical covariance between the right occipital cortex and several areas of the visual dorsal stream in a group of early blind individuals relative to sighted controls. In a separate analysis, we show that the performance of the early blind in a transposed melody discrimination task was strongly predicted by the strength of the cortical covariance between the occipital cortex and intraparietal sulcus, a region for which cortical thickness in the sighted was previously shown to predict performance in the same task. These findings therefore constitute the first evidence linking altered anatomical covariance to early sensory deprivation. Moreover, since covariation of cortical morphology could potentially be related to anatomical connectivity or driven by experience-dependent plasticity, it could consequently help guide future functional connectivity and diffusion tractography studies.

Evidence for both compensatory plastic and disuse atrophy-related neuroanatomical changes in the blind.

The behavioural and neurofunctional consequences of blindness are becoming increasingly well established, and it has become evident that the amount of reorganization is directly linked to the behavioural adaptations observed in the blind. However investigations of potential neuroanatomical changes resulting from blindness have yielded conflicting results as to the nature of the observed changes, because apparent loss of occipital tissue is difficult to reconcile with observed functional recruitment. To address this issue we used two complementary brain measures of neuroanatomy, voxel-based morphometry and magnetization transfer imaging, with the latter providing insight into myelin concentration through the magnetization transfer ratio. Both early and late blind, as well as sighted control subjects participated in the study and were tested on a series of auditory and tactile tasks to provide behavioural data that we could relate to neuroanatomy. The behavioural findings show that the early blind outperform the sighted in four of five tasks, whereas the late blind do so for only one. Moreover, correlations between the auditory and tactile performance of early blind individuals seem to indicate that they might benefit from some general-purpose compensatory plasticity mechanisms, as opposed to modality-specific ones. Neuroanatomical findings reveal three key findings: (i) occipital regions in the early blind have higher magnetization transfer ratio and grey matter concentration than in the sighted; (ii) behavioural performance of the blind is strongly predicted by magnetization transfer ratio and grey matter concentration in different occipital regions; and (iii) lower grey matter and white matter concentration was also found in other occipital areas in the early blind compared to the sighted. We thus show a clear dissociation between anatomical changes that are direct result of sensory deprivation and consequent atrophy, and those related to compensatory reorganization and behavioural adaptations. Moreover, the magnetization transfer ratio results also suggest that one mechanism for this reorganization may be related to increased myelination of intracortical neurons, or perhaps of fibres conveying information to and from remote locations.