Left Cerebellar Lesions may be Associated with an Increase in Spatial Neglect-like Symptoms.

Each cerebellar hemisphere projects to the contralateral cerebral hemisphere. Previous research suggests a lateralization of cognitive functions in the cerebellum that mirrors the cerebral cortex, with attention/visuospatial functions represented in the left cerebellar hemisphere, and language functions in the right cerebellar hemisphere. Although there is good evidence supporting the role of the right cerebellum with language functions, the evidence supporting the notion that attention and visuospatial functions are left lateralized is less clear. Given that spatial neglect is one of the most common disorders arising from right cortical damage, we reasoned that damage to the left cerebellum would result in increased spatial neglect-like symptoms, without necessarily leading to an official diagnosis of spatial neglect. To examine this disconnection hypothesis, we analyzed neglect screening data (line bisection, cancellation, figure copying) from 20 patients with isolated unilateral cerebellar stroke. Results indicated that left cerebellar patients (n = 9) missed significantly more targets on the left side of cancellation tasks compared to a normative sample. No significant effects were observed for right cerebellar patients (n = 11). A lesion overlap analysis indicated that Crus II (78% overlap), and lobules VII and IX (66% overlap) were the regions most commonly damaged in left cerebellar patients. Our results are consistent with the notion that the left cerebellum may be important for attention and visuospatial functions. Given the poor prognosis typically associated with neglect, we suggest that screening for neglect symptoms, and visuospatial deficits more generally, may be important for tailoring rehabilitative efforts to help maximize recovery in cerebellar patients.

Direction of visual shift and hand congruency enhance spatial realignment during visuomotor adaptation.

Although prism adaptation has been studied extensively for over 100 years to better understand how the motor system adapts to sensory perturbations, very few studies have systematically studied how the combination of the hand used to adapt, and the direction of visual shift, might influence adaptation. Given that sensory inputs and motor outputs from the same side are processed (at least initially) in the same hemisphere, we wondered whether there might be differences in how people adapt when the hand used and the direction of visual shift were congruent (e.g., adapting to rightward shifting prisms with the right hand), compared to incongruent (e.g., adapting to rightward shifting prisms with the left hand). In Experiment 1 we re-analyzed a previously published dataset (Striemer, Enns, and Whitwell Striemer et al., Cortex 115:201-215, 2019a) in which healthy adults (n = 17) adapted to 17° leftward or rightward optically displacing prisms using their left or right hand (tested in separate sessions, counterbalanced). Our results revealed a "congruency effect" such that adaptation aftereffects were significantly larger for reaches performed without visual feedback (i.e., straight-ahead pointing) when the direction of prism shift and the hand used were congruent, compared to incongruent. We replicated this same congruency effect in Experiment 2 in a new group of participants (n = 25). We suggest that a better understanding of the cognitive and neural mechanisms underlying the congruency effect will allow researchers to build more precise models of visuomotor learning, and may lead to the development of more effective applications of prism adaptation for the treatment of attentional disorders following brain damage.

Assessment and recovery of visually guided reaching deficits following cerebellar stroke.

The cerebellum is known to play an important role in the coordination and timing of limb movements. The present study focused on how reach kinematics are affected by cerebellar lesions to quantify both the presence of motor impairment, and recovery of motor function over time. In the current study, 12 patients with isolated cerebellar stroke completed clinical measures of cognitive and motor function, as well as a visually guided reaching (VGR) task using the Kinarm exoskeleton at baseline (∼2 weeks), as well as 6, 12, and 24-weeks post-stroke. During the VGR task, patients made unassisted reaches with visual feedback from a central 'start' position to one of eight targets arranged in a circle. At baseline, 6/12 patients were impaired across several parameters of the VGR task compared to a Kinarm normative sample (n = 307), revealing deficits in both feed-forward and feedback control. The only clinical measures that consistently demonstrated impairment were the Purdue Pegboard Task (PPT; 9/12 patients) and the Montreal Cognitive Assessment (6/11 patients). Overall, patients who were impaired at baseline showed significant recovery by the 24-week follow-up for both VGR and the PPT. A lesion overlap analysis indicated that the regions most commonly damaged in 5/12 patients (42% overlap) were lobule IX and Crus II of the right cerebellum. A lesion subtraction analysis comparing patients who were impaired (n = 6) vs. unimpaired (n = 6) on the VGR task at baseline showed that the region most commonly damaged in impaired patients was lobule VIII of the right cerebellum (40% overlap). Our results lend further support to the notion that the cerebellum is involved in both feedforward and feedback control during reaching, and that cerebellar patients tend to recover relatively quickly overall. In addition, we argue that future research should study the effects of cerebellar damage on visuomotor control from a perception-action theoretical framework to better understand how the cerebellum works with the dorsal stream to control visually guided action.

StaphAIR: A Label-Free Antigen Microarray Approach to Detecting Anti-Staphylococcus aureus Antibody Responses in Orthopedic Infections.

Arrayed imaging reflectometry (AIR) is an optical biosensor platform for simple, multiplex measurement of antigen-specific antibody responses in patient blood samples. Here, we report the development of StaphAIR, an 8-plex Staphylococcus aureus antigen array on the AIR platform for profiling antigen-specific anti-S. aureus humoral immune responses. Initial validation experiments with mouse and humanized monoclonal antibodies against the S. aureus autolysin glucosaminidase (Gmd) domain, and subsequent testing with dilution series of pooled positive human serum confirmed analytically robust behavior of the array, with all antigens displaying Langmuir-type dose-response curves. Testing a cohort of 82 patients with S. aureus musculoskeletal infections (MSKI) and 30 healthy individuals enabled discrimination of individual patient responses to different S. aureus antigens, with statistical significance between osteomyelitis patients and controls obtained overall for four individual antigens (IsdA, IsdB, Gmd, and SCIN). Multivariate analyses of the antibody titers obtained from StaphAIR revealed its utility as a potential diagnostic tool for detecting S. aureus MSKI (area under the receiver operating characteristic curve (AUC) > 0.85). We conclude that StaphAIR has utility as a high-throughput immunoassay for studying and diagnosing osteomyelitis in patients.

The Ties that Bind: Agnosia, Neglect and Selective Attention to Visual Scale.

PURPOSE OF REVIEW: Historical and contemporary treatments of visual agnosia and neglect regard these disorders as largely unrelated. It is thought that damage to different neural processes leads directly to one or the other condition, yet apperceptive variants of agnosia and object-centered variants of neglect share remarkably similar deficits in the quality of conscious experience. Here we argue for a closer association between "apperceptive" variants of visual agnosia and "object-centered" variants of visual neglect. We introduce a theoretical framework for understanding these conditions based on "scale attention", which refers to selecting boundary and surface information at different levels of the structural hierarchy in the visual array. RECENT FINDINGS: We review work on visual agnosia, the cortical structures and cortico-cortical pathways that underlie visual perception, visuospatial neglect and object-centered neglect, and attention to scale. We highlight direct and indirect pathways involved in these disorders and in attention to scale. The direct pathway involves the posterior vertical segments of the superior longitudinal fasciculus that are positioned to link the established dorsal and ventral attentional centers in the parietal cortex with structures in the inferior occipitotemporal cortex associated with visual apperceptive agnosia. The connections in the right hemisphere appear to be more important for visual conscious experience, whereas those in the left hemisphere appear to be more strongly associated with the planning and execution of visually guided grasps directed at multi-part objects such as tools. In the latter case, semantic and functional information must drive the selection of the appropriate hand posture and grasp points on the object. This view is supported by studies of grasping in patients with agnosia and in patients with neglect that show that the selection of grasp points when picking up a tool involves both scale attention and semantic contributions from inferotemporal cortex. The indirect pathways, which include the inferior fronto-occipital and horizontal components of the superior longitudinal fasciculi, involve the frontal lobe, working memory and the "multiple demands" network, which can shape the content of visual awareness through the maintenance of goal- and task-based abstractions and their influence on scale attention. Recent studies of human cortico-cortical pathways necessitate revisions to long-standing theoretical views on visual perception, visually guided action and their integrations. We highlight findings from a broad sample of seemingly disparate areas of research to support the proposal that attention to scale is necessary for typical conscious visual experience and for goal-directed actions that depend on functional and semantic information. Furthermore, we suggest that vertical pathways between the parietal and occipitotemporal cortex, along with indirect pathways that involve the premotor and prefrontal cortex, facilitate the operations of scale attention.

Cerebellar lesions disrupt spatial and temporal visual attention.

The current study represents the first comprehensive examination of spatial, temporal and sustained attention following cerebellar damage. Results indicated that, compared to controls, cerebellar damage resulted in a larger cueing effect at the longest SOA - possibly reflecting a slowed the onset of inhibition of return (IOR) during a reflexive covert attention task, and reduced the ability to detect successive targets during an attentional blink task. However, there was little evidence to support the notion that cerebellar damage disrupted voluntary covert attention or the sustained attention to response task (SART). Lesion overlay data and supplementary voxel-based lesion symptom mapping (VLSM) analyses indicated that impaired performance on the reflexive covert attention and attentional blink tasks were related to damage to Crus II of the left posterior cerebellum. In addition, subsequent analyses indicated our results are not due to either general motor impairments or to damage to the deep cerebellar nuclei. Collectively these data demonstrate, for the first time, that the same cerebellar regions may be involved in both spatial and temporal visual attention.

Blindsight.

For over a century, research has demonstrated that damage to primary visual cortex does not eliminate all capacity for visual processing in the brain. From Riddoch's (1917) early demonstration of intact motion processing for blind field stimuli, to the iconic work of Weiskrantz et al. (1974) showing reliable spatial localization, it is clear that secondary visual pathways that bypass V1 carry information to the visual brain that in turn influences behavior. In this chapter, we briefly outline the history and phenomena associated with blindsight, before discussing the nature of the secondary visual pathways that support residual visual processing in the absence of V1. We finish with some speculation as to the functional characteristics of these secondary pathways.

Cerebellar tDCS Alters the Perception of Optic Flow.

Studies have shown that the cerebellar vermis is involved in the perception of motion. However, it is unclear how the cerebellum influences motion perception. tDCS is a non-invasive brain stimulation technique that can reduce (through cathodal stimulation) or increase neuronal excitability (through anodal stimulation). To explore the nature of the cerebellar involvement on large-field global motion perception (i.e., optic flow-like motion), we applied tDCS on the cerebellar midline while participants performed an optic flow motion discrimination task. Our results show that anodal tDCS improves discrimination threshold for optic flow perception, but only for left-right motion in contrast to up-down motion discrimination. This result was evident within the first 10 min of stimulation and was also found post-stimulation. Cathodal stimulation did not have any significant effects on performance in any direction. The results show that discrimination of optic flow can be improved with tDCS of the cerebellar midline and provide further support for the role of the human midline cerebellum in the perception of optic flow.

Visuomotor adaptation in the absence of input from early visual cortex.

Prism adaptation is a time-honored tool for studying how the motor system adapts to sensory perturbations. Past research on the neural substrates of prism adaptation has implicated the posterior parietal cortex (PPC) and the cerebellum, under the assumption that these structures gain their visual input from the dominant retinogeniculate pathway to V1. Here we question whether this pathway is even required for visuomotor adaptation to occur. To investigate this, we examined prism adaptation in 'MC', someone who is blind to static stimuli following bilateral lesions that encompass much of her occipital cortex and the caudal-most areas of ventrotemporal cortex. Remarkably, MC shows evidence of prism adaptation that is similar to healthy control participants. First, when pointing with either the left or the right hand, MC shows spatial realignment; the classical after-effect exhibited by most people when adapting to displacing prisms. Second, MC demonstrates strategic recalibration - a reduction in her pointing error over time - that is similar in magnitude to healthy controls. These findings suggest that the geniculostriate pathway is not necessary for visuomotor adaptation to take place. Alternatively, we suggest that an extrageniculostriate pathway which provides visual inputs to the cerebellum from area MT and the PPC via the dorsolateral pons plays a significant and appreciable role in the guidance of unconscious automatic visuomotor adaptation.

Affective blindsight in the absence of input from face processing regions in occipital-temporal cortex.

Previous research suggests that the implicit recognition of emotional expressions may be carried out by pathways that bypass primary visual cortex (V1) and project to the amygdala. Some of the strongest evidence supporting this claim comes from case studies of "affective blindsight" in which patients with V1 damage can correctly guess whether an unseen face was depicting a fearful or happy expression. In the current study, we report a new case of affective blindsight in patient MC who is cortically blind following extensive bilateral lesions to V1, as well as face and object processing regions in her ventral visual stream. Despite her large lesions, MC has preserved motion perception which is related to sparing of the motion sensitive region MT+ in both hemispheres. To examine affective blindsight in MC we asked her to perform gender and emotion discrimination tasks in which she had to guess, using a two-alternative forced-choice procedure, whether the face presented was male or female, happy or fearful, or happy or angry. In addition, we also tested MC in a four-alternative forced-choice target localization task. Results indicated that MC was not able to determine the gender of the faces (53% accuracy), or localize targets in a forced-choice task. However, she was able to determine, at above chance levels, whether the face presented was depicting a happy or fearful (67%, p = .006), or a happy or angry (64%, p = .025) expression. Interestingly, although MC was better than chance at discriminating between emotions in faces when asked to make rapid judgments, her performance fell to chance when she was asked to provide subjective confidence ratings about her performance. These data lend further support to the idea that there is a non-conscious visual pathway that bypasses V1 which is capable of processing affective signals from facial expressions without input from higher-order face and object processing regions in the ventral visual stream.

Label-free microarray-based detection of autoantibodies in human serum.

Multiplex assays for autoantibodies have shown utility both in research towards understanding the basic biology of autoimmune disease, and as tools for clinical diagnosis. New label-free multiplex analysis methods have the potential to streamline both the process of assay development and assay workflow. We report fabrication and testing of a 5-plex autoantigen microarray using the Arrayed Imaging Reflectometry (AIR) platform. This label-free technology provides rapid, sensitive, and quantitative detection of an arbitrary number of analytes in a standard multiwell format. In this work, we demonstrate that AIR is able to detect antibodies to Ro60, La/SSB, Scl-70, BicD2, and Ro52 in single-donor human serum samples with multiplex results comparable to singleplex ELISA or Luminex assays.

Prism adaptation speeds reach initiation in the direction of the prism after-effect.

Damage to the temporal-parietal cortex in the right hemisphere often leads to spatial neglect-a disorder in which patients are unable to attend to sensory input from their contralesional (left) side. Neglect has been associated with both attentional and premotor deficits. That is, in addition to having difficulty with attending to the left side, patients are often slower to initiate leftward vs. rightward movements (i.e., directional hypokinesia). Previous research has indicated that a brief period of adaptation to rightward shifting prisms can reduce symptoms of neglect by adjusting the patient's movements leftward, toward the neglected field. Although prism adaptation has been shown to reduce spatial attention deficits in patients with neglect, very little work has examined the effects of prisms on premotor symptoms. In the current study, we examined this in healthy individuals using leftward shifting prisms to induce a rightward shift in the egocentric reference frame, similar to neglect patients prior to prism adaptation. Specifically, we examined the speed with which healthy participants initiated leftward and rightward reaches (without visual feedback) prior to and following adaptation to either 17° leftward (n = 16) or 17° rightward (n = 15) shifting prisms. Our results indicated that, following adaptation, participants were significantly faster to initiate reaches towards targets located in the direction opposite the prism shift. That is, participants were faster to initiate reaches to right targets following leftward prism adaptation and were faster to initiate reaches to left targets following rightward prism adaptation. Overall, these results are consistent with the idea that prism adaptation can influence the speed with which a reach can be initiated toward a target in the direction opposite the prism shift, possibly through altering activity in neural circuits involved in reach planning.

Prism adaptation magnitude has differential influences on perceptual versus manual responses.

Previous research has indicated that rightward prism adaptation can reduce symptoms of spatial neglect following right brain damage. In addition, leftward prism adaptation can create "neglect-like" patterns of performance in healthy adults on tasks that measure attention and spatial biases. Although a great deal of research has focused on which behaviors are influenced by prism adaptation, very few studies have focused directly on how the magnitude of visual shift induced by prisms might be related to the observed aftereffects, or the effects of prisms on measures of attentional and spatial biases. In the current study, we examined these questions by having groups of healthy adult participants complete manual line bisection and landmark tasks prior to and following adaptation to either 8.5° (15 diopter; n = 22) or 17° (30 diopter; n = 25) leftward shifting prisms. Our results demonstrated a significantly larger rightward shift in straight-ahead pointing (a measure of prism aftereffect) following adaptation to 17°, compared to 8.5° leftward shifting prisms. In addition, only 17° leftward shifting prisms resulted in a significant rightward shift in line bisection following adaptation. However, there was a significant change in performance on the landmark task pre- versus post-adaptation in both the 8.5° and 17° leftward shifting prism groups. Interestingly, correlation analyses indicated that changes in straight-ahead pointing pre- versus post-adaptation were positively correlated with changes in performance on the manual line bisection task, but not the landmark task. These data suggest that larger magnitudes of prism adaptation seem to have a greater influence on tasks that require a response with the adapted hand (i.e., line bisection), compared to tasks that only require a perceptual judgment (i.e., the landmark task). In addition, these data provide further evidence that the effects of prisms on manual and perceptual responses are not related to one another.

A label-free, multiplex competitive assay for small molecule pollutants.

Understanding the amount of exposure individuals have had to common chemical pollutants critically requires the ability to detect those compounds in a simple, sensitive, and specific manner. Doing so using label-free biosensor technology has proven challenging, however, given the small molecular weight of many pollutants of interest. To address this issue, we report the development of a pollutant microarray based on the label-free arrayed imaging reflectometry (AIR) detection platform. The sensor is able to detect three common environmental contaminants (benzo[a]pyrene, bisphenol A, and acrolein) in human serum via a competitive binding scheme.

Deficits in reflexive covert attention following cerebellar injury.

Traditionally the cerebellum has been known for its important role in coordinating motor output. Over the past 15 years numerous studies have indicated that the cerebellum plays a role in a variety of cognitive functions including working memory, language, perceptual functions, and emotion. In addition, recent work suggests that regions of the cerebellum involved in eye movements also play a role in controlling covert visual attention. Here we investigated whether regions of the cerebellum that are not strictly tied to the control of eye movements might also contribute to covert attention. To address this question we examined the effects of circumscribed cerebellar lesions on reflexive covert attention in a group of patients (n = 11) without any gross motor or oculomotor deficits, and compared their performance to a group of age-matched controls (n = 11). Results indicated that the traditional RT advantage for validly cued targets was significantly smaller at the shortest (50 ms) SOA for cerebellar patients compared to controls. Critically, a lesion overlap analysis indicated that this deficit in the rapid deployment of attention was linked to damage in Crus I and Crus II of the lateral cerebellum. Importantly, both cerebellar regions have connections to non-motor regions of the prefrontal and posterior parietal cortices-regions important for controlling visuospatial attention. Together, these data provide converging evidence that both lateral and midline regions of the cerebellum play an important role in the control of reflexive covert visual attention.

Influence of silicon dioxide capping layers on pore characteristics in nanocrystalline silicon membranes.

Porous nanocrystalline silicon (pnc-Si) membranes are a new class of membrane material with promising applications in biological separations. Pores are formed in a silicon film sandwiched between nm thick silicon dioxide layers during rapid thermal annealing. Controlling pore size is critical in the size-dependent separation applications. In this work, we systematically studied the influence of the silicon dioxide capping layers on pnc-Si membranes. Even a single nm thick top oxide layer is enough to switch from agglomeration to pore formation after annealing. Both the pore size and porosity increase with the thickness of the top oxide, but quickly reach a plateau after 10 nm of oxide. The bottom oxide layer acts as a barrier layer to prevent the a-Si film from undergoing homo-epitaxial growth during annealing. Both the pore size and porosity decrease as the thickness of the bottom oxide layer increases to 100 nm. The decrease of the pore size and porosity is correlated with the increased roughness of the bottom oxide layer, which hinders nanocrystal nucleation and nanopore formation.

Overlapping neural circuits for visual attention and eye movements in the human cerebellum.

Previous research in patients with cerebellar damage suggests that the cerebellum plays a role in covert visual attention. One limitation of some of these studies is that they examined patients with heterogeneous cerebellar damage. As a result, the patterns of reported deficits have been inconsistent. In the current study, we used functional neuroimaging (fMRI) in healthy adults (N=14) to examine whether or not the cerebellum plays a role in covert visual attention. Participants performed two covert attention tasks in which they were cued exogenously (with peripheral flashes) or endogenously (using directional arrows) to attend to marked locations in the visual periphery without moving their eyes. We compared BOLD activation in these covert attention conditions to a number of control conditions including: the same attention tasks with eye movements, a target detection task with no cueing, and a self-paced button-press task. Subtracting these control conditions from the covert attention conditions allowed us to effectively remove the contribution of the cerebellum to motor output. In addition to the usual fronto-parietal networks commonly engaged by these attention tasks, lobule VI of the vermis in the cerebellum was also activated when participants performed the covert attention tasks with or without eye movements. Interestingly, this effect was larger for exogenous compared to endogenous cueing. These results, in concert with recent patient studies, provide independent yet converging evidence that the same cerebellar structures that are involved in eye movements are also involved in visuospatial attention.

Highly porous silicon membranes fabricated from silicon nitride/silicon stacks.

Nanopore formation in silicon films has previously been demonstrated using rapid thermal crystallization of ultrathin (15 nm) amorphous Si films sandwiched between nm-thick SiO2 layers. In this work, the silicon dioxide barrier layers are replaced with silicon nitride, resulting in nanoporous silicon films with unprecedented pore density and novel morphology. Four different thin film stack systems including silicon nitride/silicon/silicon nitride (NSN), silicon dioxide/silicon/silicon nitride (OSN), silicon nitride/silicon/silicon dioxide (NSO), and silicon dioxide/silicon/silicon dioxide (OSO) are tested under different annealing temperatures. Generally the pore size, pore density, and porosity positively correlate with the annealing temperature for all four systems. The NSN system yields substantially higher porosity and pore density than the OSO system, with the OSN and NSO stack characteristics fallings between these extremes. The higher porosity of the Si membrane in the NSN stack is primarily due to the pore formation enhancement in the Si film. It is hypothesized that this could result from the interfacial energy difference between the silicon/silicon nitride and silicon/silicon dioxide, which influences the Si crystallization process.

Ultrathin silicon membranes for wearable dialysis.

The development of wearable or implantable technologies that replace center-based hemodialysis (HD) hold promise to improve outcomes and quality of life for patients with ESRD. A prerequisite for these technologies is the development of highly efficient membranes that can achieve high toxin clearance in small-device formats. Here we examine the application of the porous nanocrystalline silicon (pnc-Si) to HD. pnc-Si is a molecularly thin nanoporous membrane material that is orders of magnitude more permeable than conventional HD membranes. Material developments have allowed us to dramatically increase the amount of active membrane available for dialysis on pnc-Si chips. By controlling pore sizes during manufacturing, pnc-Si membranes can be engineered to pass middle-molecular-weight protein toxins while retaining albumin, mimicking the healthy kidney. A microfluidic dialysis device developed with pnc-Si achieves urea clearance rates that confirm that the membrane offers no resistance to urea passage. Finally, surface modifications with thin hydrophilic coatings are shown to block cell and protein adhesion.