Stopping Speed in Response to Auditory and Visual Stop Signals Depends on Go Signal Modality.

Past research has found that the speed of the action cancellation process is influenced by the sensory modality of the environmental change that triggers it. However, the effect on selective stopping processes (where participants must cancel only one component of a multicomponent movement) remains unknown, despite these complex movements often being required as we navigate our busy modern world. Thirty healthy adults (mean age = 31.1 years, SD = 10.5) completed five response-selective stop signal tasks featuring different combinations of "go signal" modality (the environmental change baring an imperative to initiate movement; auditory or visual) and "stop signal" modality (the environmental change indicating that action cancellation is required: auditory, visual, or audiovisual). EMG recordings of effector muscles allowed detailed comparison of the characteristics of voluntary action and cancellation between tasks. Behavioral and physiological measures of stopping speed demonstrated that the modality of the go signal influenced how quickly participants cancelled movement in response to the stop signal: Stopping was faster in two cross-modal experimental conditions (auditory go - visual stop; visual go - auditory stop), than in two conditions using the same modality for both signals. A separate condition testing for multisensory facilitation revealed that stopping was fastest when the stop signal consisted of a combined audiovisual stimulus, compared with all other go-stop stimulus combinations. These findings provide novel evidence regarding the role of attentional networks in action cancellation and suggest modality-specific cognitive resources influence the latency of the stopping process.

Development of a smartphone screening test for preclinical Alzheimer's disease and validation across the dementia continuum.

BACKGROUND: Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer's disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10-20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. METHODS: Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50-92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30-40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50-100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. DISCUSSION: This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Estimating presymptomatic episodic memory impairment using simple hand movement tests: A cross-sectional study of a large sample of older adults.

INTRODUCTION: Finding low-cost methods to detect early-stage Alzheimer's disease (AD) is a research priority for neuroprotective drug development. Presymptomatic Alzheimer's is associated with gait impairment but hand motor tests, which are more accessible, have hardly been investigated. This study evaluated how home-based Tasmanian (TAS) Test keyboard tapping tests predict episodic memory performance. METHODS: 1169 community participants (65.8 ± 7.4 years old; 73% female) without cognitive symptoms completed online single-key and alternate-key tapping tests and episodic memory, working memory, and executive function cognitive tests. RESULTS: All single-key (R2 adj  = 8.8%, ΔAIC = 5.2) and alternate-key (R2 adj  = 9.1%, ΔAIC = 8.8) motor features predicted episodic memory performance relative to demographic and mood confounders only (R2 adj  = 8.1%). No tapping features improved estimation of working memory. DISCUSSION: Brief self-administered online hand movement tests predict asymptomatic episodic memory impairment. This provides a potential low-cost home-based method for stratification of enriched cohorts. HIGHLIGHTS: We devised two brief online keyboard tapping tests to assess hand motor function. 1169 cognitively asymptomatic adults completed motor- and cognitive tests online. Impaired hand motor function predicted reduced episodic memory performance. This brief self-administered test may aid stratification of community cohorts.

Investigating the role of contextual cues and interhemispheric inhibitory mechanisms in response-selective stopping: a TMS study.

Response-selective stopping requires cancellation of only one component of a multicomponent action. While research has investigated how delays to the continuing action components ("stopping interference") can be attenuated by way of contextual cues of the specific stopping demands ("foreknowledge"), little is known of the underlying neural mechanisms. Twenty-seven, healthy, young adults undertook a multicomponent stop-signal task. For two thirds of trials, participants responded to an imperative (go) stimulus (IS) with simultaneous button presses using their left and right index fingers. For the remaining one third of trials, the IS was followed by a stop-signal requiring cancellation of only the left, or right, response. To manipulate foreknowledge of stopping demands, a cue preceded the IS that informed participants which hand might be required to stop (proactive) or provided no such information (reactive). Transcranial magnetic stimulation (TMS) assessed corticospinal excitability (CSE) as well as short- and long-interval interhemispheric inhibition (SIHI, LIHI) between the primary motor cortices. Proactive cues reduced, but did not eliminate, stopping interference relative to the reactive condition. Relative to TMS measures at cue onset, decreases in CSE (both hands and both cue conditions) and LIHI (both hands, proactive condition only) were observed during movement preparation. During movement cancellation, LIHI reduction in the continuing hand was greater than that in the stopping hand and greater than LIHI reductions in both hands during execution of multicomponent responses. Our results indicate that foreknowledge attenuates stopping interference and provide evidence for a novel role of LIHI, mediated via prefrontal regions, in facilitating continuing action components.

"Chemobrain" in childhood cancer survivors-the impact on social, academic, and daily living skills: a qualitative systematic review.

PURPOSE: To examine children's experiences of chemotherapy-induced cognitive impairment--colloquially "chemobrain"--and the impact on children's social, academic, and daily living skills via a qualitative systematic review. Experiencing chemotherapy as a child, when the brain is still developing, may cause lifelong detriment to survivors' lives. There is a significant gap in understanding their lived experience, including the self-identified barriers that children face following treatment. Such a gap can only be fully bridged by listening to the child's own voice and/or parent proxy report through an exploration of the qualitative research literature. METHODS: A search of MEDLINE, Embase, PsycINFO, and CINAHL databases was conducted. Inclusion criteria were qualitative studies with a focus on children (0-18 years) during and/or following chemotherapy treatment and explored children's experiences of chemobrain. RESULTS: Two synthesized findings were identified from six studies. (1) Chemobrain has an academic and psychosocial impact, which may not be understood by education providers. (2) Children and their parents have concerns about their reintegration and adaptation to school, social lives, and their future selves as independent members of society. Children's experiences primarily related to changes in their academic and social functioning. CONCLUSION: This review highlights two important considerations: (1) the lived experiences of pediatric childhood cancer survivors guiding where future interventions should be targeted, and (2) a need to perform more qualitative research studies in this area, as well as to improve the quality of reporting among the existing literature, given that this is a current gap in the field.

The TAS Test project: a prospective longitudinal validation of new online motor-cognitive tests to detect preclinical Alzheimer's disease and estimate 5-year risks of cognitive decline and dementia.

BACKGROUND: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia. METHODS: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD. DISCUSSION: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered.

New horizons in late-onset essential tremor: a pre-cognitive biomarker of dementia?

Essential tremor (ET) is the most common cause of tremor in older adults. However, it is increasingly recognised that 30-50% of ET cases are misdiagnosed. Late-onset ET, when tremor begins after the age of 60, is particularly likely to be misdiagnosed and there is mounting evidence that it may be a distinct clinical entity, perhaps better termed 'ageing-related tremor'. Compared with older adults with early-onset ET, late-onset ET is associated with weak grip strength, cognitive decline, dementia and mortality. This raises questions around whether late-onset ET is a pre-cognitive biomarker of dementia and whether modification of dementia risk factors may be particularly important in this group. On the other hand, it is possible that the clinical manifestations of late-onset ET simply reflect markers of healthy ageing, or frailty, superimposed on typical ET. These issues are important to clarify, especially in the era of specialist neurosurgical treatments for ET being increasingly offered to older adults, and these may not be suitable in people at high risk of cognitive decline. There is a pressing need for clinicians to understand late-onset ET, but this is challenging when there are so few publications specifically focussed on this subject and no specific features to guide prognosis. More rigorous clinical follow-up and precise phenotyping of the clinical manifestations of late-onset ET using accessible computer technologies may help us delineate whether late-onset ET is a separate clinical entity and aid prognostication.

Neuroimmune reactivity marker expression in rodent models of chemotherapy-induced cognitive impairment: A systematic scoping review.

BACKGROUND: Chemotherapy-induced cognitive impairment (CICI) is a debilitating side effect arising from chemotherapy treatments. The condition is characterised by a range of cognitive deficits including impairment to memory, attention, and concentration. Whilst the underlying mechanisms that contribute to CICI remain unclear, neuroinflammation has been suggested as one key contributor. METHOD: A comprehensive systematic search of EMBASE and Medline via PubMed was conducted to identify studies on neuroimmune reactivity marker expression changes and resulting cognitive changes in preclinical rodent models of CICI. RESULTS: A total of twenty studies met the eligibility criteria and were included in the scoping review. There was significant heterogeneity in the methodology employed in the included studies. Our findings demonstrate that widespread changes in cytokines, chemokines, microglia reactivity, and astrocyte reactivity are observed in CICI in the brain regions expected to be affected, given the nature of the cognitive impairment observed in CICI. CONCLUSIONS: Although there was considerable heterogeneity in study design that made comparisons between studies difficult, our findings suggest that neuroinflammation commonly occurs in CICI preclinical rodent models and shows an association with cognitive impairment.

Reporting in rodent models of 'chemobrain': a systematic review assessing compliance with the ARRIVE guidelines.

Patients diagnosed with cancer are often plagued with debilitating side effects post-chemotherapy treatment. One such side effect is chemotherapy-induced cognitive impairment or 'chemobrain'. Rodent models are commonly used to investigate pathogenesis and potential therapeutic strategies. However, concerns have been raised regarding inadequacies in reporting of animal studies rendering them unreliable and irreproducible. The aim of this systematic review was to assess compliance with the ARRIVE reporting guidelines in peer-reviewed publications evaluating chemotherapy-induced cognitive changes in rodent models, and to determine if the introduction of the ARRIVE guidelines has improved quality of reporting. A comprehensive search was conducted to identify relevant peer-reviewed publications. Ninety-seven studies met the eligibility criteria, and publication compliance with the ARRIVE guideline reporting was assessed. No studies achieved full adherence with the ARRIVE guidelines. Furthermore, no significant improvement was demonstrated in the overall compliance score post-ARRIVE. Given the lack of standardisation of animal models in this research area, these results pose particular threat to future progress and translation of findings in this area of research. These results highlight the need for stricter adherence to the ARRIVE guidelines by journal editors and reviewers. Animal Ethics Committees also have an important educative role in improving knowledge and awareness of the guidelines amongst researchers.

Visual field motion during a body pull affects compensatory standing and stepping responses.

KEY POINTS: It is unclear whether the visual input that accompanies a perturbation of a standing person can affect whether a recovery step is taken. Visual motion speeds were manipulated during unexpected forward and backward shoulder pulls. Visual motion that appeared slower than actual body motion reduced the initial in-place resistance to the perturbation. As a result of the modulation of the in-place response, less pull force was needed to trigger a step when visual velocity appeared slower than normal. The visuomotor postural response occurred earlier and was larger when the full-field visual input was paired with a mechanical perturbation. ABSTRACT: The present study aimed to determine how visual motion evoked by an upper body perturbation during standing affects compensatory postural responses. This was investigated by rotating the visual field forwards or backwards about the ankle, time-locked to a forwards or backwards shoulder pull. Kinematic, kinetic and electromyographic responses were recorded to a range of pull forces over 160 trials in 12 healthy adults (mean ± SD = 31 ± 5.8 years). Stepping threshold forces and in-place postural responses were compared between conditions. When the visual field moved in the same direction as the pull, so that the apparent velocity of the body was reduced (SLOW condition), the pull-force required to induce a step was less than when the visual field either rotated in the opposite direction (FAST) or was unaltered (NATURAL). For in-place responses, the body was displaced further in the direction of the pull in the SLOW condition. This was the result of a reduction in the resistive force from lower leg muscles 130 ms after the visual motion onset. In trials with no pull, the visual motion induced postural responses that were later (290 ms) and had smaller amplitudes compared to when visual motion is paired with an unexpected perturbation of the body. The results suggest that the apparent speed of the visual environment during a perturbation does influence whether a compensatory step is taken, not via a direct effect on the decision to step but by modulating the initial in-place response.

Stepping in circles: how locomotor signals of rotation adapt over time.

KEY POINTS: While it has been well described that prolonged rotational stepping will adapt the podokinetic sense of rotation, the mechanisms involved are not clearly understood. By studying podokinetic after-rotations following conditioning rotations not previously reported we have shown that slower rotational velocities are more readily adapted than faster velocities and adaptation occurs more quickly than previously thought. We propose a dynamic feedback model of vestibular and podokinetic adaptation that can fit rotation trajectories across multiple conditions and data sets. Two adaptation processes were identified that may reflect central and peripheral processes and the discussion unifies prior findings in the podokinetic literature under this new framework. The findings show the technique is feasible for people with locomotor turning problems. ABSTRACT: After a prolonged period stepping in circles, people walk with a curved trajectory when attempting to walk in a straight line without vision. Podokinetic adaptation shows promise in clinical populations to improve locomotor turning; however, the adaptive mechanisms involved are poorly understood. The first phase of this study asks: how does the podokinetic conditioning velocity affect the response velocity and how quickly can adaptation occur? The second phase of the study asks: can a mathematical feedback model account for the rotation trajectories across different conditioning parameters and different datasets? Twelve healthy participants stepped in place on the axis of a rotating surface ranging from 4 to 20 deg s-1 for durations of 1-10 min, while using visual cues to maintain a constant heading direction. Afterward on solid ground, participants were blindfolded and attempted to step without rotating. Participants unknowingly stepped in circles opposite to the direction of the prior platform rotation for all conditions. The angular velocity of this response peaked within 1 min and the ratio of the stimulus-to-response peak velocity fitted a decreasing power function. The response then decayed exponentially. The feedback model of podokinetic and vestibular adaptive processes had a good fit with the data and suggested that podokinetic adaptation is explained by a short (141 s) and a long (27 min) time constant. The podokinetic system adapts more quickly than previously thought and subjects adapt more readily to slower rotation than to faster rotation. These findings will have implications for clinical applications of the technique.

Patterns in Forensic Decapitations: A Review of the Literature and Case Report.

Separation of the head from the body can occur for a variety of reasons and in various locations across the neck. This study presents a review of the literature to identify the patterns of decapitations in forensic cases in relation to manner of death, age, and anatomical location (n = 88). The most common manner of death was suicide, followed by homicide and then accident. Ages ranged from 32 weeks prenatal to 85 years. Decapitation is reported at higher rates for individuals between 19 and 65. The majority of decapitations occurred at the midneck (second to fifth cervical vertebrae), followed by the upper neck and then the lower neck. This pattern holds true for all manners of death; however, in homicides, the percentage occurring at the midneck decreases. The findings of this study indicate some patterns in terms of manner of death, age, and location of decapitation, which could aid the medicolegal community in interpreting neck trauma. A case study is also briefly presented to illustrate findings.

Bilateral HPV Positive Squamous Cell Carcinoma In Situ of Conjunctiva.

A 45 year-old woman presented with blurred vision and irritation of the left eye. Clinical examination revealed a superior palpebral conjunctival lesion consistent with a diagnosis of papilloma. She was lost to follow up despite repeated attempts to schedule a biopsy, and presented again after an extended period with bilateral disease. Subsequent biopsy confirmed bilateral squamous cell carcinoma in situ which was human papilloma virus-16 positive by molecular testing. She declined further treatment; during the subsequent year, the lesions extended across the bulbar conjunctiva bilaterally.

Maintaining balance against force perturbations: impaired mechanisms unresponsive to levodopa in Parkinson's disease.

There is evidence that postural instability associated with Parkinson's disease (PD) is not adequately improved by levodopa, implying involvement of nondopaminergic pathways. However, the mechanisms contributing to postural instability have yet to be fully identified and tested for their levodopa responsiveness. In this report we investigate balance processes that resist external forces to the body when standing. These include in-place responses and the transition to protective stepping. Forward and backward shoulder pulls were delivered using two force-feedback-controlled motors and were randomized for direction, magnitude, and onset. Sixteen patients with PD were tested OFF and ON levodopa, and 16 healthy controls were tested twice. Response behavior was quantified from 3-dimensional ground reaction forces and kinematic measurements of body segments and total body center-of-mass (CoM) motion. In-place responses resisting the pull were significantly smaller in PD as reflected in reduced horizontal anteroposterior ground reaction force and increased CoM displacement. Ankle, knee, and hip moments contributing to this resistance were smaller in PD, with the knee extensor moment to backward pulls being the most affected. The threshold force needed to evoke a step was also smaller for PD in the forward direction. Protective steps evoked by suprathreshold pulls showed deficits in PD in the backward direction, with steps being shorter and more steps being required to arrest the body. Levodopa administration had no significant effect on either in-place or protective stepping deficits. We conclude that processes employed to maintain balance in the face of external forces show impairment in PD consistent with disruption to nondopaminergic systems.

OUTCOME OF DOGS WITH INTRANASAL LYMPHOMA TREATED WITH VARIOUS RADIATION AND CHEMOTHERAPY PROTOCOLS: 24 CASES.

Tumors of the nasal cavity comprise approximately 1% of all neoplasms in dogs. Canine intranasal lymphoma is rare and reports evaluating the outcome of treatment are lacking. The goal of this observational, descriptive, multi-institutional study was to evaluate the overall median survival times (MSTs) in a group of dogs with intranasal lymphoma that were treated with irradiation and/or chemotherapy. Dogs meeting these inclusion criteria were retrospectively recruited from medical archives at multiple institutions. Eighteen cases of intermediate to high grade intranasal lymphoma and six cases of low-grade intranasal lymphoma were identified. The date of diagnosis, method of diagnosis, treatment received (radiation and/or chemotherapy protocols), and date of death were recorded. Kaplan-Meier survival analysis was performed on the intermediate to high grade group to calculate overall MST. Log-rank tests were performed to compare effects of treatment with radiation therapy ± chemotherapy and chemotherapy alone. Kaplan-Meier survival analysis was performed separately on the low-grade group. The overall MST was 375 days for the intermediate to high grade group. Cases treated with radiation ± chemotherapy had an MST of 455 days (n = 12) and those treated with chemotherapy alone (n = 6) had an MST of 157 days in the intermediate to high grade group. The MST was 823 days for the low-grade group. Results support the use of radiation therapy for treatment of canine intranasal lymphoma, however a randomized, controlled, clinical trial would be needed for more definitive recommendations. The role of adjunctive chemotherapy also may require further investigation.

The effect of deep brain stimulation randomized by site on balance in Parkinson's disease.

BACKGROUND: The effect of the surgical site of DBS on balance and gait in Parkinson's Disease (PD) is uncertain. This is the first double-blind study of subjects randomized to either the STN (N = 14) or GPi (N = 14) who were assessed on a range of clinical balance measures. METHODS: Balance testing occurred before and 6 months postsurgery. A control PD group was tested over the same period without surgery (N = 9). All subjects were tested on and off medication and DBS subjects were also tested on and off DBS. The Postural Instability and Gait Disability items of the UPDRS and additional functional tests, which we call the Balance and Gait scale, were assessed. Activities of Balance Confidence and Activities of Daily Living questionnaires were also recorded. RESULTS: Balance was not different between the best-treated states before and after DBS surgery for both sites. Switching DBS on improved balance scores, and scores further improved with medication, compared to the off state. The GPi group showed improved performance in the postsurgery off state and better ratings of balance confidence after surgery, compared to the STN group. CONCLUSIONS: Clinical measures of balance function for both the STN and GPi sites showed that balance did not improve beyond the best medically treated state before surgery. Both clinical balance testing in the off/off state and self-reported balance confidence after surgery showed better performance in the GPi than the STN group.

Postural response latencies are related to balance control during standing and walking in patients with multiple sclerosis.

OBJECTIVE: To understand and examine the relation between postural response latencies obtained during postural perturbations and representative measures of balance during standing (sway variables) and walking (trunk motion). DESIGN: Cross-sectional. SETTING: University medical center. PARTICIPANTS: Persons with multiple sclerosis (MS) (n=40) were compared with similar aged control subjects (n=20). There were 20 subjects with MS in the normal walking velocity group and 20 subjects with MS who had slow walking velocity based on a timed 25-foot walk (T25FW) of <5 seconds. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Postural response latency, sway variables, trunk motion variables. RESULTS: We found that subjects with MS with both slow or normal walking velocities had significantly longer postural response latencies than the healthy control group. Postural response latency was not correlated with the T25FW. Postural response latency was significantly correlated with center of pressure sway variables during quiet standing (root mean square: ρ=.334, P=.04; range: ρ=.385, P=.017; mean velocity: ρ=.337, P=.038; total sway area: ρ=.393, P=.015). Postural response latency was also significantly correlated with motion of the trunk during walking (sagittal plane range of motion: ρ=.316, P=.05; SD of transverse plane range of motion: ρ=-.43, P=.006). CONCLUSIONS: These findings clearly indicate that slow postural responses to external perturbations in patients with MS contribute to disturbances in balance control during both standing and walking.