Action Imagery and Observation in Neurorehabilitation for Parkinson's Disease (ACTION-PD): Development of a User-Informed Home Training Intervention to Improve Functional Hand Movements.

BACKGROUND: Parkinson's disease (PD) causes difficulties with hand movements, which few studies have addressed therapeutically. Training with action observation (AO) and motor imagery (MI) improves performance in healthy individuals, particularly when the techniques are applied simultaneously (AO + MI). Both AO and MI have shown promising effects in people with PD, but previous studies have only used these separately. OBJECTIVE: This article describes the development and pilot testing of an intervention combining AO + MI and physical practice to improve functional manual actions in people with PD. METHODS: The home-based intervention, delivered using a tablet computer app, was iteratively designed by an interdisciplinary team, including people with PD, and further developed through focus groups and initial field testing. Preliminary data on feasibility were obtained via a six-week pilot randomised controlled trial (ISRCTN 11184024) of 10 participants with mild to moderate PD (6 intervention; 4 treatment as usual). Usage and adherence data were recorded during training, and semistructured interviews were conducted with participants. Exploratory outcome measures included dexterity and timed action performance. RESULTS: Usage and qualitative data provided preliminary evidence of acceptability and usability. Exploratory outcomes also suggested that subjective and objective performance of manual actions should be tested in a larger trial. The importance of personalisation, choice, and motivation was highlighted, as well as the need to facilitate engagement in motor imagery. CONCLUSIONS: The results indicate that a larger RCT is warranted, and the findings also have broader relevance for the feasibility and development of AO + MI interventions for PD and other conditions.

Quantitative EEG and cholinergic basal forebrain atrophy in Parkinson's disease and mild cognitive impairment.

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia.

Suicide, self-harm and thoughts of suicide or self-harm in infectious disease epidemics: a systematic review and meta-analysis.

AIMS: Suicide accounts for 2.2% of all years of life lost worldwide. We aimed to establish whether infectious epidemics are associated with any changes in the incidence of suicide or the period prevalence of self-harm, or thoughts of suicide or self-harm, with a secondary objective of establishing the frequency of these outcomes. METHODS: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO and AMED were searched from inception to 9 September 2020. Studies of infectious epidemics reporting outcomes of (a) death by suicide, (b) self-harm or (c) thoughts of suicide or self-harm were identified. A random-effects model meta-analysis for the period prevalence of thoughts of suicide or self-harm was conducted. RESULTS: In total, 1354 studies were screened with 57 meeting eligibility criteria, of which 7 described death by suicide, 9 by self-harm, and 45 thoughts of suicide or self-harm. The observation period ranged from 1910 to 2020 and included epidemics of Spanish Flu, severe acute respiratory syndrome, human monkeypox, Ebola virus disease and coronavirus disease 2019 (COVID-19). Regarding death by suicide, data with a clear longitudinal comparison group were available for only two epidemics: SARS in Hong Kong, finding an increase in suicides among the elderly, and COVID-19 in Japan, finding no change in suicides among children and adolescents. In terms of self-harm, five studies examined emergency department attendances in epidemic and non-epidemic periods, of which four found no difference and one showed a reduction during the epidemic. In studies of thoughts of suicide or self-harm, one large survey showed a substantial increase in period prevalence compared to non-epidemic periods, but smaller studies showed no difference. As a secondary objective, a meta-analysis of thoughts of suicide and self-harm found that the pooled prevalence was 8.0% overall (95% confidence interval (CI) 5.2-12.0%; 14 820 of 99 238 cases in 24 studies) over a time period of between seven days and six months. The quality assessment found 42 studies were of high quality, nine of moderate quality and six of high quality. CONCLUSIONS: There is little robust evidence on the association of infectious epidemics with suicide, self-harm and thoughts of suicide or self-harm. There was an increase in suicides among the elderly in Hong Kong during SARS and no change in suicides among young people in Japan during COVID-19, but it is unclear how far these findings may be generalised. The development of up-to-date self-harm and suicide statistics to monitor the effect of the current pandemic is an urgent priority.

Cholinergic Basal Forebrain Volumes Predict Gait Decline in Parkinson's Disease.

BACKGROUND: Gait disturbance is an early, disabling feature of Parkinson's disease (PD) that is typically refractory to dopaminergic medication. The cortical cholinergic system, originating in the nucleus basalis of Meynert of the basal forebrain, has been implicated. However, it is not known if degeneration in this region relates to a worsening of disease-specific gait impairment. OBJECTIVE: To evaluate associations between sub-regional cholinergic basal forebrain volumes and longitudinal progression of gait impairment in PD. METHODS: 99 PD participants and 47 control participants completed gait assessments via an instrumented walkway during 2 minutes of continuous walking, at baseline and for up to 3 years, from which 16 spatiotemporal characteristics were derived. Sub-regional cholinergic basal forebrain volumes were measured at baseline via MRI and a regional map derived from post-mortem histology. Univariate analyses evaluated cross-sectional associations between sub-regional volumes and gait. Linear mixed-effects models assessed whether volumes predicted longitudinal gait changes. RESULTS: There were no cross-sectional, age-independent relationships between sub-regional volumes and gait. However, nucleus basalis of Meynert volumes predicted longitudinal gait changes unique to PD. Specifically, smaller nucleus basalis of Meynert volume predicted increasing step time variability (P = 0.019) and shortening swing time (P = 0.015); smaller posterior nucleus portions predicted shortening step length (P = 0.007) and increasing step time variability (P = 0.041). CONCLUSIONS: This is the first study to demonstrate that degeneration of the cortical cholinergic system predicts longitudinal progression of gait impairments in PD. Measures of this degeneration may therefore provide a novel biomarker for identifying future mobility loss and falls. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pedunculopontine Nucleus Microstructure Predicts Postural and Gait Symptoms in Parkinson's Disease.

BACKGROUND: There is an urgent need to identify individuals at risk of postural instability and gait difficulties, and the resulting propensity for falls, in Parkinson's disease. OBJECTIVES: Given known relationships between posture and gait and degeneration of the cholinergic pedunculopontine nucleus, we investigated whether metrics of pedunculopontine nucleus microstructural integrity hold independent utility for predicting future postural instability and gait difficulties and whether they could be combined with other candidate biomarkers to improve prognostication of these symptoms. METHODS: We used stereotactic mapping of the pedunculopontine nucleus and diffusion tensor imaging to extract baseline pedunculopontine nucleus diffusivity metrics in 147 participants with Parkinson's disease and 65 controls enrolled in the Parkinson's Progression Markers Initiative. We also recorded known candidate markers of posture and gait changes: loss of caudate dopamine and CSF ß-amyloid 1-42 levels at baseline; as well as longitudinal progression motor symptoms over 72-months. RESULTS: Survival analyses revealed that reduced dopamine in the caudate and increased axial diffusivity in the pedunculopontine nucleus incurred independent risk of postural instability and gait difficulties. Binary logistic regression and receiver operating characteristics analysis in 117 participants with complete follow-up data at 60 months revealed that only pedunculopontine nucleus microstructure provided more accurate discriminative ability for predicting future postural instability and gait difficulties than clinical and demographic variables alone. CONCLUSION: Dopaminergic and cholinergic loss incur independent risk for future postural instability and gait difficulties, and pedunculopontine nucleus microstructure can be used to prognosticate these symptoms from early Parkinson's disease stages. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

New Developments in Cholinergic Imaging in Alzheimer and Lewy Body Disorders.

PURPOSE OF REVIEW: This paper aims to review novel trends in cholinergic neuroimaging in Alzheimer and Lewy body parkinsonian disorders. RECENT FINDINGS: The spectrum of cholinergic imaging is expanding with the availability of spatially more precise radioligands that allow assessment of previously less recognized subcortical and cortical structures with more dense cholinergic innervation. In addition, advances in MRI techniques now allow quantitative structural or functional assessment of both the cholinergic forebrain and the pedunculopontine nucleus, which may serve as non-invasive prognostic predictors. Multimodal imaging approaches, such as PET-MRI or multiligand PET offer new insights into the dynamic and interactive roles of the cholinergic system at both local and larger-scale neural network levels. SUMMARY: Our understanding of the heterogeneous roles of the cholinergic system in age-related diseases is evolving. Multimodal imaging approaches that provide complimentary views of the cholinergic system will be necessary to shed light on the impact of cholinergic degeneration on regional and large-scale neural networks that underpin clinical symptom manifestation in neurodegeneration.

Slowed sensory reweighting and postural illusions in older adults: the moving platform illusion.

We investigated whether postural aftereffects witnessed during transitions from a moving to a stable support are accompanied by a delayed perception of platform stabilization in older adults, in two experiments. In experiment 1, postural sway and muscle cocontraction were assessed in 11 healthy young, 11 healthy older, and 11 fall-prone older adults during blindfolded stance on a fixed platform, followed by a sway-referenced platform and then by a fixed platform again. The sway-referenced platform was more compliant for young adults, to induce similar levels of postural sway in both age groups. Participants were asked to press a button whenever they perceived that the platform had stopped moving. Both older groups showed significantly larger and longer postural sway aftereffects during platform stabilization compared with young adults, which were pronounced in fall-prone older adults. In both older groups elevated muscle cocontraction aftereffect was also witnessed. Importantly, these aftereffects were accompanied by an illusory perception of prolonged platform movement. After this, experiment 2 examined whether this illusory perception was a robust age effect or an experimental confound due to greater surface compliance in young adults, which could create a larger perceptual discrepancy between moving and stable conditions. Despite exposure to the same surface compliance levels during sway-reference, the perceptual illusion was maintained in experiment 2 in a new group of 14 healthy older adults compared with 11 young adults. In both studies, older adults took five times longer than young adults to perceive platform stabilization. This supports that sensory reweighting is inefficient in older adults. NEW & NOTEWORTHY This is the first paper to show that postural sway aftereffects witnessed in older adults after platform stabilization may be due to a perceptual illusion of platform movement. Surprisingly, in both experiments presented it took older adults five times longer than young adults to perceive platform stabilization. This supports a hypothesis of less efficient sensory reintegration in this age group, which may delay the formation of an accurate postural percept.

Is paliperidone palmitate more effective than other long-acting injectable antipsychotics?

BACKGROUND: Paliperidone palmitate is one of the most widely prescribed long-acting injectable (LAI) antipsychotics in the UK. However, it is relatively expensive and there are few data comparing its effectiveness to that of other LAI antipsychotics. We sought to address this issue by analyzing a large anonymized electronic health record (EHR) dataset from patients treated with LAI antipsychotics. METHODS: EHR data were obtained from 1281 patients in the South London and Maudsley NHS Foundation Trust (SLaM) who started treatment with a LAI antipsychotic between 1 April 2011 and 31 January 2015. The number of days spent as a psychiatric inpatient and the number of admissions to a psychiatric hospital were analyzed in each of the 3 years before and after LAI prescription. RESULTS: Patients treated with paliperidone palmitate (n = 430; 33.6%) had a greater number of inpatient days and a greater number of admissions in the year prior to treatment than those treated with other LAI antipsychotics. Nevertheless, in the 3 years after initiation there were no significant differences between paliperidone and the other LAI antipsychotics in the number of days as an inpatient (B coefficient 5.4 days, 95% confidence interval (CI) -57.3 to 68.2, p = 0.86) or number of hospital admissions (Incidence rate ratio 1.07, 95% CI 0.62 to 1.83, p = 0.82). CONCLUSION: Paliperidone palmitate was more likely to be prescribed in patients with more frequent and lengthy hospital admissions prior to initiation. However, the absence of differences in outcomes after initiation indicates that paliperidone palmitate was not more effective than other cheaper LAI antipsychotics.

Effects of the availability of accurate proprioceptive information on older adults' postural sway and muscle co-contraction.

During conditions of increased postural instability, older adults exhibit greater lower limb muscle co-contraction. This response has been interpreted as a compensatory postural strategy, which may be used to increase proprioceptive information from muscle spindles or to stiffen the lower limb as a general response to minimise postural sway. The current study aimed to test these two hypotheses by investigating use of muscle co-contraction during sensory transitions that manipulated proprioceptive input. Surface EMG was recorded from the bilateral tibialis anterior and gastrocnemius medialis muscles, in young (aged 18-30) and older adults (aged 68-80) during blind-folded postural assessment. This commenced on a fixed platform (baseline: 2 min), followed by 3 min on a sway-referenced platform (adaptation) and a final 3 min on a fixed platform again (reintegration). Sensory reweighting was slower in older adults, as shown by a significantly larger and longer postural sway after-effect once a stable platform was restored. Muscle co-contraction showed similar after-effects, whereby older adults showed a larger increase in co-contraction once the stable platform had been restored, compared to young adults. This co-contraction after-effect did not return to baseline until after 1 min. Our evidence for high muscle co-contraction during the reintroduction of veridical proprioceptive input suggests that increased co-contraction in older adults is not dependent on contemporaneous proprioceptive input. Rather, it is more likely that co-contraction is a general postural strategy used to minimise postural sway, which is increased during this sensory transition. Future research should examine whether muscle co-contraction is typically a reactive or anticipatory response.

Anodal Transcranial Direct Current Stimulation Shows Minimal, Measure-Specific Effects on Dynamic Postural Control in Young and Older Adults: A Double Blind, Sham-Controlled Study.

We investigated whether stimulating the cerebellum and primary motor cortex (M1) using transcranial direct current stimulation (tDCS) could affect postural control in young and older adults. tDCS was employed using a double-blind, sham-controlled design, in which young (aged 18-35) and older adults (aged 65+) were assessed over three sessions, one for each stimulatory condition-M1, cerebellar and sham. The effect of tDCS on postural control was assessed using a sway-referencing paradigm, which induced platform rotations in proportion to the participant's body sway, thus assessing sensory reweighting processes. Task difficulty was manipulated so that young adults experienced a support surface that was twice as compliant as that of older adults, in order to minimise baseline age differences in postural sway. Effects of tDCS on postural control were assessed during, immediately after and 30 minutes after tDCS. Additionally, the effect of tDCS on corticospinal excitability was measured by evaluating motor evoked potentials using transcranial magnetic stimulation immediately after and 30 minutes after tDCS. Minimal effects of tDCS on postural control were found in the eyes open condition only, and this was dependent on the measure assessed and age group. For young adults, stimulation had only offline effects, as cerebellar stimulation showed higher mean power frequency (MPF) of sway 30 minutes after stimulation. For older adults, both stimulation conditions delayed the increase in sway amplitude witnessed between blocks one and two until stimulation was no longer active. In conclusion, despite tDCS' growing popularity, we would caution researchers to consider carefully the type of measures assessed and the groups targeted in tDCS studies of postural control.

Neither interleukin-4 receptor alpha expression on CD4+ T cells, or macrophages and neutrophils is required for protective immunity to Trichinella spiralis.

The T helper type 2 (Th2) mediated expulsion of the gastrointestinal nematode Trichinella spiralis requires interleukin-4 receptor alpha (IL-4Ralpha) expression on both bone-marrow-derived and non-bone-marrow-derived cells. To more definitively investigate the role of IL-4/IL-13 responsiveness in the development of protective immunity to T. spiralis, cell-specific IL-4Ralpha signalling on CD4(+) T cells (Lck(cre) IL-4Ralpha(-/flox)) and macrophages/neutrophils (LysM(cre) IL-4Ralpha(-/flox)) was analysed on the BALB/c background. Infection of wild-type and control IL-4Ralpha(-/flox) mice induced a Th2-type immune response with elevated IL-4 cytokine production, parasite-specific immunoglobulin G1 (IgG1), total IgE, intestinal mastocytosis and enteropathy. In contrast, global IL-4Ralpha-deficient BALB/c mice showed reduced worm expulsion, antibody production, intestinal mastocytosis and gut pathology. BALB/c mice generated with cell-specific deletion of IL-4Ralpha on CD4(+) T lymphocytes or macrophages/neutrophils, controlled gastrointestinal helminth infection by eliciting a protective immune response comparable to that observed with wild-type and IL-4Ralpha(-/flox) controls. Together, this shows that the development of host protective Th2 responses accompanied by parasite loss is independent of IL-4Ralpha expression on CD4(+) T cells and macrophages/neutrophils.