Effect of dopamine on limbic network connectivity at rest in Parkinson's disease patients with freezing of gait.

Background: Freezing of gait (FOG) in Parkinson's disease (PD) has a poorly understood pathophysiology, which hinders treatment development. Recent work showed a dysfunctional fronto-striato-limbic circuitry at rest in PD freezers compared to non-freezers in the dopamine "OFF" state. While other studies found that dopaminergic replacement therapy alters functional brain organization in PD, the specific effect of dopamine medication on fronto-striato-limbic functional connectivity in freezers remains unclear. Objective: To evaluate how dopamine therapy alters resting state functional connectivity (rsFC) of the fronto-striato-limbic circuitry in PD freezers, and whether the degree of connectivity change is related to freezing severity and anxiety. Methods: Twenty-three PD FOG patients underwent MRI at rest (rsfMRI) in their clinically defined "OFF" and "ON" dopaminergic medication states. A seed-to-seed based analysis was performed between a priori defined limbic circuitry ROIs. Functional connectivity was compared between OFF and ON states. A secondary correlation analyses evaluated the relationship between Hospital Anxiety and Depression Scale (HADS)-Anxiety) and FOG Questionnaire with changes in rsFC from OFF to ON. Results: PD freezers' OFF compared to ON showed increased functional coupling between the right hippocampus and right caudate nucleus, and between the left putamen and left posterior parietal cortex (PPC). A negative association was found between HADS-Anxiety and the rsFC change from OFF to ON between the left amygdala and left prefrontal cortex, and left putamen and left PPC. Conclusion: These findings suggest that dopaminergic medication partially modulates the frontoparietal-limbic-striatal circuitry in PD freezers, and that the influence of medication on the amygdala, may be related to clinical anxiety in freezer.

Time perception among people living with and without dementia: A scoping review.

Dementia often manifests with profound alterations in perception, but it is unclear if and to what extent time perception is altered among people living with dementia compared to those experiencing normal aging. Thus, this scoping review aimed to answer the following research questions: (1) What study designs, participants, time intervals, paradigms, tests, and scores have been employed and in which countries were these methods employed to study time perception in dementia? (2) In which ways do time perception differ across individuals living with and without dementia? (3) In which ways do time perception differ across individuals living with different types of dementia? After deduplication, title and abstract screening, and full-text review, a total of 12 studies were included in this scoping review. Findings generally indicated that people living with dementia perceive time differently than people living without dementia, and that some differences across dementia diagnoses may exist, but the body of literature on time perception in dementia was quite limited. Future research should focus on replicating findings while extending the research to look beyond the dementia versus non-dementia dichotomy as differences across dementia diagnoses may exist. Moreover, if people living with dementia (and, in particular, living with different dementia diagnoses) experience time differently from those experiencing normal aging, we need to begin to address these differences in dementia-friendly initiatives to improve well-being for this population.

Abnormal higher-order network interactions in Parkinson's disease visual hallucinations.

Visual hallucinations in Parkinson's disease can be viewed from a systems-level perspective, whereby dysfunctional communication between brain networks responsible for perception predisposes a person to hallucinate. To this end, abnormal functional interactions between higher-order and primary sensory networks have been implicated in the pathophysiology of visual hallucinations in Parkinson's disease, however the precise signatures remain to be determined. Dimensionality reduction techniques offer a novel means for simplifying the interpretation of multidimensional brain imaging data, identifying hierarchical patterns in the data that are driven by both within- and between-functional network changes. Here, we applied two complementary non-linear dimensionality reduction techniques-diffusion-map embedding and t-distributed stochastic neighbour embedding (t-SNE)-to resting state functional MRI data, in order to characterize the altered functional hierarchy associated with susceptibility to visual hallucinations. Our study involved 77 people with Parkinson's disease (31 with hallucinations; 46 without hallucinations) and 19 age-matched healthy control subjects. In patients with visual hallucinations, we found compression of the unimodal-heteromodal gradient consistent with increased functional integration between sensory and higher order networks. This was mirrored in a traditional functional connectivity analysis, which showed increased connectivity between the visual and default mode networks in the hallucinating group. Together, these results suggest a route by which higher-order regions may have excessive influence over earlier sensory processes, as proposed by theoretical models of hallucinations across disorders. By contrast, the t-SNE analysis identified distinct alterations in prefrontal regions, suggesting an additional layer of complexity in the functional brain network abnormalities implicated in hallucinations, which was not apparent in traditional functional connectivity analyses. Together, the results confirm abnormal brain organization associated with the hallucinating phenotype in Parkinson's disease and highlight the utility of applying convergent dimensionality reduction techniques to investigate complex clinical symptoms. In addition, the patterns we describe in Parkinson's disease converge with those seen in other conditions, suggesting that reduced hierarchical differentiation across sensory-perceptual systems may be a common transdiagnostic vulnerability in neuropsychiatric disorders with perceptual disturbances.

Modulating arousal to overcome gait impairments in Parkinson's disease: how the noradrenergic system may act as a double-edged sword.

In stressful or anxiety-provoking situations, most people with Parkinson's disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal-some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic 'cross-talk' between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

Education and training for infection prevention and control provided by long-term care homes to family caregivers: a scoping review protocol.

OBJECTIVE: The objective of this review is to map the infection prevention and control education and training that long-term care homes use with families during a pandemic or infectious outbreak. INTRODUCTION: During the COVID-19 pandemic, restrictions were imposed on visits to long-term care homes to decrease the risk of virus transmission. These restrictions had negative consequences for both residents and families. A scoping review of infection prevention and control education and training used with families will inform family visitation practices and policies during future infectious outbreaks. INCLUSION CRITERIA: This review will examine literature describing infection prevention and control education and training provided to families in long-term care homes. Research and narrative papers, including experimental; quasi-experimental; descriptive observational quantitative and qualitative studies; and reviews, text, policy, and opinion papers, will be considered for inclusion. METHODS: A 3-step approach will be followed, in line with the JBI methodology for scoping reviews. Published literature will be searched for in databases, including CINAHL, Embase, ERIC, MEDLINE, and AgeLine. Published and unpublished papers will be considered from 1990 to the present, in English or French. The World Health Organization, Centers for Disease Control, and the Public Health Agency of Canada websites will be searched for unpublished and gray literature. Two authors will independently review and assess studies for inclusion and extract the data. The findings will be charted in a narrative summary and tables.

A whole new world: embracing the systems-level to understand the indirect impact of pathology in neurodegenerative disorders.

The direct link between neuropathology and the symptoms that emerge from damage to the brain is often difficult to discern. In this perspective, we argue that a satisfying account of neurodegenerative symptoms most naturally emerges from the consideration of the brain from the systems-level. Specifically, we will highlight the role of the neuromodulatory arousal system, which is uniquely positioned to coordinate the brain's ability to flexibly integrate the otherwise segregated structures required to support higher cognitive functions. Importantly, the neuromodulatory arousal system is highly heterogeneous, encompassing structures that are common sites of neurodegeneration across Alzheimer's and Parkinson's disease. We will review studies that implicate the dysfunctional interactions amongst distributed brain regions as a side-effect of pathological involvement of the neuromodulatory arousal system in these neurodegenerative disorders. From this perspective, we will argue that future work in clinical neuroscience should attempt to consider the inherent complexity in the brain and employ analytic techniques that do not solely focus on regional functional impairments, but rather captures the brain as an inherently dynamic, distributed, multi-scale system. Through this lens, we hope that we will devise new and improved diagnostic markers and interventional approaches to aid in the treatment of neurodegenerative disorders.

Understanding the effects of serotonin in the brain through its role in the gastrointestinal tract.

The neuromodulatory arousal system imbues the nervous system with the flexibility and robustness required to facilitate adaptive behaviour. While there are well understood mechanisms linking dopamine, noradrenaline and acetylcholine to distinct behavioural states, similar conclusions have not been as readily available for serotonin. Fascinatingly, despite clear links between serotonergic function and cognitive capacities as diverse as reward processing, exploration, and the psychedelic experience, over 95% of the serotonin in the body is released in the gastrointestinal tract, where it controls digestive muscle contractions (peristalsis). Here, we argue that framing neural serotonin as a rostral extension of the gastrointestinal serotonergic system dissolves much of the mystery associated with the central serotonergic system. Specifically, we outline that central serotonin activity mimics the effects of a digestion/satiety circuit mediated by hypothalamic control over descending serotonergic nuclei in the brainstem. We review commonalities and differences between these two circuits, with a focus on the heterogeneous expression of different classes of serotonin receptors in the brain. Much in the way that serotonin-induced peristalsis facilitates the work of digestion, serotonergic influences over cognition can be reframed as performing the work of cognition. Extending this analogy, we argue that the central serotonergic system allows the brain to arbitrate between different cognitive modes as a function of serotonergic tone: low activity facilitates cognitive automaticity, whereas higher activity helps to identify flexible solutions to problems, particularly if and when the initial responses fail. This perspective sheds light on otherwise disparate capacities mediated by serotonin, and also helps to understand why there are such pervasive links between serotonergic pathology and the symptoms of psychiatric disorders.

The Contribution of Noradrenergic Activity to Anxiety-Induced Freezing of Gait.

BACKGROUND: Freezing of gait is a complex paroxysmal phenomenon that is associated with a variety of sensorimotor, cognitive and affective deficits, and significantly impacts quality of life in patients with Parkinson's disease (PD). Despite a growing body of evidence that suggests anxiety may be a crucial contributor to freezing of gait, no research study to date has investigated neural underpinnings of anxiety-induced freezing of gait. OBJECTIVE: Here, we aimed to investigate how anxiety-inducing contexts might "set the stage for freezing," through the ascending arousal system, by examining an anxiety-inducing virtual reality gait paradigm inside functional magnetic resonance imaging (fMRI). METHODS: We used a virtual reality gait paradigm that has been validated to elicit anxiety by having participants navigate a virtual plank, while simultaneously collecting task-based fMRI from individuals with idiopathic PD with confirmed freezing of gait. RESULTS: First, we established that the threatening condition provoked more freezing when compared to the non-threatening condition. By using a dynamic connectivity analysis, we identified patterns of increased "cross-talk" within and between motor, limbic, and cognitive networks in the threatening conditions. We established that the threatening condition was associated with heightened network integration. We confirmed the sympathetic nature of this phenomenon by demonstrating an increase in pupil dilation during the anxiety-inducing condition of the virtual reality gait paradigm in a secondary experiment. CONCLUSIONS: In conclusion, our findings represent a neurobiological mechanistic pathway through which heightened sympathetic arousal related to anxiety could foster increased "cross-talk" between distributed cortical networks that ultimately manifest as paroxysmal episodes of freezing of gait. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The role of the locus coeruleus in shaping adaptive cortical melodies.

Neural dynamics are shaped and constrained by the projections of a small nucleus in the pons: the noradrenergic locus coeruleus (LC). Much like a bow to the brain's violin, activity in the LC lacks content specificity, but instead dynamically shapes the excitability and receptivity of neurons across the brain. In this review, we explain how the style of the bowing technique, which is analogous to different firing modes in the LC, affects distinct activity patterns in the rest of the brain. Through this analogical lens, we provide intuitive insights into how the complex activity of the LC acts to coordinate adaptive neural dynamics.

Structural and Functional Correlates of Hallucinations and Illusions in Parkinson's Disease.

BACKGROUND: Visual illusions (VI) in Parkinson's disease (PD) are generally considered as an early feature of the psychosis spectrum leading to fully formed visual hallucinations (VH), although this sequential relationship has not been clearly demonstrated. OBJECTIVE: We aimed to determine whether there are any overlapping, potentially graded patterns of structural and functional connectivity abnormalities in PD with VI and with VH. Such a finding would argue for a continuum between these entities, whereas distinct imaging features would suggest different neural underpinnings for the phenomena. METHODS: In this case control study, we compared structural and resting state functional MRI brain patterns of PD patients with VH (PD-H, n = 20), with VI (PD-I, n = 19), and without VH or VI (PD-C, n = 23). RESULTS: 1) PD-H had hypo-connectivity between the ILO and anterior cingulate precuneus and parahippocampal gyrus compared to PD-C and PD-I; 2) In contrast, PD-I had hyper-connectivity between the inferior frontal gyrus and the postcentral gyrus compared to PD-C and PD-H. Moreover, PD-I had higher levels of functional connectivity between the amygdala, hippocampus, insula, and fronto-temporal regions compared to PD-H, together with divergent patterns toward the cingulate. 3) Both PD-I and PD-H had functional hypo-connectivity between the lingual gyrus and the parahippocampal region vs. PD-C, and no significant grey matter volume differences was observed between PD-I and PD-H. CONCLUSION: Distinct patterns of functional connectivity characterized VI and VH in PD, suggesting that these two perceptual experiences, while probably linked and driven by at least some similar mechanisms, could reflect differing neural dysfunction.

Developing and piloting a simulated placement experience for students.

COVID-19 and rising student numbers are affecting healthcare education, particularly access to clinical placements. As healthcare education is increasingly supported by technology and non-traditional teaching methods, educational experiences gained through clinical placement also require new approaches. This article explores and discusses the use of a simulated clinical placement for a dietetic student cohort. During this virtual placement, students were able to explore and experience a virtual clinical setting and immerse themselves in a placement experience. A vast range of virtual resources were linked to the online placement portal, including statutory and mandatory training, dietetic resources, patient journeys and interprofessional communication. Advantages of this approach include that all students experience a given situation, unlike in traditional placements where workloads, variety and engagement vary; there is also no risk to patient safety. The aim is to enhance the learning experience to create effective, efficient clinicians. This virtual placement for dietetics is part of a bigger project to develop and evaluate the use of a virtual placement framework in a range of professions. The concept of virtual placement may have been brought forward by the COVID-19 crisis but was inevitable with the move to more technology-enhanced learning tools.

Limbic hypoconnectivity in idiopathic REM sleep behaviour disorder with impulse control disorders.

INTRODUCTION: Current neuroimaging research has revealed several brain alterations in idiopathic REM sleep behaviour disorder (iRBD) that mirror and precede those reported in PD. However, none have specifically addressed the presence of changes across the reward system, and their role in the emergence of impulse control disorders (ICDs). We aimed to compare the volumetric and functional connectivity characteristics of the reward system in relation to the psychobehavioral profile of patients with iRBD versus healthy controls and PD patients. METHODS: Twenty patients with polysomnography confirmed iRBD along with 17 PD patients and 14 healthy controls (HC) underwent structural and functional resting-state brain MRI analysis. Participants completed the questionnaire for impulsive-compulsive disorders in PD (QUIP), the short UPPS-P impulsive behaviour scale, as well as neuropsychological testing of cognitive function. RESULTS: A higher percentage of iRBD patients reported hypersexuality, compared to HC and PD (p = 0.008). Whole-brain and striatal voxel-based morphometry analyses showed no significant clusters of reduced grey matter volume between groups. However, iRBD compared to HC demonstrated functional hypoconnectivity between the limbic striatum and temporo-occipital regions. Furthermore, the presence of ICDs correlated with hypoconnectivity between the limbic striatum and clusters located in cuneus, lingual and fusiform gyrus. CONCLUSION: Altered functional connectivity between the limbic striatum and posterior cortical regions was associated with increased hypersexuality in iRBD. It is possible that this change may ultimately predispose individuals to the emergence of ICDs when they receive dopaminergic medications, after transitioning to PD.

Use of functional near-infrared spectroscopy to evaluate cognitive change when using healthcare simulation tools.

Background: The use of brain imaging techniques in healthcare simulation is relatively rare. However, the use of mobile, wireless technique, such as functional near-infrared spectroscopy (fNIRS), is becoming a useful tool for assessing the unique demands of simulation learning. For this study, this imaging technique was used to evaluate cognitive load during simulation learning events. Methods: This study took place in relation to six simulation activities, paired for similarity, and evaluated comparative cognitive change between the three task pairs. The three paired tasks were: receiving a (1) face-to-face and (2) video patient handover; observing a simulated scene in (1) two dimensions and (2) 360° field of vision; and on a simulated patient (1) taking a pulse and (2) taking a pulse and respiratory rate simultaneously. The total number of participants was n=12. Results: In this study, fNIRS was sensitive to variations in task difficulty in common simulation tools and scenarios, showing an increase in oxygenated haemoglobin concentration and a decrease in deoxygenated haemoglobin concentration, as tasks increased in cognitive load. Conclusion: Overall, findings confirmed the usefulness of neurohaemoglobin concentration markers as an evaluation tool of cognitive change in healthcare simulation. Study findings suggested that cognitive load increases in more complex cognitive tasks in simulation learning events. Task performance that increased in complexity therefore affected cognitive markers, with increase in mental effort required.

Comparison study of the use of 360-degree video and non-360-degree video simulation and cybersickness symptoms in undergraduate healthcare curricula.

The increasing use of emerging technologies in healthcare simulation, particularly virtual reality, has caused in increase in both use and misuse. It is the exploration and study of these types of technology that are key to their success-or failure-in simulation learning and teaching. Therefore, this exploratory study evaluated the most common perceived side effect of virtual reality, that of cybersickness. A total of n=60 undergraduate healthcare students participated in one of four identical learning outcome simulation events, using different simulation techniques. This study compared these four common simulation tools, high-fidelity manikin, standardised patient, video case study and 360-degree virtual reality video, and analysed the self-reported cybersickness symptoms. The results show that some virtual reality tools, in this case 360-degree video, are no more likely to provoke cybersickness symptoms than the other simulation methods used in this study. In addition, virtual reality is reported as less fatiguing than other methods of simulation learning. Virtual reality technologies may be a useful addition to the spectrum of simulation tools and techniques currently in use. This study suggests that there is no greater risk of cybersickness symptoms and this potential barrier to use is not borne out by this study.

Operating department practitioners and adult nurses: interprofessional education bedfellows or a bridge too far?

Background: Interprofessional education (IPE) is well embedded in undergraduate health curricula. However, scant literature exists on which health and care disciplines, such as adult nurses and operating department practitioners (ODPs), prefer to work within simulated learning events. Methods: This study took place over a number of simulated interprofessional events, with a range of health and care disciplines students, using a variety of simulation tools. The total number of participants was: adult nurses 16 and ODPs 18. Results: An ordinal logistic regression analysis was carried out on survey data collected. The OR of ODPs choosing adult nurses as the discipline they would prefer to work with at these events was 1.994 (95% CI 1.034 to 3.334) times that of adult nurses choosing ODPs as the discipline they would prefer to work with at these events, a statistically significant effect. Conclusions: It is clear that a statistical difference in preferential choice exists, with ODPs choosing to work with adult nurses almost twice that of adult nurses choosing to work with ODPs. This supports the importance of IPE and the understanding of other professions, to improve team working across health and care organisations.

Why are photosynthetic reaction centres dimeric?

All photosynthetic organisms convert solar energy into chemical energy through charge separation in dimeric reaction centres. It is unknown why early reaction centres dimerised and completely displaced their monomeric ancestors. Here, we discuss several proposed explanations for reaction-centre dimerism and conclude-with only weak assumptions about the primordial dimerisation event-that the most probable explanation for the dimerism is that it arose because it enhanced light-harvesting efficiency by deepening the excitonic trap, i.e., by enhancing the rate of exciton transfer from an antenna complex and decreasing the rate of back transfer. This effect would have outweighed the negative effect dimerisation would have had on charge transfer within the reaction centre. Our argument implies that dimerisation likely occurred after the evolution of the first antennas, and it explains why the lower-energy state of the special pair is bright.

Generalised Marcus theory for multi-molecular delocalised charge transfer.

Although Marcus theory is widely used to describe charge transfer in molecular systems, in its usual form it is restricted to transfer from one molecule to another. If a charge is delocalised across multiple donor molecules, this approach requires us to treat the entire donor aggregate as a unified supermolecule, leading to potentially expensive quantum-chemical calculations and making it more difficult to understand how the aggregate components contribute to the overall transfer. Here, we show that it is possible to describe charge transfer between groups of molecules in terms of the properties of the constituent molecules and couplings between them, obviating the need for expensive supermolecular calculations. We use the resulting theory to show that charge delocalisation between molecules in either the donor or acceptor aggregates can enhance the rate of charge transfer through a process we call supertransfer (or suppress it through subtransfer). The rate can also be enhanced above what is possible with a single donor and a single acceptor by judiciously tuning energy levels and reorganisation energies. We also describe bridge-mediated charge transfer between delocalised molecular aggregates. The equations of generalised Marcus theory are in closed form, providing qualitative insight into the impact of delocalisation on charge dynamics in molecular systems.

Health research access to personal confidential data in England and Wales: assessing any gap in public attitude between preferable and acceptable models of consent.

England and Wales are moving toward a model of 'opt out' for use of personal confidential data in health research. Existing research does not make clear how acceptable this move is to the public. While people are typically supportive of health research, when asked to describe the ideal level of control there is a marked lack of consensus over the preferred model of consent (e.g. explicit consent, opt out etc.). This study sought to investigate a relatively unexplored difference between the consent model that people prefer and that which they are willing to accept. It also sought to explore any reasons for such acceptance.A mixed methods approach was used to gather data, incorporating a structured questionnaire and in-depth focus group discussions led by an external facilitator. The sampling strategy was designed to recruit people with different involvement in the NHS but typically with experience of NHS services. Three separate focus groups were carried out over three consecutive days.The central finding is that people are typically willing to accept models of consent other than that which they would prefer. Such acceptance is typically conditional upon a number of factors, including: security and confidentiality, no inappropriate commercialisation or detrimental use, transparency, independent overview, the ability to object to any processing considered to be inappropriate or particularly sensitive.This study suggests that most people would find research use without the possibility of objection to be unacceptable. However, the study also suggests that people who would prefer to be asked explicitly before data were used for purposes beyond direct care may be willing to accept an opt out model of consent if the reasons for not seeking explicit consent are accessible to them and they trust that data is only going to be used under conditions, and with safeguards, that they would consider to be acceptable even if not preferable.