Real-World Evaluation of the Feasibility, Acceptability and Safety of a Remote, Self-Management Parkinson's Disease Care Pathway: A Healthcare Improvement Initiative.

BACKGROUND: There is significant unmet need for effective and efficiently delivered care for people with Parkinson's disease (PwP). We undertook a service improvement initiative to co-develop and implement a new care pathway, Home Based Care (HBC), based on supported self-management, remote monitoring and the ability to trigger a healthcare contact when needed. OBJECTIVE: To evaluate feasibility, acceptability and safety of Home Based Care. METHODS: We evaluated data from the first 100 patients on HBC for 6 months. Patient monitoring, performed at baseline and 6-monthly, comprised motor (MDS-UPDRS II and accelerometer), non-motor (NMSQ, PDSS-2, HADS) and quality of life (PDQ) measures. Care quality was audited against Parkinson's UK national audit standards. Process measures captured feasibility. Acceptability was assessed using a mixed-methods approach comprising questionnaires and semi-structured interviews. RESULTS: Between October 2019 and January 2021, 108 PwP were enrolled onto HBC, with data from 100 being available at 6 months. Over 90% of all questionnaires were returned, 97% were complete or had < 3 missing items. Reporting and communications occurred within agreed timeframes. Compared with baseline, after 6m on HBC, PD symptoms were stable; more PwP felt listened to (90% vs. 79%) and able to seek help (79% vs. 68%). HBC met 93% of national audit criteria. Key themes from the interviews included autonomy and empowerment. CONCLUSIONS: We have demonstrated acceptability, feasibility and safety of our novel remotely delivered Parkinson's care pathway. Ensuring scalability will widen its reach and realize its benefits for underserved communities, enabling formal comparisons with standard care and cost-effectiveness evaluation.

Enhancing Trial Delivery in Parkinson's Disease: Qualitative Insights from PD STAT.

BACKGROUND: Recruitment and retention of participants in clinical trials for Parkinson's disease (PD) is challenging. A qualitative study embedded in the PD STAT multi-centre randomised controlled trial of simvastatin for neuroprotection in PD explored the motivators, barriers and challenges of participants, care partners and research staff. OBJECTIVE: To outline a set of considerations informing a patient-centred approach to trial recruitment, retention, and delivery. METHOD: We performed semi-structured interviews and focus groups with a subset of trial participants and their care partners. Quantitative and qualitative data were obtained through surveys circulated among the 235 participants across 23 UK sites at the beginning, middle and end of the 2-year trial. We also interviewed and surveyed research staff at trial closure. RESULTS: Twenty-seven people with PD, 6 care partners and 9 researchers participated in interviews and focus groups. A total of 463 trial participant survey datasets were obtained across three timepoints, and 53 staff survey datasets at trial closure. Trial participants discussed the physical and psychological challenges they faced, especially in the context of OFF state assessments, relationships, and communication with research staff. Care partners shared their insights into OFF state challenges, and the value of being heard by research teams. Research staff echoed many concerns with suggestions on flexible, person-centred approaches to maximising convenience, comfort, and privacy. CONCLUSION: These considerations, in favour of person-centred research protocols informed by the variable needs of participants, care partners and staff, could be developed into a set of recommendations for future trials.

Mapping the effects of atomoxetine during response inhibition across cortical territories and the locus coeruleus.

RATIONALE: The effects of atomoxetine (ATO) on response inhibition have been typically examined using the stop signal task (SST) which is however confounded by attentional capture. The right inferior frontal cortex (rIFC) has been implicated in the modulation of ATO on inhibitory control, but a precise characterisation of its role is complicated by its functional inhomogeneity. OBJECTIVES: The current study aimed to directly investigate the effect of ATO in the SST using the imaging contrast unconfounded by attentional capture, to test the specific drug actions in functionally dissociable rIFC subregions, and to explore the role of locus coeruleus (LC), the main source of cortical noradrenaline, in mediating the drug effects. METHODS: This imaging study investigated the effect of ATO (40 mg) in 18 human participants during a modified SST that unconfounds attention from inhibition. Functional definitions for rIFC subdivisions were adopted in the analyses to isolate attention and inhibition during action cancellation. The LC integrity was measured in vivo using a neuromelanin-sensitive sequence. RESULTS: We identified one mechanism of ATO modulation specific to inhibitory control: ATO enhanced activity in pre-supplementary area (pre-SMA) for motor inhibition, and the recruitment of temporoparietal junction (TPJ) and inferior frontal junction (IFJ) for functional integration during response inhibition. Moreover, drug-related behavioural and neural responses correlated with variations in LC integrity. CONCLUSIONS: These findings provide a more nuanced and precise understanding of the effects of ATO on specific and domain general aspects of stopping.

Introducing the Parkinson's KinetiGraph into Routine Parkinson's Disease Care: A 3-Year Single Centre Experience.

In an effort to provide timely clinical input for people with Parkinson's disease (PD) in the face of increasing demand and resource limitation in our UK based service, we introduced remote management in place of clinic appointment, including the use of the Parkinson's KinetiGraph (PKG™), a wrist-worn device that provides a continuous measure of movement. We evaluated our reporting methods and findings, the nature of unmet need we identified, our treatment recommendations and the degree of their implementation in our patients whose feedback guided our service developments. Our evaluation highlighted opportunities and challenges associated with incorporating digital data into care traditionally delivered via in-person contact.

Conflicting emergences. Weak vs. strong emergence for the modelling of brain function.

The concept of "emergence" has become commonplace in the modelling of complex systems, both natural and man-made; a functional property" emerges" from a system when it cannot be readily explained by the properties of the system's sub-units. A bewildering array of adaptive and sophisticated behaviours can be observed from large ensembles of elementary agents such as ant colonies, bird flocks or by the interactions of elementary material units such as molecules or weather elements. Ultimately, emergence has been adopted as the ontological support of a number of attempts to model brain function. This manuscript aims to clarify the ontology of emergence and delve into its many facets, particularly into its "strong" and "weak" versions that underpin two different approaches to the modelling of behaviour. The first group of models is here represented by the "free energy" principle of brain function and the "integrated information theory" of consciousness. The second group is instead represented by computational models such as oscillatory networks that use mathematical scalable representations to generate emergent behaviours and are then able to bridge neurobiology with higher mental functions. Drawing on the epistemological literature, we observe that due to their loose mechanistic links with the underlying biology, models based on strong forms of emergence are at risk of metaphysical implausibility. This, in practical terms, translates into the over determination that occurs when the proposed model becomes only one of a large set of possible explanations for the observable phenomena. On the other hand, computational models that start from biologically plausible elementary units, hence are weakly emergent, are not limited by ontological faults and, if scalable and able to realistically simulate the hierarchies of brain output, represent a powerful vehicle for future neuroscientific research programmes.

From homeostasis to behavior: Balanced activity in an exploration of embodied dynamic environmental-neural interaction.

In recent years, there have been many computational simulations of spontaneous neural dynamics. Here, we describe a simple model of spontaneous neural dynamics that controls an agent moving in a simple virtual environment. These dynamics generate interesting brain-environment feedback interactions that rapidly destabilize neural and behavioral dynamics demonstrating the need for homeostatic mechanisms. We investigate roles for homeostatic plasticity both locally (local inhibition adjusting to balance excitatory input) as well as more globally (regional "task negative" activity that compensates for "task positive", sensory input in another region) balancing neural activity and leading to more stable behavior (trajectories through the environment). Our results suggest complementary functional roles for both local and macroscale mechanisms in maintaining neural and behavioral dynamics and a novel functional role for macroscopic "task-negative" patterns of activity (e.g., the default mode network).

Parsing the Roles of the Frontal Lobes and Basal Ganglia in Task Control Using Multivoxel Pattern Analysis.

Cognitive control has traditionally been associated with pFC based on observations of deficits in patients with frontal lesions. However, evidence from patients with Parkinson disease indicates that subcortical regions also contribute to control under certain conditions. We scanned 17 healthy volunteers while they performed a task-switching paradigm that previously dissociated performance deficits arising from frontal lesions in comparison with Parkinson disease, as a function of the abstraction of the rules that are switched. From a multivoxel pattern analysis by Gaussian Process Classification, we then estimated the forward (generative) model to infer regional patterns of activity that predict Switch/Repeat behavior between rule conditions. At 1000 permutations, Switch/Repeat classification accuracy for concrete rules was significant in the BG, but at chance in the frontal lobe. The inverse pattern was obtained for abstract rules, whereby the conditions were successfully discriminated in the frontal lobe but not in the BG. This double dissociation highlights the difference between cortical and subcortical contributions to cognitive control and demonstrates the utility of multivariate approaches in investigations of functions that rely on distributed and overlapping neural substrates.

Realising stratified psychiatry using multidimensional signatures and trajectories.

BACKGROUND: Stratified or personalised medicine targets treatments for groups of individuals with a disorder based on individual heterogeneity and shared factors that influence the likelihood of response. Psychiatry has traditionally defined diagnoses by constellations of co-occurring signs and symptoms that are assigned a categorical label (e.g. schizophrenia). Trial methodology in psychiatry has evaluated interventions targeted at these categorical entities, with diagnoses being equated to disorders. Recent insights into both the nosology and neurobiology of psychiatric disorder reveal that traditional categorical diagnoses cannot be equated with disorders. We argue that current quantitative methodology (1) inherits these categorical assumptions, (2) allows only for the discovery of average treatment response, (3) relies on composite outcome measures and (4) sacrifices valuable predictive information for stratified and personalised treatment in psychiatry. METHODS AND FINDINGS: To achieve a truly 'stratified psychiatry' we propose and then operationalise two necessary steps: first, a formal multi-dimensional representation of disorder definition and clinical state, and second, the similar redefinition of outcomes as multidimensional constructs that can expose within- and between-patient differences in response. We use the categorical diagnosis of schizophrenia-conceptualised as a label for heterogeneous disorders-as a means of introducing operational definitions of stratified psychiatry using principles from multivariate analysis. We demonstrate this framework by application to the Clinical Antipsychotic Trials of Intervention Effectiveness dataset, showing heterogeneity in both patient clinical states and their trajectories after treatment that are lost in the traditional categorical approach with composite outcomes. We then systematically review a decade of registered clinical trials for cognitive deficits in schizophrenia highlighting existing assumptions of categorical diagnoses and aggregate outcomes while identifying a small number of trials that could be reanalysed using our proposal. CONCLUSION: We describe quantitative methods for the development of a multi-dimensional model of clinical state, disorders and trajectories which practically realises stratified psychiatry. We highlight the potential for recovering existing trial data, the implications for stratified psychiatry in trial design and clinical treatment and finally, describe different kinds of probabilistic reasoning tools necessary to implement stratification.

A neurological perspective on the enhancement debate: Lessons learned from Parkinson's disease.

Cognitive enhancement is signified by adaptive behavioural change following an intervention that targets the brain. Although much of the discussion and research into cognitive enhancement focuses on the effects of neural interventions in healthy individuals, it is useful to consider evidence from clinical populations. Diseases of the central nervous system represent the primary and richest source of evidence on the effects of brain manipulations, which are in the first instance therapeutic. Parkinson's disease (PD) is used as a model for understanding the effects of pharmacological agents that target systems with a central role in cognition. The mixed outcomes of deep brain stimulation on cognition will also be discussed. By illustrating the psychopharmacological principle of diverse and malleable neurochemical optima for different cognitive functions, and the role of individual differences, it will be argued that the entire spectrum of cognitive effects in any one individual following any given manipulation, such as the administration of a drug, often includes enhancement as well as impairment. Predicting these effects represents a complex multivariate problem, and the accuracy of this predictive effort, as well as the harm prevention it connotes, is determined by our evolving understanding of the brain and cognition. A manipulation can be said to confer cognitive enhancement; however, it is argued that using the global term cognitive enhancer to refer to such a manipulation without qualification is of limited utility.

Targeting impulsivity in Parkinson's disease using atomoxetine.

Noradrenergic dysfunction may play a significant role in cognition in Parkinson's disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson's disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R(2) = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R(2) = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson's disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder.

Revisiting the effects of Parkinson's disease and frontal lobe lesions on task switching: the role of rule reconfiguration.

This study investigated the hypothesis that rule reconfiguration in task switching can isolate aspects of intact and impaired control at different stages of Parkinson's disease (PD) by comparing switches between concrete naming rules pertaining to stimulus selection, to switches between abstract rules which allocate categorization responses to these stimuli. Based on previous findings, it was hypothesized that attentional switches, where task set competition emerges at the stimulus but not response set level, highlights striatal dopaminergic function. Conversely, increasing the degree of task set competition to encompass reconfiguration of response set when switching between abstract rules, represents a condition which engages the prefrontal cortex (PFC) and renders this manipulation sensitive to frontal damage. To this end, we investigated task switching with concrete and abstract rules in unilaterally (Hoehn & Yahr stage I) and bilaterally (Hoehn & Yahr stage II) affected PD patients, as well as striatally intact frontal lesion patients. As predicted, frontal lesion patients demonstrated switching deficits only with abstract categorization rules, where switching engendered complete task set reconfiguration and a new response, as did stage II PD patients with presumed frontal cortical pathology. Replicating previous findings, stage I PD patients with relatively circumscribed striatal pathology demonstrated no such impairment. Disease severity also impacted on attentional switching indexed by naming rules, since medicated stage II but not stage I patients demonstrated switching deficits emerging from stimulus set reconfiguration, suggesting that the ameliorative efficacy of dopaminergic medication is inversely related to the severity of the striatal deficit. These findings illustrate that the nature of the rules that are switched, and its implication in terms of reconfiguring different task set elements, highlights different neural characters of cognitive flexibility. These manipulations may help decipher the differential effects of progressive neurodegeneration on parkinsonian cognition, and provide a framework in which to conceptualize the contributions of cortical and subcortical regions to cognitive control.

Cognitive impairment in Parkinson's disease: the dual syndrome hypothesis.

Research into the heterogeneous nature of cognitive impairment documented in patients with Parkinson's disease (PD) has focused on disentangling deficits that vary between individuals, evolve and respond differentially to pharmacological treatments, and relate differentially to PD dementia (PDD). We summarise studies conducted in our laboratory over the last 2 decades, outlining the incremental development of our hypotheses, the starting point for which is our early work on executive deficits mirroring fronto-striatal dysfunction. We present subsequent findings linking these deficits to a model of dopaminergic function that conforms to an inverted curvilinear function. We review studies that investigated the range of dopamine-independent attentional and visuospatial memory deficits seen in PD, demonstrating that abnormalities in these domains more accurately predict PDD. We conclude with an exposition of the dual syndrome hypothesis, which distinguishes between dopaminergically mediated fronto-striatal executive impairments and a dementia syndrome with distinctive prodromal visuospatial deficits in which cholinergic treatments offer some clinical benefits.

Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson's disease.

Cognitive impairment in patients with Parkinson's disease is gaining increased clinical significance owing to the relative success of therapeutic approaches to the motor symptoms of this disorder. Early investigations contributed to the concept of subcortical dementia associated with bradyphrenia and cognitive rigidity. For cognition in parkinsonian disorders, this notion developed into the concept of mild cognitive impairment and fronto-executive dysfunction in particular, driven mainly by dopaminergic dysmodulation and manifesting as deficits in flexibility, planning, working memory, and reinforcement learning. However, patients with Parkinson's disease could also develop a syndrome of dementia that might depend on non-dopaminergic, cholinergic cortical dysfunction. Recent findings, supplemented by advances in neuroimaging and genetic research, reveal substantial heterogeneity in the range of cognitive deficits in patients with Parkinson's disease. Remediation and management prospects for these cognitive deficits are based on neuropharmacological and cognitive rehabilitation approaches.

Learning and cognitive flexibility: frontostriatal function and monoaminergic modulation.

Learning in a constant environment, and adapting flexibly to a changing one, through changes in reinforcement contingencies or valence-free cues, depends on overlapping circuitry that interconnects the prefrontal cortex (PFC) with the striatum and is subject to several forms of neurochemical modulation. We present evidence from recent studies in animals employing electrophysiological, pharmacological and lesion techniques, and neuroimaging, neuropsychological and pharmacological investigations of healthy humans and clinical patients. Dopamine (DA) neurotransmission in the medial striatum and PFC is critical for basic reinforcement learning and the integration of negative feedback during reversal learning, whilst orbitofrontal 5-hydroxytryptamine (5-HT) likely mediates this type of low level flexibility, perhaps by reducing interference from salient stimuli. The role of prefrontal noradrenaline (NA) in higher order flexibility indexed through attentional set-shifting has recently received significant empirical support, and similar avenues appear promising in the field of task switching.

Switching between abstract rules reflects disease severity but not dopaminergic status in Parkinson's disease.

This study sought to disambiguate the impact of Parkinson's disease (PD) on cognitive control as indexed by task set switching, by addressing discrepancies in the literature pertaining to disease severity and paradigm heterogeneity. A task set is governed by a rule that determines how relevant stimuli (stimulus set) map onto specific responses (response set). Task set switching may entail reconfiguration in either or both of these components. Although previous studies have shown that PD patients are impaired at switching between stimuli, in the present study not all patients were impaired at switching entire task sets, that is, both stimulus and response sets: compared with controls, patients with unilateral signs (Hoehn & Yahr Stage I) demonstrated intact switching, even following withdrawal from dopaminergic medication, while bilaterally affected Stage II patients were impaired. The parametric measure of Unified Parkinson's Disease Rating Scale (UPDRS) score predicted increasing switch costs within the patient group. These findings suggest that switching entire task sets may be a function of extrastriatal, possibly non-dopaminergic pathology which increases as the disease progresses.