Embedding Patient Input in Outcome Measures for Long-Term Disease-Modifying Parkinson Disease Trials.

BACKGROUND: Clinical trials of disease-modifying therapies in PD require valid and responsive primary outcome measures that are relevant to patients. OBJECTIVES: The objective is to select a patient-centered primary outcome measure for disease-modification trials over three or more years. METHODS: Experts in Parkinson's disease (PD), statistics, and health economics and patient and public involvement and engagement (PPIE) representatives reviewed and discussed potential outcome measures. A larger PPIE group provided input on their key considerations for such an endpoint. Feasibility, clinimetric properties, and relevance to patients were assessed and synthesized. RESULTS: Although initial considerations favored the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in Off, feasibility, PPIE input, and clinimetric properties supported the MDS-UPDRS Part II. However, PPIE input also highlighted the importance of nonmotor symptoms, especially in the longer term, leading to the selection of the MDS-UPDRS Parts I + II sum score. CONCLUSIONS: The MDS-UPDRS Parts I + II sum score was chosen as the primary outcome for large 3-year disease-modification trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Orienting to fear under transient focal disruption of the human amygdala.

Responding to threat is under strong survival pressure, promoting the evolution of systems highly optimized for the task. Though the amygdala is implicated in 'detecting' threat, its role in the action that immediately follows-'orienting'-remains unclear. Critical to mounting a targeted response, such early action requires speed, accuracy, and resilience optimally achieved through conserved, parsimonious, dedicated systems, insured against neural loss by a parallelized functional organization. These characteristics tend to conceal the underlying substrate not only from correlative methods but also from focal disruption over time scales long enough for compensatory adaptation to take place. In a study of six patients with intracranial electrodes temporarily implanted for the clinical evaluation of focal epilepsy, we investigated gaze orienting to fear during focal, transient, unilateral direct electrical disruption of the amygdala. We showed that the amygdala is necessary for rapid gaze shifts towards faces presented in the contralateral hemifield regardless of their emotional expression, establishing its functional lateralization. Behaviourally dissociating the location of presented fear from the direction of the response, we implicated the amygdala not only in detecting contralateral faces, but also in automatically orienting specifically towards fearful ones. This salience-specific role was demonstrated within a drift-diffusion model of action to manifest as an orientation bias towards the location of potential threat. Pixel-wise analysis of target facial morphology revealed scleral exposure as its primary driver, and induced gamma oscillations-obtained from intracranial local field potentials-as its time-locked electrophysiological correlate. The amygdala is here reconceptualized as a functionally lateralized instrument of early action, reconciling previous conflicting accounts confined to detection, and revealing a neural organisation analogous to the superior colliculus, with which it is phylogenetically kin. Greater clarity on its role has the potential to guide therapeutic resection, still frequently complicated by impairments of cognition and behaviour related to threat, and inform novel focal stimulation techniques for the management of neuropsychiatric conditions.

Predicting mortality in acutely hospitalised older patients: the impact of model dimensionality.

BACKGROUND: The prediction of long-term mortality following acute illness can be unreliable for older patients, inhibiting the delivery of targeted clinical interventions. The difficulty plausibly arises from the complex, multifactorial nature of the underlying biology in this population, which flexible, multimodal models based on machine learning may overcome. Here, we test this hypothesis by quantifying the comparative predictive fidelity of such models in a large consecutive sample of older patients acutely admitted to hospital and characterise their biological support. METHODS: A set of 804 admission episodes involving 616 unique patients with a mean age of 84.5 years consecutively admitted to the Acute Geriatric service at University College Hospital were identified, in whom clinical diagnoses, blood tests, cognitive status, computed tomography of the head, and mortality within 600 days after admission were available. We trained and evaluated out-of-sample an array of extreme gradient boosted trees-based predictive models of incrementally greater numbers of investigational modalities and modelled features. Both linear and non-linear associations with investigational features were quantified. RESULTS: Predictive models of mortality showed progressively increasing fidelity with greater numbers of modelled modalities and dimensions. The area under the receiver operating characteristic curve rose from 0.67 (sd = 0.078) for age and sex to 0.874 (sd = 0.046) for the most comprehensive model. Extracranial bone and soft tissue features contributed more than intracranial features towards long-term mortality prediction. The anterior cingulate and angular gyri, and serum albumin, were the greatest intracranial and biochemical model contributors respectively. CONCLUSIONS: High-dimensional, multimodal predictive models of mortality based on routine clinical data offer higher predictive fidelity than simpler models, facilitating individual level prognostication and interventional targeting. The joint contributions of both extracranial and intracranial features highlight the potential importance of optimising somatic as well as neural functions in healthy ageing. Our findings suggest a promising path towards a high-fidelity, multimodal index of frailty.

Metabolic lesion-deficit mapping of human cognition.

In theory the most powerful technique for functional localization in cognitive neuroscience, lesion-deficit mapping is in practice distorted by unmodelled network disconnections and strong 'parasitic' dependencies between collaterally damaged ischaemic areas. High-dimensional multivariate modelling can overcome these defects, but only at the cost of commonly impracticable data scales. Here we develop lesion-deficit mapping with metabolic lesions-discrete areas of hypometabolism typically seen on interictal 18F-fluorodeoxyglucose PET imaging in patients with focal epilepsy-that inherently capture disconnection effects, and whose structural dependence patterns are sufficiently benign to allow the derivation of robust functional anatomical maps with modest data. In this cross-sectional study of 159 patients with widely distributed focal cortical impairments, we derive lesion-deficit maps of a broad range of psychological subdomains underlying affect and cognition. We demonstrate the potential clinical utility of the approach in guiding therapeutic resection for focal epilepsy or other neurosurgical indications by applying high-dimensional modelling to predict out-of-sample verbal IQ and depression from cortical metabolism alone.

Spatial and episodic memory tasks promote temporal lobe interictal spikes.

Reflex epilepsies have been demonstrated to exploit specific networks that subserve normal physiological function. It is unclear whether more common forms of epilepsy share this particular feature. By measuring interictal spikes in patients with a range of epilepsies, we show that 2 tasks known to specifically engage the hippocampus and temporal neocortex promoted increased interictal spiking within these regions, whereas a nonhippocampal dependent task did not. This indicates that interictal spike frequency may reflect the processing demands being placed on specific functional-anatomical networks in epilepsy. ANN NEUROL 2019;86:304-309.

Functional Connectivity of the Pedunculopontine Nucleus and Surrounding Region in Parkinson's Disease.

Deep brain stimulation of the pedunculopontine nucleus and surrounding region (PPNR) is a novel treatment strategy for gait freezing in Parkinson's disease (PD). However, clinical results have been variable, in part because of the paucity of functional information that might help guide selection of the optimal surgical target. In this study, we use simultaneous magnetoencephalography and local field recordings from the PPNR in seven PD patients, to characterize functional connectivity with distant brain areas at rest. The PPNR was preferentially coupled to brainstem and cingulate regions in the alpha frequency (8-12 Hz) band and to the medial motor strip and neighboring areas in the beta (18-33 Hz) band. The distribution of coupling also depended on the vertical distance of the electrode from the pontomesencephalic line: most effects being greatest in the middle PPNR, which may correspond to the caudal pars dissipata of the pedunculopontine nucleus. These observations confirm the crucial position of the PPNR as a functional node between cortical areas such as the cingulate/ medial motor strip and other brainstem nuclei, particularly in the dorsal pons. In particular they suggest a special role for the middle PPNR as this has the greatest functional connectivity with other brain regions.

A legion of potential regulatory sRNAs exists beyond the typical microRNAs microcosm.

Post ENCODE, regulatory sRNAs (rsRNAs) like miRNAs have established their status as one of the core regulatory elements of cell systems. However, large number of rsRNAs are compromised due to traditional approaches to identify miRNAs, limiting the otherwise vast world of rsRNAs mainly to hair-pin loop bred typical miRNAs. The present study has analyzed for the first time a huge volume of sequencing data from 4997 individuals and 25 cancer types to report 11 234 potentially regulatory small RNAs which appear to have deep reaching impact. The rsRNA-target interactions have been studied and validated extensively using experimental data from AGO-crosslinking, DGCR8 knockdown, CLASH, proteome and expression data. A subset of such interactions was also validated independently in the present study using multiple cell lines, by qPCR. Several of the potential rsRNAs have emerged as a critical cancer biomarker controlling some important spots of cell system. The entire study has been presented into an interactive info-analysis portal handling more than 260 GB of processed data. The possible degree of cell system regulation by sRNAs appears to be much higher than previously assumed.

Cortico-pallidal oscillatory connectivity in patients with dystonia.

Primary dystonia has been associated with an underlying dysfunction of a wide network of brain regions including the motor cortex, basal ganglia, cerebellum, brainstem and spinal cord. Dystonia can be effectively treated by pallidal deep brain stimulation although the mechanism of this effect is not well understood. Here, we sought to characterize cortico-basal ganglia functional connectivity using a frequency-specific measure of connectivity-coherence. We recorded direct local field potentials from the human pallidum simultaneously with whole head magnetoencephalography to characterize functional connectivity in the cortico-pallidal oscillatory network in nine patients with idiopathic dystonia. Three-dimensional cortico-pallidal coherence images were compared to surrogate images of phase shuffled data across patients to reveal clusters of significant coherence (family-wise error P < 0.01, voxel extent 1000). Three frequency-specific, spatially-distinct cortico-pallidal networks have been identified: a pallido-temporal source of theta band (4-8 Hz) coherence, a pallido-cerebellar source of alpha band (7-13 Hz) coherence and a cortico-pallidal source of beta band (13-30 Hz) coherence over sensorimotor areas. Granger-based directionality analysis revealed directional coupling with the pallidal local field potentials leading in the theta and alpha band and the magnetoencephalographic cortical source leading in the beta band. The degree of pallido-cerebellar coupling showed an inverse correlation with dystonic symptom severity. Our data extend previous findings in patients with Parkinson's disease describing motor cortex-basal ganglia oscillatory connectivity in the beta band to patients with dystonia. Source coherence analysis revealed two additional frequency-specific networks involving the temporal cortex and the cerebellum. Pallido-cerebellar oscillatory connectivity and its association with dystonic symptoms provides further confirmation of cerebellar involvement in dystonia that has been recently reported using functional magnetic resonance imaging and fibre tracking.

The Frontal Control of Stopping.

Stopping is a critical aspect of brain function. Like other voluntary actions, it is defined by its context as much as by its execution. Its neural substrate must therefore reflect both. Here, we distinguish those elements of the underlying brain circuit that preferentially reflect contextual aspects of stopping from those related to its execution. Contextual complexity of stopping was modulated using a novel "Stop/Change-signal" task, which also allowed us to parameterize the duration of the stopping process. Human magnetoencephalographic activity and behavioral responses were simultaneously recorded. Whereas theta/alpha frequency activity in the right inferior frontal gyrus was most closely associated with the duration of the stopping process, earlier gamma frequency activity in the pre-supplementary motor area was unique in showing contextual modulation. These results differentiate the roles of 2 key frontal regions involved in stopping, a crucial aspect of behavioral control.

Transcriptome sequencing of rhizome tissue of Sinopodophyllum hexandrum at two temperatures.

BACKGROUND: Sinopodophyllum hexandrum is an endangered medicinal herb, which is commonly present in elevations ranging between 2,400-4,500 m and is sensitive to temperature. Medicinal property of the species is attributed to the presence of podophyllotoxin in the rhizome tissue. The present work analyzed transcriptome of rhizome tissue of S. hexandrum exposed to 15°C and 25°C to understand the temperature mediated molecular responses including those associated with podophyllotoxin biosynthesis. RESULTS: Deep sequencing of transcriptome with an average coverage of 88.34X yielded 60,089 assembled transcript sequences representing 20,387 unique genes having homology to known genes. Fragments per kilobase of exon per million fragments mapped (FPKM) based expression analysis revealed genes related to growth and development were over-expressed at 15°C, whereas genes involved in stress response were over-expressed at 25°C. There was a decreasing trend of podophyllotoxin accumulation at 25°C; data was well supported by the expression of corresponding genes of the pathway. FPKM data was validated by quantitative real-time polymerase chain reaction data using a total of thirty four genes and a positive correlation between the two platforms of gene expression was obtained. Also, detailed analyses yielded cytochrome P450s, methyltransferases and glycosyltransferases which could be the potential candidate hitherto unidentified genes of podophyllotoxin biosynthesis pathway. CONCLUSIONS: The present work revealed temperature responsive transcriptome of S. hexandrum on Illumina platform. Data suggested expression of genes for growth and development and podophyllotoxin biosynthesis at 15°C, and prevalence of those associated with stress response at 25°C.

Widespread alteration of protein autoinhibition in human cancers.

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Movement-related changes in local and long-range synchronization in Parkinson's disease revealed by simultaneous magnetoencephalography and intracranial recordings.

Functional neurosurgery has afforded the opportunity to assess interactions between populations of neurons in the human cerebral cortex and basal ganglia in patients with Parkinson's disease (PD). Interactions occur over a wide range of frequencies, and the functional significance of those >30 Hz is particularly unclear. Do they improve movement, and, if so, in what way? We acquired simultaneously magnetoencephalography and direct recordings from the subthalamic nucleus (STN) in 17 PD patients. We examined the effect of synchronous and sequential finger movements and of the dopamine prodrug levodopa on induced power in the contralateral primary motor cortex (M1) and STN and on the coherence between the two structures. We observed discrete peaks in M1 and STN power at 60-90 Hz and at 300-400 Hz. All these power peaks increased with movement and levodopa treatment. Only STN activity at 60-90 Hz was coherent with activity in M1. Directionality analysis showed that STN gamma activity at 60-90 Hz tended to drive gamma activity in M1. The effects of levodopa on both local and distant synchronization at 60-90 Hz correlated with the degree of improvement in bradykinesia-rigidity as did local STN activity at 300-400 Hz. Despite this, there were no effects of movement type, nor interactions between movement type and levodopa in the STN, nor in the coherence between STN and M1. We conclude that synchronization at 60-90 Hz in the basal ganglia cortical network is prokinetic but likely through a modulatory effect rather than any involvement in explicit motor processing.

Convolution models for induced electromagnetic responses.

In Kilner et al. [Kilner, J.M., Kiebel, S.J., Friston, K.J., 2005. Applications of random field theory to electrophysiology. Neurosci. Lett. 374, 174-178.] we described a fairly general analysis of induced responses-in electromagnetic brain signals-using the summary statistic approach and statistical parametric mapping. This involves localising induced responses-in peristimulus time and frequency-by testing for effects in time-frequency images that summarise the response of each subject to each trial type. Conventionally, these time-frequency summaries are estimated using post-hoc averaging of epoched data. However, post-hoc averaging of this sort fails when the induced responses overlap or when there are multiple response components that have variable timing within each trial (for example stimulus and response components associated with different reaction times). In these situations, it is advantageous to estimate response components using a convolution model of the sort that is standard in the analysis of fMRI time series. In this paper, we describe one such approach, based upon ordinary least squares deconvolution of induced responses to input functions encoding the onset of different components within each trial. There are a number of fundamental advantages to this approach: for example; (i) one can disambiguate induced responses to stimulus onsets and variably timed responses; (ii) one can test for the modulation of induced responses-over peristimulus time and frequency-by parametric experimental factors and (iii) one can gracefully handle confounds-such as slow drifts in power-by including them in the model. In what follows, we consider optimal forms for convolution models of induced responses, in terms of impulse response basis function sets and illustrate the utility of deconvolution estimators using simulated and real MEG data.

A framework for focal and connectomic mapping of transiently disrupted brain function.

The distributed nature of the neural substrate, and the difficulty of establishing necessity from correlative data, combine to render the mapping of brain function a far harder task than it seems. Methods capable of combining connective anatomical information with focal disruption of function are needed to disambiguate local from global neural dependence, and critical from merely coincidental activity. Here we present a comprehensive framework for focal and connective spatial inference based on sparse disruptive data, and demonstrate its application in the context of transient direct electrical stimulation of the human medial frontal wall during the pre-surgical evaluation of patients with focal epilepsy. Our framework formalizes voxel-wise mass-univariate inference on sparsely sampled data within the statistical parametric mapping framework, encompassing the analysis of distributed maps defined by any criterion of connectivity. Applied to the medial frontal wall, this transient dysconnectome approach reveals marked discrepancies between local and distributed associations of major categories of motor and sensory behaviour, revealing differentiation by remote connectivity to which purely local analysis is blind. Our framework enables disruptive mapping of the human brain based on sparsely sampled data with minimal spatial assumptions, good statistical efficiency, flexible model formulation, and explicit comparison of local and distributed effects.

Outcome Measures for Disease-Modifying Trials in Parkinson's Disease: Consensus Paper by the EJS ACT-PD Multi-Arm Multi-Stage Trial Initiative.

BACKGROUND: Multi-arm, multi-stage (MAMS) platform trials can accelerate the identification of disease-modifying treatments for Parkinson's disease (PD) but there is no current consensus on the optimal outcome measures (OM) for this approach. OBJECTIVE: To provide an up-to-date inventory of OM for disease-modifying PD trials, and a framework for future selection of OM for such trials. METHODS: As part of the Edmond J Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative, an expert group with Patient and Public Involvement and Engagement (PPIE) representatives' input reviewed and evaluated available evidence on OM for potential use in trials to delay progression of PD. Each OM was ranked based on aspects such as validity, sensitivity to change, participant burden and practicality for a multi-site trial. Review of evidence and expert opinion led to the present inventory. RESULTS: An extensive inventory of OM was created, divided into: general, motor and non-motor scales, diaries and fluctuation questionnaires, cognitive, disability and health-related quality of life, capability, quantitative motor, wearable and digital, combined, resource use, imaging and wet biomarkers, and milestone-based. A framework for evaluation of OM is presented to update the inventory in the future. PPIE input highlighted the need for OM which reflect their experience of disease progression and are applicable to diverse populations and disease stages. CONCLUSION: We present a range of OM, classified according to a transparent framework, to aid selection of OM for disease-modifying PD trials, whilst allowing for inclusion or re-classification of relevant OM as new evidence emerges.

Resting oscillatory cortico-subthalamic connectivity in patients with Parkinson's disease.

Both phenotype and treatment response vary in patients with Parkinson's disease. Anatomical and functional imaging studies suggest that individual symptoms may represent malfunction of different segregated networks running in parallel through the basal ganglia. In this study, we use a newly described, electrophysiological method to describe cortico-subthalamic networks in humans. We performed combined magnetoencephalographic and subthalamic local field potential recordings in thirteen patients with Parkinson's disease at rest. Two spatially and spectrally separated networks were identified. A temporoparietal-brainstem network was coherent with the subthalamic nucleus in the alpha (7-13 Hz) band, whilst a predominantly frontal network was coherent in the beta (15-35 Hz) band. Dopaminergic medication modulated the resting beta network, by increasing beta coherence between the subthalamic region and prefrontal cortex. Subthalamic activity was predominantly led by activity in the cortex in both frequency bands. The cortical topography and frequencies involved in the alpha and beta networks suggest that these networks may be involved in attentional and executive, particularly motor planning, processes, respectively.