Monitoring the past and choosing the future: the prefrontal cortical influences on voluntary action.

Choosing between equivalent response options requires the resolution of ambiguity. One could facilitate such decisions by monitoring previous actions and implementing transient or arbitrary rules to differentiate response options. This would reduce the entropy of chosen actions. We examined voluntary action decisions during magnetoencephalography, identifying the spatiotemporal correlates of stimulus- and choice-entropy. Negative correlations between frontotemporal activity and entropy of past trials were observed after participants' responses, reflecting sequential monitoring of recent events. In contrast, choice entropy correlated negatively with prefrontal activity, before and after participants' response, consistent with transient activation of latent response-sets ahead of a decision and updating the monitor of recent decisions after responding. Individual differences in current choices were related to the strength of the prefrontal signals that reflect monitoring of the statistical regularities in previous events. Together, these results explain individual expressions of voluntary action, through differential engagement of prefrontal areas to guide sequential decisions

Optimizing treatment with tumour necrosis factor inhibitors in rheumatoid arthritis-a proof of principle and exploratory trial: is dose tapering practical in good responders?

OBJECTIVES: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. METHODS: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. RESULTS: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). CONCLUSION: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states

Treat-to-target urate-lowering therapy and hospitalisations for gout: results from a nationwide cohort study in England.

OBJECTIVE: To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalisations for gout. METHODS: Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalisations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalisations for gout. RESULTS: Of 292 270 people with incident gout, 7,719 (2.64%) had one or more hospitalisations for gout, with an incidence rate of 4.64 hospitalisations per 1000 person-years (95% CI 4.54-4.73). There was an associated increased risk of hospitalisations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT (adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70-5.58; p< 0.001). Hospitalisations did not differ significantly between people prescribed vs. not prescribed colchicine prophylaxis in fully-adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalisations (aHR 0.77; 95% CI 0.71-0.83; p< 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalisations (aHR 0.57; 95% CI 0.49-0.67; p< 0.001) when compared with people initiating ULT but not attaining this target. CONCLUSION: ULT associates with an increased risk of hospitalisations within the first 6 months of initiation but reduces hospitalisations in the long-term, particularly when serum urate targets are achieved

Artificial grammar learning in vascular and progressive non-fluent aphasias

Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA.The Association of British Neurologists, Patrick Berthoud Charitable trust and National Institute for Health Research support TEC. The Wellcome Trust supports BW (WT110198), TDG (WT106964MA), JBR (WT103838) and CP (WT102961MA). The Stroke Association supports HR (TSA 2012/02). Further study support was received from the National Institute of Health Research's Biomedical Research Centre (Cambridge) and Biomedical Research Units in Dementia (Cambridge, Newcastle)

Evidence for causal top-down frontal contributions to predictive processes in speech perception

Perception relies on the integration of sensory information and prior expectations. Here we show that selective neurodegeneration of human frontal speech regions results in delayed reconciliation of predictions in temporal cortex. These temporal regions were not atrophic, displayed normal evoked magnetic and electrical power, and preserved neural sensitivity to manipulations of sensory detail. Frontal neurodegeneration does not prevent the perceptual effects of contextual information; instead, prior expectations are applied inflexibly. The precision of predictions correlates with beta power, in line with theoretical models of the neural instantiation of predictive coding. Fronto-temporal interactions are enhanced while participants reconcile prior predictions with degraded sensory signals. Excessively precise predictions can explain several challenging phenomena in frontal aphasias, including agrammatism and subjective difficulties with speech perception. This work demonstrates that higher-level frontal mechanisms for cognitive and behavioural flexibility make a causal functional contribution to the hierarchical generative models underlying speech perception.This study was supported by the National Institute for Health Research, the Association of British Neurologists and Patrick Berthoud Charitable Trust (TEC fellowship); the Wellcome Trust (JBR Senior Fellowship, 103838); the Evelyn Trust; and the Medical Research Council Cognition and Brain Sciences unit (MC-A060-5PQ30, MC-A060-5PQ80)

Implementing treat-to-target urate-lowering therapy during hospitalisations for gout flares.

OBJECTIVES: To evaluate a strategy designed to optimise care and increase uptake of urate-lowering therapy (ULT) during hospitalisations for gout flares. METHODS: We conducted a prospective cohort study to evaluate a strategy that combined optimal in-hospital gout management with a nurse-led, follow-up appointment, followed by handover to primary care. Outcomes, including ULT initiation, urate target attainment, and re-hospitalisation rates, were compared between patients hospitalised for flares in the 12 months post-implementation and a retrospective cohort of hospitalised patients from 12 months pre-implementation. RESULTS: 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months pre- and post-implementation. For patients with 6-month follow-up data available (n = 94 and n = 97, respectively), the proportion newly initiated on ULT increased from 49.2% pre-implementation to 92.3% post-implementation (age/sex-adjusted odds ratio (aOR) 11.5; 95% confidence interval (CI) 4.36-30.5; p < 0.001). After implementation, more patients achieved a serum urate ≤360 micromol/L within 6 months of discharge (10.6% pre-implementation vs. 26.8% post-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients re-hospitalised for flares was 14.9% pre-implementation vs. 9.3% post-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). CONCLUSION: Over 90% of patients were initiated on ULT after implementing a strategy to optimise hospital gout care. Despite increased initiation of ULT during flares, recurrent hospitalisations were not more frequent following implementation. Significant relative improvements in urate target attainment were observed post-implementation; however, for the majority of hospitalised gout patients to achieve urate targets, closer primary-secondary care integration is still needed

Tau Burden and the Functional Connectome in Alzheimer's Disease and Progressive Supranuclear Palsy

Alzheimer’s Disease (AD) and Progressive Supranuclear Palsy (PSP) represent neurodegenerative Tauopathies with predominantly cortical vs subcortical disease burden. In AD, neuropathology and atrophy preferentially affect ‘hub’ brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between Tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting-state fMRI in 17 patients with AD, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more Tau pathology in AD, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in Tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing Tau burden in AD was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker ‘small-world’ properties. Conversely, in PSP, unlike in AD, those nodes that accrued pathological Tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why AD affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing Tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of Tau trafficking in humans to understanding the relationship between regional Tau burden and brain functional reorganization.The NIMROD study was funded by the National Institute for Health Research (NIHR, RG64473) Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia, PSP Association, the Wellcome Trust (JBR 103838), the Medical Research Council (MC-A060-5PQ30). T.E.C. is supported by a personal fellowship from the Association of British Neurologists and Patrick Berthoud charitable trust

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

GABAergic cortical network physiology in frontotemporal lobar degeneration

This is the final version. Available from Oxford University Press via the DOI in this record.The extended DCM is available at https://gitlab.com/tallie/edcm and works in conjunction with the modified SPM12 scripts provided therein. Source data may be available for non-commercial research purposes, on request from the senior author, subject to limitations to protect participant identity.The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients’ GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.Wellcome TrustNational Institute for Health Research Cambridge Biomedical Research CentreMedical Research CouncilMedical Research CouncilMedical Research CouncilMedical Research CouncilCambridge Centre for Parkinson-plusAssociation of British NeurologistsHolt Fellowshi

[18F]AV-1451 PET in behavioral variant frontotemporal dementia due to MAPT mutation

The validation of tau radioligands could improve the diagnosis of frontotemporal lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [18F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT 10 + 16C>T gene mutation, recapitulating the pattern of neuropathology seen in her father. Given the genetic diagnosis and the non-Alzheimer's pathology, these findings suggest that [18F]AV-1451 might be a useful biomarker in primary tauopathies. Largerscale in vivo and post-mortem studies will be needed to assess the technique's specificity.TEC is supported by the Association of British Neurologists and the Patrick Berthoud Charitable Trust. JRH, JK, and SF are supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neuron disease, from the National Health and Medical research Council of Australia program grant (1037746). JBR is supported by the Wellcome Trust (103838). The Cambridge Brain Bank, JPC, WRBJ, MGS, and LP are supported by the Cambridge Biomedical Research Centre. MGS is supported by the UK MRC.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/acn3.36