The role of Dopamine in temporal uncertainty

Abstract The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.</jats:p

Punishment-induced behavioral and neurophysiological variability reveals dopamine-dependent selection of kinematic movement parameters

Action selection describes the high-level process that selects between competing movements. In animals, behavioral variability is critical for the motor exploration required to select the action that optimizes reward and minimizes cost/punishment and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioral and neurophysiological variability on DA and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant's behavior but predetermined. Blocks highly biased toward punishment were associated with increased MA variability relative to blocks either with reward or without feedback. This increase in behavioral variability was positively correlated with neurophysiological variability, as measured by changes in corticospinal excitability with transcranial magnetic stimulation over the primary motor cortex. Following the administration of a DA antagonist, the variability associated with punishment diminished and the correlation between behavioral and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a predetermined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioral variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcome

A Similar but Distinctive Pattern of Impaired Cortical Excitability in First-Episode Schizophrenia and ADHD

Background: First-episode schizophrenia (FE-SZ) and attention deficithyperactivity disorder (ADHD) are both neuropsychiatric disordersassociated with an impaired dopaminergic transmission. Though displayingdifferent clinical phenotypes, a common pathophysiological pathway isdiscussed controversially. Several studies using transcranial magneticstimulation (TMS) revealed abnormalities in human motor cortexexcitability in both schizophrenia and ADHD patients. Studies oncortical excitability comparing these two diseases directly are lacking.Method: In this study, a total of 94 subjects were analyzed.Twenty-fiveFE-SZ patients were directly compared with 28 ADHD patients and 41healthy controls (HC). We investigated cortical excitability (inhibitoryand facilitatory networks) with single- and paired-pulse TMS to the leftand right motor cortex. Results: Compared to HC, FE-SZ/ADHD patientsdisplayed an impaired cortical inhibition over the left hemisphere.Apart from an enhanced intracortical facilitation, FE-SZ patients didnot differ compared to ADHD patients in the main outcome measures. Bothpatient groups presented a dysfunctional hemispheric pattern of corticalinhibition and facilitation in comparison with HC. Conclusion: Theresults of this study indicate a pattern of cortical disinhibition andabnormal hemispheric balance of intracortical excitability networks intwo different psychiatric diseases. These effects might be associatedwith an imbalance in GABAergic and dopaminergic transmission and mightprovide evidence for a common pathophysiological pathway of bothdiseases

Direct-current-dependent shift of theta-burst-induced plasticity in the human motor cortex

Animal studies using polarising currents have shown that induction of synaptic long-term potentiation (LTP) and long-term depression (LTD) by bursts of patterned stimulation is affected by the membrane potential of the postsynaptic neurone. The aim of the present experiments was to test whether it is possible to observe similar phenomena in humans with the aim of improving present protocols of inducing synaptic plasticity for therapeutic purposes. We tested whether the LTP/LTD-like after effects of transcranial theta-burst stimulation (TBS) of human motor cortex, an analogue of patterned electrical stimulation in animals, were affected by simultaneous transcranial direct-current stimulation (tDCS), a non-invasive method of polarising cortical neurones in humans. Nine healthy volunteers were investigated in a single-blind, balanced cross-over study; continuous TBS (cTBS) was used to introduce LTD-like after effects, whereas intermittent TBS (iTBS) produced LTP-like effects. Each pattern was coupled with concurrent application of tDCS (<200 s, anodal, cathodal, sham). Cathodal tDCS increased the response to iTBS and abolished the effects of cTBS. Anodal tDCS changed the effects of cTBS towards facilitation, but had no impact on iTBS. Cortical motor thresholds and intracortical inhibitory/facilitatory networks were not altered by any of the stimulation protocols. We conclude that the after effects of TBS can be modulated by concurrent tDCS. We hypothesise that tDCS changes the membrane potential of the apical dendrites of cortical pyramidal neurones and that this changes the response to patterned synaptic input evoked by TBS. The data show that it may be possible to enhance LTP-like plasticity after TBS in the human cortex

Pharmacological Fingerprints of Contextual Uncertainty

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. \ua9 2016 Marshall et al

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19