Trimetazidine (TMZ), an antianginal drug, can worsen the symptoms of movement disorders, therefore, the European Medicines Agency (EMA) recommended avoiding the use of this drug in Parkinson’s disease (PD). We investigated the impact of this recommendation on the observed trend of TMZ use in PD in Hungary from 2010 to 2016 by conducting a nationwide, retrospective study of health administrative data of human subjects. Interrupted time series analyses were performed to explore changes in user trends after the EMA recommendations. We found that TMZ use in PD decreased by 6.56% in each six-month interval after the EMA intervention [a change in trend of −530.22, 95% confidence interval (CI) = −645.00 to −415.44, p < 0.001 and a decrease in level of −567.26, 95% CI = −910.99 to −223.53, p  = 0.005 12 months postintervention]. TMZ discontinuation was the highest immediately after the intervention, however, its rate slowed down subsequently (a change in trend of −49.69, 95% CI = −85.14 to −14.24, p  = 0.11 withou...

Neural activity is coordinated across multiple spatial and temporal scales, and these patterns of coordination are implicated in both healthy and impaired cognitive operations. However, empirical cross-scale investigations are relatively infrequent, because of limited data availability and to the difficulty of analyzing rich multivariate datasets. Here, we applied frequency-resolved multivariate source-separation analyses to characterize a large-scale dataset comprising spiking and local field potential (LFP) activity recorded simultaneously in three brain regions (prefrontal cortex, parietal cortex, hippocampus) in freely-moving mice. We identified a constellation of multidimensional, inter-regional networks across a range of frequencies (2–200 Hz). These networks were reproducible within animals across different recording sessions, but varied across different animals, suggesting individual variability in network architecture. The theta band (∼4–10 Hz) networks had several prominent features, including ro...

When animals repeatedly receive a combination of neutral conditional stimulus (CS) and aversive unconditional stimulus (US), they learn the relationship between CS and US, and show conditioned fear responses after CS. They show passive responses such as freezing or panic movements (classical or Pavlovian fear conditioning), or active behavioral responses to avoid aversive stimuli (active avoidance). Previous studies suggested the roles of the cerebellum in classical fear conditioning but it remains elusive whether the cerebellum is involved in active avoidance conditioning. In this study, we analyzed the roles of cerebellar neural circuits during active avoidance in adult zebrafish. When pairs of CS (light) and US (electric shock) were administered to wild-type zebrafish, about half of them displayed active avoidance. The expression of botulinum toxin, which inhibits the release of neurotransmitters, in cerebellar granule cells (GCs) or Purkinje cells (PCs) did not affect conditioning-independent swimming ...

Voices are arguably among the most relevant sounds in humans’ everyday life, and several studies have suggested the existence of voice-selective regions in the human brain. Despite two decades of research, defining the human brain regions supporting voice recognition remains challenging. Moreover, whether neural selectivity to voices is merely driven by acoustic properties specific to human voices (e.g., spectrogram, harmonicity), or whether it also reflects a higher-level categorization response is still under debate. Here, we objectively measured rapid automatic categorization responses to human voices with fast periodic auditory stimulation (FPAS) combined with electroencephalography (EEG). Participants were tested with stimulation sequences containing heterogeneous non-vocal sounds from different categories presented at 4 Hz (i.e., four stimuli/s), with vocal sounds appearing every three stimuli (1.333 Hz). A few minutes of stimulation are sufficient to elicit robust 1.333 Hz voice-selective focal brai...

The lateral habenula (LHb) is a phylogenetically primitive brain structure that plays a key role in learning to inhibit distinct responses to specific stimuli. This structure is activated by primary aversive stimuli, cues predicting an imminent aversive event, unexpected reward omissions, and cues associated with the omission of an expected reward. The most widely described physiological effect of LHb activation is acutely suppressing midbrain dopaminergic signaling. However, recent studies have identified multiple means by which the LHb promotes this effect as well as other mechanisms of action. These findings reveal the complex nature of LHb circuitry. The present paper reviews the role of this structure in learning from reward omission. We approach this topic from the perspective of computational models of behavioral change that account for inhibitory learning to frame key findings. Such findings are drawn from recent behavioral neuroscience studies that use novel brain imaging, stimulation, ablation, a...

The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs during the 2 d before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here, we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual cortex of mice using depth electrode recordings from enucleated mice in vivo . Bilateral enucleation at postnatal day (P)6, one week before the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations retur...

Nociceptive stimuli disrupt sleep, but may, or may not, entail an arousal. While arousal reactions go along with the activation of a widespread cortical network, the factors enabling such activation remain unknown. Here we used intracranial EEG (iEEG) in humans to test the relation between the cortical activity immediately preceding a noxious stimulus and the capacity of such a stimulus to trigger arousal. iEEG signals were analyzed during all-night sleep in 14 epileptic patients (4 women), who received laser stimuli slightly above their individual pain threshold. During 5-seconds preceding each stimulus, the functional correlation (spectral phase-coherence) between the main spinothalamic sensory area (posterior insula) and 12 other brain regions, grouped in 4 networks, as well as their spectral contents, were contrasted according to the presence of a stimulus-induced arousal, and then fed into a logistic regression model to assess their predictive value. Enhanced pre-stimulus phase-coherence between the s...

We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light, and that eye light input is redundant to CRY. 3hr light phase delays (Friday) followed by 3hr light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning (weekend light shift, WLS). PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 days. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) osc...

Cholinergic regulation of hippocampal circuit activity has been an active area of neurophysiological research for decades. The prominent cholinergic innervation of intrinsic hippocampal circuitry, potent effects of cholinomimetic drugs, and behavioral responses to cholinergic modulation of hippocampal circuitry have driven investigators to discover diverse cellular actions of acetylcholine in distinct sites within hippocampal circuitry. Further research has illuminated how these actions organize circuit activity to optimize encoding of new information, promote consolidation and coordinate this with recall of prior memories. The development of the hippocampal slice preparation was a major advance that accelerated knowledge of how hippocampal circuits functioned and how acetylcholine modulated these circuits. Using this preparation in the early 1980’s we made a serendipitous finding of a novel presynaptic inhibitory effect of acetylcholine on Schaffer collaterals, the projections from CA3 pyramidal neurons t...

The physiological role of the amyloid-precursor protein (APP) is insufficiently understood. Recent work has implicated APP in the regulation of synaptic plasticity. Substantial evidence exists for a role of APP and its secreted ectodomain APPsα in Hebbian plasticity. Here, we addressed the relevance of APP in homeostatic synaptic plasticity using organotypic tissue cultures prepared from APP-/- mice of both sexes. In the absence of APP, dentate granule cells failed to strengthen their excitatory synapses homeostatically. Homeostatic plasticity is rescued by amyloid-β (Aβ) and not by APPsα, and it is neither observed in APP+/+ tissue treated with β- or γ-secretase inhibitors nor in synaptopodin-deficient cultures lacking the Ca2+-dependent molecular machinery of the spine apparatus. Together, these results suggest a role of APP processing via the amyloidogenic pathway in homeostatic synaptic plasticity, representing a function of relevance for brain physiology as well as for brain states associated with inc...