Progress in Neurobiology

Human attention is inherently transient and limited in span to only a few moments without lapsing. The intrinsic dynamics of large-scale neurocognitive networks are thought to contribute to these lapses and result in the unavoidable fluctuations in attention that constrain its span. However, it remains unclear how the millisecond temporal dynamics of specific electrophysiological brain states contribute to the endogenous maintenance of attention or the onset of attentional lapses. In the present study, we investigated whether the strength and millisecond dynamics of brain electric microstates differentiate states of focus from inattention and contribute to the endogenous maintenance of attention over short and long timescales. We recorded 128-channel EEG while participants maintained their attention during the wait time delay of trials in the Sustained Attention to Cue Task (SACT) and segmented the EEG into a categorized time series of microstates based on data-driven clustering of topographic voltage patterns. The findings revealed that the prevalence and rate of occurrence of microstates C and E in the wait time delay of trials differentiated trials in which the target stimulus was correctly detected from incorrectly detected. These same microstates were also implicated in the maintenance of attention over short and long timescales, with their time-varying dynamics changing systematically during the wait time delay of trials and over the course of the task session. Together, these findings demonstrate the sensitivity of microstates to variation in attentional states and suggest that the millisecond dynamics of these brain states contribute to the maintenance of attention over time.

Efficient metabolic waste clearance, via the postulated glymphatic system, is essential for neural homeostasis. However, direct visualization of tissue-cerebrospinal fluid (CSF) exchange remains limited, leading to ongoing debate in the neuroscientific field. The present work revealed evidence of tissue-CSF water exchange in the live human cortex, by employing a novel MRI technique demonstrating the flux of water molecules across the perivascular interface. We observed robust water exchange inside the cortical ribbon, which was more prominent than white matter and deep brain tissue. We validated that the signal originates from CSF and is independent of cerebral perfusion. Water exchange between tissue and CSF declined with age. Furthermore, we demonstrated for the first time that tissue-CSF exchange was impaired in Alzheimers disease (AD), in particular in regions where the perivascular space is clogged by anti-amyloid immunotherapy.

Hierarchy in the brain emerges across spatial and temporal scales, enabling transformations from rapid sensory encoding to sustained cognitive control. Hierarchical gradients are well established in sensory systems. In contrast, the hierarchical organization of the primate motor cortex remains debated, partly due to its agranular architecture and the absence of clear laminar input-output projections, that obscures the distinction between feedforward and feedback pathways. In particular, the relative hierarchical position of the dorsal premotor cortex (PMd) and the primary motor cortex (M1) cannot be resolved from anatomy alone. To investigate their relative organization, we here adopted a multimodal approach using intrinsic timescales derived from both single-unit spiking activity (SUA) and local field potentials (LFPs) in macaques performing a delayed-match-to-sample reaching task. We found convergent evidence for inter-areal temporal hierarchy, with longer spiking timescales and smaller LFP aperiodic spectral exponents in M1. Across cortical depth, however, temporal organization depended on signal modality. LFP spectral exponents were significantly smaller in deep than superficial layers in both areas, and LFP-autocorrelation timescales were longer in deep layers in M1. In contrast, spiking activity did not show significant laminar differences in intrinsic timescales. Functionally, neurons with longer timescales exhibited more stable representations of the planned movement direction during motor preparation in PMd and slower temporal evolution of movement encoding during execution in both areas. In conclusion, multimodal temporal measures converge on the same hierarchical organization across these two motor areas, with M1 placed higher than PMd. Our study provides the first characterization of intrinsic spiking timescales across cortical layers in any cortical area and shows that laminar temporal organization depends on the neural signal analyzed. This divergence likely reflects their distinct physiological origins. Spikes capture neuronal output, whereas LFPs primarily reflect synaptic and dendritic population activity, potentially integrating differential contributions from apical and basal dendritic inputs.

Working memory (WM) provides a flexible but capacity-limited workspace for maintaining information over short intervals, whereas long-term memory (LTM) serves as a vast and enduring repository for preserving information over extended periods. Decades of research suggest that they are two distinct yet connected systems that together enable adaptive behavior. The link between WM and LTM may not be straightforward, however, as recent evidence has shown that activation-dependent competition among items in WM can weaken their representations in LTM. In the current study, we examined how dynamic competition among items for limited WM resources affects their retention in LTM. We induced competition between items by manipulating temporal expectations in a WM task with either a short (1 s) or a long (4 s) memory delay. Human participants (N = 20) initially prioritized items expected to be tested early, but shifted their priority to items expected to be tested later when the early test did not occur. Using electroencephalography (EEG) and multivariate pattern analysis (MVPA), we tracked the dynamic fluctuations in WM contents based on expected task relevance across the delay window. We linked these temporal profiles during WM with the long-term recognition performance of each item and found that forgetting was associated with a marked decrease in neural evidence for items deemed no longer relevant during the later delay period. These results demonstrate that WM representations fluctuate with temporal expectations and that the de-prioritization of items during WM maintenance is what drives their long-term forgetting.

Fluctuations in attentional states, such as mind-wandering (MW), are associated with critical variability in task performance. While fMRI studies highlight the opposing roles of task-positive (e.g., dorsal attention network) and task-negative (e.g., default mode network) systems, the electrophysiological mechanisms underlying these dynamics remain poorly understood. Using intracranial electrocorticography in humans performing a sustained attention task, we identified global oscillatory dynamics linked to attentional shifts. MW was characterized by (i) reduced theta ({theta}) and alpha ({square}) power, (ii) decreased aperiodic signal components, indicating a shift toward cortical inhibition, (iii) enhanced phase synchronization across networks, and (iv) strengthened {theta} phase-behavior correlations ({rho}). These features support a non-network-specific framework in which low-frequency {theta} dynamics--captured by both {theta} power and {rho}--are associated with attentional fluctuations, while aperiodic offset relates to attentional state indirectly through its association with {rho} (Structural Equation Modeling: power[-&gt;]state {beta} = -0.118, p = 0.002; {rho}[-&gt;]state {beta} = 0.246, p < 0.001; offset[-&gt;]{rho} {beta} = -0.222, p < 0.001). Our study provides a unified neurophysiological framework for understanding how spontaneous neural activity can drive attentional fluctuations and performance variability, with implications for research on attention, learning, and neuropsychiatric disorders.

Glutamatergic neuronal synapses in the mouse neocortex mature during the first two months after birth. A key event during synaptic maturation is a change in short-term synaptic plasticity (STP), i.e. a switch from strong synaptic depression to a weaker depression or even facilitation. Glutamatergic pyramidal neurons located in the cortical layers II/III, layer V, and layer VI project axons through the corpus callosum where they release glutamate along their shafts and form glutamatergic synapses with oligodendrocyte precursor cells (OPCs). Here, we used single-cell electrophysiological recordings in brain slices to investigate synaptic plasticity at neuron-OPC synapses along axonal shafts in the white matter, and applied computation approaches to pinpoint the mechanisms of this plasticity. We found that during postnatal development of mice, there is a switch from short-term synaptic depression to short-term synaptic facilitation at glutamatergic neuron-OPC synapses in the corpus callosum. Synaptic delay of phasic neuron-OPC excitatory postsynaptic current shortens, and the amount of asynchronous release at neuron-OPC synapses decrease as animals mature, indicating that glutamate release becomes more synchronized. Our computational modelling suggests that both pre- and postsynaptic changes may contribute to the functional development and changes of plasticity at neuron-OPC synapses in the white matter. Taking together, our findings indicate that synaptic release machineries located at different sites along the same axon (i.e. axonal shaft in the white matter vs synaptic boutons in the grey matter) mature in a very similar fashion, STP occurs at both synaptic sites, and STP dynamics represent an important event during brain maturation.

Emerging evidence suggests that hippocampus contributes to visual short-term memory (VSTM). However, the role of hippocampal ripple activity--brief high-frequency oscillations associated with memory replay--in supporting VSTM of naturalistic objects remains largely unknown. Here, using intracranial EEG recordings from human participants performing a delayed match-to-sample task, we found that hippocampal ripple rates progressively ramped up during the maintenance period and supported successful VSTM. More critically, hippocampal ripples were temporally coupled with the ripples in the lateral temporal lobe (LTL), and these coupled ripples were associated with the memory reactivation in the LTL. These findings provide direct evidence that hippocampal-neocortical interaction via coupled ripples supports VSTM, extending the hippocampal ripples role to short-term mnemonic processes.

AO_SCPLOWBSTRACTC_SCPLOWMastering a perceptual skill requires maintaining high-fidelity information in the cortex to support task-relevant behavior. Yet it remains unclear how sensory and higher-order cortices jointly support this maintenance, and how experience reshapes their respective contributions. To address these questions, we trained participants on visual motion discrimination and measured sensory and mnemonic neural codes using a delayed discrimination paradigm. After learning, fMRI activation patterns in V1 exhibited enhanced sensory fidelity during the retention period, which predicted individual learning effect. In contrast, mnemonic information in the intraparietal sulcus (IPS) decreased after learning. Moreover, learning aligned the temporal dynamics between the sensory and mnemonic representations in V1. These results suggest that perceptual learning reallocates mnemonic resources from higher-order parietal regions toward high-fidelity sensory maintenance in early visual cortex, thereby optimizing the cortical implementation of visual working memory.

Reward can enhance motor performance. However, its potential to counteract motor fatigability, a reduction in motor performance during sustained movements, remains underinvestigated. This could be particularly relevant in neurological conditions such as multiple sclerosis, where increased motor fatigability is a prominent symptom. One form of motor fatigability is motor slowing, a decline in movement speed over time evoked by fast, repetitive movements. In this study, we investigated whether the possibility to earn reward attenuates motor slowing, and examined associated changes in muscle activity and pupil size, a putative marker of physical effort. Participants performed a wrist tapping task at maximal voluntary speed with or without the possibility of earning a reward. We found that wrist tapping induced motor slowing and that slowing was significantly reduced by reward. Over time, tapping became more costly as indicated by higher muscle activity and coactivation per tap. This was accompanied by a sustained pupil dilation, which could not solely be explained by tapping speed. These findings suggest that, rather than restoring efficient motor control, reward attenuates motor slowing by allowing participants to access a performance reserve and invest more resources into the task, reflected by increased muscle activation per tap and sustained pupil dilation.

Episodic memory depends on neural representations encoded in the hippocampus. Experimental and computational evidence suggests that the hippocampus encodes pattern-separated representations that support later recall of episodic event elements. While extant data in humans predominantly focus on assaying the relationship between the similarity of spatial neural patterns at encoding and later memory performance, similarity of neural patterns in the temporal domain may also reveal encoding computations predictive of future memory. To examine how the similarity among temporal patterns of hippocampal activity during encoding relates to later episodic retrieval (associative cued recall and recognition memory), hippocampal activity was recorded from human participants (n=7) with implanted intracranial electrodes while they encoded arbitrary (A-B) paired-associates. Subsequent memory analyses first revealed that hippocampal high-frequency broadband power (HFB; 70-180Hz) was linked to a graded increase in memory strength; HFB power was greater during the encoding of pairs later correctly recalled relative to events later recognized and was lowest for events later forgotten. Second, and critically, subsequent memory analyses further revealed that more distinctive temporal patterns in the hippocampus during encoding -- indexed by the similarity of the HFB timeseries elicited by a given event to that elicited by other events -- were associated with superior subsequent memory performance. Finally, exploratory analyses revealed stimulus category effects on hippocampal HFB power during encoding and retrieval cuing. These results indicate that the temporal distinctiveness of hippocampal traces during encoding is important for subsequent retrieval of episodic event elements, consistent with theories that posit that pattern separation facilitates future remembering.

To compensate for self-generated movement-induced postural disturbances, the brain generates anticipatory postural adjustments (APA), ensuring smooth, coordinated actions. APA development continues into late adolescence, yet the specific pathways and mechanisms that remain immature in children are poorly understood. We studied APA mechanisms in 24 children (7-12 years old) using magnetoencephalography (MEG) while they performed the naturalistic bimanual load-lifting task (BLLT). In the BLLT, participants lift a load placed on one forearm with the contralateral hand while keeping the postural forearm horizontal, as if lifting a glass from a tray. To counteract forearm deflection caused by unloading, the brain generates APAs, which involve anticipatory inhibition of the postural Biceps brachii. We found that stronger anticipatory Biceps brachii inhibition was associated with reduced excitability, as indexed by high-gamma (90-130 Hz) suppression, and increased high-beta power (19-29 Hz) in the contralateral Supplementary Motor Area (SMA). Analysis of transient beta events revealed two functionally distinct burst types: (1) 19-24 Hz bursts: time-locked to immediate high-gamma suppression correlated with 26-28 Hz beta power; predicted stronger muscle inhibition and received directed input from middle frontal cortex and precentral gyrus; (2) 24-29 Hz bursts: linked to delayed ([~]100 ms) high-gamma suppression correlated with 8 Hz alpha power; predicted earlier and prolonged muscle inhibition and better forearm stabilization, but did not show directional influence from other regions. Results on anticipatory inhibition-related beta bursts replicated mechanisms reported in adults, suggesting that the efferent pathways and transient inhibitory processes underlying APA may already be mature in children. In contrast, higher-frequency beta bursts revealed a child-specific, complementary APA mechanism that may compensate for imprecise anticipatory inhibition. These results reveal two oscillatory mechanisms supporting APA in children and indicate that beta bursts may reflect both immediate cortical inhibition linked to muscle control and indirect alpha-mediated inhibition likely compensating for forearm instability.

Brainstem arousal systems including the locus coeruleus noradrenaline system, re-spond transiently to behaviorally relevant events. Locus coeruleus activity also drives dilations of the pupil, which are often observed during cognitive tasks. The strength of pupil responses during encoding of stimulus material predicts the success of its later retrieval, which might reflect the impact of noradrenaline on synaptic plasticity and memory formation. The pupil also dilates in response to task-irrelevant sounds, which could therefore serve as a valuable tool for investigating causal effects of phasic, pupil-linked arousal on cognition. Here, we evaluated whether task-irrelevant white noise sounds affect memory formation and memory-based decisions. These sounds were played before, during or after the presentation of memoranda (images or spoken words). Memory success was measured in recognition and free recall tasks the day after. Trial-to-trial variations in the amplitude of pupil dilations during word encoding without task-irrelevant sounds predicted memory success. Task-irrelevant white-noise sounds also robustly dilated the pupil but did not improve memory formation for the words or the images. We conclude that pupil-linked arousal processes triggered by task-irrelevant sounds differ from those recruited endogenously during memory for-mation, for example in states of increased emotionality or attention.

Amyloid-{beta} (A{beta}) accumulation is a continuous process central to pathological aging that begins decades before cognitive impairment emerges. While subthreshold A{beta} levels have been linked to future decline in cognitive control, the neural mechanisms connecting this early accumulation to its neurocognitive impact are poorly understood. Brain circuit dynamics, which are essential for cognitive function, may offer a sensitive lens into these initial pathological changes. Here, we tested whether brain state dynamics could serve as sensitive markers for cognitive impairment at an early stage of A{beta} burden. Using the Bayesian Switching Dynamic System (BSDS) model, we identified 4 distinct latent brain states from high-temporal-resolution (800 ms) fMRI data acquired from 116 older adults, including 72 cognitively normal (CN) individuals and 44 with mild cognitive impairment (MCI), during an N-back working-memory task. Adopting a dimensional approach, we examined how latent brain state dynamics relate to early amyloid burden, cognitive performance, and clinical symptoms. While A{beta} levels failed to differentiate clinical groups or predict clinical symptoms and task performance, the dynamics of latent brain states proved highly sensitive to both early A{beta} accumulation and cognition. Canonical correlation analysis revealed a significant relationship between brain state dynamics and early A{beta} burden. Furthermore, the temporal properties of brain states were significantly predictive of working memory performance in CN individuals, a relationship that was selectively disrupted in the MCI group. The features of brain dynamics can also successfully predict cognitive impairment. Our findings establish brain state dynamics as sensitive neural markers of initial A{beta} accumulation and early cognitive impairment, offering a new framework for developing predictive models to identify individuals at risk for future cognitive decline.

Orca, wolves, chimpanzees and humans share a similarly impressive capacity for group hunting, where individuals coordinate behaviour together to capture prey. Studying hunting behaviours has important implications for understanding how behaviour in group contexts may be indicative of cognitive decline. Despite growing interest in brain circuits for prey capture, the brain regions involved in tracking prey during a hunt and the behaviours in group hunt linked to success remain unclear. Here we combined functional near infrared spectroscopy (fNIRS) and a virtual minecraft world to examine behaviour, brain dynamics and brain synchrony involved in group hunting behaviour. We focused on the prefrontal cortex (PFC) due to its known role in planning and social coordination and recorded from pairs of individuals as they either cooperated to hunt another person (prey) or simply followed another person. Hunters were more successful if they managed to keep a smaller distance to the prey and moved at speeds that were more synchronised with their co-predator. At high-range frequencies for fNIRS (0.1-0.2Hz), we found greater brain-to-brain synchrony in lateral and medial (frontopolar) PFC regions during hunting compared with chance levels. Together, these findings provide insights into what behaviours and brain dynamics associated with successful group hunting.

Environmental enrichment enhances hippocampus-dependent learning and memory, yet the underlying circuit mechanisms remain largely unknown. Here we combined miniscope calcium imaging during spatial exploration with synaptic circuit analysis in hippocampal slices to determine how enrichment experience alters hippocampal network dynamics. Prolonged enrichment reduced average firing rates and immediate early gene expression in CA1 pyramidal cells, while increasing peak firing and spatial selectivity. Population activity was sparser and more diverse, resulting in a higher Gini index. Circuit analysis revealed enhanced excitatory drive onto both pyramidal cells and somatostatin (SOM) interneurons, together with a strengthened SOM-mediated feedback inhibition onto pyramidal cells. Suppressing SOM interneurons occluded the enrichment-induced augmentation of sparsity and Gini index and prevented improvements in hippocampus-dependent learning. These findings demonstrate that environmental enrichment dynamically enhances hippocampal sparse coding through potentiation of SOM-mediated feedback inhibition, linking experience-dependent inhibitory plasticity to enhanced memory performance.

Metacognition refers to the capacity to monitor ones own actions, internal states, and cognitive processes. A central question in cognitive neuroscience is whether metacognitive evaluation operates as a direct readout of performance signals or requires computationally independent neural mechanisms. Single-process theories propose that both arise from shared decision variables, while the Higher-Order Representation theory holds that metacognition requires re-representation through distinct computational processes. To test these frameworks, participants produced timed motor intervals and evaluated their own performance without external feedback, termed temporal error monitoring (TEM). Vision Transformer decoding applied to PCA-optimized single-trial EEG captured {theta}, , and {beta} dynamics during both task phases. First-order timing was decodable from any individual frequency band, whereas second-order metacognitive inference required simultaneous integration across all three bands before action termination. Individuals whose metacognitive states were more accurately decoded showed stronger TEM precision, with no equivalent relationship observed for first-order performance decoding. These findings establish metacognitive evaluation as a computationally distinct process requiring higher-order multi-band neural integration rather than a direct readout of first-order timing signals.

Age-related cognitive decline reflects progressive atrophic changes that advance through broad neural networks. There is no effective treatment. However, brain ageing is not homogenous, so treating the earliest-affected circuits may be successful in reversing and/or preventing ongoing neuronal atrophy and therefore cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique that modulates cortical excitability, induces activity-dependent neuronal plasticity. Here we investigate short- and long-term effects of low intensity rTMS (LI-rTMS) on the cerebellum, which is adversely affected early during ageing. With age, cerebellar genes related to inflammation are strongly upregulated, whereas processes of synaptic-maintenance are reduced. Both abnormalities are rapidly corrected by LI-rTMS in a protocol-dependent manner. In parallel, LI-rTMS increases neuronal spine density and dendritic complexity, in association with improved spatial memory in both young adult and aged mice. These responses of the ageing cerebellum to low-intensity magnetic stimulation are extremely encouraging for treating age-related cognitive decline, but reinforce that appropriate stimulation parameters must be identified for effective treatment.

Synapses are known to remodel their proteome during sleep. However, the exact mechanisms driving this remodelling and its impact on synaptic function or cognition are not well understood. We combine 24-hour EEG recordings with time-resolved synaptic proteomics in a model of SYNGAP1-Related Disorders to reveal a mechanism by which slow-waves and spindles, two NREM sleep oscillations, mediate the remodelling of the synaptic proteome. Moreover, we uncover that this remodelling promotes synaptic stabilization, which could support sleep-dependent memory consolidation. In contrast, the increase of slow-waves and decrease of spindles found in Syngap1+/- mice would activate molecular pathways involved in synaptic weakening instead of stabilization. This is consistent with the proposed roles of slow-waves and spindles in synaptic downscaling and potentiation, respectively. Here, we provide evidence on how NREM oscillations regulate the synaptic proteome and reveal a pathological mechanism that could be of relevance to all neurodevelopmental disorders coursing with sleep disturbances.

In brain-heart interactions, several pathways have been proposed to mediate feedback loops between systems. Among these, cerebrovascular dynamics operate at their interface. However, how cardiovascular control, ventilation mechanisms, and cerebral autoregulation interact is not well characterized, especially in ageing and post-stroke conditions, where perfusion can be compromised. In a cohort of 57 elderly participants, including 30 stroke survivors, we investigated the relationship between cardiac sympathetic activity and both, cerebral blood flow regulation and ventilatory status. Sympathetic reflexes, assessed via cardiac sympathetic index (CSI) during sit-to-stand transitions, were preserved across all participants, with marginal group differences between stroke and non-stroke populations. However, among individuals with constrained ventilation, indexed by reduced end-tidal CO2 at baseline, we identified a more elevated CSI following postural change, scaling with the degree of CO2 dysregulation. Furthermore, transcranial Doppler measurements revealed exaggerated changes in mean flow velocity (MFV) within the right middle cerebral artery in most participants. These MFV shifts significantly correlated with the magnitude of cardiac sympathetic change under orthostatic stress, suggesting that CSI can capture maladaptive cerebrovascular responses. Together, these findings highlight a distinct cardiac-cerebrovascular crosstalk in elderly individuals, revealing patterns consistent with compensatory or maladaptive sympathetic overactivation under conditions of impaired cerebrovascular control.

It is critical to identify which factors induce specific brain states as these large-scale patterns of coordinated neural activity drive downstream processing and behavior. The retrieval state, a brain state engaged when attempting to retrieve the past, is thought to specifically support episodic memory, remembering experiences within a spatiotemporal context, as opposed to semantic memory, remembering general knowledge. However, we hypothesize that the retrieval state reflects internal attention engaged to access stored episodic and semantic information. To test these alternatives, we recorded scalp electroencephalography while participants made episodic, semantic, or perceptual judgments, and applied an independently validated mnemonic state classifier to measure retrieval state engagement. We found that retrieval state engagement was greater for both episodic and semantic judgments compared to perceptual judgments. These findings suggest that the retrieval state reflects a domain-general internal attention process that supports not just episodic memory, but internally directed cognition.