In humans, impaired response inhibition is characteristic of a wide range of psychiatric diseases and of normal aging. It is hypothesised that the right inferior frontal cortex plays a key role by inhibiting the motor cortex via the basal ganglia. The electroencephalography-derived beta rhythm (15-29 Hz) is thought to reflect communication within this network, with increased right frontal beta power often observed prior to successful response inhibition. Recent literature suggests that averaging spectral power obscures the transient, burst-like nature of beta activity. There is evidence that the rate of beta bursts following a Stop signal is higher when a motor response is successfully inhibited. However, other characteristics of beta burst events, and their topographical properties, have not yet been examined. Here, we used a large human (male and female) electroencephalography Stop Signal Task dataset (n=218) to examine averaged normalised beta power, beta burst rate and beta burst ‘volume’ (which we def...

Understanding speech in background noise is a difficult task. The tracking of speech rhythms such as the rate of syllables and words by cortical activity has emerged as a key neural mechanism for speech-in-noise comprehension. In particular, recent investigations have used transcranial alternating current stimulation (tACS) with the envelope of a speech signal to influence the cortical speech tracking, demonstrating that this type of stimulation modulates comprehension and therefore evidencing a functional role of the cortical tracking in speech processing. Cortical activity has been found to track the rhythms of a background speaker as well, but the functional significance of this neural response remains unclear. Here we employ a speech-comprehension task with a target speaker in the presence of a distractor voice to show that tACS with the speech envelope of the target voice as well as tACS with the envelope of the distractor speaker both modulate the comprehension of the target speech. Because the envel...

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder and a major cause of dementia. Some of the hallmarks of AD include presence of amyloid plaques in brain parenchyma, calcium dysregulation within individual neurons, and neuroinflammation. A promising therapeutic would reverse or stymie these pathophysiologies in an animal model of AD. We tested the effect of NB-02, previously known as DA-9803, a novel multimodal therapeutic, on amyloid deposition, neuronal calcium regulation and neuroinflammation in 8-10 month old APP/PS1 mice, an animal model of AD. In vivo multiphoton microscopy revealed that 2 month-long administration of NB-02 halted amyloid plaque deposition and cleared amyloid in the cortex. Post-mortem analysis verified NB-02-dependent decrease in plaque deposition in the cortex as well as hippocampus. Furthermore, drug treatment reversed neuronal calcium elevations, thus restoring neuronal function. Finally, NB-02 restored spine density and transformed the morphology of astrocytes ...

Insulin-like growth factor-I (IGF-I) signalling plays a key role in learning and memory processes. While the effects of IGF-I on neurons have been studied extensively, the involvement of astrocytes in IGF-I signalling and the consequences on synaptic plasticity and animal behavior remain unknown. We have found that IGF-I induces long-term potentiation (LTP, here called LTPIGFI) of the postsynaptic potentials that is caused by a long-term depression (LTD) of inhibitory synaptic transmission in mice. We have demonstrated that this long-lasting decrease in the inhibitory transmission is evoked by astrocytic activation through its IGF-IRs. We show that LTPIGFI not only increases the output of pyramidal neurons, but also favours the N-methyl-D-aspartate (NMDAR) dependent LTP, resulting in the crucial information processing at the Barrel cortex since specific deletion of IGF-IR in cortical astrocytes (IGF-IR-/-) impairs the whisker discrimination task. Our work reveals a novel mechanism and functional consequenc...

The integral capacity of human language together with semantic memory drives the linkage of words and their meaning, which theoretically is subject to cognitive control. However, it remains unknown whether, across different language modalities and input/output formats, there is a shared system in the human brain for word-meaning binding and how this system interacts with cognitive control. Here, we conducted a functional magnetic resonance imaging experiment based on a large cohort of subjects (50 females, 50 males) to comprehensively measure the brain responses evoked by semantic processing in spoken and written word comprehension and production tasks (listening, speaking, reading, and writing). We found that heteromodal word input and output tasks involved distributed brain regions within a frontal-parietal-temporal network and focally coactivated the anterior lateral visual word form area (VWFA), which is located in the basal occipitotemporal area. Directed connectivity analysis revealed that the VWFA w...

To assemble the functional circuits of the nervous system, the neuronal axonal growth cones must be precisely guided to their proper targets, which can be achieved through cell–surface guidance receptor activation by ligand binding in the periphery. We investigated the function of paxillin, a focal adhesion protein, as an essential growth cone guidance intermediary in the context of spinal lateral motor column (LMC) motor axon trajectory selection in the limb mesenchyme. Using in situ mRNA detection, we first show paxillin expression in LMC neurons of chick and mouse embryos at the time of spinal motor axon extension into the limb. Paxillin loss-of-function and gain-of-function using in ovo electroporation in chick LMC neurons, of either sex, perturbed LMC axon trajectory selection, demonstrating an essential role of paxillin in motor axon guidance. In addition, a neuron-specific paxillin deletion in mice led to LMC axon trajectory selection errors. We also show that knocking down paxillin attenuates the g...

The release of small extracellular vesicles (sEVs) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein-binding and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest, because HDAC2 regulates spine development, and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activa...

Our recent work suggests that non-lesional epileptic brain tissue is capable of generating normal neurophysiological responses during cognitive tasks, which are then seized by ongoing pathologic epileptic activity. Here, we aim to extend the scope of our work to epileptic periventricular heterotopias (PVH) and examine whether the PVH tissue also exhibits normal neurophysiological responses and network-level integration with other non-lesional cortical regions. As part of routine clinical assessment, three adult patients with PVH underwent implantation of intracranial electrodes and participated in experimental cognitive tasks. We obtained simultaneous recordings from PVH and remote cortical sites during rest as well as controlled experimental conditions. In all three subjects (two females), cognitive experimental conditions evoked significant electrophysiological responses in discrete locations within the PVH tissue that were correlated with responses seen in non-epileptic cortical sites. Moreover, the res...

Gravity is a pervasive environmental stimulus, and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or vestibular implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal VI-mediated angular head velocity information, but it remains unknown whether a canal VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity. Here, w...