Digital twins for understanding mechanisms of learning disabilities: Personalized deep neural networks reveal impact of neuronal hyperexcitability.

Learning disabilities affect a significant proportion of children worldwide, with far-reaching consequences for their academic, professional, and personal lives. Here we develop digital twins - biologically plausible personalized Deep Neural Networks (pDNNs) - to investigate the neurophysiological mechanisms underlying learning disabilities in children. Our pDNN reproduces behavioral and neural activity patterns observed in affected children, including lower performance accuracy, slower learning rates, neural hyper-excitability, and reduced neural differentiation of numerical problems.

Plug-and-Play Stability for Intracortical Brain-Computer Interfaces: A One-Year Demonstration of Seamless Brain-to-Text Communication.

Intracortical brain-computer interfaces (iBCIs) have shown promise for restoring rapid communication to people with neurological disorders such as amyotrophic lateral sclerosis (ALS). However, to maintain high performance over time, iBCIs typically need frequent recalibration to combat changes in the neural recordings that accrue over days. This requires iBCI users to stop using the iBCI and engage in supervised data collection, making the iBCI system hard to use.

Simultaneous invasive and non-invasive recordings in humans: A novel Rosetta stone for deciphering brain activity.

Simultaneous noninvasive and invasive electrophysiological recordings provide a unique opportunity to achieve a comprehensive understanding of human brain activity, much like a Rosetta stone for human neuroscience. In this review we focus on the increasingly-used powerful combination of intracranial electroencephalography (iEEG) with scalp electroencephalography (EEG) or magnetoencephalography (MEG). We first provide practical insight on how to achieve these technically challenging recordings.

A unifying framework for functional organization in early and higher ventral visual cortex.

A key feature of cortical systems is functional organization: the arrangement of functionally distinct neurons in characteristic spatial patterns. However, the principles underlying the emergence of functional organization in the cortex are poorly understood. Here, we develop the topographic deep artificial neural network (TDANN), the first model to predict several aspects of the functional organization of multiple cortical areas in the primate visual system.

A flexible intracortical brain-computer interface for typing using finger movements.

Keyboard typing with finger movements is a versatile digital interface for users with diverse skills, needs, and preferences. Currently, such an interface does not exist for people with paralysis. We developed an intracortical brain-computer interface (BCI) for typing with attempted flexion/extension movements of three finger groups on the right hand, or both hands, and demonstrated its flexibility in two dominant typing paradigms.

Detection of Language Lateralization Using Spectral Analysis of EEG.

Purpose: Language lateralization relies on expensive equipment and can be difficult to tolerate. We assessed if lateralized brain responses to a language task can be detected with spectral analysis of electroencephalography (EEG).

Methods: Twenty right-handed, neurotypical adults (28 ± 10 years; five males) performed a verb generation task and two control tasks (word listening and repetition).

Post-retrieval stress impairs subsequent memory depending on hippocampal memory trace reinstatement during reactivation.

Upon retrieval, memories can become susceptible to meaningful events, such as stress. Post-retrieval memory changes may be attributed to an alteration of the original memory trace during reactivation-dependent reconsolidation or, alternatively, to the modification of retrieval-related memory traces that impact future remembering. Hence, how post-retrieval memory changes emerge in the human brain is unknown.

Spatial Coding Dysfunction and Network Instability in the Aging Medial Entorhinal Cortex.

Across species, spatial memory declines with age, possibly reflecting altered hippocampal and medial entorhinal cortex (MEC) function. However, the integrity of cellular and network-level spatial coding in aged MEC is unknown. Here, we leveraged electrophysiology to assess MEC function in young, middle-aged, and aged mice navigating virtual environments.

Antisense oligonucleotide therapeutic approach for Timothy syndrome.

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A.

Force-Based Neuromodulation.

Technologies for neuromodulation have rapidly developed in the past decade with a particular emphasis on creating noninvasive tools with high spatial and temporal precision. The existence of such tools is critical in the advancement of our understanding of neural circuitry and its influence on behavior and neurological disease. Existing technologies have employed various modalities, such as light, electrical, and magnetic fields, to interface with neural activity.

An accurate and rapidly calibrating speech neuroprosthesis.

Brain-computer interfaces can enable rapid, intuitive communication for people with paralysis by transforming the cortical activity associated with attempted speech into text on a computer screen. Despite recent advances, communication with brain-computer interfaces has been restricted by extensive training data requirements and inaccurate word output. A man in his 40's with ALS with tetraparesis and severe dysarthria (ALSFRS-R = 23) was enrolled into the BrainGate2 clinical trial.

Optimizing Antidepressant Efficacy: Generalizable Multimodal Neuroimaging Biomarkers for Prediction of Treatment Response.

Major depressive disorder (MDD) is a common and often severe condition that profoundly diminishes quality of life for individuals across ages and demographic groups. Unfortunately, current antidepressant and psychotherapeutic treatments exhibit limited efficacy and unsatisfactory response rates in a substantial number of patients. The development of effective therapies for MDD is hindered by the insufficiently understood heterogeneity within the disorder and its elusive underlying mechanisms.

CD20/MS4A1 is a mammalian olfactory receptor expressed in a subset of olfactory sensory neurons that mediates innate avoidance of predators.

The mammalian olfactory system detects and discriminates between millions of odorants to elicit appropriate behavioral responses. While much has been learned about how olfactory sensory neurons detect odorants and signal their presence, how specific innate, unlearned behaviors are initiated in response to ethologically relevant odors remains poorly understood. Here, we show that the 4-transmembrane protein CD20, also known as MS4A1, is expressed in a previously uncharacterized subpopulation of olfactory sensory neurons in the main olfactory epithelium of the murine nasal cavity and functions as a mammalian olfactory receptor that recognizes compounds produced by mouse predators.

Inter-subject correlation of electroencephalographic and behavioural responses reflects time-varying engagement with natural music.

Musical engagement can be conceptualized through various activities, modes of listening and listener states. Recent research has reported that a state of focused engagement can be indexed by the inter-subject correlation (ISC) of audience responses to a shared naturalistic stimulus. While statistically significant ISC has been reported during music listening, we lack insight into the temporal dynamics of engagement over the course of musical works-such as those composed in the Western classical style-which involve the formulation of expectations that are realized or derailed at subsequent points of arrival.

Robust and replicable functional brain signatures of 22q11.2 deletion syndrome and associated psychosis: a deep neural network-based multi-cohort study.

A major genetic risk factor for psychosis is 22q11.2 deletion (22q11.2DS).

Reliability of the TMS-evoked potential in dorsolateral prefrontal cortex.

We currently lack a reliable method to probe cortical excitability noninvasively from the human dorsolateral prefrontal cortex (dlPFC). We recently found that the strength of early and local dlPFC transcranial magnetic stimulation (TMS)-evoked potentials (EL-TEPs) varied widely across dlPFC subregions. Despite these differences in response amplitude, reliability at each target is unknown.

A PTER-dependent pathway of taurine metabolism linked to energy balance.

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites. One such taurine metabolite is N-acetyltaurine.

CSF proteomic profiling with amyloid/tau positivity identifies distinctive sex-different alteration of multiple proteins involved in Alzheimer's disease.

In Alzheimer's disease (AD), the most common cause of dementia, females have higher prevalence and faster progression, but sex-specific molecular findings in AD are limited. Here, we comprehensively examined and validated 7,006 aptamers targeting 6,162 proteins in cerebral spinal fluid (CSF) from 2,077 amyloid/tau positive cases and controls to identify sex-specific proteomic signatures of AD. In discovery (N=1,766), we identified 330 male-specific and 121 female-specific proteomic alternations in CSF (FDR <0.

A Data-Driven Latent Variable Approach to Validating the Research Domain Criteria Framework.

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns, we employed a latent variable approach using bifactor analysis. We examined 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with 6,192 participants.

Space wandering in the rodent default mode network.

The default mode network (DMN) is a large-scale brain network known to be suppressed during a wide range of cognitive tasks. However, our comprehension of its role in naturalistic and unconstrained behaviors has remained elusive because most research on the DMN has been conducted within the restrictive confines of MRI scanners. Here, we use multisite GCaMP (a genetically encoded calcium indicator) fiber photometry with simultaneous videography to probe DMN function in awake, freely exploring rats.

Restoration of neuronal progenitors by partial reprogramming in the aged neurogenic niche.

Partial reprogramming (pulsed expression of reprogramming transcription factors) improves the function of several tissues in old mice. However, it remains largely unknown how partial reprogramming impacts the old brain. Here we use single-cell transcriptomics to systematically examine how partial reprogramming influences the subventricular zone neurogenic niche in aged mouse brains.

Sensory cells in tunicates: insights into mechanoreceptor evolution.

Tunicates, the sister group of vertebrates, offer a unique perspective for evolutionary developmental studies (Evo-Devo) due to their simple anatomical organization. Moreover, the separation of tunicates from vertebrates predated the vertebrate-specific genome duplications. As adults, they include both sessile and pelagic species, with very limited mobility requirements related mainly to water filtration.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear.

Efficient coding of natural images in the mouse visual cortex.

How the activity of neurons gives rise to natural vision remains a matter of intense investigation. The mid-level visual areas along the ventral stream are selective to a common class of natural images-textures-but a circuit-level understanding of this selectivity and its link to perception remains unclear. We addressed these questions in mice, first showing that they can perceptually discriminate between textures and statistically simpler spectrally matched stimuli, and between texture types.

SRF transcriptionally regulates the oligodendrocyte cytoskeleton during CNS myelination.

Myelination of neuronal axons is essential for nervous system development. Myelination requires dramatic cytoskeletal dynamics in oligodendrocytes, but how actin is regulated during myelination is poorly understood. We recently identified serum response factor (SRF)-a transcription factor known to regulate expression of actin and actin regulators in other cell types-as a critical driver of myelination in the aged brain.