Biology subjects

Leonard, M. K.

Publications and source records attributed to Leonard, M. K..

8 recordsLinked to original sources

bioRxiv2025

A comprehensive view of somatic mosaicism by single-cell DNA analysis

Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues--insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.

genomics↗

bioRxiv2025

Dynamics of auditory word form encoding in human speech cortex

When we hear continuous speech, we perceive it as a series of discrete words, despite the lack of clear boundaries in the acoustic signal. The superior temporal gyrus (STG) encodes phonetic elements like consonants and vowels, but how it extracts whole words as perceptual units remains unclear. Using high-density cortical recordings, we investigated how the brain represents auditory word forms--integrating acoustic-phonetic, prosodic, and lexical features--while participants listened to spoken narratives. Our results show that STG neural populations exhibit a distinctive reset in activity at word boundaries, marked by a brief, sharp drop in cortical activity. Between these resets, the STG consistently encodes distinct acoustic-phonetic, prosodic, and lexical information, supporting the integration of phonological features into coherent word forms. Notably, this process tracks the relative elapsed time within each word, independent of its absolute duration, providing a flexible temporal scaffolding for encoding variable word lengths. We observed similar word form dynamics in the deeper layers of a self-supervised artificial speech network, suggesting a potential convergence with computational models. Additionally, in a bistable word perception task, STG responses were aligned with participants perceived word boundaries on a trial-by-trial basis, further emphasizing the role of dynamic encoding in word recognition. Together, these findings support a new dynamical model of auditory word forms, highlighting their importance as perceptual units for accessing linguistic meaning.

neuroscience↗

bioRxiv2024

Human precentral gyrus neurons link speech sequences from listening to speaking

Speech perception and production are interconnected processes, but the underlying neural mechanisms remain unclear. We investigated this relationship by recording large-scale single-neuron activity in the human brain during a delayed sentence repetition task. Contrary to the traditional view that the precentral gyrus is solely responsible for motor execution, we found that neurons there encoded activity across all task phases of listening, delay, initiation, and speaking. Notably, we discovered "mirror" neurons that activated transiently after hearing and before producing specific speech sounds, and "bridge" neurons that maintained activity between the same speech elements during listening and speaking. Population analysis revealed distinct latent components for each task phase and persistent dynamics for specific sentences. Overall, this study provides novel insights into the neuronal basis of speech processing, emphasizing the intricate interplay between perception, production, and verbal working memory.

neuroscience↗

bioRxiv2024

Parallel Encoding of Speech in Human Frontal and Temporal Lobes

Models of speech perception are centered around a hierarchy in which auditory representations in the thalamus propagate to primary auditory cortex, then to the lateral temporal cortex, and finally through dorsal and ventral pathways to sites in the frontal lobe. However, evidence for short latency speech responses and low-level spectrotemporal representations in frontal cortex raises the question of whether speech-evoked activity in frontal cortex strictly reflects downstream processing from lateral temporal cortex or whether there are direct parallel pathways from the thalamus or primary auditory cortex to the frontal lobe that supplement the traditional hierarchical architecture. Here, we used high-density direct cortical recordings, high-resolution diffusion tractography, and hemodynamic functional connectivity to evaluate for evidence of direct parallel inputs to frontal cortex from low-level areas. We found that neural populations in the frontal lobe show speech-evoked responses that are synchronous or occur earlier than responses in the lateral temporal cortex. These short latency frontal lobe neural populations encode spectrotemporal speech content indistinguishable from spectrotemporal encoding patterns observed in the lateral temporal lobe, suggesting parallel auditory speech representations reaching temporal and frontal cortex simultaneously. This is further supported by white matter tractography and functional connectivity patterns that connect the auditory nucleus of the thalamus (medial geniculate body) and the primary auditory cortex to the frontal lobe. Together, these results support the existence of a robust pathway of parallel inputs from low-level auditory areas to frontal lobe targets and illustrate long-range parallel architecture that works alongside the classical hierarchical speech network model.

neuroscience↗

bioRxiv2023

Encoding of melody in the human auditory cortex

Melody is a core component of music in which discrete pitches are serially arranged to convey emotion and meaning. Perception of melody varies along several pitch-based dimensions: (1) the absolute pitch of notes, (2) the difference in pitch between successive notes, and (3) the higher-order statistical expectation of each note conditioned on its prior context. While humans readily perceive melody, how these dimensions are collectively represented in the brain and whether their encoding is specialized for music remains unknown. Here, we recorded high-density neurophysiological activity directly from the surface of human auditory cortex while Western participants listened to Western musical phrases. Pitch, pitch-change, and expectation were selectively encoded at different cortical sites, indicating a spatial code for representing distinct dimensions of melody. The same participants listened to spoken English, and we compared evoked responses to music and speech. Cortical sites selective for music were systematically driven by the encoding of expectation. In contrast, sites that encoded pitch and pitch-change used the same neural code to represent equivalent properties of speech. These findings reveal the multidimensional nature of melody encoding, consisting of both music-specific and domain-general sound representations in auditory cortex. TeaserThe human brain contains both general-purpose and music-specific neural populations for processing distinct attributes of melody.

neuroscience↗

bioRxiv2022

Low amplitude transcutaneous auricular vagus nerve stimulation modulates performance but not pupil size during non-native speech category learning

Sub-threshold transcutaneous auricular vagus nerve stimulation (taVNS) synchronized with behavioral training can selectively enhance non-native speech category learning in adults. Prior work has demonstrated behavioral performance increases when taVNS is paired with easier-to-learn Mandarin tone categories in native English listeners, relative to when taVNS is paired with harder-to-learn Mandarin tone categories or without taVNS. Mechanistically, this temporally-precise plasticity has been attributed to noradrenergic modulation. However, prior work did not specifically utilize methodologies that indexed noradrenergic modulation and, therefore, were unable to explicitly test this hypothesis. Our goals for the current study were to use pupillometry to gain mechanistic insights into taVNS behavioral effects. Participants learned to categorize Mandarin tones while pupillometry was recorded. In a double-blind design, participants were divided into two taVNS groups that, as in the prior study, differed according to whether taVNS was paired with easier-to-learn tones or harder-to-learn tones. We found that taVNS led to faster rates of learning on trials paired with stimulation. Lower amplitude taVNS also led to faster rates of learning compared to higher amplitude taVNS. However, these effects were not group specific, and we did not find evidence of a taVNS correlate in the pupillary response. The results suggest that stimulation amplitude may be a critical determinant of learning outcomes and pupillary modulation. Future studies on subthreshold taVNS need to systematically evaluate the effect of stimulation intensity on behavioral plasticity and potential taVNS biomarkers.

physiology↗

bioRxiv2021

High density single-unit human cortical recordings using the Neuropixels probe

A fundamental unit of neural computation is the action potential. While significant advances have been made in the ability to sample action potentials of large numbers of individual neurons in animal models, translation of these methodologies to humans has been lacking due to clinical time constraints, electrical noise in the operating room, and reliability of the methodology. Here we present a reliable method for intraoperative recording of dozens of neurons in humans using the Neuropixels probe, yielding up to [~]100 simultaneously-recorded single-units (n=596 across 11 recordings in 8 participants). Most single-units were active within 1 minute of reaching target depth, compatible with clinical time constraints. Cell pairs active close in time were spatially closer in most recordings, demonstrating the power to resolve complex cortical dynamics. Altogether, this approach provides access to population single-unit activity across the depth of human neocortex at scales previously only accessible in animal models. HighlightsO_LISingle units in 8 patients, yielding 596 putative single units across 11 recordings C_LIO_LIThe majority of putative neurons fire at least 1 spike within one minute after reaching target depth C_LIO_LIPutative neurons take longer to fire at least one spike in anesthetized compared to awake participants C_LIO_LICell-pairs that fire action potentials close in time are spatially closer together than those fire further apart in time C_LI

neuroscience↗

bioRxiv2017

Neural Encoding of Auditory Features during Music Perception and Imagery: Insight into the Brain of a Piano Player

It remains unclear how the human cortex represents spectrotemporal sound features during auditory imagery, and how this representation compares to auditory perception. To assess this, we recorded electrocorticographic signals from an epileptic patient with proficient music ability in two conditions. First, the participant played two piano pieces on an electronic piano with the sound volume of the digital keyboard on. Second, the participant replayed the same piano pieces, but without auditory feedback, and the participant was asked to imagine hearing the music in his mind. In both conditions, the sound output of the keyboard was recorded, thus allowing precise time-locking between the neural activity and the spectrotemporal content of the music imagery. For both conditions, we built encoding models to predict high gamma neural activity (70-150Hz) from the spectrogram representation of the recorded sound. We found robust similarities between perception and imagery - in frequency and temporal tuning properties in auditory areas.\n\nAbbreviations

neuroscience↗