Biology subjects

Grossman, N.

Publications and source records attributed to Grossman, N..

16 recordsLinked to original sources

bioRxiv2026

Artefact-free EEG during temporal interference stimulation reveals phase-specific modulation of the human visual cortex

Background: Temporal interference (TI) stimulation applies kHz electric fields whose envelope is modulated at a difference frequency ({Delta}f), allowing non-invasive deep-brain targeting. Measuring the neural response during stimulation with EEG is essential for establishing mechanisms and for closed-loop control. However, non-linearities in the recording chain mix the kHz carriers, producing an artefact at exactly {Delta}f. Objectives: To establish a method for recording EEG during TI without the {Delta}f artefact, and to test whether TI modulates neural activity at {Delta}f. Methods: A front-end analogue low-pass filter (7th order; 90 Hz cut-off; [≥]130 dB attenuation at 1 kHz) was bench-tested. In 22 healthy participants, residual artefact was assessed per recording with a two-stage detection pipeline in stimulation-only blocks. TI targeted the right primary visual cortex at 10 or 15.5 Hz, in-phase or anti-phase with multi-frequency photic stimulation (4.5, 10, 15.5 Hz), during a choice reaction time task. Results: The filter suppressed the {Delta}f artefact below the noise floor on a resistive load. In vivo, residual artefact was confirmed in two participants and could not be excluded in two more; all four were excluded from EEG analyses. Steady-state visual evoked potential (SSVEP) amplitude at 11, 14.5 and 15.5 Hz predicted faster responses. In-phase 15.5 Hz TI increased SSVEP amplitude at 14.5 and 15.5 Hz and shortened response times relative to both sham and anti-phase TI, which did not differ from sham. Conclusions: With front-end filtering and per-recording verification, EEG can measure TI neuromodulation during stimulation and at {Delta}f, revealing phase-specific modulation of visual entrainment linked to behaviour.

neuroscience↗

bioRxiv2026

Hippocampal stimulation timed to memory reactivation shapes human sleep oscillatory dynamics and consolidation

Memory consolidation during sleep depends on the precisely timed coordination of hippocampal reactivation with cortical slow oscillations and spindles. In humans this coupling has been characterised correlationally, while causal investigations have required intracranial stimulation in restricted patient cohorts or used non-invasive approaches targeting cortical regions, often obscuring the underlying sleep rhythms. Here we stimulated the human hippocampus during sleep for the first time, applying temporal interference stimulation to the left hippocampal head either concurrently with or prior to induced memory reactivation. Stimulation concurrent with reactivation reduced associative memory forgetting relative to mistimed stimulation and enhanced fast spindle amplitude, preserving the association between slow oscillation-spindle coupling and memory. This behavioural benefit was mediated by a distributed, left-lateralised set of spindle and coupling features. Non-invasively engaging deep hippocampal circuits during sleep offers both a means to probe human memory and a scalable basis for intervention where consolidation fails.

neuroscience↗

bioRxiv2025

Non-invasive in vivo acoustoelectric neuromodulation and its contribution to ultrasound stimulation

Non-invasive brain stimulation offers therapeutic potential without the risks of surgery, yet current electrical approaches lack spatial precision and depth due to the long wavelengths of electric fields. Here we demonstrate that the acoustoelectric interaction--the nonlinear coupling between applied acoustic and electric fields--can overcome these limitations to achieve spatially focused, non-invasive neuromodulation. Using in vitro and in vivo rodent electrophysiology, we show motor-evoked potentials that depend on both the amplitude and frequency of the acoustoelectric field, with artefactual controls excluding purely acoustic or electrical origins. We further identify an acoustoelectric contribution to conventional ultrasound stimulation, arising from the interaction between ultrasound-induced electrical signals and propagating acoustic waves. These findings establish acoustoelectric neuromodulation as a distinct mechanism of neural activation and a significant contributor to how ultrasound stimulation influences brain activity, opening new directions for precise, non-invasive neuromodulation and neurotherapeutic development.

neuroscience↗

bioRxiv2025

A universal dynamic routing architecture governs the flow of human cortical activity

Behaviour requires distributed neural processing to be flexibly integrated and segregated, which in turn demands that information be dynamically routed across the brain. However, whether a unifying principle governs the routing of neural activity remains unknown. Here, we report that the flow of cortical activity is directed through canonical routing modes that are conserved across individuals, robust to variations in age, frequency band, brain state, and even the presence of neurodegeneration. These modes are constructed from the divergence and vorticity of the time-varying unit-phase vector field derived from electroencephalogram (EEG) recordings. We show that the canonical routing modes are flexibly combined to generate distinct, state- and function-dependent flow architectures that remain consistent across individuals. Disruption to the routing mode dynamics mechanistically links structural abnormalities and cognitive impairment in Alzheimers disease. Together, these canonical routing modes provide a unified framework for describing, modelling, and predicting the dynamic integration and segregation of macroscopic brain activity underpinning behaviour.

neuroscience↗

bioRxiv2025

Temporal Interference Stimulation Enhances Neural Regeneration

Neural regeneration therapies aim to treat neurodegeneration by promoting the proliferation and maturation of exogenous or endogenous neural progenitor cells (NPCs). However, their efficacy has been limited. Deep brain stimulation (DBS) via implanted electrodes has been shown to promote neurogenesis. However, its invasiveness precludes deployment in research and widespread clinical use. Temporal interference (TI) has emerged as a strategy for non-invasive, high-precision DBS using multiple kHz-range electric fields, with a frequency difference within the range of neural activity. Here, we validate the potential of TI stimulation for neural regeneration augmentation. We demonstrate that TI stimulation with a theta-band frequency difference enhances the maturation of embryonic neural progenitor cells in vitro. We then demonstrate that theta-band TI stimulation targeting the hippocampus enhances endogenous hippocampal neurogenesis in an in vivo mouse model of Alzheimers disease. By uncovering frequency-specific control of stem cell fate, we propose a clinically relevant regeneration strategy which avoids pharmacological or genetic manipulation. Our results demonstrate focal, non-invasive augmentation of deep-brain neural regeneration. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/670811v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@984165org.highwire.dtl.DTLVardef@1ed8bbdorg.highwire.dtl.DTLVardef@715057org.highwire.dtl.DTLVardef@151882f_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

Neurophysiological Correlates of Phase-Specific Enhancement of Motor Memory Consolidation via Slow-Wave Closed-Loop Targeted Memory Reactivation

Memory consolidation can be enhanced during sleep using targeted memory reactivation (TMR) and closed-loop (CL) acoustic stimulation on the up-phase of slow oscillations (SOs). Here, we tested whether applying TMR at specific phases of the SOs (up vs. down vs. no reactivation) could influence the behavioral and neural correlates of motor memory consolidation in healthy young adults. Results showed that up- (as compared to down-) state cueing resulted in greater performance improvement. Sleep electrophysiological data indicated that up-stimulated SOs exhibited higher amplitude and greater peak-nested sigma power. Task-related functional magnetic resonance images revealed that up-state cueing strengthened activity in - and segregation of - striato-motor and hippocampal networks; and that these modulations were related to the beneficial effect of TMR on sleep features and performance. Overall, these findings highlight the potential of CL-TMR to induce phase-specific modulations of motor performance, sleep oscillations and brain responses during motor memory consolidation.

neuroscience↗

bioRxiv2023

Effects of hippocampal noninvasive theta-burst stimulation on consolidation of associative memory in healthy older adults

Stimulation of deep brain areas can offer benefits against cognitive impairments associated with aging. So far, this was only possible via invasive methods accompanied by risks. Grossman et al. proposed a new noninvasive stimulation technique, transcranial temporal interference electric stimulation (tTIS), which can be steered to target and modulate activity of deep brain structures. Memory capacity depends on subcortical structures such as the hippocampus, hence, modulation of hippocampal activity could benefit declining cognitive functions. The current study investigates whether theta-burst patterned tTIS targeting the hippocampus influences performance of associative memory in older adults. We found that theta-burst patterned tTIS, but not the control stimulation, improved recollection time in a follow-up 24h after the stimulation, suggesting that theta-burst patterned tTIS can influence the efficiency of longer-term encoding. This outcome indicates that tTIS may provide a new noninvasive deep brain stimulation method to modulate senescent memory processes.

neuroscience↗

bioRxiv2023

Just a phase? Causal probing reveals spurious phasic dependence of sensory perception

For over a decade, electrophysiological studies have reported correlations between sensory perception and the phase of spontaneous pre-stimulus brain oscillations. To date, these findings have been interpreted as evidence that the brain uses neural oscillations to sample and predict upcoming stimuli. Yet, evidence from simulations have shown that analysis artefacts could also lead to spurious pre-stimulus oscillations that appear to predict future brain responses. To address this discrepancy, we conducted an experiment in which visual stimuli were presented timed to specific phases of spontaneous alpha and theta oscillations. This allowed us to causally probe the role of ongoing neural activity in visual processing independent of the stimulus-evoked dynamics. Our findings did not support a causal link between spontaneous alpha / theta rhythms and behaviour. However, spurious correlations between theta phase and behaviour emerged offline using gold-standard acausal time-frequency analyses. These findings demonstrate that care should be taken when inferring causal relationships between neural activity and behaviour using acausal analyses. HIGHLIGHTSO_LIWe causally probed the role of spontaneous EEG rhythms in visual attention via phase-locking. C_LIO_LITheta phase predicted behaviour offline, but cues presented in real-time with theta had no effect on behaviour. C_LIO_LISpurious theta rhythmic sampling is an artefact of the evoked potential and acausal filtering. C_LIO_LIecHT accurately computes the phase in real-time and mitigates erroneous phase-behaviour correlations. C_LI

neuroscience↗

bioRxiv2023

The neuron mixer and its impact on human brain dynamics

A signal mixer made of a transistor or a diode facilitates rich computation, which has been the building block of modern telecommunications. The mixing produces new signals at the sum and difference frequencies of the input, thereby enabling powerful operations such as frequency conversion (aka heterodyning), phase detection, and multiplexing. Here, we report that a neural cell is also a signal mixer. We found through ex-vivo and in-vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies. We show, using pharmacological manipulation, that the neural mixing originates in the voltage-gated ion channels. Furthermore, we demonstrate that the neural mixing dynamic is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram (EEG) displays distinct clusters of local and inter-region mixing interactions. By quantifying the strength of these interactions before a task, we show that converting the salient posterior alpha-beta oscillations into gamma-band oscillations regulates the visual attention state. Neural circuit oscillations have been observed in nearly every cognitive domain and species, and abnormal spectra of neural oscillations have been found in almost all brain disorders. Signal mixing enables individual neurons to actively sculpt the spectrum of their circuit oscillations and utilize them for computational operations, which have only been seen in modern telecommunication until now.

neuroscience↗

bioRxiv2022

Perfect Timing: Effects of Auditory Stimulation on Alpha Oscillations During Wakefulness and the Transition to Sleep are Phase-dependent in Humans

Alpha oscillations play a vital role in managing the brains resources, inhibiting neural activity as a function of their phase and amplitude, and are changed in many brain disorders. Developing minimally invasive tools to modulate alpha activity and identifying the parameters that determine its response to exogenous modulators, is essential for the implementation of focussed interventions. We introduce Alpha Closed-Loop Auditory Stimulation (CLAS) as an EEG-based method to augment and investigate these brain rhythms in humans with specificity and selectivity, using targeted auditory stimulation. Across three independent studies, we demonstrate that CLAS alters alpha power, frequency, and connectivity in a phase, amplitude and topography-dependent manner. Using a single-pulse-CLAS evoked potentials approach we show that the effects of auditory stimuli on alpha oscillations and resulting evoked potentials can be explained within the theoretical framework of oscillator theory and a phase-reset mechanism. Finally, we demonstrate the functional relevance of our approach by showing that CLAS modulates sleep onset dynamics in an alpha phase-dependent manner.

neuroscience↗

bioRxiv2022

LTP-like noninvasive striatal brain stimulation enhances striatal activity and motor skill learning in humans

The stimulation of deep brain structures has thus far only been possible with invasive methods. Transcranial electrical temporal interference stimulation (tTIS) is a novel, noninvasive technology that might overcome this limitation. The initial proof-of-concept was obtained through modeling, physics experiments and rodent models. Here, we show for the first time successful noninvasive neuromodulation of the striatum via tTIS in humans using computational modeling, fMRI studies and behavioral evaluations. Theta-burst patterned striatal tTIS increased activity in the striatum and associated motor network. Furthermore, striatal tTIS enhanced motor performance, especially in healthy older participants as they have lower natural learning skills than younger subjects. These findings place tTIS as exciting new method to target deep brain structures in humans noninvasively, thus enhancing our understanding of their functional roles. Moreover, our results lay the groundwork for innovative, noninvasive treatment strategies for brain disorders in which deep striatal structures play key pathophysiological roles.

neuroscience↗

bioRxiv2022

Non-invasive temporal interference electrical stimulation of the human hippocampus

Deep brain stimulation (DBS) via implanted electrodes is used worldwide to treat patients with severe neurological and psychiatric disorders however its invasiveness precludes widespread clinical use and deployment in research. Temporal interference (TI) is a strategy for non-invasive steerable DBS using multiple kHz-range electric fields with a difference frequency within the range of neural activity. Here we report the validation of the non-invasive DBS concept in humans. We used electric field modelling and measurements in a human cadaver to verify that the locus of the transcranial TI stimulation can be steerably focused in the hippocampus with minimal exposure to the overlying cortex. We then used functional magnetic resonance imaging (fMRI) and behaviour experiments to show that TI stimulation can focally modulate hippocampal activity and enhance the accuracy of episodic memories in healthy humans. Our results demonstrate targeted, non-invasive electrical stimulation of deep structures in the human brain.

neuroscience↗

bioRxiv2022

Human and murine Cryptococcus neoformans infection selects for common genomic changes in an environmental isolate.

A pet cockatoo was the suspected source of Cryptococcus neoformans recovered from the cerebral spinal fluid (CSF) of an immunocompromised patient with cryptococcosis based on the molecular analyses available in 2000. Here we report whole genome sequence analysis of the clinical and cockatoo strains. Both are closely related MAT strains belonging to the VNII lineage, confirming that the human infection likely originated from pet bird exposure. The two strains differ by 61 single nucleotide polymorphisms, including 8 nonsynonymous changes involving 7 genes. To ascertain whether changes in these genes are selected during mammalian infection, we passaged the cockatoo strain in mice. Remarkably, isolates obtained from mouse tissue possess a frame-shift mutation in one of the seven genes altered in the human sample, a gene predicted to encode a SWI-SNF chromatin-remodeling complex protein. Both cockatoo and patient strains as well as mouse passaged isolates obtained from brain tissue had a premature stop codon in a homolog of ZFC3, a predicted single-zinc finger containing protein, which is associated with larger capsules when deleted and appears to have reverted to a full-length protein in the mouse passaged isolates obtained from lung tissue. The patient strain and mouse passaged isolates show variability in the expression of virulence factors, with differences in capsule size, melanization, and rates on non-lytic expulsion from macrophages observed. Our results establish that environmental strains undergo genomic and phenotypic changes during mammalian passage, suggesting that animal virulence can be a mechanism for genetic change and that the genomes of clinical isolates may provide a readout of mutations acquired during infection.

genomics↗

bioRxiv2022

Focal Non-invasive Deep-brain Stimulation with Temporal Interference for the Suppression of Epileptic Biomarkers

Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 -165Hz, to various deep-seated targets such as for instance the Mesio-temporal lobe (MTL) which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs). In the current study, we use Temporal Interference stimulation to provide a non-invasive focal DBS (130 Hz) of the MTL, specifically the hippocampus, which increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. The method could potentially revolutionize how DBS, certainly in epilepsy, is performed, and we therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs TCS in human cadavers. Results show the better penetration of TI fields into the human hippocampus as compared with TCS. Finally, we provide evidence of the efficacy of the specific form of Pulse-width Modulated TI (PWM-TI), implemented with square waves, which is used in this study. One Sentence SummaryA non-invasive deep brain stimulation applied via temporal interference achieves the suppression of biomarkers of epilepsy in mice and is scaled to humans.

neuroscience↗

bioRxiv2020

Non-invasive Amelioration of Essential Tremor via Phase-Locked Disruption of its Temporal Coherence

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be noninvasively suppressed via electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained after the end of the stimulation and can be phenomenologically predicted. Finally, using feature-based statistical-learning and neurophysiological-modelling we show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the oscillation via perturbation of the tremor generating a cascade of synchronous activity in the olivocerebellar loop. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may represent a powerful neuromodulatory strategy to treat brain disorders.

neuroscience↗

bioRxiv2017

First Draft Genome Sequence of the Pathogenic Fungus Lomentospora prolificans (formerly Scedosporium prolificans)

Here we describe the sequencing and assembly of the pathogenic fungus Lomentospora prolificans using a combination of short, highly accurate Illumina reads and additional coverage in very long Oxford Nanopore reads. The resulting assembly is highly contiguous, containing a total of 37,630,066 bp with over 98% of the sequence in just 26 scaffolds. Annotation identified 8,656 protein-coding genes. Pulsed-field gel analysis suggests that this organism contains at least 7 and possibly 11 chromosomes, the two longest of which have sizes corresponding closely to the sizes of the longest scaffolds, at 6.6 and 5.7 Mb.

microbiology↗