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Schindler, J.

Publications and source records attributed to Schindler, J..

3 recordsLinked to original sources

Aperiodic dynamics track cortical state shifts during sleep K-complexes

Sleep microarchitecture is defined by brief electrophysiological events such as K-complexes(KCs), which are traditionally interpreted as discrete oscillatory phenomena involved in sleep maintenance, sensory gating, and cortical down-states. However, electroencephalography(EEG) also contains aperiodic, broadband activity that reflects non-oscillatory population dynamics and varies systematically across sleep stages. Because KCs are large, low-frequency transient waveforms, they also manifest across a broader frequency range, which creates a bidirectional measurement problem in which discrete events and aperiodic activity are difficult to disentangle. This is because aperiodic dynamics alone can generate fluctuations that resemble KCs, while conversely, the KC waveform itself can inflate the low-frequency end of the spectrum, steepening the fitted exponent even when the underlying aperiodic state is unchanged. These confounds blur what constitutes a real KC and a real aperiodic change in the presence of a KC. A KC-locked change in the aperiodic exponent could therefore reflect a genuine cortical state shift, a measurement artifact from the waveform biasing the spectral fit, or both. Here, we use time-resolved spectral parameterization of overnight sleep EEG to characterize aperiodic dynamics around expert-annotated KCs, with a series of controls designed to separate genuine aperiodic state changes from waveform artifacts. A component of the KC-locked aperiodic change survives these controls, suggesting that KCs are accompanied by a genuine shift toward a higher-exponent, inhibition-dominated cortical state. These findings establish aperiodic activity as a meaningful index of state dynamics during KCs and highlight measurement confounds that any event-locked spectral analysis of large transients must consider.

neuroscience↗

A corticostriatal circuit updates subjective beliefs about latent task states

Beliefs about states of the world profoundly impact decision-making and learning, but little is known about how neural circuits represent and update beliefs. We performed projection-specific recordings and perturbations from neurons in the orbitofrontal cortex (OFC) projecting to the intermediate or rostral cau-date putamen (CPi/CPr) in rats performing a task with hidden reward states. Stimulating OFC[->]CPi neurons biased rats beliefs towards high reward states. Recordings from optogenetically-tagged OFC[->]CPi neurons showed that they encoded categorical evidence for high reward states, shaped by a saturating non-linearity in neural responses. Downstream neurons could, in principle, decode the full belief distribution over reward states as rats deliberated about deci-sions. Finally, projection-specific perturbations disrupted encoding of hidden states within OFC. These findings reveal the circuit implementation of a core cognitive computation, updating subjective beliefs about abstract latent states of the environment.

neuroscience↗

Coupling multiplex pre-amplification and droplet digital PCR for longitudinal monitoring of ESR1 and PIK3CA mutations from plasma cell-free DNA

Here we report on the development of a sensitive and cost-effective method to longitudinally track ESR1 and PIK3CA mutations from cfDNA in patients with metastatic breast cancer (MBC) using a streamlined and de-centralized workflow. Hotspot mutations in ESR1 have been shown to cause resistance to aromatase inhibitor-based and anti-estrogenic therapies, while PIK3CA mutations have high prevalence in MBC. As a result, their utility as circulating biomarkers to predict or monitor response in the clinical development of investigational compounds has been the focus of many studies. Six regions in ESR1 and PIK3CA genes containing 20 hotspot mutations were pre-amplified, followed by optimized singleplex ddPCR assays to detect allele frequencies of individual mutations. Without pre-amplification, the limit of detection (LOD) and limit of linearity (LOL) of individual ddPCR assays were at 0.05-0.1% and 0.25% level, respectively. With pre-amplification, the LOD and LOL were slightly elevated at 0.1-0.25% and 0.25-0.5% levels, respectively. High concordance was achieved to the BEAMing assay (Sysmex Inostics) for mutation positive assays (r=0.98, P<0.0001). In conclusion, coupling pre-amplification and ddPCR assays allowed us for the detection of up to 20 hot spot mutations in ESR1 and PIK3CA with high sensitivity and reproducibility.

genetics↗