Persistent synaptic inhibition of the subthalamic nucleus by high frequency stimulation

Background: Deep brain stimulation (DBS) provides symptomatic relief in a growing number of neurological indications, but local synaptic dynamics in response to electrical stimulation that may relate to its mechanism of action have not been fully characterized. Objective: The objectives of this study were to (1) study local synaptic dynamics during high frequency extracellular stimulation of the subthalamic nucleus (STN), and (2) compare STN synaptic dynamics with those of the neighboring substantia nigra pars reticulata (SNr). Methods: Two microelectrodes were advanced into the STN and SNr of patients undergoing DBS surgery for PD. Neuronal firing and evoked field potentials (fEPs) were recorded with one microelectrode during stimulation from an adjacent microelectrode. Results: Excitatory and inhibitory fEPs could be discerned within the STN and their amplitudes predicted bidirectional effects on neuronal firing (p = .007). There were no differences between STN and SNr inhibitory fEP dynamics at low stimulation frequencies (p > .999). However, inhibitory neuronal responses were sustained over time in STN during high frequency stimulation, but not SNr (p < .001) where depression of inhibitory input was coupled with a return of neuronal firing (p = .003). Interpretation: Persistent inhibitory input to the STN suggests a local synaptic mechanism for the suppression of subthalamic firing during high frequency stimulation. Moreover, differences in the resiliency versus vulnerability of inhibitory inputs to the STN and SNr suggest a projection source- and frequency-specificity for this mechanism. The feasibility of targeting electrophysiologically-identified neural structures may provide insight into how DBS achieves frequency-specific modulation of neuronal projections.

Transcranial magnetic stimulation entrains alpha oscillatory activity in occipital cortex

Parieto-occipital alpha rhythms (8–12 Hz) underlie cortical excitability and influence visual performance. Whether the synchrony of intrinsic alpha rhythms in the occipital cortex can be entrained by transcranial magnetic stimulation (TMS) is an open question. We applied 4-pulse, 10-Hz rhythmic TMS to entrain intrinsic alpha oscillators targeting right V1/V2, and tested four predictions with concurrent electroencephalogram (EEG): (1) progressive enhancement of entrainment across time windows, (2) output frequency specificity, (3) dependence on the intrinsic oscillation phase, and (4) input frequency specificity to individual alpha frequency (IAF) in the neural signatures. Two control conditions with an equal number of pulses and duration were arrhythmic-active and rhythmic-sham stimulation. The results confirmed the first three predictions. Rhythmic TMS bursts significantly entrained local neural activity. Near the stimulation site, evoked oscillation amplitude and inter-trial phase coherence (ITPC) were increased for 2 and 3 cycles, respectively, after the last TMS pulse. Critically, ITPC following entrainment positively correlated with IAF rather than with the degree of similarity between IAF and the input frequency (10 Hz). Thus, we entrained alpha-band activity in occipital cortex for ~ 3 cycles (~ 300 ms), and IAF predicts the strength of entrained occipital alpha phase synchrony indexed by ITPC.

Molecular Mechanisms for Frequency Specificity in a Drosophila Hearing Organ

Discrimination for sound frequency is essential for auditory communications in animals. Here, by combining in vivo calcium imaging and behavioral assay, we found that Drosophila larvae can sense a wide range of sound frequency and the behavioral specificity is mediated with the selectivity of the lch5 chordotonal organ neurons to sounds that forms a combinatorial coding of frequency. We also disclosed that Brivido1 (Brv1) and Piezo-like (Pzl), each expresses in a subset of lch5 neurons and mediate hearing sensation to certain frequency ranges. Intriguingly, mouse Piezo2 can rescue pzl-mutant's phenotypes, suggesting a conserved role of the Piezo family proteins in high-frequency hearing.

TMS entrains occipital alpha activity: Individual alpha frequency predicts the strength of entrained phase-locking

Parieto-occipital alpha rhythms (8–12 Hz) underlie cortical excitability and influence visual performance. Whether the synchrony of intrinsic alpha rhythms in the occipital cortex can be entrained by transcranial magnetic stimulation (TMS) is an open question. We applied 4-pulse, 10-Hz rhythmic TMS to entrain intrinsic alpha oscillators targeting right V1/V2, and tested four predictions with concurrent electroencephalogram (EEG): (1) progressive enhancement of entrainment across time windows, (2) output frequency specificity, (3) dependence on the intrinsic oscillation phase, and (4) input frequency specificity to individual alpha frequency (IAF) in the neural signatures. Two control conditions with an equal number of pulses and duration were arrhythmic-active and rhythmic-sham stimulation. The results confirmed the first three predictions. Rhythmic TMS bursts significantly entrained local neural activity. Near the stimulation site, evoked oscillation amplitude and inter-trial phase coherence (ITPC) were increased for 2 and 3 cycles, respectively, after the last TMS pulse. Critically, ITPC following entrainment positively correlated with IAF rather than with the degree of similarity between IAF and the input frequency (10 Hz). Thus, we entrained alpha-band activity in occipital cortex for ~ 3 cycles (~ 300 ms), and IAF predicts the strength of entrained occipital alpha phase synchrony indexed by ITPC.

Three auditory brainstem response (ABR) methods tested and compared in two anuran species

Hearing sensitivity has been extensively investigated, often by measuring the auditory brainstem response (ABR). ABR measurements are relatively non-invasive, easy to reproduce, and allow the assessment of sensitivity when psychophysical data are difficult to obtain. However, the experimental methods differ greatly in respect to stimulation, which may result in different audiograms.We used three different methods in the same individual frogs: Stimulating with brief tone bursts (tABR), long-duration tones (ltABR), and masked ABR (mABR) where transients are masked by a long-duration sinusoid, and the sensitivity is assessed by the difference between unmasked and masked ABR.We measured sensitivity in a range from 100 to 3500 Hz, and the resulting audiograms show two sensitivity peaks at 400-600 Hz and 1500-1600 Hz (both sensitive down to 30 dB re. 20 µPa). We found similar results below 1000 Hz, but when stimulating with long-duration tones, the sensitivity decreased more rapidly above this frequency. We showed that the frequency specificity of tone bursts becomes poorly defined with shorter duration at low frequencies. Comparisons between subjectively (visual inspection by researchers) and objectively (thresholds defined by SNR) defined audiograms showed very little variation. In conclusion the mABR method gave the most sensitive audiograms. The tABR method showed a similar audiogram, when using relatively long-duration tone bursts (25 ms). The ltABR method is not a good choice for studying hearing thresholds above 1000 Hz, because of the bias introduced by spike rate saturation in the nerve fibers and their inability to phase lock.

Narrowband multivariate source separation for semi-blind discovery of experiment contrasts

BackgroundElectrophysiological recordings contain mixtures of signals from distinct neural sources, impeding a straightforward interpretation of the sensor-level data. This mixing is particularly detrimental when distinct sources resonate in overlapping frequencies. Fortunately, the mixing is linear and instantaneous. Multivariate source separation methods may therefore successfully separate statistical sources, even with overlapping spatial distributions.New MethodWe demonstrate a feature-guided multivariate source separation method that is tuned to narrowband frequency content as well as binary condition differences. This method — comparison scanning generalized eigendecomposition, csGED — harnesses the covariance structure of multichannel data to find directions (i.e., eigenvectors) that maximally separate two subsets of data. To drive condition specificity and frequency specificity, our data subsets were taken from different task conditions and narrowband-filtered prior to applying GED.ResultsTo validate the method, we simulated MEG data in two conditions with shared noise characteristics and unique signal. csGED outperformed the best sensor at reconstructing the ground truth signals, even in the presence of large amounts of noise. We next applied csGED to a published empirical MEG dataset on visual perception vs. imagery. csGED identified sources in alpha, beta, and gamma bands, and successfully separated distinct networks in the same frequency band.Comparison with Existing Method(s)GED is a flexible feature-guided decomposition method that has previously successfully been applied. Our combined frequency- and condition-tuning is a novel adaptation that extends the power of GED in cognitive electrophysiology.ConclusionsWe demonstrate successful condition-specific source separation by applying csGED to simulated and empirical data.

The Derived-Band Envelope Following Response and its Sensitivity to Sensorineural Hearing Deficits

The envelope following response (EFR) has been proposed as a non-invasive marker of synaptopathy in animal models. However, its amplitude is affected by the spread of basilar-membrane excitation and other coexisting sensorineural hearing deficits. This study aims to (i) improve frequency specificity of the EFR by introducing a derived-band EFR (DBEFR) technique and (ii) investigate the effect of lifetime noise exposure, age and outer-hair-cell (OHC) damage on DBEFR magnitudes. Additionally, we adopt a modelling approach to validate the frequency-specificity of the DBEFR and test how different aspects of sensorineural hearing loss affect peripheral generators. The combined analysis of simulations and experimental data proposes that the DBEFRs extracted from the [2-6]-kHz frequency band is a sensitive and frequency-specific measure of synaptopathy in humans. Individual variability in DBEFR magnitudes among listeners with normal audiograms was explained by their self-reported amount of experienced lifetime noise-exposure and corresponded to amplitude variability predicted by synaptopathy. Older listeners consistently had reduced DBEFR magnitudes in comparison to young normal-hearing listeners, in correspondence to how age-induced synaptopathy affects EFRs and compromises temporal envelope encoding. Lastly, OHC damage was also seen to affect the DBEFR magnitude, hence this marker should be combined with a sensitive marker of OHC-damage to offer a differential diagnosis of synaptopathy in listeners with impaired audiograms.