Electrophysiology publications

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

Experiencing a single severe stressor is sufficient to drive sexually dimorphic psychiatric disease development. The ventral subiculum (vSUB) emerges as a site where stress may induce sexually dimorphic adaptations due to its sex-specific organization and pivotal role in stress integration. Using a 1-hr acute restraint stress model, we uncover that stress causes a net decrease in vSUB activity in females that is potent, long-lasting, and driven by adrenergic receptor signaling. By contrast, males exhibit a net increase in vSUB activity that is transient and driven by corticosterone signaling. We further identified sex-dependent changes in vSUB output to the bed nucleus of the stria terminalis and in anxiety-like behavior in response to stress. These findings reveal striking changes in psychiatric disease-relevant brain regions and behavior following stress with sex-, cell-type, and synapse-specificity that contribute to our understanding of sex-dependent adaptations that may shape stress-related psychiatric disease risk. Highlights vSUB BS cells are uniquely stress sensitive Stress causes sex-dependent changes to BS cell E/I balance Stress causes sex-dependent changes to vSUB activity to aBNST in vivo Stress causes anxiety-like behavior in females, but not males

Objective . Oscillations figure prominently as neurological disease hallmarks and neuromodulation targets. To detect oscillations in a neuron’s spiking, one might attempt to seek peaks in the spike train’s power spectral density (PSD) which exceed a flat baseline. Yet for a non-oscillating neuron, the PSD is not flat: The recovery period (‘RP’, the post-spike drop in spike probability, starting with the refractory period) introduces global spectral distortion. An established ‘shuffling’ procedure corrects for RP distortion by removing the spectral component explained by the inter-spike interval (ISI) distribution. However, this procedure sacrifices oscillation-related information present in the ISIs, and therefore in the PSD. We asked whether point process models (PPMs) might achieve more selective RP distortion removal, thereby enabling improved oscillation detection. Approach . In a novel ‘residuals’ method, we first estimate the RP duration ( n r ) from the ISI distribution. We then fit the spike train with a PPM that predicts spike likelihood based on the time elapsed since the most recent of any spikes falling within the preceding n r milliseconds. Finally, we compute the PSD of the model’s residuals. Main results . We compared the residuals and shuffling methods’ ability to enable accurate oscillation detection with flat baseline-assuming tests. Over synthetic data, the residuals method generally outperformed the shuffling method in classification of true- versus false-positive oscillatory power, principally due to enhanced sensitivity in sparse spike trains. In single-unit data from the internal globus pallidus (GPi) and ventrolateral anterior thalamus (VLa) of a parkinsonian monkey—in which alpha-beta oscillations (8–30 Hz) were anticipated—the residuals method reported the greatest incidence of significant alpha-beta power, with low firing rates predicting residuals-selective oscillation detection. Significance . These results encourage continued development of the residuals approach, to support more accurate oscillation detection. Improved identification of oscillations could promote improved disease models and therapeutic technologies.

A major challenge in neuroscience is to understand how neural representations of sensory information are transformed by the network of ascending and descending connections in each sensory system. By recording from neurons at several levels of the auditory pathway, we show that much of the nonlinear encoding of complex sounds in auditory cortex can be explained by transformations in the midbrain and thalamus. Modeling cortical neurons in terms of their inputs across these subcortical populations enables their responses to be predicted with unprecedented accuracy. By contrast, subcortical responses cannot be predicted from descending cortical inputs, indicating that ascending transformations are irreversible, resulting in increasingly lossy, higher-order representations across the auditory pathway. Rather, auditory cortex selectively modulates the nonlinear aspects of thalamic auditory responses and the functional coupling between subcortical neurons without affecting the linear encoding of sound. These findings reveal the fundamental role of subcortical transformations in shaping cortical responses.

Negative-going responses in sensory cortex co-vary with perceptual awareness of sensory stimuli. Given that this awareness negativity has also been observed for undetected stimuli, some have challenged its role for perception. To address this question, we combined magnetoencephalography, electroencephalography, and pupillometry to study how sustained attention and response criterion affect the auditory awareness negativity. Participants first detected distractor sounds and denied hearing task-irrelevant near-threshold tones, which evoked neither awareness negativity nor pupil dilation. These same tones evoked both responses when task-relevant, stronger for hit but also present for miss trials. Participants then rated their perception on a six-point scale to test whether response criterion explains the presence of these responses for miss trials. Decreasing perception ratings were associated with gradually reduced evoked responses, consistent with signal detection theory. These results support the concept of an awareness negativity that is modulated by attention but does not require a non-linear threshold mechanism.

Study of the foreign body reaction to implanted electrodes in the brain is an important area of research for the future development of neuroprostheses and experimental electrophysiology. After electrode implantation in the brain, microglial activation, reactive astrogliosis, and neuronal cell death create an environment immediately surrounding the electrode that is significantly altered from its homeostatic state. Objective. To uncover physiological changes potentially affecting device function and longevity, spatial transcriptomics (ST) was implemented to identify changes in gene expression driven by electrode implantation and compare this differential gene expression to traditional metrics of glial reactivity, neuronal loss, and electrophysiological recording quality. Approach. For these experiments, rats were chronically implanted with functional Michigan-style microelectrode arrays, from which electrophysiological recordings (multi-unit activity, local field potential) were taken over a six-week time course. Brain tissue cryosections surrounding each electrode were then mounted for ST processing. The tissue was immunolabeled for neurons and astrocytes, which provided both a spatial reference for ST and a quantitative measure of glial fibrillary acidic protein and neuronal nuclei immunolabeling surrounding each implant. Main results . Results from rat motor cortex within 300 µ m of the implanted electrodes at 24 h, 1 week, and 6 weeks post-implantation showed up to 553 significantly differentially expressed (DE) genes between implanted and non-implanted tissue sections. Regression on the significant DE genes identified the 6–7 genes that had the strongest relationship to histological and electrophysiological metrics, revealing potential candidate biomarkers of recording quality and the tissue response to implanted electrodes. Significance . Our analysis has shed new light onto the potential mechanisms involved in the tissue response to implanted electrodes while generating hypotheses regarding potential biomarkers related to recorded signal quality. A new approach has been developed to understand the tissue response to electrodes implanted in the brain using genes identified through transcriptomics, and to screen those results for potential relationships with functional outcomes.

In vivo glutamate sensing has provided valuable insight into the physiology and pathology of the brain. Electrochemical glutamate biosensors, constructed by cross-linking glutamate oxidase onto an electrode and oxidizing H2O2 as a proxy for glutamate, are the gold standard for in vivo glutamate measurements for many applications. While glutamate sensors have been employed ubiquitously for acute measurements, there are almost no reports of long-term, chronic glutamate sensing in vivo, despite demonstrations of glutamate sensors lasting for weeks in vitro. To address this, we utilized a platinum electrode with nanometer-scale roughness (nanoPt) to improve the glutamate sensors' sensitivity and longevity. NanoPt improved the GLU sensitivity by 67.4% and the sensors were stable in vitro for 3 weeks. In vivo, nanoPt glutamate sensors had a measurable signal above a control electrode on the same array for 7 days. We demonstrate the utility of the nanoPt sensors by studying the effect of traumatic brain injury on glutamate in the rat striatum with a flexible electrode array and report measurements of glutamate taken during the injury itself. We also show the flexibility of the nanoPt platform to be applied to other oxidase enzyme-based biosensors by measuring γ-aminobutyric acid in the porcine spinal cord. NanoPt is a simple, effective way to build high sensitivity, robust biosensors harnessing enzymes to detect neurotransmitters in vivo.

Working memory is essential for cognition, facilitating the temporary maintenance and manipulation of information to produce goal-directed behavior. While both cortical and subcortical structures are involved, their precise roles and interactions are not fully understood. To investigate this, we simultaneously recorded neural activity from the frontal and parietal cortex, higher-order thalamic nuclei, and core basal ganglia structures during color and spatial working memory tasks in non-human primates. We found widespread yet differential encoding of color and spatial information, marked by area-specific temporal dynamics and modulation according to task demands. Both cortical and subcortical information increased towards working memory-dependent actions, suggesting a task-specific reloading of information. Directed interactions between cortical and subcortical regions were extensive and reciprocal, with dominant directions of information flow, especially from frontoparietal areas. These interactions were dynamically modulated and partially task specific. Our findings provide comprehensive insights into the large-scale circuit dynamics underlying primate working memory and suggest that flexible goal-directed behavior relies on the selective processing of task-relevant memory information within information-specific cortico-subcortical networks.

Background Plasticity from auditory experience shapes the brain’s encoding and perception of sound. Though prior research demonstrates that neural entrainment (i.e., brain-to-acoustic synchronization) aids speech perception, how long- and short-term plasticity influence entrainment to concurrent speech has not been investigated. Here, we explored neural entrainment mechanisms and the interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Method Participants learned to identify double-vowel mixtures during ∼45 min training sessions with concurrent high-density EEG recordings. We examined the degree to which brain responses entrained to the speech-stimulus train (∼9 Hz) to investigate whether entrainment to speech prior to behavioral decision predicted task performance. Source and directed functional connectivity analyses of the EEG probed whether behavior was driven by group differences auditory-motor coupling. Results Both musicians and nonmusicians showed rapid perceptual learning in accuracy with training. Interestingly, listeners’ neural entrainment strength prior to target speech mixtures predicted behavioral identification performance; stronger neural synchronization was observed preceding incorrect compared to correct trial responses. We also found stark hemispheric biases in auditory-motor coupling during speech entrainment, with greater auditory-motor connectivity in the right compared to left hemisphere for musicians (R>L) but not in nonmusicians (R=L). Conclusions Our findings confirm stronger neuroacoustic synchronization and auditory-motor coupling during speech processing in musicians. Stronger neural entrainment to rapid stimulus trains preceding incorrect behavioral responses supports the notion that alpha-band (∼10 Hz) arousal/suppression in brain activity is an important modulator of trial-by-trial success in perceptual processing.

The Inferior Colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a “climbing effect” in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

Background Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. Method Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. Results Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an ‘off-disc’ stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. Conclusion The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications.

Neuronal responses during behavior are diverse, ranging from highly reliable ‘classical’ responses to irregular ‘non-classically responsive’ firing. While a continuum of response properties is observed across neural systems, little is known about the synaptic origins and contributions of diverse responses to network function, perception, and behavior. To capture the heterogeneous responses measured from auditory cortex of rodents performing a frequency recognition task, we use a novel task-performing spiking recurrent neural network incorporating spike-timing-dependent plasticity. Reliable and irregular units contribute differentially to task performance via output and recurrent connections, respectively. Excitatory plasticity shifts the response distribution while inhibition constrains its diversity. Together both improve task performance with full network engagement. The same local patterns of synaptic inputs predict spiking response properties of network units and auditory cortical neurons from in vivo whole-cell recordings during behavior. Thus, diverse neural responses contribute to network function and emerge from synaptic plasticity rules.

Objective. Measures of functional connectivity (FC) can elucidate which cortical regions work together in order to complete a variety of behavioral tasks. This study’s primary objective was to expand a previously published model of measuring FC to include multiple subjects and several regions of interest. While FC has been more extensively investigated in vision and other sensorimotor tasks, it is not as well understood in audition. The secondary objective of this study was to investigate how auditory regions are functionally connected to other cortical regions when attention is directed to different distinct auditory stimuli. Approach. This study implements a linear dynamic system (LDS) to measure the structured time-lagged dependence across several cortical regions in order to estimate their FC during a dual-stream auditory attention task. Results. The model’s output shows consistent functionally connected regions across different listening conditions, indicative of an auditory attention network that engages regardless of endogenous switching of attention or different auditory cues being attended. Significance. The LDS implemented in this study implements a multivariate autoregression to infer FC across cortical regions during an auditory attention task. This study shows how a first-order autoregressive function can reliably measure functional connectivity from M/EEG data. Additionally, the study shows how auditory regions engage with the supramodal attention network outlined in the visual attention literature.

The overall focus of this research program is to investigate the viability and safety of microelectrode arrays (MEAs) and ultramicroelectrode arrays (UMEAs) for microstimulation (µStim) in the brain. We aim to assess their potential to deliver adequate electrical stimulation for neural activation without causing electrode or tissue damage. To this end, here we conducted galvanostatic Electrochemical Impedance Spectroscopy (EIS) to assess the behavior of electrodes of various diameters both pre- and post-stimulation in a rat model. Our first-generation electrode arrays (G1) were designed with electrode diameters spanning 3 orders of magnitude and including subcellular dimensions. Using these devices, we delivered 0.4 nC/phase stimulation in vivo. We conducted in vitro EIS measurements before and after the current pulsing. Our findings show that these electrode arrays, including UMEAs, exhibit stable electrochemical behavior following a 0.4 nC/phase current pulse. To validate the EIS frequency range used for the G1 measurements, we designed a second-generation electrode array (G2) that included a terminating lead and a looping lead. This array provided the ability to assess the accuracy contour plot of our EIS system and electrode array platform. This exploratory research contributes to the ongoing knowledge of UMEAs in µStim applications. These developments may result in high-fidelity, non-damaging multichannel µStim, and improved neuromodulation technology for the treatment of neural diseases and injuries.

In autism spectrum disorder (ASD), atypical sensory experiences are often associated with irregularities in predictive coding, which proposes that the brain creates hierarchical sensory models via a bidirectional process of predictions and prediction errors. However, it remains unclear how these irregularities manifest across different functional hierarchies in the brain. To address this, we study a marmoset model of ASD induced by valproic acid (VPA) treatment. We record high-density electrocorticography (ECoG) during an auditory task with two layers of temporal control, and applied a quantitative model to quantify the integrity of predictive coding across two distinct hierarchies. Our results demonstrate a persistent pattern of sensory hypersensitivity and unstable predictions across two brain hierarchies in VPA-treated animals, and reveal the associated spatio-spectro-temporal neural signatures. Despite the regular occurrence of imprecise predictions in VPA-treated animals, we observe diverse configurations of underestimation or overestimation of sensory regularities within the hierarchies. Our results demonstrate the coexistence of the two primary Bayesian accounts of ASD: overly-precise sensory observations and weak prior beliefs, and offer a potential multi-layered biomarker for ASD, which could enhance our understanding of its diverse symptoms.

3D printing has been widely used for on-demand prototyping of complex three-dimensional structures. In biomedical applications, PEDOT:PSS has emerged as a promising material in versatile bioelectronics due to its tissue-like mechanical properties and suitable electrical properties. However, previously developed PEDOT:PSS inks have not been able to fully utilize the advantages of commercial 3D printing due to its long post treatment times, difficulty in high aspect ratio printing, and low conductivity. We propose a one-shot strategy for the fabrication of PEDOT:PSS ink that is able to simultaneously achieve on-demand biocompatibility (no post treatment), structural integrity during 3D printing for tall three-dimensional structures, and high conductivity for rapid-prototyping. By using ionic liquid-facilitated PEDOT:PSS colloidal stacking induced by a centrifugal protocol, a viscoplastic PEDOT:PSS-ionic liquid colloidal (PILC) ink was developed. PILC inks exhibit high-aspect ratio vertical stacking, omnidirectional printability for generating suspended architectures, high conductivity (~286 S/cm), and high-resolution printing (~50 µm). We demonstrate the on-demand and versatile applicability of PILC inks through the fabrication of 3D circuit boards, on-skin physiological signal monitoring e-tattoos, and implantable bioelectronics (opto-electrocorticography recording, low voltage sciatic nerve stimulation and recording from deeper brain layers via 3D vertical spike arrays).

Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial–neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.

Visual object memory is a fundamental element of various cognitive abilities, and the underlying neural mechanisms have been extensively examined especially in the anterior temporal cortex of primates. However, both macroscopic large-scale functional network in which this region is embedded and microscopic neuron-level dynamics of top-down regulation it receives for object memory remains elusive. Here, we identified the orbitofrontal node as a critical partner of the anterior temporal node for object memory by combining whole-brain functional imaging during rest and a short-term object memory task in male macaques. Focal chemogenetic silencing of the identified orbitofrontal node downregulated both the local orbitofrontal and remote anterior temporal nodes during the task, in association with deteriorated mnemonic, but not perceptual, performance. Furthermore, imaging-guided neuronal recordings in the same monkeys during the same task causally revealed that orbitofrontal top-down modulation enhanced stimulus-selective mnemonic signal in individual anterior temporal neurons while leaving bottom-up perceptual signal unchanged. Furthermore, similar activity difference was also observed between correct and mnemonic error trials before silencing, suggesting its behavioral relevance. These multifaceted but convergent results provide a multiscale causal understanding of dynamic top-down regulation of the anterior temporal cortex along the ventral fronto-temporal network underpinning short-term object memory in primates.

Background Implantable vagus nerve stimulation is a promising approach for restoring autonomic cardiovascular functions after heart transplantation. For successful treatment a system should have multiple electrodes to deliver precise stimulation and complex neuromodulation patterns. Methods This paper presents an implantable multi-channel stimulation system for vagal-cardiac neuromodulation studies in swine species. The system comprises an active electrode array implant percutaneously connected to an external wearable controller. The active electrode array implant has an integrated stimulator ASIC mounted on a ceramic substrate connected to an intraneural electrode array via micro-rivet bonding. The implant is silicone encapsulated for biocompatibility and implanted lifetime. The stimulation parameters are remotely transmitted via a Bluetooth telemetry link. Results The size of the encapsulated active electrode array implant is 8 mm × 10 mm × 3 mm. The stimulator ASIC has 10-bit current amplitude resolution and 16 independent output channels, each capable of delivering up to 550 µA stimulus current and a maximum voltage of 20 V. The active electrode array implant was subjected to in vitro accelerated lifetime testing at 70 °C for 7 days with no degradation in performance. After over 2 h continuous stimulation, the surface temperature change of the implant was less than 0.5 °C. In addition, in vivo testing on the sciatic nerve of a male Göttingen minipig demonstrated that the implant could effectively elicit an EMG response that grew progressively stronger on increasing the amplitude of the stimulation. Conclusions The multi-channel stimulator is suitable for long term implantation. It shows potential as a useful tool in vagal-cardiac neuromodulation studies in animal models for restoring autonomic cardiovascular functions after heart transplantation.

Little is known about the electrophysiologic activity of the intact human spinal cord during volitional movement. We analyzed epidural spinal recordings from a total of five human subjects of both sexes during a variety of upper extremity movements and found that these spinal epidural electrograms contain spectral information distinguishing periods of movement, rest, and sensation. Cervical epidural electrograms also contained spectral changes time-locked with movement. We found that these changes were primarily associated with increased power in the theta (4–8 Hz) band and feature increased theta phase to gamma amplitude coupling, and this increase in theta power can be used to topographically map distinct upper extremity movements onto the cervical spinal cord in accordance with established myotome maps of the upper extremity. Our findings have implications for the development of neurostimulation protocols and devices focused on motor rehabilitation for the upper extremity, and the approach presented here may facilitate spatiotemporal mapping of naturalistic movements.