Characterization and closed-loop control of infrared thalamocortical stimulation produces spatially constrained single-unit responses.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to midinfrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in rat thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning (RL) for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Neurometric amplitude modulation detection in the inferior colliculus of Young and Aged rats.

Amplitude modulation is an important acoustic cue for sound discrimination, and humans and animals are able to detect small modulation depths behaviorally. In the inferior colliculus (IC), both firing rate and phase-locking may be used to detect amplitude modulation. How neural representations that detect modulation change with age are poorly understood, including the extent to which age-related changes may be attributed to the inherited properties of ascending inputs to IC neurons. Here, simultaneous measures of local field potentials (LFPs) and single-unit responses were made from the inferior colliculus of Young and Aged rats using both noise and tone carriers in response to sinusoidally amplitude-modulated sounds of varying depths. We found that Young units had higher firing rates than Aged for noise carriers, whereas Aged units had higher phase-locking (vector strength), especially for tone carriers. Sustained LFPs were larger in Young animals for modulation frequencies 8-16 Hz and comparable at higher modulation frequencies. Onset LFP amplitudes were much larger in Young animals and were correlated with the evoked firing rates, while LFP onset latencies were shorter in Aged animals. Unit neurometric thresholds by synchrony or firing rate measures did not differ significantly across age and were comparable to behavioral thresholds in previous studies whereas LFP thresholds were lower than behavior.

Rapid and objective assessment of auditory temporal processing using dynamic amplitude-modulated stimuli.

Auditory neural coding of speech-relevant temporal cues can be noninvasively probed using envelope following responses (EFRs), neural ensemble responses phase-locked to the stimulus amplitude envelope. EFRs emphasize different neural generators, such as the auditory brainstem or auditory cortex, by altering the temporal modulation rate of the stimulus. EFRs can be an important diagnostic tool to assess auditory neural coding deficits that go beyond traditional audiometric estimations. Existing approaches to measure EFRs use discrete amplitude modulated (AM) tones of varying modulation frequencies, which is time consuming and inefficient, impeding clinical translation. Here we present a faster and more efficient framework to measure EFRs across a range of AM frequencies using stimuli that dynamically vary in modulation rates, combined with spectrally specific analyses that offer optimal spectrotemporal resolution. EFRs obtained from several species (humans, Mongolian gerbils, Fischer-344 rats, and Cba/CaJ mice) showed robust, high-SNR tracking of dynamic AM trajectories (up to 800Hz in humans, and 1.4 kHz in rodents), with a fivefold decrease in recording time and thirtyfold increase in spectrotemporal resolution. EFR amplitudes between dynamic AM stimuli and traditional discrete AM tokens within the same subjects were highly correlated (94% variance explained) across species. Hence, we establish a time-efficient and spectrally specific approach to measure EFRs. These results could yield novel clinical diagnostics for precision audiology approaches by enabling rapid, objective assessment of temporal processing along the entire auditory neuraxis.

Suppressing fear in the presence of a safety cue requires infralimbic cortical signaling to central amygdala.

Stressful events can have lasting and impactful effects on behavior, especially by disrupting normal regulation of fear and reward processing. Accurate discrimination among environmental cues predicting threat, safety or reward adaptively guides behavior. Post-traumatic stress disorder (PTSD) represents a condition in which maladaptive fear persists in response to explicit safety-predictive cues that coincide with previously learned threat cues, but without threat being present. Since both the infralimbic cortex (IL) and amygdala have each been shown to be important for fear regulation to safety cues, we tested the necessity of specific IL projections to the basolateral amygdala (BLA) or central amygdala (CeA) during safety recall. Male Long Evans rats were used since prior work showed female Long Evans rats did not acquire the safety discrimination task used in this study. Here, we show the infralimbic projection to the central amygdala was necessary for suppressing fear cue-induced freezing in the presence of a learned safety cue, and the projection to the basolateral amygdala was not. The loss of discriminative fear regulation seen specifically during IL->CeA inhibition is similar to the behavioral disruption seen in PTSD individuals that fail to regulate fear in the presence of a safety cue.

Practical Bayesian Inference in Neuroscience: Or How I Learned To Stop Worrying and Embrace the Distribution.

Typical statistical practices in the biological sciences have been increasingly called into question due to difficulties in replication of an increasing number of studies, many of which are confounded by the relative difficulty of null significance hypothesis testing designs and interpretation of p-values. Bayesian inference, representing a fundamentally different approach to hypothesis testing, is receiving renewed interest as a potential alternative or complement to traditional null significance hypothesis testing due to its ease of interpretation and explicit declarations of prior assumptions. Bayesian models are more mathematically complex than equivalent frequentist approaches, which have historically limited applications to simplified analysis cases. However, the advent of probability distribution sampling tools with exponential increases in computational power now allows for quick and robust inference under any distribution of data. Here we present a practical tutorial on the use of Bayesian inference in the context of neuroscientific studies. We first start with an intuitive discussion of Bayes' rule and inference followed by the formulation of Bayesian-based regression and ANOVA models using data from a variety of neuroscientific studies. We show how Bayesian inference leads to easily interpretable analysis of data while providing an open-source toolbox to facilitate the use of Bayesian tools.

Spatially specific, closed-loop infrared thalamocortical deep brain stimulation.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically-mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to mid-infrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Bronchiolitis Simulation Module in the Pediatric Preclerkship Educational Exercises (PRECEDE) Curriculum.

Introduction: Acute bronchiolitis is a viral infection infecting 90% of children under the age of 2 years, with approximately 200,000 deaths per year. The current standard of care remains largely respiratory support and prevention. Therefore, understanding how to assess and escalate respiratory supportive care is paramount for health care providers taking care of children. Methods: We used a high-fidelity simulator to simulate an infant with progressing respiratory distress in the setting of acute bronchiolitis. The participants were pediatric clerkship medical students during their preclerkship educational exercises (PRECEDE). The students were asked to evaluate and treat the simulated patient. After debriefing, the students repeated the simulation. We assessed both performances via a weighted checklist specifically developed for this case to measure team performance. Students also completed an overall course evaluation. Results: Ninety out of 121 pediatric clerkship students were enrolled. Performance improved from 57% to 86% ( p < .05). Donning appropriate personal protection equipment was the most missed item both pre- and postdebriefing. Overall, the course was well liked and received. Participants requested more simulation opportunities within PRECEDE as well as a summary document to reinforce learning. Discussion: Pediatric clerkship students improved their performance managing progressing respiratory distress due to acute bronchiolitis via a performance-based assessment tool with sound validity evidence. Improvements going forward include improving faculty diversity and offering more simulation opportunities.

Comparison of age-related declines in behavioral auditory responses versus electrophysiological measures of amplitude modulation.

Amplitude and frequency modulations are important for speech intelligibility, especially in noise. Neurophysiological responses assessed by envelope following responses (EFRs) are smaller at faster amplitude modulation frequencies (AMF) in older subjects compared to younger subjects. A typical assumption is that a decline in EFRs necessarily results in corresponding perceptual deficits. To test this in an animal model, we investigated the behavioral AMF discrimination of young and aged Fischer-344 rats and compared those abilities to their EFRs. A modified version of prepulse inhibition of the acoustic startle reflex was used to measure behavior. When AMF differences and modulation depths were large, young and aged animals' behavioral performances were comparable. Aged animals' discrimination abilities declined as the difference between background and prepulse AMF decreased and as modulation depth decreased. These declines were larger than in younger animals, even compared to young rats with similar peripheral activation (ABR wave I amplitudes), whose EFR amplitudes were smaller than the aged animals. The results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception in aging.

Corticothalamic projections deliver enhanced responses to medial geniculate body as a function of the temporal reliability of the stimulus.

Ageing and challenging signal-in-noise conditions are known to engage the use of cortical resources to help maintain speech understanding. Extensive corticothalamic projections are thought to provide attentional, mnemonic and cognitive-related inputs in support of sensory inferior colliculus (IC) inputs to the medial geniculate body (MGB). Here we show that a decrease in modulation depth, a temporally less distinct periodic acoustic signal, leads to a jittered ascending temporal code, changing MGB unit responses from adapting responses to responses showing repetition enhancement, posited to aid identification of important communication and environmental sounds. Young-adult male Fischer Brown Norway rats, injected with the inhibitory opsin archaerhodopsin T (ArchT) into the primary auditory cortex (A1), were subsequently studied using optetrodes to record single-units in MGB. Decreasing the modulation depth of acoustic stimuli significantly increased repetition enhancement. Repetition enhancement was blocked by optical inactivation of corticothalamic terminals in MGB. These data support a role for corticothalamic projections in repetition enhancement, implying that predictive anticipation could be used to improve neural representation of weakly modulated sounds. KEY POINTS: In response to a less temporally distinct repeating sound with low modulation depth, medial geniculate body (MGB) single units show a switch from adaptation towards repetition enhancement. Repetition enhancement was reversed by blockade of MGB inputs from the auditory cortex. Collectively, these data argue that diminished acoustic temporal cues such as weak modulation engage cortical processes to enhance coding of those cues in auditory thalamus.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows. Specifically, many peripheral measures of auditory function either recover or exhibit subclinical deficits, masking deficits in processing complex, real-world stimuli that may recover differently. Thus, examining the acute time course and pattern of neurophysiological impairment using appropriate stimuli is critical to better understanding and intervening in bTBI-induced auditory system impairments. Here, we compared auditory brainstem response, middle-latency auditory-evoked potentials, and envelope following responses. Stimuli were clicks, tone pips, amplitude-modulated tones in quiet and in noise, and speech-like stimuli (iterated rippled noise pitch contours) in adult male rats subjected to mild blast and sham exposure over the course of 2 mo. We found that blast animals demonstrated drastic threshold increases and auditory transmission deficits immediately after blast exposure, followed by substantial recovery during the window of 7-14 days postblast, although with some deficits remaining even after 2 mo. Challenging conditions and speech-like stimuli can better elucidate mild bTBI-induced auditory deficit during this period. Our results suggest multiphasic recovery and therefore potentially different time windows for treatment, and deficits can be best observed using a small battery of sound stimuli.NEW & NOTEWORTHY Few studies on blast-induced hearing deficits go beyond simple sounds and sparsely track postexposure. Therefore, the recovery arc for potential therapies and real-world listening is poorly understood. Evidence suggested multiple recovery phases over 2 mo postexposure. Hearing thresholds largely recovered within 14 days and partially explained recovery. However, midlatency responses, responses to amplitude modulation in noise, and speech-like pitch sweeps exhibited extended changes, implying persistent central auditory deficits and the importance of subclinical threshold shifts.

In vivo whole-cell recordings of stimulus-specific adaptation in the inferior colliculus.

The inferior colliculus is an auditory structure where inputs from multiple lower centers converge, allowing the emergence of complex coding properties of auditory information such as stimulus-specific adaptation. Stimulus-specific adaptation is the adaptation of neuronal responses to a specific repeated stimulus, which does not entirely generalize to other new stimuli. This phenomenon provides a mechanism to emphasize saliency and potentially informative sensory inputs. Stimulus-specific adaptation has been traditionally studied analyzing the somatic spiking output. However, studies that correlate within the same inferior colliculus neurons their intrinsic properties, subthreshold responses and the level of acoustic stimulus-specific adaptation are still pending. For this, we recorded in vivo whole-cell patch-clamp neurons in the mouse inferior colliculus while stimulating with current injections or the classic auditory oddball paradigm. Our data based on cases of ten neuron, suggest that although passive properties were similar, intrinsic properties differed between adapting and non-adapting neurons. Non-adapting neurons showed a sustained-regular firing pattern that corresponded to central nucleus neurons and adapting neurons at the inferior colliculus cortices showed variable firing patterns. Our current results suggest that synaptic stimulus-specific adaptation was variable and could not be used to predict the presence of spiking stimulus-specific adaptation. We also observed a small trend towards hyperpolarized membrane potentials in adapting neurons and increased synaptic inhibition with consecutive stimulus repetitions in all neurons. This finding indicates a more simple type of adaptation, potentially related to potassium conductances. Hence, these data represent a modest first step in the intracellular study of stimulus-specific adaptation in inferior colliculus neurons in vivo that will need to be expanded with pharmacological manipulations to disentangle specific ionic channels participation.

Short-wave Infrared Neural Stimulation Drives Graded Sciatic Nerve Activation Across A Continuum of Wavelengths.

Infrared neural stimulation (INS) is an optical stimulation technique which uses coherent light to stimulate nerves and neurons and which shows increased spatial selectivity compared to electrical stimulation. This could improve deep brain, high channel count, or vagus nerve stimulation. In this study, we seek to understand the wavelength dependence of INS in the near-infrared optical window. Rat sciatic nerves were excised ex vivo and stimulated with wavelengths between 700 and 900 nm. Recorded compound nerve action potentials (CNAPs) showed that stimulation was maximized in the 700 nm window despite comparable laser power levels across wavelengths. Computational models demonstrated that wavelength-based activation dependencies were not a result of passive optical properties. This data demonstrates that INS is both wavelength and power level dependent, which inform stimulation systems to actively target neural microcircuits in humans.

Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening.

Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.

Use of Breast Milk and Other Feeding Practices Following Gastrointestinal Surgery in Infants.

OBJECTIVES: The aim of the study was to characterize the enteral feeding practices in infants after gastrointestinal surgery. METHODS: We performed a retrospective analysis of infants who underwent intestinal surgery at age <6 months who survived to be fed enterally between January 2012 and June 2017. Demographics, surgical characteristics, feeding practices, and growth-related outcomes during hospitalization, discharge, and follow-up (3, 6, and 12 months) were obtained from the electronic medical records. Descriptive statistics compared infants by their initial diagnosis. RESULTS: We reviewed 111 infants: necrotizing enterocolitis (NEC) = 21, gastroschisis = 28, atresia = 27, spontaneous intestinal perforation (SIP) = 18, and other diagnoses = 17. Most infants (77%) received mother's milk (MM) as the first postoperative feed, but this differed by diagnosis (P = 0.004). Donor milk was used in 11%, most commonly in infants with NEC and SIP. Infants with NEC were least likely to continue MM in the hospital (7%, P = 0.0014) and were more likely to receive elemental formula. Only 44% of infants received MM at discharge. After 1 year, 25% were fed MM. The majority of infants were discharged with feeding tubes (nasogastric: 35%, gastric: 23%). Although all groups had acceptable weights at discharge, infants with NEC (z score: -1.8) and SIP (z score: -1.1) showed growth failure at 3 months (z scores: -3.3, -3.2, respectively, P < 0.0001), but had appropriate gain by 1 year (z scores: -1.1, -1.7, respectively). CONCLUSIONS: Despite most infants receiving MM in the early postoperative period, <50% at discharge and only 33% at 1-year still received MM. Weight gain after discharge in infants with NEC and SIP warrants close monitoring.

Aging alters envelope representations of speech-like sounds in the inferior colliculus.

Hearing impairment in older people is thought to arise from impaired temporal processing in auditory circuits. We used a systems-level (scalp recordings) and a microcircuit-level (extracellular recordings) approach to investigate how aging affects the sensitivity to temporal envelopes of speech-like sounds in rats. Scalp-recorded potentials suggest an age-related increase in sensitivity to temporal regularity along the ascending auditory pathway. The underlying cellular changes in the midbrain were examined using extracellular recordings from inferior colliculus neurons. We observed an age-related increase in sensitivity to the sound's onset and temporal regularity (i.e., periodicity envelope) in the spiking output of inferior colliculus neurons, relative to their synaptic inputs (local field potentials). This relative enhancement for aged animals was most prominent for multi-unit (relative to single-unit) spiking activity. Spontaneous multi-unit, but not single-unit, activity was also enhanced in aged compared with young animals. Our results suggest that aging is associated with altered sensitivity to a sound's temporal regularities, and that these effects may be due to increased gain of neural network activity in the midbrain.

Age-related Changes in Neural Coding of Envelope Cues: Peripheral Declines and Central Compensation.

Aging listeners often experience difficulties in perceiving temporally complex acoustic cues in noisy environments. These difficulties likely have neurophysiological contributors from various levels of auditory processing. Cochlear synapses between inner hair cells and auditory nerve fibers exhibit a progressive decline with age which is not reflected in the threshold audiogram. The functional consequences of this loss for the coding of suprathreshold sound remain poorly understood. Recent studies suggest that cochlear synaptopathy results in degraded representations of temporal envelope cues at the earliest levels of the auditory pathway. Central nuclei downstream of the auditory nerve exhibit a compensatory plasticity in response to this deafferentation, in the form of altered gain. This results in a modulation frequency selective increase in the representation of envelope cues at the level of the auditory midbrain and cortex. These changes may be shaped by mechanisms such as decreased inhibitory neurotransmission occurring with age across various central auditory nuclei. Altered representations of the differing temporal components of speech due to these interactions between multiple levels of the auditory pathway may contribute to the age-related difficulties hearing speech in noisy environments.

Masking Differentially Affects Envelope-following Responses in Young and Aged Animals.

Age-related hearing decline typically includes threshold shifts as well as reduced wave I auditory brainstem response (ABR) amplitudes due to cochlear synaptopathy/neuropathy, which may compromise precise coding of suprathreshold speech envelopes. This is supported by findings with older listeners, who have difficulties in envelope and speech processing, especially in noise. However, separating the effects of threshold elevation, synaptopathy, and degradation by noise on physiological representations may be difficult. In the present study, the effects of notched, low- and high-pass noise on envelope-following responses (EFRs) in aging were compared when sound levels (aged: 85-dB SPL; young: 60- to 80-dB SPL) were matched between groups peripherally, by matching wave I ABR amplitudes, or centrally by matching EFR amplitudes. Low-level notched noise reduced EFRs to sinusoidally amplitude-modulated (SAM) tones in young animals for notch widths up to 2 octaves. High-pass noise above the carrier frequency reduced EFRs. Young animals showed EFR reductions at lower noise levels. Low-pass noise did not reduce EFRs in either young or aged animals. High-pass noise may affect EFR amplitudes in young animals more than aged by reducing the contributions of high-frequency-sensitive inputs. EFRs to SAM tones in modulated noise (NAM) suggest that neurons of young animals can synchronize to NAM at lower sound levels and maintain dual AM representations better than older animals. The overall results show that EFR amplitudes are strongly influenced by aging and the presence of a competing sound that likely reduces or shifts the pool of responsive neurons.

A Community-Building Framework for Collaborative Research Coordination across the Education and Biology Research Disciplines.

Since 2009, the U.S. National Science Foundation Directorate for Biological Sciences has funded Research Coordination Networks (RCN) aimed at collaborative efforts to improve participation, learning, and assessment in undergraduate biology education (UBE). RCN-UBE projects focus on coordination and communication among scientists and educators who are fostering improved and innovative approaches to biology education. When faculty members collaborate with the overarching goal of advancing undergraduate biology education, there is a need to optimize collaboration between participants in order to deeply integrate the knowledge across disciplinary boundaries. In this essay we propose a novel guiding framework for bringing colleagues together to advance knowledge and its integration across disciplines, the "Five 'C's' of Collaboration: Commitment, Collegiality, Communication, Consensus, and Continuity." This guiding framework for professional network practice is informed by both relevant literature and empirical evidence from community-building experience within the RCN-UBE Advancing Competencies in Experimentation-Biology (ACE-Bio) Network. The framework is presented with practical examples to illustrate how it might be used to enhance collaboration between new and existing participants in the ACE-Bio Network as well as within other interdisciplinary networks.

Age-related changes in envelope-following responses at equalized peripheral or central activation.

Previous work has debated about the comparisons of hearing abilities faced with alterations in hearing thresholds and evoked potentials between groups following acoustic trauma- or age-related changes. This study compares envelope-following responses (EFRs) of young and aged rats when sound levels were matched according to (1) wave I amplitudes of auditory brainstem responses (ABRs) elicited by 8-kHz tones or (2) EFR amplitudes evoked by sinusoidally amplitude-modulated (SAM) tones at 100% depth. Matched wave I amplitudes across age corresponded to approximately 20-dB sound level differences. For matched wave I, no age-related differences were observed in wave V amplitudes. However, EFRs recorded in silence were enhanced with aging at 100% but not at 25% depth, consistent with enhanced central gain in aging. For matched EFRs, there were no age-related differences in EFRs of amplitude modulation (AM) depth and AM frequency processing. These results suggest novel, objective measures beyond threshold to compensate for differences in auditory nerve activation and to differentiate peripheral and central contributions of EFRs.