Wireless Heart Sensor for Capturing Cardiac Orienting Response for Prediction of Neurodevelopmental Delay in Infants.

Early identification of infants at risk of neurodevelopmental delay is an essential public health aim. Such a diagnosis allows early interventions for infants that maximally take advantage of the neural plasticity in the developing brain. Using standardized physiological developmental tests, such as the assessment of neurophysiological response to environmental events using cardiac orienting responses (CORs), is a promising and effective approach for early recognition of neurodevelopmental delay. Previous CORs have been collected on children using large bulky equipment that would not be feasible for widespread screening in routine clinical visits. We developed a portable wireless electrocardiogram (ECG) system along with a custom application for IOS tablets that, in tandem, can extract CORs with sufficient physiologic and timing accuracy to reflect the well-characterized ECG response to both auditory and visual stimuli. The sensor described here serves as an initial step in determining the extent to which COR tools are cost-effective for the early screening of children to determine who is at risk of developing neurocognitive deficits and may benefit from early interventions. We demonstrated that our approach, based on a wireless heartbeat sensor system and a custom mobile application for stimulus display and data recording, is sufficient to capture CORs from infants. The COR monitoring approach described here with mobile technology is an example of a desired standardized physiologic assessment that is a cost-and-time efficient, scalable method for early recognition of neurodevelopmental delay.

Coordinated prefrontal-hippocampal activity and navigation strategy-related prefrontal firing during spatial memory formation.

Learning the location of relevant places in the environment is crucial for survival. Such capacity is supported by a distributed network comprising the prefrontal cortex and hippocampus, yet it is not fully understood how these structures cooperate during spatial reference memory formation. Hence, we examined neural activity in the prefrontal-hippocampal circuit in mice during acquisition of spatial reference memory. We found that interregional oscillatory coupling increased with learning, specifically in the slow-gamma frequency (20 to 40 Hz) band during spatial navigation. In addition, mice used both spatial and nonspatial strategies to navigate and solve the task, yet prefrontal neuronal spiking and oscillatory phase coupling were selectively enhanced in the spatial navigation strategy. Lastly, a representation of the behavioral goal emerged in prefrontal spiking patterns exclusively in the spatial navigation strategy. These results suggest that reference memory formation is supported by enhanced cortical connectivity and evolving prefrontal spiking representations of behavioral goals.

Smart Electronic Eyedrop Bottle for Unobtrusive Monitoring of Glaucoma Medication Adherence.

Glaucoma, the leading cause of irreversible blindness, affects >70 million people worldwide. Lowering intraocular pressure via topical administration of eye drops is the most common first-line therapy for glaucoma. This treatment paradigm has notoriously high non-adherence rates: ranging from 30% to 80%. The advent of smart phone enabled technologies creates promise for improving eyedrop adherence. However, previous eyedrop electronic monitoring solutions had awkward medication bottle adjuncts and crude software for monitoring the administration of a drop that adversely affected their ability to foster sustainable improvements in adherence. The current work begins to address this unmet need for wireless technology by creating a "smart drop" bottle. This medication bottle is instrumented with sensing electronics that enable detection of each eyedrop administered while maintaining the shape and size of the bottle. This is achieved by a thin electronic force sensor wrapped around the bottle and underneath the label, interfaced with a thin electronic circuit underneath the bottle that allows for detection and wireless transmission to a smart-phone application. We demonstrate 100% success rate of wireless communication over 75 feet with <1% false positive and false negative rates of single drop deliveries, thus providing a viable solution for eyedrop monitoring for glaucoma patients.

The activity of discrete sets of neurons in the posterior insula correlates with the behavioral expression and extinction of conditioned fear.

The interoceptive insular cortex is known to be involved in the perception of bodily states and emotions. Increasing evidence points to an additional role for the insula in the storage of fear memories. However, the activity of the insula during fear expression has not been studied. We addressed this issue by recording single units from the posterior insular cortex (pIC) of awake behaving rats expressing conditioned fear during its extinction. We found a set of pIC units showing either significant increase or decrease in activity during high fear expression to the auditory cue ("freezing units"). Firing rate of freezing units showed high correlation with freezing and outlasted the duration of the auditory cue. In turn, a different set of units showed either significant increase or decrease in activity during low fear state ("extinction units"). These findings show that expression of conditioned freezing is accompanied with changes in pIC neural activity and suggest that the pIC is important to regulate the behavioral expression of fear memory. NEW & NOTEWORTHY Here, we show novel single-unit data from the interoceptive insula underlying the behavioral expression of fear. We show that different populations of neurons in the insula codify expression and extinction of conditioned fear. Our data add further support for the insula as an important player in the regulation of emotions.

Local cortical activity of distant brain areas can phase-lock to the olfactory bulb's respiratory rhythm in the freely behaving rat.

An important unresolved question about neural processing is the mechanism by which distant brain areas coordinate their activities and relate their local processing to global neural events. A potential candidate for the local-global integration are slow rhythms such as respiration. In this study, we asked if there are modulations of local cortical processing that are phase-locked to (peripheral) sensory-motor exploratory rhythms. We studied rats on an elevated platform where they would spontaneously display exploratory and rest behaviors. Concurrent with behavior, we monitored whisking through electromyography and the respiratory rhythm from the olfactory bulb (OB) local field potential (LFP). We also recorded LFPs from dorsal hippocampus, primary motor cortex, primary somatosensory cortex, and primary visual cortex. We defined exploration as simultaneous whisking and sniffing above 5 Hz and found that this activity peaked at ~8 Hz. We considered rest as the absence of whisking and sniffing, and in this case, respiration occurred at ~3 Hz. We found a consistent shift across all areas toward these rhythm peaks accompanying behavioral changes. We also found, across areas, that LFP gamma (70-100 Hz) amplitude could phase-lock to the animal's OB respiratory rhythm, a finding indicative of respiration-locked changes in local processing. In a subset of animals, we also recorded the hippocampal theta activity and found that occurred at frequencies overlapped with respiration but was not spectrally coherent with it, suggesting a different oscillator. Our results are consistent with the notion of respiration as a binder or integrator of activity between brain regions.

Nucleus Accumbens Shell Neurons Encode the Kinematics of Reward Approach Locomotion.

The nucleus accumbens (NAc) is considered an interface between motivation and action, with NAc neurons playing an important role in promoting reward approach. However, the encoding by NAc neurons that contributes to this role remains unknown. We recorded 62 NAc neurons in male Wistar rats (n = 5) running towards rewarded locations in an 8-arm radial maze. Variables related to locomotor approach kinematics were the best predictors of the firing rate for most NAc neurons. Nearly 18% of the recorded neurons were inhibited during the entire approach run (locomotion-off cells), suggesting that reduction in firing of these neurons promotes initiation of locomotor approach. 27% of the neurons presented a peak of activity during acceleration followed by a valley during deceleration (acceleration-on cells). Together, these neurons accounted for most of the speed and acceleration encoding identified in our analysis. In contrast, a further 16% of neurons presented a valley during acceleration followed by a peak just prior to or after reaching reward (deceleration-on cells). These findings suggest that these three classes of NAc neurons influence the time course of speed changes during locomotor approach to reward.

Susceptibility to express amphetamine locomotor sensitization correlates with dorsolateral striatum bursting activity and GABAergic synapses in the globus pallidus.

Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

Miniaturized wireless gastric pacing via inductive power transfer with non-invasive monitoring using cutaneous Electrogastrography.

BACKGROUND: Gastroparesis is a debilitating disease that is often refractory to pharmacotherapy. While gastric electrical stimulation has been studied as a potential treatment, current devices are limited by surgical complications and an incomplete understanding of the mechanism by which electrical stimulation affects physiology. METHODS: A leadless inductively-powered pacemaker was implanted on the gastric serosa in an anesthetized pig. Wireless pacing was performed at transmitter-to-receiver distances up to 20 mm, frequency of 0.05 Hz, and pulse width of 400 ms. Electrogastrogram (EGG) recordings using cutaneous and serosal electrode arrays were analyzed to compute spectral and spatial statistical parameters associated with the slow wave. RESULTS: Our data demonstrated evident change in EGG signal patterns upon initiation of pacing. A buffer period was noted before a pattern of entrainment appeared with consistent and low variability in slow wave direction. A spectral power increase in the EGG frequency band during entrainment also suggested that pacing increased strength of the slow wave. CONCLUSION: Our preliminary in vivo study using wireless pacing and concurrent EGG recording established the foundations for a minimally invasive approach to understand and optimize the effect of pacing on gastric motor activity as a means to treat conditions of gastric dysmotility.

Building a Simple and Versatile Illumination System for Optogenetic Experiments.

Controlling biological processes using light has increased the accuracy and speed with which researchers can manipulate many biological processes. Optical control allows for an unprecedented ability to dissect function and holds the potential for enabling novel genetic therapies. However, optogenetic experiments require adequate light sources with spatial, temporal, or intensity control, often a bottleneck for researchers. Here we detail how to build a low-cost and versatile LED illumination system that is easily customizable for different available optogenetic tools. This system is configurable for manual or computer control with adjustable LED intensity. We provide an illustrated step-by-step guide for building the circuit, making it computer-controlled, and constructing the LEDs. To facilitate the assembly of this device, we also discuss some basic soldering techniques and explain the circuitry used to control the LEDs. Using our open-source user interface, users can automate precise timing and pulsing of light on a personal computer (PC) or an inexpensive tablet. This automation makes the system useful for experiments that use LEDs to control genes, signaling pathways, and other cellular activities that span large time scales. For this protocol, no prior expertise in electronics is required to build all the parts needed or to use the illumination system to perform optogenetic experiments.

Interoceptive insular cortex participates in sensory processing of gastrointestinal malaise and associated behaviors.

The insular cortex plays a central role in the perception and regulation of bodily needs and emotions. Its modular arrangement, corresponding with different sensory modalities, denotes a complex organization, and reveals it to be a hub that is able to coordinate autonomic and behavioral responses to many types of stimuli. Yet, little is known about the dynamics of its electrical activity at the neuronal level. We recorded single neurons in behaving rats from the posterior insula cortex (pIC), a subdivision considered as a primary interoceptive cortex, during gastrointestinal (GI) malaise, a state akin to the emotion of disgust in humans. We found that a large proportion of pIC neurons were modulated during the rodent compensatory behaviors of lying on belly (LOB) and Pica. Furthermore, we demonstrated that LOB was correlated with low-frequency oscillations in the field potentials and spikes at the theta (8 Hz) band, and that low-frequency electrical microstimulation of pIC elicited LOB and Pica. These findings demonstrate that pIC neurons play a critical role in GI malaise perception, and that the pIC influences the expression of behaviors that alleviate GI malaise. Our model provides an accessible approach at the single cell level to study innate emotional behaviors, currently elusive in humans.

Individual Differences in Amphetamine Locomotor Sensitization are Accompanied with Changes in Dopamine Release and Firing Pattern in the Dorsolateral Striatum of Rats.

Not all the people that consume drugs of abuse develop addiction. In this sense, just a percentage of rats express locomotor sensitization after repeated psychostimulant exposure. Neurochemical evidence has shown that locomotor sensitization is associated with changes in dorsolateral striatum (DLS) activity. However, it is unknown if individual differences observed in locomotor sensitization are related to differential neuro-adaptations in DLS activity. In this study, we measured basal dopamine (DA) levels and single unit activity in the DLS of anesthetized rats, after repeated amphetamine (AMPH) administration. Rats were treated with AMPH 1.0 mg/kg ip or saline ip for 5 days. Following 5 days of withdrawal, a challenge dose of AMPH 1.0 mg/kg ip was injected. In-vivo microdialysis experiments and single unit recording were carried out twenty-four hours after the last AMPH injection. Sensitized rats showed increased basal DA levels and baseline firing rate of medium spiny neurons (MSNs) compared to non-sensitized rats. The local variation index (Lv) was used to measure the firing pattern of MSNs. In saline rats, a bursty firing pattern was observed in MSNs. A decrease in MSNs baseline Lv accompanies the expression of AMPH locomotor sensitization. Moreover, a decrease in Lv after an acute AMPH 1.0 mg/kg injection was only observed in saline and sensitized rats. Our results show individual differences in DLS basal DA levels and firing pattern after repeated AMPH administration, suggesting that an hyperfunction of nigrostriatal pathway, accompanied by a decrease in DLS MSNs firing irregularity underlies the expression of AMPH locomotor sensitization.

Impact of Stress on Gamma Oscillations in the Rat Nucleus Accumbens During Spontaneous Social Interaction.

Alteration in social behavior is one of the most debilitating symptoms of major depression, a stress related mental illness. Social behavior is modulated by the reward system, and gamma oscillations in the nucleus accumbens (NAc) seem to be associated with reward processing. In this scenario, the role of gamma oscillations in depression remains unknown. We hypothesized that gamma oscillations in the rat NAc are sensitive to the effects of social distress. One group of male Sprague-Dawley rats were exposed to chronic social defeat stress (CSDS) while the other group was left undisturbed (control group). Afterward, a microelectrode array was implanted in the NAc of all animals. Local field potential (LFP) activity was acquired using a wireless recording system. Each implanted rat was placed in an open field chamber for a non-social interaction condition, followed by introducing another unfamiliar rat, creating a social interaction condition, where the implanted rat interacted freely and continuously with the unfamiliar conspecific in a natural-like manner (see Supplementary Videos). We found that the high-gamma band power in the NAc of non-stressed rats was higher during the social interaction compared to a non-social interaction condition. Conversely, we did not find significant differences at this level in the stressed rats when comparing the social interaction- and non-social interaction condition. These findings suggest that high-gamma oscillations in the NAc are involved in social behavior. Furthermore, alterations at this level could be an electrophysiological signature of the effect of chronic social stress on reward processing.