LFP publications

The subthalamic nucleus is a key site controlling motor function in humans. Deep brain stimulation of the subthalamic nucleus can improve movements in patients with Parkinson's disease; however, for unclear reasons, it can also have cognitive effects. Here, we show that the human subthalamic nucleus is monosynaptically connected with cognitive brain areas such as the prefrontal cortex. Single neurons and field potentials in the subthalamic nucleus are modulated during cognitive processing and are coherent with 4-Hz oscillations in medial prefrontal cortex. These data predict that low-frequency deep brain stimulation may alleviate cognitive deficits in Parkinson's disease patients. In line with this idea, we found that novel 4-Hz deep brain stimulation of the subthalamic nucleus improved cognitive performance. These data support a role for the human hyperdirect pathway in cognitive control, which could have relevance for brain-stimulation therapies aimed at cognitive symptoms of human brain disease.awx300media15660002226001.

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA A agonist Gaboxadol. We find a transitional sleep stage associated with a 7–10 Hz oscillation in the central brain during spontaneous sleep. Oscillatory activity is also evident when we acutely activate sleep-promoting neurons in the dorsal fan-shaped body (dFB) of Drosophila . In contrast, sleep following Gaboxadol exposure is characterized by low-amplitude LFPs, during which dFB-induced effects are suppressed. Sleep in flies thus appears to involve at least two distinct stages: increased oscillatory activity, particularly during sleep induction, followed by desynchronized or decreased brain activity.

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat.

Oscillatory neural activity in different frequency bands and phase-amplitude coupling (PAC) are hypothesized to be biomarkers of Parkinson’s disease (PD) that could explain dysfunction in the motor circuit and be used for closed-loop deep brain stimulation (DBS). How these putative biomarkers change from the normal to the parkinsonian state across nodes in the motor circuit and within the same subject, however, remains unknown. In this study, we characterized how parkinsonism and vigilance altered oscillatory activity and PAC within the primary motor cortex (M1), subthalamic nucleus (STN), and globus pallidus (GP) in two nonhuman primates. Static and dynamic analyses of local field potential (LFP) recordings indicate that 1) after induction of parkinsonism using the neurotoxin MPTP, low-frequency power (8–30 Hz) increased in the STN and GP in both subjects, but increased in M1 in only one subject; 2) high-frequency power (~330 Hz) was present in the STN in both normal subjects but absent in the parkinsonian condition; 3) elevated PAC measurements emerged in the parkinsonian condition in both animals, but in different sites in each animal (M1 in one subject and GPe in the other); and 4) the state of vigilance significantly impacted how oscillatory activity and PAC were expressed in the motor circuit. These results support the hypothesis that changes in low- and high-frequency oscillatory activity and PAC are features of parkinsonian pathophysiology and provide evidence that closed-loop DBS systems based on these biomarkers may require subject-specific configurations as well as adaptation to changes in vigilance. NEW & NOTEWORTHY Chronically implanted electrodes were used to record neural activity across multiple nodes in the basal ganglia-thalamocortical circuit simultaneously in a nonhuman primate model of Parkinson’s disease, enabling within-subject comparisons of electrophysiological biomarkers between normal and parkinsonian conditions and different vigilance states. This study improves our understanding of the role of oscillatory activity and phase-amplitude coupling in the pathophysiology of Parkinson’s disease and supports the development of more effective DBS therapies based on pathophysiological biomarkers.

Rodents lick to consume fluids. The reward value of ingested fluids is likely to be encoded by neuronal activity entrained to the lick cycle. Here, we investigated relationships between licking and reward signaling by the medial frontal cortex (MFC), a key cortical region for reward-guided learning and decision-making. Multielectrode recordings of spike activity and field potentials were made in male rats as they performed an incentive contrast licking task. Rats received access to higher- and lower-value sucrose rewards over alternating 30 s periods. They learned to lick persistently when higher-value rewards were available and to suppress licking when lower-value rewards were available. Spectral analysis of spikes and fields revealed evidence for reward value being encoded by the strength of phase-locking of a 6–12 Hz theta rhythm to the rats' lick cycle. Recordings during the initial acquisition of the task found that the strength of phase-locking to the lick cycle was strengthened with experience. A modification of the task, with a temporal gap of 2 s added between reward deliveries, found that the rhythmic signals persisted during periods of dry licking, a finding that suggests the MFC encodes either the value of the currently available reward or the vigor with which rats act to consume it. Finally, we found that reversible inactivations of the MFC in the opposite hemisphere eliminated the encoding of reward information. Together, our findings establish that a 6–12 Hz theta rhythm, generated by the rodent MFC, is synchronized to rewarded actions. SIGNIFICANCE STATEMENT The cellular and behavioral mechanisms of reward signaling by the medial frontal cortex (MFC) have not been resolved. We report evidence for a 6–12 Hz theta rhythm that is generated by the MFC and synchronized with ongoing consummatory actions. Previous studies of MFC reward signaling have inferred value coding upon temporally sustained activity during the period of reward consumption. Our findings suggest that MFC activity is temporally sustained due to the consumption of the rewarding fluids, and not necessarily the abstract properties of the rewarding fluid. Two other major findings were that the MFC reward signals persist beyond the period of fluid delivery and are generated by neurons within the MFC.

Following learning, increased coupling between spindle oscillations in the medial prefrontal cortex (mPFC) and ripple oscillations in the hippocampus is thought to underlie memory consolidation. However, whether learning-induced increases in ripple-spindle coupling are necessary for successful memory consolidation has not been tested directly. In order to decouple ripple-spindle oscillations, here we chemogenetically inhibited parvalbumin-positive (PV+) interneurons, since their activity is important for regulating the timing of spiking activity during oscillations. We found that contextual fear conditioning increased ripple-spindle coupling in mice. However, inhibition of PV+ cells in either CA1 or mPFC eliminated this learning-induced increase in ripple-spindle coupling without affecting ripple or spindle incidence. Consistent with the hypothesized importance of ripple-spindle coupling in memory consolidation, post-training inhibition of PV+ cells disrupted contextual fear memory consolidation. These results indicate that successful memory consolidation requires coherent hippocampal-neocortical communication mediated by PV+ cells.

We detect objects more readily if they differ from their surroundings in motion, color, or texture. This increased saliency is thought to be related to increased responses in the visual cortex. The superior colliculus is another brain area involved in vision and especially in directing gaze and attention. In this study, we show that differences in texture orientation also increase responses in the superficial layers of the superior colliculus that receive retinal and cortical input. We found that gratings evoke more neural response when surrounded by orthogonal gratings than when surrounded by parallel gratings, particularly in the awake mouse. This pop-out is not originating from the visual cortex, and silencing visual cortex increased the relative difference in response. A model shows that this can result from retinotopically matched excitation from visual cortex to the superior colliculus. We suggest that the perceptual saliency of a stimulus differing from its surround in a low-level feature like grating orientation could depend on visual processing in the superior colliculus.

The basal forebrain (BF) has long been implicated in attention, learning and memory, and recent studies have established a causal relationship between artificial BF activation and arousal. However, neural ensemble dynamics in the BF still remains unclear. Here, recording neural population activity in the BF and comparing it with simultaneously recorded cortical population under both anesthetized and unanesthetized conditions, we investigate the difference in the structure of spontaneous population activity between the BF and the auditory cortex (AC) in mice. The AC neuronal population show a skewed spike rate distribution, a higher proportion of short (≤80 ms) inter-spike intervals (ISIs) and a rich repertoire of rhythmic firing across frequencies. Although the distribution of spontaneous firing rate in the BF is also skewed, a proportion of short ISIs can be explained by a Poisson model at short time scales (≤20 ms) and spike count correlations are lower compared to AC cells, with optogenetically identified cholinergic cell pairs showing exceptionally higher correlations. Furthermore, a smaller fraction of BF neurons shows spike-field entrainment across frequencies: a subset of BF neurons fire rhythmically at slow (≤6 Hz) frequencies, with varied phase preferences to ongoing field potentials, in contrast to a consistent phase preference of AC populations. Firing of these slow rhythmic BF cells is correlated to a greater degree than other rhythmic BF cell pairs. Overall, the fundamental difference in the structure of population activity between the AC and BF is their temporal coordination, in particular their operational timescales. These results suggest that BF neurons slowly modulate downstream populations whereas cortical circuits transmit signals on multiple timescales. Thus, the characterization of the neural ensemble dynamics in the BF provides further insight into the neural mechanisms, by which brain states are regulated.

The sensitivity of ocular dominance to regulation by monocular deprivation is the canonical model of plasticity confined to a critical period. However, we have previously shown that visual deprivation through dark exposure (DE) reactivates critical period plasticity in adults. Previous work assumed that the elimination of visual input was sufficient to enhance plasticity in the adult mouse visual cortex. In contrast, here we show that light reintroduction (LRx) after DE is responsible for the reactivation of plasticity. LRx triggers degradation of the ECM, which is blocked by pharmacological inhibition or genetic ablation of matrix metalloproteinase-9 (MMP-9). LRx induces an increase in MMP-9 activity that is perisynaptic and enriched at thalamo-cortical synapses. The reactivation of plasticity by LRx is absent in Mmp9−/− mice, and is rescued by hyaluronidase, an enzyme that degrades core ECM components. Thus, the LRx-induced increase in MMP-9 removes constraints on structural and functional plasticity in the mature cortex.

Extracellular field potentials (EFPs) are an important source of information in neuroscience, but their physiological basis is in many cases still a matter of debate. Axonal sources are typically discounted in modeling and data analysis because their contributions are assumed to be negligible. Here, we established experimentally and theoretically that contributions of axons to EFPs can be significant. Modeling action potentials propagating along axons, we showed that EFPs were prominent in the presence of terminal zones where axons branch and terminate in close succession, as found in many brain regions. Our models predicted a dipolar far field and a polarity reversal at the center of the terminal zone. We confirmed these predictions using EFPs from the barn owl auditory brainstem where we recorded in nucleus laminaris using a multielectrode array. These results demonstrate that axonal terminal zones can produce EFPs with considerable amplitude and spatial reach.

Prolonged low-level noise exposure alters loudness perception in humans, presumably by decreasing the gain of the central auditory system. Here we test the central gain hypothesis by measuring the acute and chronic physiologic changes at the level of the cochlea and inferior colliculus (IC) after a 75-dB SPL, 10-20-kHz noise exposure for 5weeks. The compound action potential (CAP) and summating potential (SP) were used to assess the functional status of the cochlea and 16 channel electrodes were used to measure the local field potentials (LFP) and multi-unit spike discharge rates (SDR) from the IC immediately after and one-week post-exposure. Measurements obtained immediately post-exposure demonstrated a significant reduction in supra-threshold CAP amplitudes. In contrast to the periphery, sound-evoked activity in the IC was enhanced in a frequency-dependent manner consistent with models of enhanced central gain. Surprisingly, one-week post-exposure supra-threshold responses from the cochlea had not only recovered, but were significantly larger than normal, and thresholds were significantly better than controls. Moreover, sound-evoked hyperactivity in the IC was sustained within the noise exposure frequency band but suppressed at higher frequencies. When response amplitudes representing the neural output of the cochlea and IC activity at one-week post exposure were compared with control animal responses, a central attenuation phenomenon becomes evident, which may play a key role in understanding why low-level noise can sometimes ameliorate tinnitus and hyperacusis percepts.

Closed-loop brain stimulation is a promising alternative to treat drug-resistant epilepsies. In contrast to optogenetic interventions, transcranial electrical stimulation (TES) does not require cellular modification of neurons to be effective, and it is less invasive compared to deep brain stimulation. Furthermore, on-demand TES of targeted brain regions allows the potential for normal function of these networks during interictal periods, a possibility that is eliminated by resective surgical treatment approaches. To further explore the translation of closed-loop TES for treatment of epilepsy, we show here for the first time that unsupervised closed-loop TES in rats can consistently interrupt seizures for 6 weeks and has the potential to control seizure activity up to 4 months (longest periods examined). On-demand TES significantly reduced the time spent in seizure and the individual seizure duration, although significantly higher seizure rate was observed during the treatment. The 6 week long stimulation had no residual adverse effects on the electrophysiologic characteristics of the brain after the termination of the treatment and did not induce glial remodelling in the brain. Our findings demonstrate the safety and effectiveness of minimally invasive, potentially lifelong TES treatment of epilepsy either alone or as a complement to drug treatments.

The most widespread measures of human brain activity are the blood-oxygen-level dependent (BOLD) signal and surface field potential. Prior studies report a variety of relationships between these signals. To develop an understanding of how to interpret these signals and the relationship between them, we developed a model of (a) neuronal population responses and (b) transformations from neuronal responses into the functional magnetic resonance imaging (fMRI) BOLD signal and electrocorticographic (ECoG) field potential. Rather than seeking a transformation between the two measures directly, this approach interprets each measure with respect to the underlying neuronal population responses. This model accounts for the relationship between BOLD and ECoG data from human visual cortex in V1, V2, and V3, with the model predictions and data matching in three ways: across stimuli, the BOLD amplitude and ECoG broadband power were positively correlated, the BOLD amplitude and alpha power (8-13 Hz) were negatively correlated, and the BOLD amplitude and narrowband gamma power (30-80 Hz) were uncorrelated. The two measures provide complementary information about human brain activity, and we infer that features of the field potential that are uncorrelated with BOLD arise largely from changes in synchrony, rather than level, of neuronal activity.

Behavioral and neurophysiological evidence suggests that the slow (≤1 Hz) oscillation (SO) during sleep plays a role in consolidating hippocampal (HIPP)‐dependent memories. The effects of the SO on HIPP activity have been studied in rodents and cats both during natural sleep and during anesthetic administration titrated to mimic sleep‐like slow rhythms. In this study, we sought to document these effects in primates. First, HIPP field potentials were recorded during ketamine‐dexmedetomidine sedation and during natural sleep in three rhesus macaques. Sedation produced regionally‐specific slow and gamma (∼40 Hz) oscillations with strong coupling between the SO phase and gamma amplitude. These same features were seen in slow‐wave sleep (SWS), but the coupling was weaker and the coupled gamma oscillation had a higher frequency (∼70 Hz) during SWS. Second, electrical stimuli were delivered to HIPP afferents in the parahippocampal gyrus (PHG) during sedation to assess the effects of sleep‐like SO on excitability. Gamma bursts after the peak of SO cycles corresponded to periods of increased gain of monosynaptic connections between the PHG and HIPP. However, the two PHG‐HIPP connectivity gains during sedation were both substantially lower than when the animal was awake. We conclude that the SO is correlated with rhythmic excitation and inhibition of the PHG‐HIPP network, modulating connectivity and gamma generators intrinsic to this network. Ketamine‐dexmedetomidine sedation produces a similar effect, but with a decreased contribution of the PHG to HIPP activity and gamma generation.

The spectral analysis of the spontaneous activity recorded with an electrode positioned near the round window of the guinea pig cochlea shows a broad energy peak between 800 and 1,000 Hz. This spontaneous electric activity is called round window noise or ensemble background activity. In guinea pigs, the proposed origin of this peak is the random sum of the extracellular field potentials generated by action potentials of auditory nerve neurons. In this study, we used a non-invasive method to record the tympanic electric noise (TEN) in humans by means of a tympanic wick electrode. We recorded a total of 24 volunteers, under silent conditions or in response to stimuli of different modalities, including auditory, vestibular, and motor activity. Our results show a reliable peak of spontaneous activity at ~1,000 Hz in all studied subjects. In addition, we found stimulus-driven responses with broad-band noise that in most subjects produced an increase in the magnitude of the energy band around 1,000 Hz (between 650 and 1,200 Hz). Our results with the vestibular stimulation were not conclusive, as we found responses with all caloric stimuli, including 37°C. No responses were observed with motor tasks, like eye movements or blinking. We demonstrate the feasibility of recording neural activity from the electric noise of the tympanic membrane with a non-invasive method. From our results, we suggest that the 1,000 Hz component of the TEN has a mixed origin including peripheral and central auditory pathways. This research opens up the possibility of future clinical non-invasive techniques for the functional study of auditory and vestibular nerves in humans.

Retinal neuromodulation is an emerging therapeutic approach to restore functional vision to those suffering retinal photoreceptor degeneration. The retina encodes visual information and transmits it to the brain. Replicating this retinal code through electrical stimulation is essential to improving the performance of visual prostheses. In doing so, the first step relies on precise neural recordings from visual centers that allow studying the response of these neurons to electrical stimulation of the retina. This paper demonstrates the feasibility of a rat model to conduct highly reliable electrophysiological studies in the field of retinal neuromodulation. A disc electrode, implanted in the retrobulbar space was used to stimulate the retina of Long-Evans rats. Buzsaki multi-electro arrays were inserted in the superior colliculus (SC) to record electrical activity propagated from the retinal ganglion cells (RGCs). Activation thresholds calculated from local field potentials (visual cortex) and from neural spikes (SC) were contrasted. Both values were comparable to those in humans and in other animal models, and were slightly higher when estimated from SC recordings. However, differences were not statistically significant.

Maturation of GABAergic circuits in primary visual cortex (V1) opens a critical period (CP), a developmental window of enhanced plasticity for visual functions. However, how inhibition promotes the plasticity remains unclear. Here, we investigated the developmental dynamics of auditory responses and audiovisual interactions in mouse V1. Modulation of V1 spiking activity by a transient sound was temporally dynamic with alternating enhancement and suppression phases. When paired with grating visual stimuli, sound-driven spike enhancement and suppression were weaker and stronger with preferred orientation than with non-preferred orientations, respectively, leading to impaired net orientation selectivity in V1 neurons. Strikingly, the net orientation selectivity was impervious to sound specifically during the CP due to equal total amounts of sound-driven spike enhancements and suppressions. This balance of spike modulations at the CP was achieved by the preferential maturation of sound-driven spike suppression. However, further maturation of sound-driven spike enhancement broke the balance after the CP. Spectral analysis of field potentials revealed the enhancement of a GABA-mediated sound-driven power suppression specifically at CP. Reduction of inhibition by 10-day dark-exposure or genetic deletion of GAD65 gene dampened sound-driven spike suppression in V1. Furthermore, acute suppression of either parvalbumin-expressing (PV) or somatostatinexpressing (SST) neurons suggested their early or late recruitments by sound, respectively. Our results point to the dampened net non-visual sensory influence as one of the functional roles of GABA circuit maturation during a developmental CP. The insensitivity of visual selectivity to sound during the CP may promote functional maturation of V1 as visual cortex.

Species differences in perception have been linked to divergence in gross neuroanatomical features of sensory pathways. The anatomical and physiological basis of evolutionary change in sensory processing at cellular and circuit levels, however, is poorly understood. Here, we show how specific changes to a sensory microcircuit are associated with the evolution of a novel perceptual ability. In mormyrid fishes, the ability to detect variation in electric communication signals is correlated with an enlargement of the midbrain exterolateral nucleus (EL), and a differentiation into separate anterior (ELa) and posterior (ELp) regions. We show that the same cell types and connectivity are found in both EL and ELa/ELp. The evolution of ELa/ELp, and the concomitant ability to detect signal variation, is associated with a lengthening of incoming hindbrain axons to form delay lines, allowing for fine temporal analysis of signals. The enlargement of this brain region is also likely due to an overall increase in cell numbers, which would allow for processing of a wider range of timing information.

Animal models have demonstrated that tinnitus is a pathology of dysfunctional excitability in the central auditory system, in particular in the dorsal cochlear nucleus (DCN) of the brainstem. We used a murine model and studied whether acoustic over-exposure leading to hearing loss and tinnitus, affects long-term potentiation (LTP) at DCN multisensory synapses. Whole cell and field potential recordings were used to study the effects on release probability and synaptic plasticity, respectively in brainstem slices. Shifts in hearing threshold were quantified by auditory brainstem recordings, and gap-induced prepulse inhibition of the acoustic startle reflex was used as an index for tinnitus. An increased release probability that saturated LTP and thereby induced metaplasticity at DCN multisensory synapses, was observed 4-5days following acoustic over-exposure. Perfusion of an NMDA receptor antagonist or decreasing extracellular calcium concentration, decreased the release probability and restored LTP following acoustic over-exposure. In vivo administration of magnesium-threonate following acoustic over-exposure restored LTP at DCN multisensory synapses, and reduced gap detection deficits observed four months following acoustic over-exposure. These observations suggest that consequences of noise-induced metaplasticity could underlie the gap detection deficits that follow acoustic over-exposure, and that early therapeutic intervention could target metaplasticity and alleviate tinnitus.

Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.