Electrophysiology publications

The primate brain is specialized for social visual perception. Previous work indicates that recognition draws upon an internal comparison between a viewed face and an internally stored average face. Here we demonstrate that this comparison takes the form of a delayed, dynamic suppression of face averageness among single neurons. In three macaque face patches, spiking responses to low-identity morphed faces met with a synchronous attenuation starting approximately 200 ms after onset. Analysis showed that a late-emerging V-shaped identity tuning was sometimes superimposed on linear ramp tuning. This pattern could not be ascribed to repetition suppression within a given session. The results indicate that the brain’s analysis of faces is enhanced through predictive normalization of identity, which increases sensitivity among face-selective neurons to distinctive facial features known to drive recognition.

The functional organization of human auditory cortex can be probed by characterizing responses to various classes of sound at different anatomical locations. Along with histological studies this approach has revealed a primary field in posteromedial Heschl's gyrus (HG) with pronounced induced high-frequency (70–150 Hz) activity and short-latency responses that phase-lock to rapid transient sounds. Low-frequency neural oscillations are also relevant to stimulus processing and information flow, however, their distribution within auditory cortex has not been established. Alpha activity (7–14 Hz) in particular has been associated with processes that may differentially engage earlier versus later levels of the cortical hierarchy, including functional inhibition and the communication of sensory predictions. These theories derive largely from the study of occipitoparietal sources readily detectable in scalp electroencephalography. To characterize the anatomical basis and functional significance of less accessible temporal-lobe alpha activity we analyzed responses to sentences in seven human adults (4 female) with epilepsy who had been implanted with electrodes in superior temporal cortex. In contrast to primary cortex in posteromedial HG, a non-primary field in anterolateral HG was characterized by high spontaneous alpha activity that was strongly suppressed during auditory stimulation. Alpha-power suppression decreased with distance from anterolateral HG throughout superior temporal cortex, and was more pronounced for clear compared to degraded speech. This suppression could not be accounted for solely by a change in the slope of the power spectrum. The differential manifestation and stimulus-sensitivity of alpha oscillations across auditory fields should be accounted for in theories of their generation and function. SIGNIFICANCE STATEMENT To understand how auditory cortex is organized in support of perception, we recorded from patients implanted with electrodes for clinical reasons. This allowed measurement of activity in brain regions at different levels of sensory processing. Oscillations in the alpha range (7–14 Hz) have been associated with functions including sensory prediction and inhibition of regions handling irrelevant information, but their distribution within auditory cortex is not known. A key finding was that these oscillations dominated in one particular non-primary field, anterolateral Heschl's gyrus, and were suppressed when subjects listened to sentences. These results build on our knowledge of the functional organization of auditory cortex and provide anatomical constraints on theories of the generation and function of alpha oscillations.

Mammalian sleep is characterized by dramatic changes in neuronal activity, and waking neuronal activity is thought to increase sleep need. Changes in other brain cells (glia) across the natural sleep-wake cycle and their role in sleep regulation are comparatively unexplored. We show that sleep is also accompanied by large changes in astroglial activity as measured by intracellular calcium concentrations in unanesthetized mice. These changes in calcium vary across different vigilance states and are most pronounced in distal astroglial processes. We find that reducing intracellular calcium in astrocytes impaired the homeostatic response to sleep deprivation. Thus, astroglial calcium changes dynamically across vigilance states and is a component of the sleep homeostat. One Sentence Summary Astroglial calcium concentrations vary with sleep and wake, change after sleep deprivation, and mediate sleep need.

Objective: Reanimation of muscles paralyzed by disease states such as spinal cord injury remains a highly sought therapeutic goal of neuroprosthetic research. Optogenetic stimulation of peripheral motor nerves expressing light-sensitive opsins is a promising approach to muscle reanimation that may overcome several drawbacks of traditional methods such as functional electrical stimulation (FES). However, the utility of these methods has only been demonstrated in rodents to date, while translation to clinical practice will likely first require demonstration and refinement of these gene therapy techniques in non-human primates. Approach: Three rhesus macaques were injected intramuscularly with either one or both of two optogenetic constructs (AAV6-hSyn-ChR2-eYFP and/or AAV6-hSyn-Chronos-eYFP) to transduce opsin expression in the corresponding nerves. Neuromuscular junctions were targeted for virus delivery using an electrical stimulating injection technique. Functional opsin expression was periodically evaluated up to 13 weeks post-injection by optically stimulating targeted nerves with a 472 nm fiber-coupled laser while recording electromyographic (EMG) responses. Main Results: One monkey demonstrated functional expression of ChR2 at 8 weeks post-injection in each of two injected muscles, while the second monkey briefly exhibited contractions coupled to optical stimulation in a muscle injected with the Chronos construct at 10 weeks. A third monkey injected only in one muscle with the ChR2 construct showed strong optically coupled contractions at 5 ½ weeks which then disappeared by 9 weeks. EMG responses to optical stimulation of ChR2-transduced nerves demonstrated graded recruitment relative to both stimulus pulse-width and light intensity, and followed stimulus trains up to 16 Hz. In addition, the EMG response to prolonged stimulation showed delayed fatigue over several minutes. Significance: These results demonstrate the feasibility of viral transduction of peripheral motor nerves for functional optical stimulation of motor activity in non-human primates, a variable timeline of opsin expression in a animal model closer to humans, and fundamental EMG response characteristics to optical nerve stimulation. Together, they represent an important step in translating these optogenetic techniques as a clinically viable gene therapy.

Auditory cortex is required for sound localisation, but how neural firing in auditory cortex underlies our perception of sound sources in space remains unclear. Specifically, whether neurons in auditory cortex represent spatial cues or an integrated representation of auditory space across cues is not known. Here, we measured the spatial receptive fields of neurons in primary auditory cortex (A1) while ferrets performed a relative localisation task. Manipulating the availability of binaural and spectral localisation cues had little impact on ferrets’ performance, or on neural spatial tuning. A subpopulation of neurons encoded spatial position consistently across localisation cue type. Furthermore, neural firing pattern decoders outperformed two-channel model decoders using population activity. Together, these observations suggest that A1 encodes the location of sound sources, as opposed to spatial cue values.

Local field potential (LFP) oscillations are primarily shaped by the superposition of postsynaptic currents. Hippocampal LFP oscillations in the 25- to 50-Hz range (“slow γ”) are proposed to support memory retrieval independent of other frequencies. However, θ harmonics extend up to 48 Hz, necessitating a study to determine whether these oscillations are fundamentally the same. We compared the spectral analysis methods of wavelet, ensemble empirical-mode decomposition (EEMD), and Fourier transform. EEMD, as previously applied, failed to account for the θ harmonics. Depending on analytical parameters selected, wavelet may convolve over high-order θ harmonics due to the variable time-frequency atoms, creating the appearance of a broad 25- to 50-Hz rhythm. As an illustration of this issue, wavelet and EEMD depicted slow γ in a synthetic dataset that only contained θ and its harmonics. Oscillatory transience cannot explain the difference in approaches as Fourier decomposition identifies ripples triggered to epochs of high-power, 120- to 250-Hz events. When Fourier is applied to high power, 25- to 50-Hz events, only θ harmonics are resolved. This analysis challenges the identification of the slow γ rhythm as a unique fundamental hippocampal oscillation. While there may be instances in which slow γ is present in the rat hippocampus, the analysis presented here shows that unless care is exerted in the application of EEMD and wavelet techniques, the results may be misleading, in this case misrepresenting θ harmonics. Moreover, it is necessary to reconsider the characteristics that define a fundamental hippocampal oscillation as well as theories based on multiple independent γ bands.

Tactile working memory engages a broad network of cortical regions in primates. To assess whether the conclusions drawn from primates apply to rodents, we examined the vibrissal primary somatosensory cortex (vS1) and the prelimbic cortex (PL) in a delayed comparison task. Rats compared the speeds of two vibrissal vibrations, stimulus1 and stimulus2, separated by a delay of 2 s. Neuronal firing rates in vS1 and PL encode both stimuli in real time. Across the delay, the stimulus1 representation declines more precipitously in vS1 than in PL. Theta-band local field potential (LFP) coherence between vS1 and PL peaks at trial onset and remains elevated during the interstimulus interval; simultaneously, vS1 spikes become phase locked to PL LFP. Phase locking is stronger on correct (versus error) trials. Tactile working memory in rats appears to be mediated by a posterior (vS1) to anterior (PL) flow of information, with performance facilitated through coherent LFP oscillation.

Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed of experiments designed to test the chronic effects of target inhibition in epilepsy models. We developed a novel in vitro screening platform based on microwire recordings from an organotypic hippocampal culture model of acquired epilepsy. This platform enables the direct, parallel determination of the effects of compounds on spontaneous epileptiform activity. The platform also enables repeated recordings from the same culture over two-week long experiments. We screened 45 kinase inhibitors and quantified their effects on seizure duration, the frequency of paroxysmal activity, and electrographic load. We identified several inhibitors with previously unknown antiepileptic properties. We also used kinase inhibition profile cross-referencing to identify kinases that are inhibited by seizure-suppressing compounds, but not by compounds that had no effect on seizures.

Throughout the past decade, silicon-based neural probes have become a driving force in neural engineering. Such probes comprise sophisticated, integrated CMOS electronics which provide a large number of recording sites along slender probe shanks. Using such neural probes in a chronic setting often requires them to be mechanically anchored with respect to the skull. However, any relative motion between brain and implant causes recording instabilities and tissue responses such as glial scarring, thereby shielding recordable neurons from the recording sites integrated on the probe and thus decreasing the signal quality. In the current work, we present a comparison of results obtained using mechanically fixed and floating silicon neural probes chronically implanted into the cortex of a non-human primate. We demonstrate that the neural signal quality estimated by the quality of the spiking and local field potential (LFP) recordings over time is initially superior for the floating probe compared to the fixed device. Nonetheless, the skull-fixed probe also allowed long-term recording of multi-unit activity (MUA) and low frequency signals over several months, especially once pulsations of the brain were properly controlled.

Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term, the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a temporal framework for the creation of both the short-term and long-term changes in cerebellar output.

The accuracy of the neural code depends on the relative embedding of signal and noise in the activity of neural populations. Despite a wealth of theoretical work on population codes, there are few empirical characterizations of the high-dimensional signal and noise subspaces. We studied the geometry of population codes in the rat auditory cortex across brain states along the activation-inactivation continuum, using sounds varying in difference and mean level across the ears. As the cortex becomes more activated, single-hemisphere populations go from preferring contralateral loud sounds to a symmetric preference across lateralizations and intensities, gain-modulation effectively disappears, and the signal and noise subspaces become approximately orthogonal to each other and to the direction corresponding to global activity modulations. Level-invariant decoding of sound lateralization also becomes possible in the active state. Our results provide an empirical foundation for the geometry and state-dependence of cortical population codes.

In Parkinson's disease, the degeneration of the midbrain dopaminergic neurons is consistently associated with modified metabolic activity in the cerebellum. Here we examined the functional reorganization taking place in the cerebello-cerebral circuit in a murine model of Parkinson's disease with 6-OHDA lesion of midbrain dopaminergic neurons. Cerebellar optogenetic stimulations evoked similar movements in control and lesioned mice, suggesting a normal coupling of cerebellum to the motor effectors after the lesion. In freely moving animals, the firing rate in the primary motor cortex was decreased after the lesion, while cerebellar nuclei neurons showed an increased firing rate. This increase may result from reduced inhibitory Purkinje cells inputs, since a population of slow and irregular Purkinje cells was observed in the cerebellar hemispheres of lesioned animals. Moreover, cerebellar stimulations generated smaller electrocortical responses in the motor cortex of lesioned animals suggesting a weaker cerebello-cerebral coupling. Overall these results indicate the presence of functional changes in the cerebello-cerebral circuit, but their ability to correct cortical dysfunction may be limited due to functional uncoupling between the cerebellum and cerebral cortex.

Processing incentive and drive is essential for control of goal-directed behavior. The limbic part of the basal ganglia has been emphasized in these processes, yet the exact neuronal mechanism has remained elusive. In this study, we examined the neuronal activity of the ventral pallidum (VP) and its upstream area, the rostromedial caudate (rmCD), while two male macaque monkeys performed an instrumental lever release task in which a visual cue indicated the forthcoming reward size. We found that the activity of some neurons in VP and rmCD reflected the expected reward size transiently following the cue. Reward size coding appeared earlier and stronger in VP than in rmCD. We also found that the activity in these areas was modulated by the satiation level of monkeys, which also occurred more frequently in VP than in rmCD. The information regarding reward size and satiation level was independently signaled in the neuronal populations of these areas. The data thus highlighted the neuronal coding of key variables for goal-directed behavior in VP. Furthermore, pharmacological inactivation of VP induced more severe deficit of goal-directed behavior than inactivation of rmCD, which was indicated by abnormal error repetition and diminished satiation effect on the performance. These results suggest that VP encodes incentive value and internal drive and plays a pivotal role in the control of motivation to promote goal-directed behavior. SIGNIFICANCE STATEMENT The limbic part of the basal ganglia has been implicated in the motivational control of goal-directed action. Here, we investigated how the ventral pallidum (VP) and the rostromedial caudate (rmCD) encode incentive value and internal drive and control goal-directed behavior. Neuronal recording and subsequent pharmacological inactivation revealed that VP had stronger coding of reward size and satiation level than rmCD. Reward size and satiation level were independently encoded in the neuronal population of these areas. Furthermore, VP inactivation impaired goal-directed behavior more severely than rmCD inactivation. These results highlight the central role of VP in the motivational control of goal-directed action.

Mesoscale cortical activity can be defined as the organization of activity of large neuron populations into collective action, forming time-dependent patterns such as traveling waves. Although collective action may play an important role in the cross-scale integration of brain activity and in the emergence of cognitive behavior, a comprehensive formulation of the laws governing its dynamics is still lacking. Because collective action processes are macroscopic with respect to neuronal activity, these processes cannot be described directly with methods and models developed for the microscale (individual neurons).To identify the characteristic features of mesoscopic dynamics, and to lay the foundations for a theoretical description of mesoscopic activity in the hippocampus, we conduct a comprehensive examination of observational data of hippocampal local field potential (LFP) recordings. We use the strong correlation between rat running-speed and the LFP power to parameterize the energy input into the hippocampus, and show that both the power and non-linearity of collective action (e.g., theta and gamma rhythms) increase with increased speed. Our results show that collective-action dynamics are stochastic (the precise state of a single neuron is irrelevant), weakly non-linear, and weakly dissipative. These are the principles of the theory of weak turbulence. Therefore, we propose weak turbulence a theoretical framework for the description of mesoscopic activity in the hippocampus. The weak turbulence framework provides a complete description of the cross-scale energy exchange (the energy cascade). It uncovers the mechanism governing major features of LFP spectra and bispectra, such as the physical meaning of the exponent α of power-law LFP spectra (e.g., f -α, where f is the frequency), the strengthening of theta-gamma coupling with energy input into the hippocampus, as well as specific phase lags associated with their interaction. Remarkably, the weak turbulence framework is consistent with the theory of self organized criticality, which provides a simple explanation for the existence of the power-law background spectrum. Together with self-organized criticality, weak turbulence could provide a unifying approach to modeling the dynamics of mesoscopic activity.

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading behavioral responses. Neuronal and behavioral changes did not occur in two cell-specific mouse models with impaired long-term potentiation at their parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.

Glassy carbon (GC) has high potential to serve as a biomaterial in neural applications because it is biocompatible, electrochemically inert and can be incorporated in polyimide-based implantable devices. Miniaturization and applicability of GC is, however, thought to be partially limited by its electrical conductivity. For this study, ultra-conformable polyimide-based electrocorticography (ECoG) devices with different-diameter GC electrodes were fabricated and tested in vitro and in rat models. For achieving conformability to the rat brain, polyimide was patterned in a finger-like shape and its thickness was set to 8 µm. To investigate different electrode sizes, each ECoG device was assigned electrodes with diameters of 50, 100, 200 and 300 µm. They were electrochemically characterized and subjected to 10 million biphasic pulses—for achieving a steady-state—and to X-ray photoelectron spectroscopy, for examining their elemental composition. The electrodes were then implanted epidurally to evaluate the ability of each diameter to detect neural activity. Results show that their performance at low frequencies (up to 300 Hz) depends on the distance from the signal source rather than on the electrode diameter, while at high frequencies (above 200 Hz) small electrodes have higher background noises than large ones, unless they are coated with poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS).

Perceptual constancy requires neural representations that are selective for object identity, but also tolerant across identity-preserving transformations. How such representations arise in the brain and support perception remains unclear. Here, we study tolerant representation of sound identity in the auditory system by recording neural activity in auditory cortex of ferrets during perceptual constancy. Ferrets generalize vowel identity across variations in fundamental frequency, sound level and location, while neurons represent sound identity robustly across acoustic variations. Stimulus features are encoded with distinct time-courses in all conditions, however encoding of sound identity is delayed when animals fail to generalize and during passive listening. Neurons also encode information about task-irrelevant sound features, as well as animals’ choices and accuracy, while population decoding out-performs animals’ behavior. Our results show that during perceptual constancy, sound identity is represented robustly in auditory cortex across widely varying conditions, and behavioral generalization requires conserved timing of identity information.

Multisensory integration is a process by which signals from different sensory modalities are combined to facilitate detection and localization of external events. One substrate for multisensory integration is the midbrain superior colliculus (SC) which plays an important role in orienting behavior. In rodent SC, visual and somatosensory (whisker) representations are in approximate registration, but whether and how these signals interact is unclear. We measured spiking activity in SC of anesthetized hooded rats, during presentation of visual- and whisker stimuli that were tested simultaneously or in isolation. Visual responses were found in all layers, but were primarily located in superficial layers. Whisker responsive sites were primarily found in intermediate layers. In single- and multi-unit recording sites, spiking activity was usually only sensitive to one modality, when stimuli were presented in isolation. By contrast, we observed robust and primarily suppressive interactions when stimuli were presented simultaneously to both modalities. We conclude that while visual and whisker representations in SC of rat are partially overlapping, there is limited excitatory convergence onto individual sites. Multimodal integration may instead rely on suppressive interactions between modalities.

Electrical nerve recording and stimulation technologies are critically needed to monitor and modulate nerve activity to treat a variety of neurological diseases. However, current neuromodulation technologies presented in the literature or commercially available products cannot support simultaneous recording and stimulation on the same nerve. To solve this problem, a new bidirectional neuromodulation system-on-chip (SoC) is proposed in this paper, which includes a frequency-shaping neural recorder and a fully integrated neural stimulator with charge balancing capability. In addition, auxiliary circuits consisting of power management and data transmission circuits are designed to provide the necessary power supply for the SoC and the bidirectional data communication between the SoC and an external computer via a universal serial bus (USB) interface, respectively. To achieve sufficient low input noise for sensing nerve activity at a sub-10 μ V range, several noise reduction techniques are developed in the neural recorder. The designed SoC was fabricated in a 0.18 μ m high-voltage Bipolar CMOS DMOS (BCD) process technology that was described in a previous publication and it has been recently tested in animal experiments that demonstrate the proposed SoC is capable of achieving reliable and simultaneous electrical stimulation and recording on the same nerve.