Electrophysiology publications

Electrocorticogram (ECoG) recordings of the 6-hydroxydopamine (6-OHDA)–lesioned parkinsonian rat have shown an increase in the power of cortical β-band (15–30 Hz) oscillations ipsilateral to the lesion. The power of these oscillations is decreased with dopamine agonist administration. Here, we demonstrate that stimulation of an electrode implanted in the subthalamic nucleus alters the power of cortical β and γ oscillations in 6-OHDA–lesioned animals. These alterations are dependent on stimulation frequency, charge, and amplitude/pulse width. Oscillations were significantly reduced during 200- and 350-Hz stimulation. A minimum charge of 4 nC was required to elicit a reduction in oscillation power. A number of amplitude and pulse width combinations that reached 4 nC were tested; it was found that only the combinations of 33 μA/120 μs and 65 μA/60 μs significantly reduced cortical oscillations. The reduction in β/γ oscillation power due to deep brain stimulation (DBS) was consistent with a significant reduction in the animals' rotational behavior, a typical symptom of parkinsonism in the rat. A significant shift from high β to low γ was observed in the peak frequencies of ECoG recordings while animals were at rest versus walking on a treadmill. However, DBS exhibited no differential effect on oscillations between these two states. EEG recordings from rodent models of DBS may provide surrogate information about the neural signatures of Parkinson's disease relative to the efficacy of DBS.

Responses of neural units in two areas of the medial auditory belt (middle medial area [MM] and rostral medial area [RM]) were tested with tones, noise bursts, monkey calls (MC), and environmental sounds (ES) in microelectrode recordings from two alert rhesus monkeys. For comparison, recordings were also performed from two core areas (primary auditory area [A1] and rostral area [R]) of the auditory cortex. All four fields showed cochleotopic organization, with best (center) frequency [BF(c)] gradients running in opposite directions in A1 and MM than in R and RM. The medial belt was characterized by a stronger preference for band-pass noise than for pure tones found medially to the core areas. Response latencies were shorter for the two more posterior (middle) areas MM and A1 than for the two rostral areas R and RM, reaching values as low as 6 ms for high BF(c) in MM and A1, and strongly depended on BF(c). The medial belt areas exhibited a higher selectivity to all stimuli, in particular to noise bursts, than the core areas. An increased selectivity to tones and noise bursts was also found in the anterior fields; the opposite was true for highly temporally modulated ES. Analysis of the structure of neural responses revealed that neurons were driven by low-level acoustic features in all fields. Thus medial belt areas RM and MM have to be considered early stages of auditory cortical processing. The anteroposterior difference in temporal processing indices suggests that R and RM may belong to a different hierarchical level or a different computational network than A1 and MM.

Auditory neuropathy is a hearing disorder characterized by normal function of outer hair cells, evidenced by intact cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), with absent or severely dys-synchronized auditory brainstem responses (ABRs). To determine if selective lesions of inner hair cells (IHCs) and auditory nerve fibers (ANFs) can account for these primary clinical features of auditory neuropathy, we measured physiological responses from chinchillas with large lesions of ANFs (about 85%) and IHCs (45% loss in the apical half of the cochlea; 73% in the basal half). Distortion product OAEs and CM potentials were significantly enhanced, whereas summating potentials and compound action potentials (CAPs) were significantly reduced. CAP threshold was elevated by 7.5dB, but response synchrony was well preserved down to threshold levels of stimulation. Similarly, ABR threshold was elevated by 5.6dB, but all waves were present and well synchronized down to threshold levels in all animals. Thus, large lesions of IHCs and ANFs reduced response amplitudes but did not abolish or severely dys-synchronize CAPs or ABRs. Pathologies other than or in addition to ANF and IHC loss are likely to account for the evoked potential dys-synchrony that is a clinical hallmark of auditory neuropathy in humans.

There are many different needs for intraoperative mapping in both rodent as well as human brain. Whether the goal of the procedure is for epileptic mapping, removal of cancerous tissue, mapping the motor and sensory cortices, or understanding the underlying neural networks within the brain, dense three-dimensional electrode arrays are necessary. In this study, we outlined and validated thicker silicon probe designs for use in intracortical mapping applications. Multiple shank and electrode site configurations were implanted successfully through rat dura as a model for human pia, and all devices maintained the electrical functionality necessary for electrophysiological mapping applications.

Three-dimensional electrode arrays have a variety of potential applications in the fields of both intracortical mapping as well as basic research studies designed to characterize and understand the physiology of the brain. While higher channels counts are desired in brain-machine interface applications, the ability to analyze synchronous data from multiple cortical locations, including various depths is pivotal to fully mapping the underlying neurophysiology of sensory cortices. Within this study, we present a proof of concept validation of a 3D probe technology consisting of 16 silicon shanks in a 4x4 grid arrangement with four electrode sites per shank. This 3D array has been implanted in a rat primary auditory cortex and electrophysiological data are presented showing the utility of electrode sites spanning multilateral cortical space as well as cortical depth.

Current research in motor neural prosthetics has focused primarily on issues related to the extraction of motor command signals from the brain (e.g. brain-machine interfaces) to direct the motion of prosthetic limbs. Patients using these types of systems could benefit from a somatosensory neural interface that conveys natural tactile and kinesthetic sensations for the prosthesis. Electrical microstimulation within the dorsal root ganglia (DRG) has been proposed as one method to accomplish this, yet little is known about the recruitment properties of electrical microstimulation in activating nerve fibers in this structure. Current-controlled microstimulation pulses in the range of 1-15 microA (200 micros, leading cathodic pulse) were delivered to the L7 DRG in four anesthetized cats using penetrating microelectrode arrays. Evoked responses and their corresponding conduction velocities (CVs) were measured in the sciatic nerve with a 5-pole nerve cuff electrode arranged as two adjacent tripoles. It was found that in 76% of the 69 electrodes tested, the stimulus threshold was less than or equal to 3 microA, with the lowest recorded threshold being 1.1 microA. The CVs of afferents recruited at threshold had a bimodal distribution with peaks at 70 m s(-1) and 85 m s(-1). In 53% of cases, the CV of the response at threshold was slower (i.e. smaller diameter fiber) than the CVs of responses observed at increasing stimulation amplitudes. In summary, we found that microstimulation applied through penetrating microelectrodes in the DRG provides selective recruitment of afferent fibers from a range of sensory modalities (as identified by CVs) at very low stimulation intensities. We conclude that the DRG may serve as an attractive location from which to introduce surrogate somatosensory feedback into the nervous system.

The need to sleep grows with the duration of wakefulness and dissipates with time spent asleep, a process called sleep homeostasis. What are the consequences of staying awake on brain cells, and why is sleep needed? Surprisingly, we do not know whether the firing of cortical neurons is affected by how long an animal has been awake or asleep. Here, we found that after sustained wakefulness cortical neurons fire at higher frequencies in all behavioral states. During early NREM sleep after sustained wakefulness, periods of population activity (ON) are short, frequent, and associated with synchronous firing, while periods of neuronal silence are long and frequent. After sustained sleep, firing rates and synchrony decrease, while the duration of ON periods increases. Changes in firing patterns in NREM sleep correlate with changes in slow-wave activity, a marker of sleep homeostasis. Thus, the systematic increase of firing during wakefulness is counterbalanced by staying asleep.

Hearing relies on Ca 2+ influx-triggered exocytosis in cochlear inner hair cells (IHCs). Here we studied the role of the Ca 2+ channel subunit Ca V β 2 in hearing. Of the Ca V β 1–4 mRNAs, IHCs predominantly contained Ca V β 2 . Hearing was severely impaired in mice lacking Ca V β 2 in extracardiac tissues ( Ca V β 2 −/− ). This involved deficits in cochlear amplification and sound encoding. Otoacoustic emissions were reduced or absent in Ca V β 2 −/− mice, which showed strongly elevated auditory thresholds in single neuron recordings and auditory brainstem response measurements. Ca V β 2 −/− IHCs showed greatly reduced exocytosis (by 68%). This was mostly attributable to a decreased number of membrane-standing Ca V 1.3 channels. Confocal Ca 2+ imaging revealed presynaptic Ca 2+ microdomains albeit with much lower amplitudes, indicating synaptic clustering of fewer Ca V 1.3 channels. The coupling of the remaining Ca 2+ influx to IHC exocytosis appeared unaffected. Extracellular recordings of sound-evoked spiking in the cochlear nucleus and auditory nerve revealed reduced spike rates in the Ca V β 2 −/− mice. Still, sizable onset and adapted spike rates were found during suprathreshold stimulation in Ca V β 2 −/− mice. This indicated that residual synaptic sound encoding occurred, although the number of presynaptic Ca V 1.3 channels and exocytosis were reduced to one-third. The normal developmental upregulation, clustering, and gating of large-conductance Ca 2+ activated potassium channels in IHCs were impaired in the absence of Ca V β 2 . Moreover, we found the developmental efferent innervation to persist in Ca V β 2 -deficient IHCs. In summary, Ca V β 2 has an essential role in regulating the abundance and properties of Ca V 1.3 channels in IHCs and, thereby, is critical for IHC development and synaptic encoding of sound.

A brain-computer interface (BCI) is a communication system that takes recorded brain signals and translates them into real-time actions, in this case movement of a cursor on a computer screen. This work applied Fitts' law to the evaluation of performance on a target acquisition task during sensorimotor rhythm-based BCI training. Fitts' law, which has been used as a predictor of movement time in studies of human movement, was used here to determine the information transfer rate, which was based on target acquisition time and target difficulty. The information transfer rate was used to make comparisons between control modalities and subject groups on the same task. Data were analyzed from eight able-bodied and five motor disabled participants who wore an electrode cap that recorded and translated their electroencephalogram (EEG) signals into computer cursor movements. Direct comparisons were made between able-bodied and disabled subjects, and between EEG and joystick cursor control in able-bodied subjects. Fitts' law aptly described the relationship between movement time and index of difficulty for each task movement direction when evaluated separately and averaged together. This study showed that Fitts' law can be successfully applied to computer cursor movement controlled by neural signals.

Recent findings have revealed the importance of orthonasal and retronasal olfaction in food memory, especially in conditioned odor aversion (COA); however, little is known about the dynamics of the cerebral circuit involved in the recognition of an odor as a toxic food signal and whether the activated network depends on the way (orthonasal vs retronasal) the odor was first experienced. In this study, we mapped the modulations of odor-induced oscillatory activities through COA learning using multisite recordings of local field potentials in behaving rats. During conditioning, orthonasal odor alone or associated with ingested odor was paired with immediate illness. For all animals, COA retrieval was assessed by orthonasal smelling only. Both types of conditioning induced similarly strong COA. Results pointed out (1) a predictive correlation between the emergence of powerful beta (15–40 Hz) activity and the behavioral expression of COA and (2) a differential network distribution of this beta activity according to the way the animals were exposed to the odor during conditioning. Indeed, for both types of conditioning, the aversive behavior was predicted by the emergence of a strong beta oscillatory activity in response to the odor in the olfactory bulb, piriform cortex, orbitofrontal cortex, and basolateral amygdala. This network was selectively extended to the infralimbic and insular cortices when the odor was ingested during acquisition. These differential networks could participate in different food odor memory; these results are discussed in line with recent behavioral results that indicate that COA can be formed over long odor-illness delays only if the odor is ingested.

Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5-6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT-PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT-PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.

For analyses of complex sounds, many neurons integrate information across different spectral elements via suppressive effects that are distant from the neurons' excitatory tuning. In the mustached bat, suppression evoked by sounds within the first sonar harmonic (23–30 kHz) or in the subsonar band (<23 kHz) alters responsiveness to the higher best frequencies of many neurons. This study examined features and mechanisms associated with low-frequency (LF) suppression among neurons of the lateral lemniscal nuclei (NLL). We obtained extracellular recordings from neurons in the intermediate and ventral nuclei of the lateral lemniscus, observing different forms of LF suppression related to the two above-cited frequency bands. To understand the mechanisms underlying this suppression in NLL neurons, we examined the roles of glycinergic and GABAergic input through local microiontophoretic application of strychnine, an antagonist to glycine receptors (GlyRs), or bicuculline, an antagonist to γ-aminobutyric acid type A receptors (GABA A Rs). With blockade of GABA A Rs, neurons showed an increase in firing rate to best frequency (BF) and/or LF tones but retained LF suppression of BF sounds. For neurons that displayed LF suppression tuned to 23–30 kHz, the suppression was eliminated or nearly eliminated by GlyR blockade. In contrast, GABA A R blockade did not eliminate nor had any consistent effect on suppression tuned to these frequencies. We conclude that LF suppression tuned in the 23- to 30-kHz range results from neuronal inhibition within the NLL via glycinergic inputs. For neurons displaying suppression tuned <23 kHz, neither GlyR nor GABAR blockade altered LF suppression. We conclude that such suppression originates at a lower auditory level, perhaps a result of cochlear mechanisms. These findings demonstrate that neuronal interactions within NLL create a particular form of LF suppression that contributes to the analysis of complex acoustic signals.

In the normal guinea pig, contralateral sound inhibits more than a third of ventral cochlear nucleus (VCN) neurons but excites <4% of these neurons. However, unilateral conductive hearing loss (CHL) and cochlear ablation (CA) result in a major enhancement of contralateral excitation. The response properties of the contralateral excitation produced by CHL and CA are similar, suggesting similar pathways are involved for both types of hearing loss. Here we used the neurotoxin melittin to test the hypothesis that this “compensatory” contralateral excitation is mediated either by direct glutamatergic CN-commissural projections or by cholinergic neurons of the olivocochlear bundle (OCB) that send collaterals to the VCN. Unit responses were recorded from the left VCN of anesthetized, unilaterally deafened guinea pigs (CHL via ossicular disruption, or CA via mechanical destruction). Neural responses were obtained with 16-channel electrodes to enable simultaneous data collection from a large number of single- and multiunits in response to ipsi- and contralateral tone burst and noise stimuli. Lesions of each pathway had differential effects on the contralateral excitation. We conclude that contralateral excitation has a fast and a slow component. The fast excitation is likely mediated by glutamatergic neurons located in medial regions of VCN that send their commissural axons to the other CN via the dorsal/intermediate acoustic striae. The slow component is likely mediated by the OCB collateral projections to the CN. Commissural neurons that leave the CN via the trapezoid body are an additional source of fast, contralateral excitation.

Frequency tuning of auditory cortical neurons is typically determined by integrating spikes over the entire duration of a tone stimulus. However, this approach may mask functionally significant variations in tuning over the time course of the response. To explore this possibility, frequency response functions (FRFs) based on population multiunit activity evoked by pure tones of 175 or 200 ms duration were examined within four time windows relative to stimulus onset corresponding to "on" (10-30 ms), "early sustained" (30-100 ms), "late sustained" (100-175 ms), and "off" (185-235 or 210-260 ms) portions of responses in primary auditory cortex (A1) of 5 awake macaques. FRFs of "on" and "early sustained" responses displayed a good concordance, with best frequencies (BFs) differing, on average, by less than 0.25 octaves. In contrast, FRFs of "on" and "late sustained" responses differed considerably, with a mean difference in BF of 0.68 octaves. At many sites, tuning of "off" responses was inversely related to that of "on" responses, with "off" FRFs displaying a trough at the BF of "on" responses. Inversely correlated "on" and "off" FRFs were more common at sites with a higher "on" BF, thus suggesting functional differences between sites with low and high "on" BF. These results indicate that frequency tuning of population responses in A1 may vary considerably over the course of the response to a tone, thus revealing a temporal dimension to the representation of sound spectrum in A1.

The purpose of this study was to determine the effect of signal level and signal-to-noise ratio (SNR) on the latency and amplitude of evoked cortical activity to further our understanding of how the human central auditory system encodes signals in noise. Cortical auditory evoked potentials (CAEPs) were recorded from 15 young normal-hearing adults in response to a 1000 Hz tone presented at two tone levels in quiet and while continuous background noise levels were varied in five equivalent SNR steps. These 12 conditions were used to determine the effects of signal level and SNR level on CAEP components P1, N1, P2, and N2. Based on prior signal-in-noise experiments conducted in animals, we hypothesized that SNR, would be a key contributor to human CAEP characteristics. As hypothesized, amplitude increased and latency decreased with increasing SNR; in addition, there was no main effect of tone level across the two signal levels tested (60 and 75 dB SPL). Morphology of the P1-N1-P2 complex was driven primarily by SNR, highlighting the importance of noise when recording CAEPs. Results are discussed in terms of the current interest in recording CAEPs in hearing aid users.

Changes in oscillatory brain activity have been related to perceptual and cognitive processes such as selective attention and memory matching. Here we examined brain oscillations, measured with electroencephalography (EEG), during a semantic speech processing task that required both lexically mediated memory matching and selective attention. Participants listened to nouns spoken in male and female voices, and detected an animate target (p=20%) in a train of inanimate standards or vice versa. For a control task, subjects listened to the same words and detected a target male voice in standards of a female voice or vice versa. The standard trials of the semantic task showed enhanced upper beta (25-30 Hz) and gamma band (GBA, 30-60 Hz) activity compared to the voice task. Upper beta and GBA enhancement was accompanied by a suppression of alpha (8-12 Hz) and lower to mid beta (13-20 Hz) activity mainly localized to posterior electrodes. Enhancement of phase-locked theta activity peaking near 275 ms also occurred over the midline electrodes. Theta, upper beta, and gamma band enhancement may reflect lexically mediated template matching in auditory memory, whereas the alpha and beta suppression likely indicate increased attentional processes and memory demands.

The medial prefrontal cortex is involved in working memory and executive control. However, the collective spatiotemporal organization of the cellular network has not been possible to explain during different brain states. We show that pyramidal cells in the prelimbic cortex fire synchronized to hippocampal theta and local spindle oscillations in anesthetized rats. To identify which types of interneurons contribute to the synchronized activity, we recorded and juxtacellularly labeled parvalbumin- and calbindin-expressing (PV+/CB+) basket cells and CB-expressing, PV-negative (CB+/PV−) dendrite-targeting interneurons during both network oscillations. All CB+/PV− dendrite-targeting cells strongly decreased their firing rate during hippocampal theta oscillations. Most PV+/CB+ basket cells fired at the peak of dorsal CA1 theta cycles, similar to prefrontal pyramidal cells. We show that pyramidal cells in the ventral hippocampus also fire around the peak of dorsal CA1 theta cycles, in contrast to previously reported dorsal hippocampal pyramidal cells. Therefore, prefrontal neurons might be driven by monosynaptic connections from the ventral hippocampus during theta oscillations. During prefrontal spindle oscillations, the majority of pyramidal cells and PV+/CB+ basket cells fired preferentially at the trough and early ascending phase, but CB+/PV− dendrite-targeting cells fired uniformly at all phases. We conclude that PV+/CB+ basket cells contribute to rhythmic responses of prefrontal pyramidal cells in relation to hippocampal and thalamic inputs and CB+/PV− dendrite-targeting cells modulate the excitability of dendrites and spines regardless of these field rhythms. Distinct classes of GABAergic interneuron in the prefrontal cortex contribute differentially to the synchronization of pyramidal cells during network oscillations.

Sensory systems often encode stimulus information into the temporal pattern of action potential activity. However, little is known about how the information contained within these patterns is extracted by postsynaptic neurons. Similar to temporal coding by sensory neurons, social information in mormyrid fish is encoded into the temporal patterning of an electric organ discharge. In the current study, sensitivity to temporal patterns of electrosensory stimuli was found to arise within the midbrain posterior exterolateral nucleus (ELp). Whole-cell patch recordings from ELp neurons in vivo revealed three patterns of interpulse interval (IPI) tuning: low-pass neurons tuned to long intervals, high-pass neurons tuned to short intervals, and bandpass neurons tuned to intermediate intervals. Many neurons within each class also responded preferentially to either increasing or decreasing IPIs. Playback of electric signaling patterns recorded from freely behaving fish revealed that the IPI and direction tuning of ELp neurons resulted in selective responses to particular social communication displays characterized by distinct IPI patterns. The postsynaptic potential responses of many neurons indicated a combination of excitatory and inhibitory synaptic input, and the IPI tuning of ELp neurons was directly related to rate-dependent changes in the direction and amplitude of postsynaptic potentials. These results suggest that differences in the dynamics of short-term synaptic plasticity in excitatory and inhibitory pathways may tune central sensory neurons to particular temporal patterns of presynaptic activity. This may represent a general mechanism for the processing of behaviorally relevant stimulus information encoded into temporal patterns of activity by sensory neurons.

Neuroanatomical studies have revealed a vast network of corticocortical connections among the various fields that form cat auditory cortex. However, few studies have explored the functional communicative properties of these connections. The purpose of the present study was to examine the bidirectional processing contributions between the primary auditory cortex (A1) and the nonprimary anterior auditory field (AAF). Using acute recording techniques, multiunit neuronal activity was collected from the right hemisphere of nine mature cats. Cortical maps were generated, and the precise location of A1 and AAF was identified. Subsequently, the synaptic activity of A1 or AAF was suppressed with reversible thermal deactivation procedures while the neuronal response to tonal stimuli of the non-inactivated area (A1 or AAF) was measured. We examined response strength and latency, characteristic frequency, bandwidth, and neuronal threshold of A1 and AAF receptive fields before and during epochs of deactivation. Three major changes in A1 response properties were observed during AAF neuronal suppression: a decrease in response strength, an increase in neuronal thresholds, and a sharpening of receptive field bandwidths. In contrast, A1 deactivation did not produce any discernible changes in AAF neuronal responses. Collectively, these results suggest that the modulation of acoustic information between A1 and AAF in cat auditory cortex is dominated by a unidirectional AAF to A1 pathway.

Object Control signals for brain-machine interfaces may be obtained from a variety of sources, each with their own relative merits. Electrocorticography (ECoG) provides better spatial and spectral resolution than scalp electroencephalography and does not include the risks attendant upon penetration of the brain parenchyma associated with single and multiunit recordings. For these reasons, subdural electrode recordings have been proposed as useful primary or adjunctive control signals for brain-machine interfaces. The goal of the present study was to determine if 2D control signals could be decoded from ECoG. Methods Six patients undergoing invasive monitoring for medically intractable epilepsy using subdural grid electrodes were asked to perform a motor task involving moving a joystick in 1 of 4 cardinal directions (up, down, left, or right) and a fifth condition (“trigger”). Evoked activity was synchronized to joystick movement and analyzed in the theta, alpha, beta, gamma, and high-gamma frequency bands. Results Movement-related cortical potentials could be accurately differentiated from rest with very high accuracy (83–96%). Further distinguishing the movement direction (up, down, left, or right) could also be resolved with high accuracy (58–86%) using information only from the high-gamma range, whereas distinguishing the trigger condition from the remaining directions provided better accuracy. Conclusions Two-dimensional control signals can be derived from ECoG. Local field potentials as measured by ECoG from subdural grids will be useful as control signals for a brain-machine interface.