Microwire Recordings Research Articles

Simulation of background neuronal activity and noise in human intracranial microwire recordings

BackgroundHuman intracranial microwire recordings allow measurement of neuronal activity in human subjects at a fine temporal and spatial scale. The recorded extracellular potentials represent a mixture of action potentials from nearby neurons, local field potentials, and other noise sources. Signal processing of these recordings is used to separate the activity of putative single neurons from other background and noise. To better understand the separation of single neuron activity, one approach is to simulate the signals produced by neurons firing action potentials combined with background activity and noise. New methodThis paper characterizes the background activity and noise in human intracranial microwire recordings and presents an accurate and efficient method of simulation using an infinite impulse response filter to color white noise. Results and comparisonThis method reproduces the power spectral density of the background activity and noise over a frequency range of 1–5000 Hz and is over 200 times faster than previously used methods. It thus facilitates large scale studies of variation of noise sources, field potentials, and processing parameters. It performs equivalently in terms of spike sorting to simulation using white noise. Another advantage is that the simulated signals are known to arise from a pseudorandom number generator and cannot be the result of detecting simulated background spiking activity. ConclusionsThis approach provides a rapid and accurate method of simulating background noise and neural activity in human intracranial microwire recordings. It is suitable for use in large scale simulations to study spike sorting in this type of recording.

A Learned Map for Places and Concepts in the Human Medial Temporal Lobe.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.

Local neuronal excitation and global inhibition during epileptic fast ripples in humans.

Understanding the neuronal basis of epileptic activity is a major challenge in neurology. Cellular integration into larger scale networks is all the more challenging. In the local field potential, interictal epileptic discharges can be associated with fast ripples (200-600 Hz), which are a promising marker of the epileptogenic zone. Yet, how neuronal populations in the epileptogenic zone and in healthy tissue are affected by fast ripples remain unclear. Here, we used a novel 'hybrid' macro-micro depth electrode in nine drug-resistant epileptic patients, combining classic depth recording of local field potentials (macro-contacts) and two or three tetrodes (four micro-wires bundled together) enabling up to 15 neurons in local circuits to be simultaneously recorded. We characterized neuronal responses (190 single units) with the timing of fast ripples (2233 fast ripples) on the same hybrid and other electrodes that target other brain regions. Micro-wire recordings reveal signals that are not visible on macro-contacts. While fast ripples detected on the closest macro-contact to the tetrodes were always associated with fast ripples on the tetrodes, 82% of fast ripples detected on tetrodes were associated with detectable fast ripples on the nearest macro-contact. Moreover, neuronal recordings were taken in and outside the epileptogenic zone of implanted epileptic subjects and they revealed an interlay of excitation and inhibition across anatomical scales. While fast ripples were associated with increased neuronal activity in very local circuits only, they were followed by inhibition in large-scale networks (beyond the epileptogenic zone, even in healthy cortex). Neuronal responses to fast ripples were homogeneous in local networks but differed across brain areas. Similarly, post-fast ripple inhibition varied across recording locations and subjects and was shorter than typical inter-fast ripple intervals, suggesting that this inhibition is a fundamental refractory process for the networks. These findings demonstrate that fast ripples engage local and global networks, including healthy tissue, and point to network features that pave the way for new diagnostic and therapeutic strategies. They also reveal how even localized pathological brain dynamics can affect a broad range of cognitive functions.

Encoding of Race Categories by Single Neurons in the Human Brain.

Previous research has suggested that race-specific features are automatically processed during face perception, often with out-group faces treated categorically. Functional imaging has illuminated the hemodynamic correlates of this process, with fewer studies examining single-neuron responses. In the present experiment, epilepsy patients undergoing microwire recordings in preparation for surgical treatment were shown realistic computer-generated human faces, which they classified according to the emotional expression shown. Racial categories of the stimulus faces varied independently of the emotion shown, being irrelevant to the patients' primary task. Nevertheless, we observed race-driven changes in neural firing rates in the amygdala, anterior cingulate cortex, and hippocampus. These responses were broadly distributed, with the firing rates of 28% of recorded neurons in the amygdala and 45% in the anterior cingulate cortex predicting one or more racial categories. Nearly equal proportions of neurons responded to White and Black faces (24% vs. 22% in the amygdala and 26% vs. 28% in the anterior cingulate cortex). A smaller fraction (12%) of race-responsive neurons in the hippocampus predicted only White faces. Our results imply a distributed representation of race in brain areas involved in affective judgments, decision making, and memory. They also support the hypothesis that race-specific cues are perceptually coded even when those cues are task-irrelevant.

Patterns of single-neuron activity during associative recognition memory in the human medial temporal lobe

Electrophysiological activity in medial temporal lobe (MTL) structures is pivotal for declarative long-term memory. Single-neuron and microcircuit findings capitalizing on human microwire recordings from the medial temporal lobe are still fragmentary. In particular, it is an open question whether identical or different groups of neurons participate in different memory functions. Here, we investigated category-specific responses in the human MTL based on single-neuron recordings in presurgical epilepsy patients performing an associative long-term memory task. Additionally, auditory beat stimuli were presented during encoding and retrieval to modulate memory performance. We describe the proportion of neurons in amygdala, entorhinal cortex, hippocampus and parahippocampal cortex belonging to different response classes. These entail neurons coding stimulus-familiarity, neurons coding successful item memory, and neurons coding associated source memory, as well as the overlap between these classes. As major results we demonstrate that neurons responding to stimulus familiarity (old/new effect) can be identified in the MTL even when using previously known rather than entirely novel stimulus material (words). We observed a significant overlap between familiarity-related neurons and neurons coding item retrieval (remembered/forgotten effect). The largest fraction of familiarity-related neurons was found in the parahippocampal cortex, and a considerable fraction of all parahippocampal neurons was related to successful item retrieval. Neurons related to successful source retrieval were different from the neurons coding the associated information. Most importantly, there was no overlap between neurons coding item memory and those coding associated source memory strongly suggesting that these functions are facilitated by different sets of neurons.

Estimates of distributed coding of visual objects by single neurons in the human brain depend on which spike sorting technique is used

Objective. To determine whether the estimated fraction and degree of distribution of visual responsive neurons in human intracranial microwire recordings depends upon the spike sorting method used. Approach. A large dataset of human intracranial microwire recordings from four brain areas was sorted into single unit activity (SUA) and multiunit activity (MUA) using 4 spike sorting methods previously applied to this type of recording. The responses were examined for visual responses to 33 objects which were presented. Main results. The 4 spike sorting techniques examined here yielded fractions of responsive SUA varying from 8% in the left anterior cingulate cortex to 27% in the right amgdala. The fraction of responsive SUA and MUA depended on the type of spike sorting being used as well as brain area and side being recorded from. Agreement between spike sorting techniques was low (0.04–0.16 on the 0–1 AMIall scale). Significance. Prior estimates of the fraction of single neurons in the human medial temporal lobe coding semantic memory of visual objects have yielded fractions ranging from 0.04% by very strict response criteria to 47% by other criteria. A variety of explanations of these differences have been posited, including differences in the type of memory being tested, differences in visual stimuli, as well as technical differences such as spike sorting techniques. This study shows the dependence of the reported fraction of neurons encoding visual objects on the spike sorting technique employed and confirms a distributed representation of visual objects by single neurons in the human brain. Both the variation in the responsive fractions with spike sorting technique and low levels of agreement between techniques highlight the need for better understanding of the signals being extracted in human intracranial microwire recordings.

Kinase Inhibitors with Antiepileptic Properties Identified with a Novel in Vitro Screening Platform.

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.

One month in the life of a neuron: longitudinal single-unit electrophysiology in the monkey visual system.

Conventional recording methods generally preclude following the activity of the same neurons in awake animals across days. This limits our ability to systematically investigate the principles of neuronal specialization, or to study phenomena that evolve over multiple days such as experience-dependent plasticity. To redress this shortcoming, we developed a drivable, chronically implanted microwire recording preparation that allowed us to follow visual responses in inferotemporal (IT) cortex in awake behaving monkeys across multiple days, and in many cases across months. The microwire bundle and other implanted components were MRI compatible and thus permitted in the same animals both functional imaging and long-term recording from multiple neurons in deep structures within a region the approximate size of one voxel (<1 mm). The distinct patterns of stimulus selectivity observed in IT neurons, together with stable features in spike waveforms and interspike interval distributions, allowed us to track individual neurons across weeks and sometimes months. The long-term consistency of visual responses shown here permits large-scale mappings of neuronal properties using massive image libraries presented over the course of days. We demonstrate this possibility by screening the visual responses of single neurons to a set of 10,000 stimuli.

Firing behavior and network activity of single neurons in human epileptic hypothalamic hamartoma.

Objective: Human hypothalamic hamartomas (HH) are intrinsically epileptogenic and are associated with treatment-resistant gelastic seizures. The basic cellular mechanisms responsible for seizure onset within HH are unknown. We used intra-operative microwire recordings of single neuron activity to measure the spontaneous firing rate of neurons and the degree of functional connection between neurons within the tumor.Technique: Fourteen patients underwent transventricular endoscopic resection of HH for treatment-resistant epilepsy. Prior to surgical resection, single neuron recordings from bundled microwires (total of nine contacts) were obtained from HH tissue. Spontaneous activity was recorded for two or three 5-min epochs under steady-state general anesthesia. Off-line analysis included cluster analysis of single unit activity and probability analysis of firing relationships between pairs of neurons.Results: Altogether, 222 neurons were identified (mean 6 neurons per recording epoch). Cluster analysis of single neuron firing utilizing a mixture of Gaussians model identified two distinct populations on the basis of firing rate (median firing frequency 0.6 versus 15.0 spikes per second; p < 10−5). Cluster analysis identified three populations determined by levels of burst firing (median burst indices of 0.015, 0.18, and 0.39; p < 10−15). Unbiased analysis of spontaneous single unit behavior showed that 51% of all possible neuron pairs within each recording epoch had a significant level of firing synchrony (p < 10−15). The subgroup of neurons with higher median firing frequencies was more likely to demonstrate synchronous firing (p < 10−7).Conclusion: Hypothalamic hamartoma tissue in vivo contains neurons which fire spontaneously. The activity of single neurons is diverse but distributes into at least two electrophysiological phenoytpes. Functional linkage between single neurons suggests that HH neurons exist within local networks that may contribute to ictogenesis.

The amygdala to periaqueductal gray pathway: Plastic changes induced by audiogenic kindling and reversal by gabapentin

Repeated, periodic induction of AGS (AGS kindling) in GEPR-9s increases seizure duration and induces an additional generalized clonus phase [post-tonic clonus (PTC)], which involves expansion of the localized brainstem AGS network to the amygdala. The pathway between central amygdala (CeA) and ventrolateral periaqueductal gray (vlPAG) is implicated in several disorders, including pain and anxiety. This pathway is also implicated in the network of audiogenic seizures (AGS) in genetically epilepsy-prone rats (GEPR-9s). We examined AGS kindling-induced changes in vlPAG extracellular action potentials evoked by electrical stimuli in CeA in awake, behaving GEPR-9s, using chronically-implanted stimulation electrodes in CeA and microwire recording electrodes in vlPAG. The effect of gabapentin, an anticonvulsant drug that is also effective in pain and anxiety disorders, on the CeA to vlPAG pathway in AGS-kindled GEPR-9s was also evaluated. Electrical stimulation in CeA evoked consistent, short latency and intensity-dependent vlPAG neuronal firing increases. However, in AGS-kindled GEPR-9s these responses showed a precipitous firing increase with increasing stimulus intensity, as compared to non-kindled GEPR-9s. Gabapentin (50mg/kg, i.p.) significantly reduced vlPAG neuronal responses to CeA stimulation to pre-AGS-kindled levels and reversibly blocked PTC in AGS-kindled GEPR-9s. These data suggest that the amygdala to vlPAG pathway may be critical in mediating the emergence of PTC during AGS kindling. The ability of gabapentin to suppress this pathway may be important for its anticonvulsant effects in AGS-kindled GEPR-9s, and this effect may contribute to gabapentin′s effectiveness in anxiety and pain in which the amygdala to PAG pathway is also implicated.

Interictal high frequency oscillations in an animal model of infantile spasms

While infantile spasms is the most common catastrophic epilepsy of infancy and early-childhood, very little is known about the basic mechanisms responsible for this devastating disorder. In experiments reported here, spasms were induced in rats by the chronic infusion of TTX into the neocortex beginning on postnatal days 10–12. Studies of focal epilepsy suggest that high frequency EEG oscillations (HFOs) occur interictally at sites that are most likely responsible for seizure generation. Thus, our goal was to determine if HFOs occurred and where they occurred in cortex in the TTX model. We also undertook multiunit recordings to begin to analyze the basic mechanisms responsible for HFOs. Our results show that HFOs occur most frequently during hypsarrhythmia and NREM sleep and are most prominent contralateral to the TTX infusion site in the homotopic cortex and anterior to this region in frontal cortex. While HFOs were largest and most frequent in these contralateral regions, they were also commonly recorded synchronously across multiple and widely-spaced recordings sites. The amplitude and spatial distribution of interictal HFOs were found to be very similar to the high frequency bursts seen at seizure onset. However, the latter differed from the interictal events in that the high frequency activity was more intense at seizure onset. Microwire recordings showed that neuronal unit firing increased abruptly with the generation of HFOs. A similar increase in neuronal firing occurred at the onset of the ictal events. Taken together, results suggest that neocortical networks are abnormally excitable, particularly contralateral to TTX infusion, and that these abnormalities are not restricted to small areas of cortex. Multiunit firing coincident with HFOs is fully consistent with a neocortical hyperexcitability hypothesis particularly since they both occur at seizure onset.

IN SITU SINGLE-UNIT RECORDING OF HYPOTHALAMIC HAMARTOMAS UNDER ENDOSCOPIC DIRECT VISUALIZATION

Hypothalamic hamartomas (HHs) are associated with refractory epilepsy and are amenable to surgical treatment. The gelastic seizures associated with HHs originate within the HH lesion, but the responsible cellular mechanisms are unknown. Microelectrode patch-clamp recordings from HH neurons in resected slice preparations show that small HH neurons spontaneously fire with intrinsic pacemaker-like activity. We questioned whether spontaneous firing of HH neurons was present in situ, and we hypothesized that single-unit field recordings from HH tissue could be obtained with instrumentation passed through the endoscope before surgical resection. After informed consent was obtained, patients undergoing transventricular, endoscopic resection of an HH for intractable epilepsy were eligible for study. After placement of the endoscope, a bundled microwire (total of 9 contacts) was placed into the HH under direct visualization. Spontaneous activity was recorded for two or three 5-minute epochs, under steady-state general anesthesia. The wire was advanced 0.5 to 1 mm within the lesion between recording epochs. A total of thirteen 5-minute recordings were obtained from 5 patients. Noise levels were comparable to extraoperative microwire recordings for temporal lobe epilepsy. Single-neuron spike activity was isolated from a total of 5 channels obtained during recording of 3 sessions in 3 patients. We have shown that single-unit recordings from HH lesions can be successfully obtained in situ under direct endoscopic visualization. We believe that this is the first report using the working channel of a neuroendoscope to make physiological recordings of deep structures in humans.

Interference and Noise in Human Intracranial Microwire Recordings

Human intracranial microwire recordings have typically had poor signal-to-noise ratios (SNRs), often below 10 dB. The physiological signal source is a fixed-amplitude one; thus, SNR must be improved by reducing either noise or interference. An understanding of the interference sources, how they are coupled to the recording system, and their relative magnitudes is needed to improve SNR. We measured potentially interfering sources in a controlled laboratory model of microwire recordings. Specifically considered were interference from power lines, fluorescent lights, radio transmitters, and other nearby electrical devices. In the presence of typical mismatches in impedance (100 kohm) and loop area (30 cm2), the greatest sources of interference are capacitive coupling to power lines (11.4 microV(rms)), capacitive coupling to fluorescent lights (9.7 microV(rms)), and nonpower line capacitive interference (8.6 microV(rms)). The model and techniques employed here to study human microwire recordings may also be applied to other neurophysiological recordings.

High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings.

Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80-250 Hz) and fast ripple (250-1000 Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC - 9000 Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 +/- 49.3 Hz versus 116.3 +/- 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.

A modification of the Harper–McGinty microdrive for use in chronically prepared rabbits

We describe a modification of the Harper–McGinty microdrive for use with extracellular, microwire recording in conscious, chronically prepared rabbits. Improvements over existing designs are in ease of assembly and mechanical stability. The microdrive is easily fabricated with hand tools and readily available parts. In addition, assembly of the microdrive utilizes epoxy, avoiding the difficult task of soldering stainless steel parts. Finally, the microdrive is mounted directly to the skull enhancing mechanical stability and eliminating the need to allow space for screw travel. Importantly, this microdrive has proven to be durable as well as functional in our preparation.

Diverse firing properties of single motor units in the inner and outer portions of the guinea pig anterior digastric muscle

Microwire recordings from the histochemically heterogeneous inner compartment of the guinea pig anterior digastric muscle (ADG) revealed tonic firing of single motor units, which were spontaneously active and could also be recruited following orofacial afferent stimulation and during rhythmic jaw movements (RJM). As units with tonic firing were not observed in the homogeneously fast-twitch outer ADG, the tonic units were classified as slow-twitch motor units. Irregular patterns of motor-unit firing at variable frequencies were observed after orofacial stimulation and during RJM in the outer and inner compartments. The irregular firing pattern of units in the fast-twitch outer compartment was characterized by shorter and less variable bursts than that of units in the heterogeneous inner compartment. A phasic, centrally driven firing pattern was observed during RJM in outer and inner ADG units. The firing frequency of some of these units was modulated during the rhythmical bursts. It is suggested that, as in limb muscles, functionally specialized ADG motor units are recruited in an orderly sequence, starting with spontaneously active, slow-twitch units in the inner compartment, continuing with fast-twitch units recruited upon enhancement of the synaptic drive (as in the case of orofacial stimulation), and ending with massive, rhythmical recruitment of slow- and fast-twitch units during RJM.

Methods of single unit recording from medullary neural substrates in awake, behaving guinea pigs

An electrophysiological procedure that permits extracellular single neuronal recording in the medulla of unanesthetized, freely behaving animals is described. System components consist of 1) a flexible, single-strand microwire as recording electrode, 2) a miniature, skull-mounted miniature microdrive used for isolation of single unit activity, and 3) a head-mounted voltage follower that conditions and stabilizes the neuronal signals prior to amplification and transmission for further processing. A unique advantage of this procedure is the latitude and provision for microwire replacement in the event that multiple penetrations are desired or the tip of the microwire recording electrode is insulated as a result of gliomatosis. With minor modification, this technique can be used for single unit recording virtually anywhere along the supra-segmental neuraxis. Technical aspects of this procedure, together with details of design and fabrication of implantable devices, chronic instrumentation procedure, and potentials for other chronic applications, are discussed.