Neuronal Spiking Responses to Direct Electrical Microstimulation in the Human Cortex.

Microstimulation can modulate the activity of individual neurons to affect behavior, but the effects of stimulation on neuronal spiking are complex and remain poorly understood. This is especially challenging in the human brain where the response properties of individual neurons are sparse and heterogeneous. Here we use microelectrode arrays in the human anterior temporal lobe in 6 participants (3 female) to examine the spiking responses of individual neurons to microstimulation delivered through multiple distinct stimulation sites. We demonstrate that individual neurons can be driven with excitation or inhibition using different stimulation sites, which suggests an approach for providing direct control of spiking activity at the single-neuron level. Spiking responses are inhibitory in neurons that are close to the site of stimulation, while excitatory responses are more spatially distributed. Together, our data demonstrate that spiking responses of individual neurons can be reliably identified and manipulated in the human cortex.SIGNIFICANCE STATEMENT One of the major limitations in our ability to interface directly with the human brain is that the effects of stimulation on the activity of individual neurons remain poorly understood. This study examines the spiking responses of neurons in the human temporal cortex in response to pulses of microstimulation. This study finds that individual neurons can either be excited or inhibited depending on the site of stimulation. These data suggest an approach for modulating the spiking activity of individual neurons in the human brain.

Temporal Coding of Reward Value in Monkey Ventral Striatal Tonically Active Neurons.

The rostromedioventral striatum is critical for behavior dependent on evaluating rewards. We asked what contribution tonically active neurons (TANs), the putative striatal cholinergic interneurons, make in coding reward value in this part of the striatum. Two female monkeys were given the option to accept or reject an offered reward in each trial, the value of which was signaled by a visual cue. Forty-five percent of the TANs use temporally modulated activity to encode information about discounted value. These responses were significantly better represented using principal component analysis than by just counting spikes. The temporal coding is straightforward: the spikes are distributed according to a sinusoidal envelope of activity that changes gain, ranging from positive to negative according to discounted value. Our results show that the information about the relative value of an offered reward is temporally encoded in neural spike trains of TANs. This temporal coding may allow well tuned, coordinated behavior to emerge.SIGNIFICANCE STATEMENT Ever since the discovery that neurons use trains of pulses to transmit information, it seemed self-evident that information would be encoded into the pattern of the spikes. However, there is not much evidence that spike patterns encode cognitive information. We find that a set of interneurons, the tonically active neurons (TANs) in monkeys' striatum, use temporal patterns of response to encode information about the discounted value of offered rewards. The code seems straightforward: a sinusoidal envelope that changes gain according to the discounted value of the offer, describes the rate of spiking across time. This temporal modulation may provide a means to synchronize these interneurons and the activity of other neural elements including principal output neurons.

Surface based electrode localization and standardized regions of interest for intracranial EEG.

Intracranial recordings captured from subdural electrodes in patients with drug resistant epilepsy offer clinicians and researchers a powerful tool for examining neural activity in the human brain with high spatial and temporal precision. There are two major challenges, however, to interpreting these signals both within and across individuals. Anatomical distortions following implantation make accurately identifying the electrode locations difficult. In addition, because each implant involves a unique configuration, comparing neural activity across individuals in a standardized manner has been limited to broad anatomical regions such as cortical lobes or gyri. We address these challenges here by introducing a semi-automated method for localizing subdural electrode contacts to the unique surface anatomy of each individual, and by using a surface-based grid of regions of interest (ROIs) to aggregate electrode data from similar anatomical locations across individuals. Our localization algorithm, which uses only a postoperative CT and preoperative MRI, builds upon previous spring-based optimization approaches by introducing manually identified anchor points directly on the brain surface to constrain the final electrode locations. This algorithm yields an accuracy of 2 mm. Our surface-based ROI approach involves choosing a flexible number of ROIs with different spatial resolutions. ROIs are registered across individuals to represent identical anatomical locations while accounting for the unique curvature of each brain surface. This ROI based approach therefore enables group level statistical testing from spatially precise anatomical regions.

Dual origins of measured phase-amplitude coupling reveal distinct neural mechanisms underlying episodic memory in the human cortex.

Phase-amplitude coupling (PAC) is hypothesized to coordinate neural activity, but its role in successful memory formation in the human cortex is unknown. Measures of PAC are difficult to interpret, however. Both increases and decreases in PAC have been linked to memory encoding, and PAC may arise due to different neural mechanisms. Here, we use a waveform analysis to examine PAC in the human cortex as participants with intracranial electrodes performed a paired associates memory task. We found that successful memory formation exhibited significant decreases in left temporal lobe and prefrontal cortical PAC, and these two regions exhibited changes in PAC within different frequency bands. Two underlying neural mechanisms, nested oscillations and sharp waveforms, were responsible for the changes in these regions. Our data therefore suggest that decreases in measured cortical PAC during episodic memory reflect two distinct underlying mechanisms that are anatomically segregated in the human brain.

Humans and monkeys use different strategies to solve the same short-term memory tasks.

The neural mechanisms underlying human working memory are often inferred from studies using old-world monkeys. Humans use working memory to selectively memorize important information. We recently reported that monkeys do not seem to use selective memorization under experimental conditions that are common in monkey research, but less common in human research. Here we compare the performance of humans and monkeys under the same experimental conditions. Humans selectively remember important images whereas monkeys largely rely on recency information from nonselective memorization. Working memory studies in old-world monkeys must be interpreted cautiously when making inferences about the mechanisms underlying human working memory.

Cortical Low-Frequency Power and Progressive Phase Synchrony Precede Successful Memory Encoding.

Neural activity preceding an event can influence subsequent memory formation, yet the precise cortical dynamics underlying this activity and the associated cognitive states remain unknown. We investigate these questions here by examining intracranial EEG recordings as 28 participants with electrodes placed for seizure monitoring participated in a verbal paired-associates memory task. We found that, preceding successfully remembered word pairs, an orientation cue triggered a low-frequency 2-4 Hz phase reset in the right temporoparietal junction with concurrent increases in low-frequency power across cortical regions that included the prefrontal cortex and left temporal lobe. Regions that exhibited a significant increase in 2-4 Hz power were functionally bound together through progressive low-frequency 2-4 Hz phase synchrony. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded. SIGNIFICANCE STATEMENT: Here we investigate the spatiotemporal cortical dynamics that precede successful memory encoding. Using intracranial EEG, we observed significant changes in oscillatory power, intertrial phase consistency, and pairwise phase synchrony that predict successful encoding. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded.

Monkeys rely on recency of stimulus repetition when solving short-term memory tasks.

Seven monkeys performed variants of two short-term memory tasks that others have used to differentiate between selective and nonselective memory mechanisms. The first task was to view a list of sequentially presented images and identify whether a test matched any image from the list, but not a distractor from a preceding list. Performance was best when the test matched the most recently presented image. Response rates depended linearly on recency of repetition whether the test matched a sample from the current list or a distractor from a preceding list, suggesting nonselective memorization of all images viewed instead of just the sample images. The second task was to remember just the first image in a list selectively and ignore subsequent distractors. False alarms occurred frequently when the test matched a distractor presented near the beginning of the sequence. In a pilot experiment, response rates depended linearly on recency of repetition irrespective of whether the test matched the first image or a distractor, again suggesting nonselective memorization of all images instead of just the first image. Modification of the second task improved recognition of the first image, but did not abolish use of recency. Monkeys appear to perform nonspatial visual short-term memory tasks often (or exclusively) using a single, nonselective, memory mechanism that conveys the recency of stimulus repetition.

Refractoriness enhances temporal coding by auditory nerve fibers.

A universal property of spiking neurons is refractoriness, a transient decrease in discharge probability immediately following an action potential (spike). The refractory period lasts only one to a few milliseconds, but has the potential to affect temporal coding of acoustic stimuli by auditory neurons, which are capable of submillisecond spike-time precision. Here this possibility was investigated systematically by recording spike times from chicken auditory nerve fibers in vivo while stimulating with repeated pure tones at characteristic frequency. Refractory periods were tightly distributed, with a mean of 1.58 ms. A statistical model was developed to recapitulate each fiber's responses and then used to predict the effect of removing the refractory period on a cell-by-cell basis for two largely independent facets of temporal coding: faithful entrainment of interspike intervals to the stimulus frequency and precise synchronization of spike times to the stimulus phase. The ratio of the refractory period to the stimulus period predicted the impact of refractoriness on entrainment and synchronization. For ratios less than ∼0.9, refractoriness enhanced entrainment and this enhancement was often accompanied by an increase in spike-time precision. At higher ratios, little or no change in entrainment or synchronization was observed. Given the tight distribution of refractory periods, the ability of refractoriness to improve temporal coding is restricted to neurons responding to low-frequency stimuli. Enhanced encoding of low frequencies likely affects sound localization and pitch perception in the auditory system, as well as perception in nonauditory sensory modalities, because all spiking neurons exhibit refractoriness.

Potassium conductance dynamics confer robust spike-time precision in a neuromorphic model of the auditory brain stem.

A fundamental question in neuroscience is how neurons perform precise operations despite inherent variability. This question also applies to neuromorphic engineering, where low-power microchips emulate the brain using large populations of diverse silicon neurons. Biological neurons in the auditory pathway display precise spike timing, critical for sound localization and interpretation of complex waveforms such as speech, even though they are a heterogeneous population. Silicon neurons are also heterogeneous, due to a key design constraint in neuromorphic engineering: smaller transistors offer lower power consumption and more neurons per unit area of silicon, but also more variability between transistors and thus between silicon neurons. Utilizing this variability in a neuromorphic model of the auditory brain stem with 1,080 silicon neurons, we found that a low-voltage-activated potassium conductance (g(KL)) enables precise spike timing via two mechanisms: statically reducing the resting membrane time constant and dynamically suppressing late synaptic inputs. The relative contribution of these two mechanisms is unknown because blocking g(KL) in vitro eliminates dynamic adaptation but also lengthens the membrane time constant. We replaced g(KL) with a static leak in silico to recover the short membrane time constant and found that silicon neurons could mimic the spike-time precision of their biological counterparts, but only over a narrow range of stimulus intensities and biophysical parameters. The dynamics of g(KL) were required for precise spike timing robust to stimulus variation across a heterogeneous population of silicon neurons, thus explaining how neural and neuromorphic systems may perform precise operations despite inherent variability.

Backbone spiking sequence as a basis for preplay, replay, and default states in human cortex.

Sequences of spiking activity have been heavily implicated as potential substrates of memory formation and retrieval across many species. A parallel line of recent evidence also asserts that sequential activity may arise from and be constrained by pre-existing network structure. Here we reconcile these two lines of research in the human brain by measuring single unit spiking sequences in the temporal lobe cortex as participants perform an episodic memory task. We find the presence of an average backbone spiking sequence identified during pre-task rest that is stable over time and different cognitive states. We further demonstrate that these backbone sequences are composed of both rigid and flexible sequence elements, and that flexible elements within these sequences serve to promote memory specificity when forming and retrieving new memories. These results support the hypothesis that pre-existing network dynamics serve as a scaffold for ongoing neural activity in the human cortex.

The medial temporal lobe supports the quality of visual short-term memory representation.

The quality of short-term memory (STM) underlies our ability to recall the exact details of a recent event, yet how the human brain enables this core cognitive function remains poorly understood. Here we use multiple experimental approaches to test the hypothesis that the quality of STM, such as its precision or fidelity, relies on the medial temporal lobe (MTL), a region commonly associated with the ability to distinguish similar information remembered in long-term memory. First, with intracranial recordings, we find that delay-period MTL activity retains item-specific STM content that is predictive of subsequent recall precision. Second, STM recall precision is associated with an increase in the strength of intrinsic MTL-to-neocortical functional connections during a brief retention interval. Finally, perturbing the MTL through electrical stimulation or surgical removal can selectively reduce STM precision. Collectively, these findings provide converging evidence that the MTL is critically involved in the quality of STM representation.

Micro-scale functional modules in the human temporal lobe.

The sensory cortices of many mammals are often organized into modules in the form of cortical columns, yet whether modular organization at this spatial scale is a general property of the human neocortex is unknown. The strongest evidence for modularity arises when measures of connectivity, structure, and function converge. Here we use microelectrode recordings in humans to examine functional connectivity and neuronal spiking responses in order to assess modularity in submillimeter scale networks. We find that the human temporal lobe consists of temporally persistent spatially compact modules approximately 1.3mm in diameter. Functionally, the information coded by single neurons during an image categorization task is more similar for neurons belonging to the same module than for neurons from different modules. The geometry, connectivity, and spiking responses of these local cortical networks provide converging evidence that the human temporal lobe is organized into functional modules at the micro scale.

Distinct deficits of repetition priming following lateral versus anteromedial frontal cortex damage.

Object repetition commonly leads to long-lasting improvements in identification speed and accuracy, a behavioral facilitation referred to as "repetition priming". Neuroimaging and non-invasive electromagnetic stimulation studies have most often implicated the involvement of left lateral frontal cortex in repetition priming, although convergent evidence from neuropsychological studies is lacking. In the current study, we examine the impact of surgical resection for the treatment of epilepsy on the magnitude of repetition priming at relatively short-term (30-60 min delay) and long-term (3 months) delays in 41 patients with varying seizure foci and resection locations. Overall, patients exhibited significant repetition priming at both short-term and long-term delays. However, patients with frontal resections (largely anterior and medial frontal) differed significantly from those with right anterior temporal resections in showing fully intact short-term priming but absent long-term priming. In a comparison set of 10 recovered aphasic patients, patients with left lateral frontal damage exhibited impaired short-term priming relative to other frontal damage locations, suggesting the differential involvement of lateral and anteromedial frontal regions in mediating repetition priming at short-lag and long-lag timescales, respectively.

Ripples reflect a spectrum of synchronous spiking activity in human anterior temporal lobe.

Direct brain recordings have provided important insights into how high-frequency activity captured through intracranial EEG (iEEG) supports human memory retrieval. The extent to which such activity is comprised of transient fluctuations that reflect the dynamic coordination of underlying neurons, however, remains unclear. Here, we simultaneously record iEEG, local field potential (LFP), and single unit activity in the human temporal cortex. We demonstrate that fast oscillations within the previously identified 80-120 Hz ripple band contribute to broadband high-frequency activity in the human cortex. These ripple oscillations exhibit a spectrum of amplitudes and durations related to the amount of underlying neuronal spiking. Ripples in the macro-scale iEEG are related to the number and synchrony of ripples in the micro-scale LFP, which in turn are related to the synchrony of neuronal spiking. Our data suggest that neural activity in the human temporal lobe is organized into transient bouts of ripple oscillations that reflect underlying bursts of spiking activity.

Replay of cortical spiking sequences during human memory retrieval.

Episodic memory retrieval is thought to rely on the replay of past experiences, yet it remains unknown how human single-unit activity is temporally organized during episodic memory encoding and retrieval. We found that ripple oscillations in the human cortex reflect underlying bursts of single-unit spiking activity that are organized into memory-specific sequences. Spiking sequences occurred repeatedly during memory formation and were replayed during successful memory retrieval, and this replay was associated with ripples in the medial temporal lobe. Together, these data demonstrate that human episodic memory is encoded by specific sequences of neural activity and that memory recall involves reinstating this temporal order of activity.

Characterizing and predicting cortical evoked responses to direct electrical stimulation of the human brain.

BACKGROUND: Direct electrical stimulation of the human brain has been used to successfully treat several neurological disorders, but the precise effects of stimulation on neural activity are poorly understood. Characterizing the neural response to stimulation, however, could allow clinicians and researchers to more accurately predict neural responses, which could in turn lead to more effective stimulation for treatment and to fundamental knowledge regarding neural function. OBJECTIVE: Here we use a linear systems approach in order to characterize the response to electrical stimulation across cortical locations and then to predict the responses to novel inputs. METHODS: We use intracranial electrodes to directly stimulate the human brain with single pulses of stimulation using amplitudes drawn from a random distribution. Based on the evoked responses, we generate a simple model capturing the characteristic response to stimulation at each cortical site. RESULTS: We find that the variable dynamics of the evoked response across cortical locations can be captured using the same simple architecture, a linear time-invariant system that operates separately on positive and negative input pulses of stimulation. We demonstrate that characterizing the response to stimulation using this simple and tractable model of evoked responses enables us to predict the responses to subsequent stimulation with single pulses with novel amplitudes, and the compound response to stimulation with multiple pulses. CONCLUSION: Our data suggest that characterizing the response to stimulation in an approximately linear manner can provide a powerful and principled approach for predicting the response to direct electrical stimulation.

Large-Scale Communication in the Human Brain Is Rhythmically Modulated through Alpha Coherence.

Recent evidence has suggested that coherent neuronal oscillations may serve as a gating mechanism for flexibly modulating communication between brain regions. For this to occur, such oscillations should be robust and coherent between brain regions that also demonstrate time-locked correlations, with time delays that match the phase delays of the coherent oscillations. Here, by analyzing functional connectivity in both the time and frequency domains, we demonstrate that alpha oscillations satisfy these constraints and are well suited for modulating communication over large spatial scales in the human brain. We examine intracranial EEG in the human temporal lobe and find robust alpha oscillations that are coherent between brain regions with center frequencies that are consistent within each individual participant. Regions demonstrating coherent narrowband oscillations also exhibit time-locked broadband correlations with a consistent time delay, a requirement for an efficient communication channel. The phase delays of the coherent alpha oscillations match the time delays of the correlated components, and importantly, both broadband correlations and neuronal spiking activity are modulated by the phase of the oscillations. These results are specific to the alpha band and build upon emerging evidence suggesting that alpha oscillations may play an active role in cortical function. Our data therefore provide evidence that large-scale communication in the human brain may be rhythmically modulated by alpha oscillations.

Changing temporal context in human temporal lobe promotes memory of distinct episodes.

Memories of experiences that occur around the same time are linked together by a shared temporal context, represented by shared patterns of neural activity. However, shared temporal context may be problematic for selective retrieval of specific memories. Here, we examine intracranial EEG (iEEG) in the human temporal lobe as participants perform a verbal paired associates memory task that requires the encoding of distinct word pairs in memory. We find that the rate of change in patterns of low frequency (3-12 Hz) power distributed across the temporal lobe is significantly related to memory performance. We also find that exogenous electrical stimulation affects how quickly these neural representations of temporal context change with time, which directly affects the ability to successfully form memories for distinct items. Our results indicate that the ability to retrieve distinct episodic memories is related to how quickly neural representations of temporal context change over time during encoding.

Publisher Correction: Attention improves memory by suppressing spiking-neuron activity in the human anterior temporal lobe.

In the version of this article originally published, the reference citations in the Methods section were misnumbered. This has now been corrected in the HTML and PDF versions of the paper.

Perceptual processing in the ventral visual stream requires area TE but not rhinal cortex.

There is an on-going debate over whether area TE, or the anatomically adjacent rhinal cortex, is the final stage of visual object processing. Both regions have been implicated in visual perception, but their involvement in non-perceptual functions, such as short-term memory, hinders clear-cut interpretation. Here, using a two-interval forced choice task without a short-term memory demand, we find that after bilateral removal of area TE, monkeys trained to categorize images based on perceptual similarity (morphs between dogs and cats), are, on the initial viewing, badly impaired when given a new set of images. They improve markedly with a small amount of practice but nonetheless remain moderately impaired indefinitely. The monkeys with bilateral removal of rhinal cortex are, under all conditions, indistinguishable from unoperated controls. We conclude that the final stage of the integration of visual perceptual information into object percepts in the ventral visual stream occurs in area TE.