Transcranial electrical stimulation: How can a simple conductor orchestrate complex brain activity?

Transcranial electrical stimulation (tES) is one of the oldest and yet least understood forms of brain stimulation. The idea that a weak electrical stimulus, applied outside the head, can meaningfully affect neural activity is often regarded as mysterious. Here, we argue that the direct effects of tES are not so mysterious: Extensive data from a wide range of model systems shows it has appreciable effects on the activity of individual neurons. Instead, the real mysteries are how tES interacts with the brain's own activity and how these dynamics can be controlled to produce desirable therapeutic effects. These are challenging problems, akin to repairing a complex machine while it is running, but they are not unique to tES or even neuroscience. We suggest that models of coupled oscillators, a common tool for studying interactions in other fields, may provide valuable insights. By combining these tools with our growing, interdisciplinary knowledge of brain dynamics, we are now in a good position to make progress in this area and meet the high demand for effective neuromodulation in neuroscience and psychiatry.

Brain stimulation competes with ongoing oscillations for control of spike timing in the primate brain.

Transcranial alternating current stimulation (tACS) is a popular method for modulating brain activity noninvasively. In particular, tACS is often used as a targeted intervention that enhances a neural oscillation at a specific frequency to affect a particular behavior. However, these interventions often yield highly variable results. Here, we provide a potential explanation for this variability: tACS competes with the brain's ongoing oscillations. Using neural recordings from alert nonhuman primates, we find that when neural firing is independent of ongoing brain oscillations, tACS readily entrains spiking activity, but when neurons are strongly entrained to ongoing oscillations, tACS often causes a decrease in entrainment instead. Consequently, tACS can yield categorically different results on neural activity, even when the stimulation protocol is fixed. Mathematical analysis suggests that this competition is likely to occur under many experimental conditions. Attempting to impose an external rhythm on the brain may therefore often yield precisely the opposite effect.

Asymmetric stimulus representations bias visual perceptual learning.

The primate visual cortex contains various regions that exhibit specialization for different stimulus properties, such as motion, shape, and color. Within each region, there is often further specialization, such that particular stimulus features, such as horizontal and vertical orientations, are over-represented. These asymmetries are associated with well-known perceptual biases, but little is known about how they influence visual learning. Most theories would predict that learning is optimal, in the sense that it is unaffected by these asymmetries. However, other approaches to learning would result in specific patterns of perceptual biases. To distinguish between these possibilities, we trained human observers to discriminate between expanding and contracting motion patterns, which have a highly asymmetrical representation in the visual cortex. Observers exhibited biased percepts of these stimuli, and these biases were affected by training in ways that were often suboptimal. We simulated different neural network models and found that a learning rule that involved only adjustments to decision criteria, rather than connection weights, could account for our data. These results suggest that cortical asymmetries influence visual perception and that human observers often rely on suboptimal strategies for learning.

tACS entrains neural activity while somatosensory input is blocked.

Transcranial alternating current stimulation (tACS) modulates brain activity by passing electrical current through electrodes that are attached to the scalp. Because it is safe and noninvasive, tACS holds great promise as a tool for basic research and clinical treatment. However, little is known about how tACS ultimately influences neural activity. One hypothesis is that tACS affects neural responses directly, by producing electrical fields that interact with the brain's endogenous electrical activity. By controlling the shape and location of these electric fields, one could target brain regions associated with particular behaviors or symptoms. However, an alternative hypothesis is that tACS affects neural activity indirectly, via peripheral sensory afferents. In particular, it has often been hypothesized that tACS acts on sensory fibers in the skin, which in turn provide rhythmic input to central neurons. In this case, there would be little possibility of targeted brain stimulation, as the regions modulated by tACS would depend entirely on the somatosensory pathways originating in the skin around the stimulating electrodes. Here, we directly test these competing hypotheses by recording single-unit activity in the hippocampus and visual cortex of alert monkeys receiving tACS. We find that tACS entrains neuronal activity in both regions, so that cells fire synchronously with the stimulation. Blocking somatosensory input with a topical anesthetic does not significantly alter these neural entrainment effects. These data are therefore consistent with the direct stimulation hypothesis and suggest that peripheral somatosensory stimulation is not required for tACS to entrain neurons.

Eye movements shape visual learning.

Most people easily learn to recognize new faces and places, and with more extensive practice they can become experts at visual tasks as complex as radiological diagnosis and action video games. Such perceptual plasticity has been thoroughly studied in the context of training paradigms that require constant fixation. In contrast, when observers learn under more natural conditions, they make frequent saccadic eye movements. Here we show that such eye movements can play an important role in visual learning. Observers performed a task in which they executed a saccade while discriminating the motion of a cued visual stimulus. Additional stimuli, presented simultaneously with the cued one, permitted an assessment of the perceptual integration of information across visual space. Consistent with previous results on perisaccadic remapping [M. Szinte, D. Jonikaitis, M. Rolfs, P. Cavanagh, H. Deubel, J. Neurophysiol. 116, 1592-1602 (2016)], most observers preferentially integrated information from locations representing the presaccadic and postsaccadic retinal positions of the cue. With extensive training on the saccade task, these observers gradually acquired the ability to perform similar motion integration without making eye movements. Importantly, the newly acquired pattern of spatial integration was determined by the metrics of the saccades made during training. These results suggest that oculomotor influences on visual processing, long thought to subserve the function of perceptual stability, also play a role in visual plasticity.

Transcranial alternating current stimulation entrains single-neuron activity in the primate brain.

Spike timing is thought to play a critical role in neural computation and communication. Methods for adjusting spike timing are therefore of great interest to researchers and clinicians alike. Transcranial electrical stimulation (tES) is a noninvasive technique that uses weak electric fields to manipulate brain activity. Early results have suggested that this technique can improve subjects' behavioral performance on a wide range of tasks and ameliorate some clinical conditions. Nevertheless, considerable skepticism remains about its efficacy, especially because the electric fields reaching the brain during tES are small, whereas the likelihood of indirect effects is large. Our understanding of its effects in humans is largely based on extrapolations from simple model systems and indirect measures of neural activity. As a result, fundamental questions remain about whether and how tES can influence neuronal activity in the human brain. Here, we demonstrate that tES, as typically applied to humans, affects the firing patterns of individual neurons in alert nonhuman primates, which are the best available animal model for the human brain. Specifically, tES consistently influences the timing, but not the rate, of spiking activity within the targeted brain region. Such effects are frequency- and location-specific and can reach deep brain structures; control experiments show that they cannot be explained by sensory stimulation or other indirect influences. These data thus provide a strong mechanistic rationale for the use of tES in humans and will help guide the development of future tES applications.

Fruit flies are multistable geniuses.

Our sensory systems have evolved to provide us with information about the external world. Such information is useful only insofar as it leads to actions that enhance fitness, and thus, the link between sensation and action has been thoroughly studied in many species. In insects, for example, specific visual stimuli lead to highly stereotyped responses. In contrast, humans can exhibit a wide range of responses to the same stimulus, as occurs most notably in the phenomenon of multistable perception. On this basis, one might think that humans have a fundamentally different way of generating actions from sensory inputs, but Toepfer et al. show that flies show evidence of multistable perception as well. Specifically, when confronted with a sensory stimulus that can yield different motor responses, flies switch from one response to another with temporal dynamics that are similar to those of humans and other animals. This suggests that the mechanisms that give rise to the rich repertoire of sensory experience in humans have correlates in much simpler nervous systems.

Visual perceptual learning generalizes to untrained effectors.

Visual perceptual learning (VPL) is an improvement in visual function following training. Although the practical utility of VPL was once thought to be limited by its specificity to the precise stimuli used during training, more recent work has shown that such specificity can be overcome with appropriate training protocols. In contrast, relatively little is known about the extent to which VPL exhibits motor specificity. Previous studies have yielded mixed results. In this work, we have examined the effector specificity of VPL by training observers on a motion discrimination task that maintains the same visual stimulus (drifting grating) and task structure, but that requires different effectors to indicate the response (saccade vs. button press). We find that, in these conditions, VPL transfers fully between a manual and an oculomotor response. These results are consistent with the idea that VPL entails the learning of a decision rule that can generalize across effectors.

Coherent alpha oscillations link current and future receptive fields during saccades.

Oscillations are ubiquitous in the brain, and they can powerfully influence neural coding. In particular, when oscillations at distinct sites are coherent, they provide a means of gating the flow of neural signals between different cortical regions. Coherent oscillations also occur within individual brain regions, although the purpose of this coherence is not well understood. Here, we report that within a single brain region, coherent alpha oscillations link stimulus representations as they change in space and time. Specifically, in primate cortical area V4, alpha coherence links sites that encode the retinal location of a visual stimulus before and after a saccade. These coherence changes exhibit properties similar to those of receptive field remapping, a phenomenon in which individual neurons change their receptive fields according to the metrics of each saccade. In particular, alpha coherence, like remapping, is highly dependent on the saccade vector and the spatial arrangement of current and future receptive fields. Moreover, although visual stimulation plays a modulatory role, it is neither necessary nor sufficient to elicit alpha coherence. Indeed, a similar pattern of coherence is observed even when saccades are made in darkness. Together, these results show that the pattern of alpha coherence across the retinotopic map in V4 matches many of the properties of receptive field remapping. Thus, oscillatory coherence might play a role in constructing the stable representation of visual space that is an essential aspect of conscious perception.

A Unifying Motif for Spatial and Directional Surround Suppression.

In the visual system, the response to a stimulus in a neuron's receptive field can be modulated by stimulus context, and the strength of these contextual influences vary with stimulus intensity. Recent work has shown how a theoretical model, the stabilized supralinear network (SSN), can account for such modulatory influences, using a small set of computational mechanisms. Although the predictions of the SSN have been confirmed in primary visual cortex (V1), its computational principles apply with equal validity to any cortical structure. We have therefore tested the generality of the SSN by examining modulatory influences in the middle temporal area (MT) of the macaque visual cortex, using electrophysiological recordings and pharmacological manipulations. We developed a novel stimulus that can be adjusted parametrically to be larger or smaller in the space of all possible motion directions. We found, as predicted by the SSN, that MT neurons integrate across motion directions for low-contrast stimuli, but that they exhibit suppression by the same stimuli when they are high in contrast. These results are analogous to those found in visual cortex when stimulus size is varied in the space domain. We further tested the mechanisms of inhibition using pharmacological manipulations of inhibitory efficacy. As predicted by the SSN, local manipulation of inhibitory strength altered firing rates, but did not change the strength of surround suppression. These results are consistent with the idea that the SSN can account for modulatory influences along different stimulus dimensions and in different cortical areas.SIGNIFICANCE STATEMENT Visual neurons are selective for specific stimulus features in a region of visual space known as the receptive field, but can be modulated by stimuli outside of the receptive field. The SSN model has been proposed to account for these and other modulatory influences, and tested in V1. As this model is not specific to any particular stimulus feature or brain region, we wondered whether similar modulatory influences might be observed for other stimulus dimensions and other regions. We tested for specific patterns of modulatory influences in the domain of motion direction, using electrophysiological recordings from MT. Our data confirm the predictions of the SSN in MT, suggesting that the SSN computations might be a generic feature of sensory cortex.

Seeing and Feeling Motion: Canonical Computations in Vision and Touch.

While the different sensory modalities are sensitive to different stimulus energies, they are often charged with extracting analogous information about the environment. Neural systems may thus have evolved to implement similar algorithms across modalities to extract behaviorally relevant stimulus information, leading to the notion of a canonical computation. In both vision and touch, information about motion is extracted from a spatiotemporal pattern of activation across a sensory sheet (in the retina and in the skin, respectively), a process that has been extensively studied in both modalities. In this essay, we examine the processing of motion information as it ascends the primate visual and somatosensory neuraxes and conclude that similar computations are implemented in the two sensory systems.

Mechanisms of Saccadic Suppression in Primate Cortical Area V4.

UNLABELLED: Psychophysical studies have shown that subjects are often unaware of visual stimuli presented around the time of an eye movement. This saccadic suppression is thought to be a mechanism for maintaining perceptual stability. The brain might accomplish saccadic suppression by reducing the gain of visual responses to specific stimuli or by simply suppressing firing uniformly for all stimuli. Moreover, the suppression might be identical across the visual field or concentrated at specific points. To evaluate these possibilities, we recorded from individual neurons in cortical area V4 of nonhuman primates trained to execute saccadic eye movements. We found that both modes of suppression were evident in the visual responses of these neurons and that the two modes showed different spatial and temporal profiles: while gain changes started earlier and were more widely distributed across visual space, nonspecific suppression was found more often in the peripheral visual field, after the completion of the saccade. Peripheral suppression was also associated with increased noise correlations and stronger local field potential oscillations in the α frequency band. This pattern of results suggests that saccadic suppression shares some of the circuitry responsible for allocating voluntary attention. SIGNIFICANCE STATEMENT: We explore our surroundings by looking at things, but each eye movement that we make causes an abrupt shift of the visual input. Why doesn't the world look like a film recorded on a shaky camera? The answer in part is a brain mechanism called saccadic suppression, which reduces the responses of visual neurons around the time of each eye movement. Here we reveal several new properties of the underlying mechanisms. First, the suppression operates differently in the central and peripheral visual fields. Second, it appears to be controlled by oscillations in the local field potentials at frequencies traditionally associated with attention. These results suggest that saccadic suppression shares the brain circuits responsible for actively ignoring irrelevant stimuli.

Inferring Cortical Variability from Local Field Potentials.

The responses of sensory neurons can be quite different to repeated presentations of the same stimulus. Here, we demonstrate a direct link between the trial-to-trial variability of cortical neuron responses and network activity that is reflected in local field potentials (LFPs). Spikes and LFPs were recorded with a multielectrode array from the middle temporal (MT) area of the visual cortex of macaques during the presentation of continuous optic flow stimuli. A maximum likelihood-based modeling framework was used to predict single-neuron spiking responses using the stimulus, the LFPs, and the activity of other recorded neurons. MT neuron responses were strongly linked to gamma oscillations (maximum at 40 Hz) as well as to lower-frequency delta oscillations (1-4 Hz), with consistent phase preferences across neurons. The predicted modulation associated with the LFP was largely complementary to that driven by visual stimulation, as well as the activity of other neurons, and accounted for nearly half of the trial-to-trial variability in the spiking responses. Moreover, the LFP model predictions accurately captured the temporal structure of noise correlations between pairs of simultaneously recorded neurons, and explained the variation in correlation magnitudes observed across the population. These results therefore identify signatures of network activity related to the variability of cortical neuron responses, and suggest their central role in sensory cortical function. SIGNIFICANCE STATEMENT: The function of sensory neurons is nearly always cast in terms of representing sensory stimuli. However, recordings from visual cortex in awake animals show that a large fraction of neural activity is not predictable from the stimulus. We show that this variability is predictable given the simultaneously recorded measures of network activity, local field potentials. A model that combines elements of these signals with the stimulus processing of the neuron can predict neural responses dramatically better than current models, and can predict the structure of correlations across the cortical population. In identifying ways to understand stimulus processing in the context of ongoing network activity, this work thus provides a foundation to understand the role of sensory cortex in combining sensory and cognitive variables.

High-resolution retinotopic maps estimated with magnetoencephalography.

Magnetoencephalography (MEG) is used in clinical and fundamental studies of brain functions, primarily for the excellent temporal resolution it provides. The spatial resolution is often assumed to be poor, because of the ill-posed nature of MEG source modeling. However, the question of spatial resolution in MEG has seldom been studied in quantitative detail. Here we use the well-known retinotopic organization of the primary visual cortex (V1) as a benchmark for estimating the spatial resolution of MEG source imaging. Using a standard visual stimulation paradigm in human subjects, we find that individual MEG sources exhibit well-delineated visual receptive fields that collectively follow the known mapping of the retinal surface onto the cortex. Based on the size of these receptive fields and the variability of the signal, we are able to resolve MEG signals separated by approximately 7 mm in smooth regions of cortex and less than 1 mm for signals near curved gyri. The maximum resolution is thus comparable to that of the spacing of hypercolumns in human visual cortex. Overall, our results suggest that the spatial resolution of MEG can approach or in some cases exceed that of fMRI.

IL-18 acts in synergy with IL-7 to promote ex vivo expansion of T lymphoid progenitor cells.

Although IL-18 has not previously been shown to promote T lymphopoiesis, results obtained via a novel data mining algorithm (global microarray meta-analysis) led us to explore a predicted role for this cytokine in T cell development. IL-18 is a member of the IL-1 cytokine family that has been extensively characterized as a mediator of inflammatory immune responses. To assess a potential role for IL-18 in T cell development, we sort-purified mouse bone marrow-derived common lymphoid progenitor cells, early thymic progenitors (ETPs), and double-negative 2 thymocytes and cultured these populations on OP9-Delta-like 4 stromal layers in the presence or absence of IL-18 and/or IL-7. After 1 wk of culture, IL-18 promoted proliferation and accelerated differentiation of ETPs to the double-negative 3 stage, similar in efficiency to IL-7. IL-18 showed synergy with IL-7 and enhanced proliferation of both the thymus-derived progenitor cells and the bone marrow-derived common lymphoid progenitor cells. The synergistic effect on the ETP population was further characterized and found to correlate with increased surface expression of c-Kit and IL-7 receptors on the IL-18-treated cells. In summary, we successfully validated the global microarray meta-analysis prediction that IL-18 affects T lymphopoiesis and demonstrated that IL-18 can positively impact bone marrow lymphopoiesis and T cell development, presumably via interaction with the c-Kit and IL-7 signaling axis.

Perisaccadic perception of visual space in people with schizophrenia.

Corollary discharge signals are found in the nervous systems of many animals, where they serve a large variety of functions related to the integration of sensory and motor signals. In humans, an important corollary discharge signal is generated by oculomotor structures and communicated to sensory systems in concert with the execution of each saccade. This signal is thought to serve a number of purposes related to the maintenance of accurate visual perception. The properties of the oculomotor corollary discharge can be probed by asking subjects to localize stimuli that are flashed briefly around the time of a saccade. The results of such experiments typically reveal large errors in localization. Here, we have exploited these well-known psychophysical effects to assess the potential dysfunction of corollary discharge signals in people with schizophrenia. In a standard perisaccadic localization task, we found that, compared with controls, patients with schizophrenia exhibited larger errors in localizing visual stimuli. The pattern of errors could be modeled as an overdamped corollary discharge signal that encodes instantaneous eye position. The dynamics of this signal predicted symptom severity among patients, suggesting a possible mechanistic basis for widely observed behavioral manifestations of schizophrenia.

Synapse formation changes the rules for desensitization of PKC translocation in Aplysia.

Protein kinase Cs (PKCs) are activated by translocating from the cytoplasm to the membrane. We have previously shown that serotonin-mediated translocation of PKC to the plasma membrane in Aplysia sensory neurons was subject to desensitization, a decrease in the ability of serotonin to induce translocation after previous application of serotonin. In Aplysia, changes in the strength of the sensory-motor neuron synapse are important for behavioral sensitization and PKC regulates a number of important aspects of this form of synaptic plasticity. We have previously suggested that the desensitization of PKC translocation in Aplysia sensory neurons may partially explain the differences between spaced and massed training, as spaced applications of serotonin, a cellular analog of spaced training, cause greater desensitization of PKC translocation than one massed application of serotonin, a cellular analog of massed training. Our previous studies were performed in isolated sensory neurons. In the present study, we monitored translocation of fluorescently-tagged PKC to the plasma membrane in living sensory neurons that were co-cultured with motor neurons to allow for synapse formation. We show that desensitization now becomes similar during spaced and massed applications of serotonin. We had previously modeled the signaling pathways that govern desensitization in isolated sensory neurons. We now modify this mathematical model to account for the changes observed in desensitization dynamics following synapse formation. Our study shows that synapse formation leads to significant changes in the molecular signaling networks that underlie desensitization of PKC translocation.

Parietal cortex signals come unstuck in time.

Humans and other animals are surprisingly adept at estimating the duration of temporal intervals, even without the use of watches and clocks. This ability is typically studied in the lab by asking observers to indicate their estimate of the time between two external sensory events. The results of such studies confirm that humans can accurately estimate durations on a variety of time scales. Although many brain areas are thought to contribute to the representation of elapsed time, recent neurophysiological studies have linked the parietal cortex in particular to the perception of sub-second time intervals. In this Primer, we describe previous work on parietal cortex and time perception, and we highlight the findings of a study published in this issue of PLOS Biology, in which Schneider and Ghose characterize single-neuron responses during performance of a novel "Temporal Production" task. During temporal production, the observer must track the passage of time without anticipating any external sensory event, and it appears that the parietal cortex may use a unique strategy to support this type of measurement.

Hierarchical processing of complex motion along the primate dorsal visual pathway.

Neurons in the medial superior temporal (MST) area of the primate visual cortex respond selectively to complex motion patterns defined by expansion, rotation, and deformation. Consequently they are often hypothesized to be involved in important behavioral functions, such as encoding the velocities of moving objects and surfaces relative to the observer. However, the computations underlying such selectivity are unknown. In this work we have developed a unique, naturalistic motion stimulus and used it to probe the complex selectivity of MST neurons. The resulting data were then used to estimate the properties of the feed-forward inputs to each neuron. This analysis yielded models that successfully accounted for much of the observed stimulus selectivity, provided that the inputs were combined via a nonlinear integration mechanism that approximates a multiplicative interaction among MST inputs. In simulations we found that this type of integration has the functional role of improving estimates of the 3D velocity of moving objects. As this computation is of general utility for detecting complex stimulus features, we suggest that it may represent a fundamental aspect of hierarchical sensory processing.