Transcranial direct current stimulation (tDCS) has emerged as a potentially safe and effective brain stimulation modality that alters cortical excitability by passing a small, constant electric current through the scalp. tDCS creates an electric field that weakly modulates the membrane voltage of a large number of cortical neurons. Recent human studies have suggested that sine-wave stimulation waveforms [transcranial alternating current stimulation (tACS)] represent a more targeted stimulation paradigm for the enhancement of cortical oscillations. Yet, the underlying mechanisms of how periodic, weak global perturbations alter the spatiotemporal dynamics of large-scale cortical network dynamics remain a matter of debate. Here, we simulated large-scale networks of spiking neuron models to address this question in endogenously rhythmic networks. We identified distinct roles of the depolarizing and hyperpolarizing phases of tACS in entrainment, which entailed moving network activity toward and away from a strong nonlinearity provided by the local excitatory coupling of pyramidal cells. Together, these mechanisms gave rise to resonance dynamics characterized by an Arnold tongue centered on the resonance frequency of the network. We then performed multichannel extracellular recordings of multiunit firing activity during tACS in anesthetized ferrets (Mustela putoris furo), a model species with a gyrencephalic brain, to verify that weak global perturbations can selectively enhance oscillations at the applied stimulation frequency. Together, these results provide a detailed mechanistic understanding of tACS at the level of large-scale network dynamics and support the future design of activity-dependent feedback tACS paradigms that dynamically tailor stimulation frequency to the spectral peak of ongoing brain activity.

No abstract

Highlights d We investigated the effects of brain stimulation on mood state in epilepsy patients d Lateral OFC stimulation improved mood state in subjects with depression symptoms d This stimulation induced neural features associated with positive mood states d Lateral OFC is a promising new stimulation target for treatment of mood disorders

Anesthesia is widely used in medicine and research to achieve altered states of consciousness and cognition. Whereas changes to macroscopic cortical activity patterns by anesthesia measured at the spatial resolution of electroencephalography have been widely studied, modulation of mesoscopic and microscopic network dynamics by anesthesia remain poorly understood. To address this gap in knowledge, we recorded spontaneous mesoscopic (local field potential) and microscopic (multiunit activity) network dynamics in primary visual cortex (V1) and prefrontal cortex (PFC) of awake and isoflurane anesthetized ferrets ( Mustela putoris furo). This approach allowed for examination of activity as a function of cortical area, cortical layer, and anesthetic depth with much higher spatial and temporal resolution than in previous studies. We hypothesized that a primary sensory area and an association cortical area would exhibit different patterns of network modulation by anesthesia due to their different functional roles. Indeed, we found effects specific to cortical area and cortical layer. V1 exhibited minimal changes in rhythmic structure with anesthesia but differential modulation of input layer IV. In contrast, anesthesia profoundly altered spectral power in PFC, with more uniform modulation across cortical layers. Our results demonstrate that anesthesia modulates spontaneous cortical activity in an area- and layer-specific manner. These finding provide the basis for 1) refining anesthesia monitoring algorithms, 2) reevaluating the large number of systems neuroscience studies performed in anesthetized animals, and 3) increasing our understanding of differential dynamics across cortical layers and areas.

During general anesthesia, global brain activity and behavioral state are profoundly altered. Yet it remains mostly unknown how anesthetics alter sensory processing across cortical layers and modulate functional cortico-cortical connectivity. To address this gap in knowledge of the micro- and mesoscale effects of anesthetics on sensory processing in the cortical microcircuit, we recorded multiunit activity and local field potential in awake and anesthetized ferrets (Mustela putoris furo) during sensory stimulation. To understand how anesthetics alter sensory processing in a primary sensory area and the representation of sensory input in higher-order association areas, we studied the local sensory responses and long-range functional connectivity of primary visual cortex (V1) and prefrontal cortex (PFC). Isoflurane combined with xylazine provided general anesthesia for all anesthetized recordings. We found that anesthetics altered the duration of sensory-evoked responses, disrupted the response dynamics across cortical layers, suppressed both multimodal interactions in V1 and sensory responses in PFC, and reduced functional cortico-cortical connectivity between V1 and PFC. Together, the present findings demonstrate altered sensory responses and impaired functional network connectivity during anesthesia at the level of multiunit activity and local field potential across cortical layers.

The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.

Cognitive impairment represents one of the most debilitating and most difficult symptom to treat of many psychiatric illnesses. Human neurophysiology studies have suggested specific pathologies of cortical network activity correlate with cognitive impairment. However, we lack (1) demonstration of causal relationships between specific network activity patterns and cognitive capabilities and (2) treatment modalities that directly target impaired network dynamics of cognition. Transcranial alternating current stimulation (tACS), a novel non-invasive brain stimulation approach, may provide a crucial tool to tackle these challenges. We here propose that tACS can be used to elucidate the causal role of cortical synchronization in cognition and, eventually, to enhance pathologically weakened synchrony that may underlie cognitive deficits. To accelerate such development of tACS as a treatment for cognitive deficits, we discuss studies on tACS and cognition (all performed in healthy participants) according to the Research Domain Criteria (RDoC) of the National Institute of Mental Health.

Resting state functional magnetic resonance imaging (rsfMRI) has emerged as a versatile tool for non-invasive measurement of functional connectivity patterns in the brain. RsfMRI brain dynamics in rodents, non-human primates, and humans share similar properties; however, little is known about the resting state functional connectivity patterns in the ferret, an animal model with high potential for developmental and cognitive translational study. To address this knowledge-gap, we performed rsfMRI on anesthetized ferrets using a 9.4 tesla MRI scanner, and subsequently performed group-level independent component analysis (gICA) to identify functionally connected brain networks. Group-level ICA analysis revealed distributed sensory, motor, and higher-order networks in the ferret brain. Subsequent connectivity analysis showed interconnected higher-order networks that constituted a putative default mode network (DMN), a network that exhibits altered connectivity in neuropsychiatric disorders. Finally, we assessed ferret brain topological efficiency using graph theory analysis and found that the ferret brain exhibits small-world properties. Overall, these results provide additional evidence for pan-species resting-state networks, further supporting ferret-based studies of sensory and cognitive function.