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.

Reversible deactivation of motor cortex reveals that areas in parietal cortex are differentially dependent on motor cortex for the generation of movement.

Primates are characterized by specializations for manual manipulation, including expansion of posterior parietal cortex (PPC) and, in Catarrhines, evolution of a dexterous hand and opposable thumb. Previous studies examined functional interactions between motor cortex and PPC in New World monkeys and galagos, by inactivating M1 and evoking movements from PPC. These studies found that portions of PPC depend on M1 to generate movements. We now add a species that more closely resembles humans in hand morphology and PPC: macaques. Inactivating portions of M1 resulted in all evoked movements being reduced (28%) or completely abolished (72%) at the PPC sites tested (in areas 5L, PF, and PFG). Anterior parietal area 2 was similarly affected (26% reduced and 74% abolished) and area 1 was the least affected (12% no effect, 54% reduced, and 34% abolished). Unlike previous studies in New World monkeys and galagos, interactions between both nonanalogous (heterotopic) and analogous (homotopic) M1 and parietal movement domains were commonly found in most areas. These experiments demonstrate that there may be two parallel networks involved in motor control: a posterior parietal network dependent on M1 and a network that includes area 1 that is relatively independent of M1. Furthermore, it appears that the relative size and number of cortical fields in parietal cortex in different species correlates with homotopic and heterotopic effect prevalence. These functional differences in macaques could contribute to more numerous and varied muscle synergies across major muscle groups, supporting the expansion of the primate manual behavioral repertoire observed in Old World monkeys.NEW & NOTEWORTHY Motor cortex and anterior and posterior parietal cortex form a sensorimotor integration network. We tested the extent to which parietal areas could initiate movements independent of M1. Our findings support the contention that, although areas 2, 5L, PF, and PFG are highly dependent on M1 to produce movement, area 1 may constitute a parallel corticospinal pathway that can function somewhat independently of M1. A similar functional architecture may underlie dexterous tool use in humans.

Complex forelimb movements and cortical topography evoked by intracortical microstimulation in male and female mice.

The motor cortex is crucial for the voluntary control of skilled movement in mammals and is topographically organized into representations of the body (motor maps). Intracortical microstimulation of the motor cortex with long-duration pulse trains (LD-ICMS; ~500 ms) evokes complex movements, occurring in multiple joints or axial muscles, with characteristic movement postures and cortical topography across a variety of mammalian species. Although the laboratory mouse is extensively used in basic and pre-clinical research, high-resolution motor maps elicited with electrical LD-ICMS in both sexes of the adult mouse has yet to be reported. To address this knowledge gap, we performed LD-ICMS of the forelimb motor cortex in both male (n = 10) and naturally cycling female (n = 8) C57/BL6J mice under light ketamine-xylazine anesthesia. Complex and simple movements were evoked from historically defined caudal (CFA) and rostral (RFA) forelimb areas. Four complex forelimb movements were identified consisting of Elevate, Advance, Dig, and Retract postures with characteristic movement sequences and endpoints. Furthermore, evoked complex forelimb movements and cortical topography in mice were organized within the CFA in a unique manner relative to a qualitative comparison with the rat.

Functional imaging and anatomical connections in squirrel monkeys reveal parietal-frontal circuits underlying eye movements.

The posterior parietal cortex (PPC) of squirrel monkeys contains subregions where long trains of intracortical microstimulation evoke complex, behaviorally meaningful movements. Recently, we showed that such stimulation of a part of the PPC in the caudal lateral sulcus (LS) elicits eye movements in these monkeys. Here, we studied the functional and anatomical connections of this oculomotor region we call parietal eye field (PEF) with frontal eye field (FEF) and other cortical regions in 2 squirrel monkeys. We demonstrated these connections with intrinsic optical imaging and injections of anatomical tracers. Optical imaging of frontal cortex during stimulation of the PEF evoked focal functional activation within FEF. Tracing studies confirmed the functional PEF-FEF connections. Moreover, tracer injections revealed PEF connections with other PPC regions on the dorsolateral and medial brain surface, cortex in the caudal LS, and visual and auditory cortical association areas. Subcortical projections of PEF were primarily with superior colliculus, and pontine nuclei as well as nuclei of the dorsal posterior thalamus and caudate. These findings suggest that PEF in squirrel monkey is homologous to lateral intraparietal (LIP) area of macaque, supporting the notion that these brain circuits are organized similarly to mediate ethologically relevant oculomotor behaviors.

Microstimulation in the primary visual cortex: activity patterns and their relation to visual responses and evoked saccades.

Intracortical microstimulation (ICMS) in the primary visual cortex (V1) can generate the visual perception of a small point of light, termed phosphene, and evoke saccades directed to the receptive field of the stimulated neurons. Although ICMS is widely used, a direct measurement of the spatio-temporal patterns of neural activity evoked by ICMS and their relation to the neural responses evoked by visual stimuli or how they relate to ICMS-evoked saccades are still missing. To investigate this, we combined ICMS with voltage-sensitive dye imaging in V1 of behaving monkeys and measured neural activity at a high spatial (meso-scale) and temporal resolution. We then compared the population response evoked by small visual stimuli to those evoked by microstimulation. Both stimulation types evoked population activity that spread over few millimeters in V1 and propagated to extrastriate areas. However, the population responses evoked by ICMS have shown faster dynamics for the activation transients and the horizontal propagation of activity revealed a wave-like propagation. Finally, neural activity in the ICMS condition was higher for trials with evoked saccades as compared with trials without saccades. Our results uncover the spatio-temporal patterns evoked by ICMS and their relation to visual processing and saccade generation.

In-vivo testing of a novel wireless intraspinal microstimulation interface for restoration of motor function following spinal cord injury.

BACKGROUND: Spinal cord injury causes a drastic loss in motor and sensory function. Intraspinal microstimulation (ISMS) is an electrical stimulation method developed for restoring motor function by activating the spinal networks below the level of injury. Current ISMS technology uses fine penetrating microwires to stimulate the ventral horn of the lumbar enlargement. The penetrating wires traverse the dura mater through a transdural conduit that connects to an implantable pulse generator. OBJECTIVE: A wireless, fully intradural ISMS implant was developed to mitigate the potential complications associated with the transdural conduit, including tethering and leakage of cerebrospinal fluid. METHODS: Two wireless floating microelectrode array (WFMA) devices were implanted in the lumbar enlargement of an adult domestic pig. Voltage transients were used to assess the electrochemical stability of the interface. Manual flexion and extension movements of the spine were performed to evaluate the mechanical stability of the interface. Post-mortem 9T MRI imaging was used to confirm the location of the electrodes. RESULTS: The WFMA-based ISMS interface successfully evoked extension and flexion movements of the hip joint. Stimulation thresholds remained stable following manual extension and flexion of the spine. CONCLUSION: The preliminary results demonstrate the surgical feasibility as well as the functionality of the proposed wireless ISMS system.

Chronic Stimulation Improves Motor Performance in an Ambulatory Rat Model of Spinal Cord Injury.

BACKGROUND: The purpose of this proof-of-concept feasibility study was to determine if spike-triggered intraspinal microstimulation (ISMS), a form of activity dependent stimulation (ADS), results in improved motor performance in an ambulatory rat model of spinal cord injury (SCI). METHODS: Experiments were carried out in adult male Sprague Dawley rats with moderate thoracic contusion injury. Rats were assigned to one of two groups: Control or ADS therapy. Four weeks post-SCI, all rats were implanted with a recording microelectrode in the left hindlimb motor cortex and a fine-wire stimulating electrode in the contralateral lumbar spinal cord. ADS was administered for 4 hours/day, 4 days/week, for 4 weeks. During therapy sessions, single-unit spikes were discriminated in real time in the hindlimb motor cortex and used to trigger stimulation in the spinal cord ventral horn. Control rats were similarly implanted with electrodes but did not receive stimulation therapy. RESULTS: Motor performances of each rat were evaluated before SCI contusion, once a week post-SCI for four weeks (prior to electrode implantation), and once a week post-conditioning for four weeks. Basso, Beattie, and Bresnahan (BBB) locomotor scores were significantly improved in ADS rats compared to Control rats at 1 and 2 weeks after initiation of therapy. Foot fault scores on the Horizontal Ladder were significantly improved in ADS rats compared to pre-therapy ADS and Control rats after 1 week of therapy and recovered to near pre-injury scores after 3 weeks of therapy. The Ledged Beam test showed deficits after SCI in both ADS and Control rats but there were no significant differences between groups after 4 weeks of ADS therapy. CONCLUSIONS: These results show that chronic stimulation after spinal cord injury using a methodology of spike-triggered ISMS enhances behavioral recovery of locomotor function as measured by the BBB score and the Horizontal Ladder task. However, it is still uncertain if the behavioral improvements seen were dependent on spike-triggered ISMS.

The Neurophysiological Representation of Imagined Somatosensory Percepts in Human Cortex.

Intracortical microstimulation (ICMS) in human primary somatosensory cortex (S1) has been used to successfully evoke naturalistic sensations. However, the neurophysiological mechanisms underlying the evoked sensations remain unknown. To understand how specific stimulation parameters elicit certain sensations we must first understand the representation of those sensations in the brain. In this study we record from intracortical microelectrode arrays implanted in S1, premotor cortex, and posterior parietal cortex of a male human participant performing a somatosensory imagery task. The sensations imagined were those previously elicited by ICMS of S1, in the same array of the same participant. In both spike and local field potential recordings, features of the neural signal can be used to classify different imagined sensations. These features are shown to be stable over time. The sensorimotor cortices only encode the imagined sensation during the imagery task, while posterior parietal cortex encodes the sensations starting with cue presentation. These findings demonstrate that different aspects of the sensory experience can be individually decoded from intracortically recorded human neural signals across the cortical sensory network. Activity underlying these unique sensory representations may inform the stimulation parameters for precisely eliciting specific sensations via ICMS in future work.SIGNIFICANCE STATEMENT Electrical stimulation of human cortex is increasingly more common for providing feedback in neural devices. Understanding the relationship between naturally evoked and artificially evoked neurophysiology for the same sensations will be important in advancing such devices. Here, we investigate the neural activity in human primary somatosensory, premotor, and parietal cortices during somatosensory imagery. The sensations imagined were those previously elicited during intracortical microstimulation (ICMS) of the same somatosensory electrode array. We elucidate the neural features during somatosensory imagery that significantly encode different aspects of individual sensations and demonstrate feature stability over almost a year. The correspondence between neurophysiology elicited with or without stimulation for the same sensations will inform methods to deliver more precise feedback through stimulation in the future.

Microstimulation of the Premotor Cortex of the Cat Produces Phase-Dependent Changes in Locomotor Activity.

To determine the functional organization of premotor areas in the cat pericruciate cortex we applied intracortical microstimulation (ICMS) within multiple cytoarchitectonically identified subregions of areas 4 and 6 in the awake cat, both at rest and during treadmill walking. ICMS in most premotor areas evoked clear twitch responses in the limbs and/or head at rest. During locomotion, these same areas produced phase-dependent modifications of muscle activity. ICMS in the primary motor cortex (area 4γ) produced large phase-dependent responses, mostly restricted to the contralateral forelimb or hindlimb. Stimulation in premotor areas also produced phase-dependent responses that, in some cases, were as large as those evoked from area 4γ. However, responses from premotor areas had more widespread effects on multiple limbs, including the ipsilateral limbs, than did stimulation in 4γ. During locomotion, responses in both forelimb and hindlimb muscles were evoked from cytoarchitectonic areas 4γ, 4δ, 6aα, and 6aγ. However, the prevalence of effects in a given limb varied from one area to another. The results suggest that premotor areas may contribute to the production, modification, and coordination of activity in the limbs during locomotion and may be particularly pertinent during modifications of gait.

Endometrial microstimulation effects on endometrial receptivity assessed by transvaginal color Doppler sonography.

OBJECTIVE: This study investigated the effect of endometrial microstimulation (EM) on endometrial receptivity using transvaginal color Doppler sonography (TVCDS). METHOD: Women of childbearing age who were preparing to conceive (n = 90) were randomly divided into the EM group (n = 30), who were examined by EM on days 3-5 of the menstrual cycle, and the control group (n = 60). TVCDS was conducted during the implantation window phase, and endometrial thickness, endometrial pattern, endometrial movement, blood flow type, and uterine and spiral arterial hemodynamic parameter measurements were made. The groups were compared to identify differences. RESULTS: Endometrial thickness (0.97 ± 0.18 cm and 0.95 ± 0.17 cm), endometrial movement (type 1: 46.7% and 51.7%; type 2: 30.0% and 28.3%; type 3: 6.7% and 5.0%; type 5: 16.7% and 15.0%), and hemodynamic parameters of the uterine (pulsatility index [PI]: 2.46 ± 0.50 and 2.41 ± 0.48; resistance index [RI]: 0.85 ± 0.05 and 0.84 ± 0.05) and spiral (PI: 1.11 ± 0.32 and 1.19 ± 0.33; RI: 0.48 ± 0.11 and 0.51 ± 0.08) arteries did not differ significantly between groups (P > 0.05). However, the endometrial pattern (a trilaminar pattern: 80.0% and 58.3%; P = 0.041) and blood flow type (type I: 16.7% and 43.3%; type II: 63.3% and 40.0%; type III 20.0% and 16.7%; P = 0.038) differed significantly between groups. CONCLUSION: Endometrial microstimulation did not alter endometrial pathological staging, endometrial thickness, or movement, nor did it affect uterine and spiral arterial blood flow parameters. However, it may be able to abrade abnormal endometrial tissue, optimizing the endometrial pattern. Endometrial microstimulation may support local spiral artery regeneration and increase endometrial blood supply in new cycles.

Learning active sensing strategies using a sensory brain-machine interface.

Diverse organisms, from insects to humans, actively seek out sensory information that best informs goal-directed actions. Efficient active sensing requires congruity between sensor properties and motor strategies, as typically honed through evolution. However, it has been difficult to study whether active sensing strategies are also modified with experience. Here, we used a sensory brain-machine interface paradigm, permitting both free behavior and experimental manipulation of sensory feedback, to study learning of active sensing strategies. Rats performed a searching task in a water maze in which the only task-relevant sensory feedback was provided by intracortical microstimulation (ICMS) encoding egocentric bearing to the hidden goal location. The rats learned to use the artificial goal direction sense to find the platform with the same proficiency as natural vision. Manipulation of the acuity of the ICMS feedback revealed distinct search strategy adaptations. Using an optimization model, the different strategies were found to minimize the effort required to extract the most salient task-relevant information. The results demonstrate that animals can adjust motor strategies to match novel sensor properties for efficient goal-directed behavior.

Multistable properties of human subthalamic nucleus neurons in Parkinson's disease.

To understand the function and dysfunction of neural circuits, it is necessary to understand the properties of the neurons participating in the behavior, the connectivity between these neurons, and the neuromodulatory status of the circuits at the time they are producing the behavior. Such knowledge of human neural circuits is difficult, at best, to obtain. Here, we study firing properties of human subthalamic neurons, using microelectrode recordings and microstimulation during awake surgery for Parkinson's disease. We demonstrate that low-amplitude, brief trains of microstimulation can lead to persistent changes in neuronal firing behavior including switching between firing rates, entering silent periods, or firing several bursts then entering a silent period. We suggest that these multistable states reflect properties of finite state machines and could have implications for the function of circuits involving the subthalamic nucleus. Furthermore, understanding these states could lead to therapeutic strategies aimed at regulating the transitions between states.

Principles of Intrinsic Motor Cortex Connectivity in Primates.

The forelimb representation in motor cortex (M1) is an important model system in contemporary neuroscience. Efforts to understand the organization of the M1 forelimb representation in monkeys have focused on inputs and outputs. In contrast, intrinsic M1 connections remain mostly unexplored, which is surprising given that intra-areal connections universally outnumber extrinsic connections. To address this knowledge gap, we first mapped the M1 forelimb representation with intracortical microstimulation (ICMS) in male squirrel monkeys. Next, we determined the connectivity of individual M1 sites with ICMS + intrinsic signal optical imaging (ISOI). Every stimulation site activated a distinctive pattern of patches (∼0.25 to 1.0 mm radius) that we quantified in relation to the motor map. Arm sites activated patches that were mostly in arm zones. Hand sites followed the same principle, but to a lesser extent. The results collectively indicate that preferential connectivity between functionally matched patches is a prominent organizational principle in M1. Connectivity patterns for a given site were conserved across a range of current amplitudes, train durations, pulse frequencies, and microelectrode depths. In addition, we found close correspondence in somatosensory cortex between connectivity that we revealed with ICMS+ISOI and connections known from tracers. ICMS+ISOI is therefore an effective tool for mapping cortical connectivity and is particularly advantageous for sampling large numbers of sites. This feature was instrumental in revealing the spatial specificity of intrinsic M1 connections, which appear to be woven into the somatotopic organization of the forelimb representation. Such a framework invokes the modular organization well-established for sensory cortical areas.SIGNIFICANCE STATEMENT Intrinsic connections are fundamental to the operations of any cortical area. Surprisingly little is known about the organization of intrinsic connections in motor cortex (M1). We addressed this knowledge gap using intracortical microstimulation (ICMS) concurrently with intrinsic signal optical imaging (ISOI). Quantifying the activation patterns from dozens of M1 sites allowed us to uncover a fundamental principle of M1 organization: M1 patches are preferentially connected with functionally matched patches. Relationship between intrinsic connections and neurophysiological map is well-established for sensory cortical areas, but our study is the first to extend this framework to M1. Microstimulation+imaging opened a unique possibility for investigating the connectivity of dozens of tightly spaced M1 sites, which was the linchpin for uncovering organizational principles.

Dynamic encoding of saccade sequences in primate frontal eye field.

The frontal eye field (FEF) is a key part of the oculomotor system, with dominant responses to the direction of single saccades. However, whether and how FEF contributes to sequential saccades remain largely unknown. By training rhesus monkeys to perform saccade sequences, we found sequence-related activities in FEF neurons, whose selectivity to saccade direction undergoes dynamic changes during sequential vs. single saccades. These sequence-related activities are context-dependent, exhibiting different firing activities during memory- vs. visually guided sequences. When the monkey was performing the sequential saccade task, the thresholds of microstimulation to evoke saccades in FEF were increased and the percentage of the successfully induced saccades was significantly reduced compared with the fixation condition. Pharmacological inactivation of FEF impaired the monkey's performance of previously learned sequential saccades, with different effects on the same actions depending on its position within the sequence. These results reveal the context-dependent, sequence-specific dynamic encoding of saccades in FEF, and underscore the crucial role of FEF in the planning and execution of sequential saccades. KEY POINTS: FEF neurons respond differently during sequential vs. single saccades Sequence-related FEF activity is context-dependent The microstimulation threshold in FEF was increased during the sequential task but the evoked saccade did not alter the sequence structure FEF inactivation severely impaired the performance of sequential saccades.

Mapping functional gradients of the striatal circuit using simultaneous microelectric stimulation and ultrahigh-field fMRI in non-human primates.

Advances in functional magnetic resonance imaging (fMRI) have significantly enhanced our understanding of the striatal system of both humans and non-human primates (NHP) over the last few decades. However, its circuit-level functional anatomy remains poorly understood, partly because in-vivo fMRI cannot directly perturb a brain system and map its casual input-output relationship. Also, routine 3T fMRI has an insufficient spatial resolution. We performed electrical microstimulation (EM) of the striatum in lightly-anesthetized NHPs while simultaneously mapping whole-brain activation, using contrast-enhanced fMRI at ultra-high-field 7T. By stimulating multiple positions along the striatum's main (dorsal-to-ventral) axis, we revealed its complex functional circuit concerning mutually connected subsystems in both cortical and subcortical areas. Indeed, within the striatum, there were distinct brain activation patterns across different stimulation sites. Specifically, dorsal stimulation revealed a medial-to-lateral elongated shape of activation in upper caudate and putamen areas, whereas ventral stimulation evoked areas confined to the medial and lower caudate. Such dorsoventral gradients also appeared in neocortical and thalamic activations, indicating consistent embedding profiles of the striatal system across the whole brain. These findings reflect different forms of within-circuit and inter-regional neuronal connectivity between the dorsal and ventromedial striatum. These patterns both shared and contrasted with previous anatomical tract-tracing and in-vivo resting-state fMRI studies. Our approach of combining microstimulation and whole-brain fMRI mapping in NHPs provides a unique opportunity to integrate our understanding of a targeted brain area's meso- and macro-scale functional systems.

Combining brain perturbation and neuroimaging in non-human primates.

Brain perturbation studies allow detailed causal inferences of behavioral and neural processes. Because the combination of brain perturbation methods and neural measurement techniques is inherently challenging, research in humans has predominantly focused on non-invasive, indirect brain perturbations, or neurological lesion studies. Non-human primates have been indispensable as a neurobiological system that is highly similar to humans while simultaneously being more experimentally tractable, allowing visualization of the functional and structural impact of systematic brain perturbation. This review considers the state of the art in non-human primate brain perturbation with a focus on approaches that can be combined with neuroimaging. We consider both non-reversible (lesions) and reversible or temporary perturbations such as electrical, pharmacological, optical, optogenetic, chemogenetic, pathway-selective, and ultrasound based interference methods. Method-specific considerations from the research and development community are offered to facilitate research in this field and support further innovations. We conclude by identifying novel avenues for further research and innovation and by highlighting the clinical translational potential of the methods.

Development and plasticity of complex movement representations.

The mammalian motor cortex is topographically organized into representations of discrete body parts (motor maps). Studies in adult rats using long-duration intracortical microstimulation (LD-ICMS) reveal that forelimb motor cortex is functionally organized into several spatially distinct areas encoding complex, multijoint movement sequences: elevate, advance, grasp, and retract. The topographical arrangement of complex movements during development and the influence of skilled learning are unknown. Here, we determined the emergence and topography of complex forelimb movement representations in rats between postnatal days (PND) 13 and 60. We further investigated the expression of the maps for complex movements under conditions of reduced cortical inhibition and whether skilled forelimb motor training could alter their developing topography. We report that simple forelimb movements are first evoked at PND 25 and are confined to the caudal forelimb area (CFA), whereas complex movements first reliably appear at PND 30 and are observed in both the caudal and rostral forelimb areas (RFA). During development, the topography of complex movement representations undergoes reorganization with "grasp" and "elevate" movements predominantly observed in the RFA and all four complex movements observed in CFA. Under reduced cortical inhibition, simple and complex movements were first observed in the CFA on PND 15 and 20, respectively, and the topography is altered relative to a saline control. Further, skilled motor learning was associated with increases in "grasp" and "retract" representations specific to the trained limb. Our results demonstrate that early-life motor experience during development can modify the topography of complex forelimb movement representations.NEW & NOTEWORTHY The motor cortex is topographically organized into maps of different body parts. We used to think that the function of motor cortex was to drive individual muscles, but more recently we have learned that it is also organized to make complex movements. However, the development and plasticity of those complex movements is completely unknown. In this paper, the emergence and topography of complex movement representation, as well as their plasticity during development, is detailed.

Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques.

The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.

Focal Electrical Stimulation of Cortical Functional Networks.

Traditional electrical stimulation of brain tissue typically affects relatively large volumes of tissue spanning multiple millimeters. This low spatial resolution stimulation results in nonspecific functional effects. In addition, a primary shortcoming of these designs was the failure to take advantage of inherent functional organization in the cerebral cortex. Here, we describe a new method to electrically stimulate the brain which achieves selective targeting of single feature-specific domains in visual cortex. We provide evidence that this paradigm achieves mesoscale, functional network-specificity, and intensity dependence in a way that mimics visual stimulation. Application of this approach to known feature domains (such as color, orientation, motion, and depth) in visual cortex may lead to important functional improvements in the specificity and sophistication of brain stimulation methods and has implications for visual cortical prosthetic design.

Neural basis of location-specific pupil luminance modulation.

Spatial attention enables us to focus visual processing toward specific locations or stimuli before the next fixation. Recent evidence has suggested that local luminance at the spatial locus of attention or saccade preparation influences pupil size independent of global luminance levels. However, it remains to be determined which neural pathways produce this location-specific modulation of pupil size. The intermediate layers of the midbrain superior colliculus (SC) form part of the network of brain areas involved in spatial attention and modulation of pupil size. Here, we demonstrated that pupil size was altered according to local luminance level at the spatial location corresponding to a microstimulated location in the intermediate SC (SCi) map of monkeys. Moreover, local SCi inactivation through injection of lidocaine reversed this local luminance modulation. Our findings reveal a causal role of the SCi in preparing pupil size for local luminance conditions at the next saccadic goal.