Consistent linear and non-linear responses to invasive electrical brain stimulation across individuals and primate species with implanted electrodes.

BACKGROUND: Electrical neuromodulation via implanted electrodes is used in treating numerous neurological disorders, yet our knowledge of how different brain regions respond to varying stimulation parameters is sparse. OBJECTIVE/HYPOTHESIS: We hypothesized that the neural response to electrical stimulation is both region-specific and non-linearly related to amplitude and frequency. METHODS: We examined evoked neural responses following 400 ms trains of 10-400 Hz electrical stimulation ranging from 0.1 to 10 mA. We stimulated electrodes implanted in cingulate cortex (dorsal anterior cingulate and rostral anterior cingulate) and subcortical regions (nucleus accumbens, amygdala) of non-human primates (NHP, N = 4) and patients with intractable epilepsy (N = 15) being monitored via intracranial electrodes. Recordings were performed in prefrontal, subcortical, and temporal lobe locations. RESULTS: In subcortical regions as well as dorsal and rostral anterior cingulate cortex, response waveforms depended non-linearly on frequency (Pearson's linear correlation r < 0.39), but linearly on current (r > 0.58). These relationships between location, and input-output characteristics were similar in homologous brain regions with average Pearson's linear correlation values r > 0.75 between species and linear correlation values between participants r > 0.75 across frequency and current values per brain region. Evoked waveforms could be described by three main principal components (PCs) which allowed us to successfully predict response waveforms across individuals and across frequencies using PC strengths as functions of current and frequency using brain region specific regression models. CONCLUSIONS: These results provide a framework for creation of an atlas of input-output relationships which could be used in the principled selection of stimulation parameters per brain region.

An Unsupervised Compressed Sensing Algorithm for Multi-Channel Neural Recording and Spike Sorting.

We propose an unsupervised compressed sensing (CS)-based framework to compress, recover, and cluster neural action potentials. This framework can be easily integrated into high-density multi-electrode neural recording VLSI systems. Embedding spectral clustering and group structures in dictionary learning, we extend the proposed framework to unsupervised spike sorting without prior label information. Additionally, we incorporate group sparsity concepts in the dictionary learning to enable the framework for multi-channel neural recordings, as in tetrodes. To further improve spike sorting success rates in the CS framework, we embed template matching in sparse coding to jointly predict clusters of spikes. Our experimental results demonstrate that the proposed CS-based framework can achieve a high compression ratio (8:1 to 20:1), with a high quality reconstruction performance (>8 dB) and a high spike sorting accuracy (>90%).

Multimodal Encoding of Novelty, Reward, and Learning in the Primate Nucleus Basalis of Meynert.

Associative learning is crucial for daily function, involving a complex network of brain regions. One region, the nucleus basalis of Meynert (NBM), is a highly interconnected, largely cholinergic structure implicated in multiple aspects of learning. We show that single neurons in the NBM of nonhuman primates (NHPs; n = 2 males; Macaca mulatta) encode learning a new association through spike rate modulation. However, the power of low-frequency local field potential (LFP) oscillations decreases in response to novel, not-yet-learned stimuli but then increase as learning progresses. Both NBM and the dorsolateral prefrontal cortex encode confidence in novel associations by increasing low- and high-frequency LFP power in anticipation of expected rewards. Finally, NBM high-frequency power dynamics are anticorrelated with spike rate modulations. Therefore, novelty, learning, and reward anticipation are separately encoded through differentiable NBM signals. By signaling both the need to learn and confidence in newly acquired associations, NBM may play a key role in coordinating cortical activity throughout the learning process.SIGNIFICANCE STATEMENT Degradation of cells in a key brain region, the nucleus basalis of Meynert (NBM), correlates with Alzheimer's disease and Parkinson's disease progression. To better understand the role of this brain structure in learning and memory, we examined neural activity in the NBM in behaving nonhuman primates while they performed a learning and memory task. We found that single neurons in NBM encoded both salience and an early learning, or cognitive state, whereas populations of neurons in the NBM and prefrontal cortex encode learned state and reward anticipation. The NBM may thus encode multiple stages of learning. These multimodal signals might be leveraged in future studies to develop neural stimulation to facilitate different stages of learning and memory.

Cuprizone does not induce CNS demyelination in nonhuman primates.

Cognitive decline is a common symptom in multiple sclerosis patients, with profound effects on the quality of life. A nonhuman primate model of multiple sclerosis would be best suited to test the effects of demyelination on complex cognitive functions such as learning and reasoning. Cuprizone has been shown to reliably induce brain demyelination in mice. To establish a nonhuman primate model of multiple sclerosis, young adult cynomolgus monkeys were administered cuprizone per os as a dietary supplement. The subjects received increasing cuprizone doses (0.3-3% of diet) for up to 18 weeks. Magnetic resonance imaging and immunohistological analyses did not reveal demyelination in these monkeys.

Studying task-related activity of individual neurons in the human brain.

Single-neuronal studies remain the gold standard for studying brain function. Here we describe a protocol for studying task-related single-neuronal activity in human subjects during neurosurgical procedures involving microelectrode recordings. This protocol has two phases: a preoperative phase and an intraoperative phase. During the preoperative phase, we discuss informed consent, equipment setup and behavioral testing. During the intraoperative phase, we discuss the procedure for microelectrode recordings. Because patients are often awake during these procedures, this protocol can be performed in conjunction with behavioral tasks for studying a variety of cognitive functions. We describe the protocol in detail and provide two examples of expected results. In addition, we discuss the potential difficulties and pitfalls related to intraoperative studies. This protocol takes ∼1.5 h to complete.

Intra-operative behavioral tasks in awake humans undergoing deep brain stimulation surgery.

Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments.

Comparative neurobiology of feeding in the opisthobranch sea slug, Aplysia, and the pulmonate snail, Helisoma: evolutionary considerations.

The motor systems that generate feeding-related behaviors of gastropod mollusks provide exceptional opportunities for increasing our understanding of neural homologies and the evolution of neural networks. This report examines the neural control of feeding in Helisoma trivolvis, a pulmonate snail that ingests food by rasping or scraping material from the substrate, and Aplysia californica, an opisthobranch sea slug that feeds by using a grasping or seizing motion. Two classes of neurons that are present in the buccal ganglia of both species are considered: (1) clusters of peptidergic mechanoafferent cells that transmit sensory information from the tongue-like radula/odontophore complex to the central motor circuit; and (2) sets of octopamine-immunoreactive interneurons that are intrinsic to the feeding network. We review evidence that suggests homology of these cell types and propose that their roles have been largely conserved in the control of food-scraping and food-grasping consummatory behaviors. We also consider significant differences in the feeding systems of Aplysia and Helisoma that are associated with the existence of radular closure in Aplysia, an action that does not occur in Helisoma. It is hypothesized that a major adaptation in the innervation patterns of analogous, possibly homologous muscles could distinguish the food-scraping versus food-grasping species. It appears that although core CPG elements have been largely conserved in this system, the neuromuscular elements that they regulate have been more evolutionarily labile.

Localization of biogenic amines in the foregut of Aplysia californica: catecholaminergic and serotonergic innervation.

This study examined the catecholaminergic and serotonergic innervation of the foregut of Aplysia californica, a model system in which the control of feeding behaviors can be investigated at the cellular level. Similar numbers (15-25) of serotonin-like-immunoreactive (5HTli) and tyrosine hydroxylase-like-immunoreactive (THli) fibers were present in each (bilateral) esophageal nerve (En), the major source of pregastric neural innervation in this system. The majority of En 5HTli and THli fibers originated from the anterior branch (En(2)), which innervates the pharynx and the anterior esophagus. Fewer fibers were present in the posterior branch (En(1)), which innervates the majority of the esophagus and the crop. Backfills of the two En branches toward the central nervous system (CNS) labeled a single, centrifugally projecting serotonergic fiber, originating from the metacerebral cell (MCC). The MCC fiber projected only to En(2). No central THli neurons were found to project to the En. Surveys of the pharynx and esophagus revealed major differences between their patterns of catecholaminergic (CA) and serotonergic innervation. Whereas THli fibers and cell bodies were distributed throughout the foregut, 5HTli fibers were present in restricted plexi, and no 5HTli somata were detected. Double-labeling experiments in the periphery revealed THli neurons projecting toward the buccal ganglion via En(2). Other afferents received dense perisomatic serotonergic innervation. Finally, qualitative and quantitative differences were observed between the buccal motor programs (BMPs) produced by stimulation of the two En branches. These observations increase our understanding of aminergic contributions to the pregastric regulation of Aplysia feeding behaviors.

Endogenous motor neuron properties contribute to a program-specific phase of activity in the multifunctional feeding central pattern generator of Aplysia.

Multifunctional central pattern generators (CPGs) are circuits of neurons that can generate manifold actions from a single effector system. This study examined a bilateral pair of pharyngeal motor neurons, designated B67, that participate in the multifunctional feeding network of Aplysia californica. Fictive buccal motor programs (BMPs) were elicited with four distinct stimulus paradigms to assess the activity of B67 during ingestive versus egestive patterns. In both classes of programs, B67 fired during the phase of radula protraction and received a potent inhibitory postsynaptic potential (IPSP) during fictive radula retraction. When programs were ingestive, the retraction phase IPSP exhibited a depolarizing sag and was followed by a postinhibitory rebound (PIR) that could generate a postretraction phase of impulse activity. When programs were egestive, the depolarizing sag potential and PIR were both diminished or were not present. Examination of the membrane properties of B67 disclosed a cesium-sensitive depolarizing sag, a corresponding I(h)-like current, and PIR in its responses to hyperpolarizing pulses. Direct IPSPs originating from the influential CPG retraction phase interneuron B64 were also found to activate the sag potential and PIR of B67. Dopamine, a modulator that can promote ingestive behavior in this system, enhanced the sag potential, I(h)-like current, and PIR of B67. Finally, a pharyngeal muscle contraction followed the radula retraction phase of ingestive, but not egestive motor patterns. It is proposed that regulation of the intrinsic properties of this motor neuron can contribute to generating a program-specific phase of motor activity.