Angular Head Velocity Cells within Brainstem Nuclei Projecting to the Head Direction Circuit.

The sense of orientation of an animal is derived from the head direction (HD) system found in several limbic structures and depends on an intact vestibular labyrinth. However, how the vestibular system influences the generation and updating of the HD signal remains poorly understood. Anatomical and lesion studies point toward three key brainstem nuclei as key components for generating the HD signal-nucleus prepositus hypoglossi, supragenual nucleus, and dorsal paragigantocellularis reticular nuclei. Collectively, these nuclei are situated between the vestibular nuclei and the dorsal tegmental and lateral mammillary nuclei, which are thought to serve as the origin of the HD signal. To determine the types of information these brain areas convey to the HD network, we recorded neurons from these regions while female rats actively foraged in a cylindrical enclosure or were restrained and rotated passively. During foraging, a large subset of cells in all three nuclei exhibited activity that correlated with the angular head velocity (AHV) of the rat. Two fundamental types of AHV cells were observed; (1) symmetrical AHV cells increased or decreased their firing with increases in AHV regardless of the direction of rotation, and (2) asymmetrical AHV cells responded differentially to clockwise and counterclockwise head rotations. When rats were passively rotated, some AHV cells remained sensitive to AHV, whereas firing was attenuated in other cells. In addition, a large number of AHV cells were modulated by linear head velocity. These results indicate the types of information conveyed from the vestibular nuclei that are responsible for generating the HD signal.SIGNIFICANCE STATEMENT Extracellular recording of brainstem nuclei (nucleus prepositus hypoglossi, supragenual nucleus, and dorsal paragigantocellularis reticular nucleus) that project to the head direction circuit identified different types of AHV cells while rats freely foraged in a cylindrical environment. The firing of many cells was also modulated by linear velocity. When rats were restrained and passively rotated, some cells remained sensitive to AHV, whereas others had attenuated firing. These brainstem nuclei provide critical information about the rotational movement of the head of the rat in the azimuthal plane.

Angular head velocity cells within brainstem nuclei projecting to the head direction circuit.

An animal's perceived sense of orientation depends upon the head direction (HD) system found in several limbic structures and depends upon an intact peripheral vestibular labyrinth. However, how the vestibular system influences the generation, maintenance, and updating of the HD signal remains poorly understood. Anatomical and lesion studies point towards three key brainstem nuclei as being potential critical components in generating the HD signal: nucleus prepositus hypoglossi (NPH), supragenual nucleus (SGN), and dorsal paragigantocellularis reticular nuclei (PGRNd). Collectively, these nuclei are situated between the vestibular nuclei and the dorsal tegmental and lateral mammillary nuclei, which are thought to serve as the origin of the HD signal. To test this hypothesis, extracellular recordings were made in these areas while rats either freely foraged in a cylindrical environment or were restrained and rotated passively. During foraging, a large subset of cells in all three nuclei exhibited activity that correlated with changes in the rat's angular head velocity (AHV). Two fundamental types of AHV cells were observed: 1) symmetrical AHV cells increased or decreased their neural firing with increases in AHV regardless of the direction of rotation; 2) asymmetrical AHV cells responded differentially to clockwise (CW) and counter-clockwise (CCW) head rotations. When rats were passively rotated, some AHV cells remained sensitive to AHV whereas others had attenuated firing. In addition, a large number of AHV cells were modulated by linear head velocity. These results indicate the types of information conveyed in the ascending vestibular pathways that are responsible for generating the HD signal. Significance Statement: Extracellular recording of brainstem nuclei (nucleus prepositus hypoglossi, supragenual nucleus, and dorsal paragigantocellularis reticular nucleus) that project to the head direction circuit identified different types of angular head velocity (AHV) cells while rats freely foraged in a cylindrical environment. The firing of many cells was also modulated by linear velocity. When rats were restrained and passively rotated some cells remained sensitive to AHV, whereas others had attenuated firing. These brainstem nuclei provide critical information about the rotational movement of the rat's head in the azimuthal plane.

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.

A neural mass model to predict electrical stimulation evoked responses in human and non-human primate brain.

OBJECTIVE: Deep brain stimulation (DBS) is a valuable tool for ameliorating drug resistant pathologies such as movement disorders and epilepsy. DBS is also being considered for complex neuro-psychiatric disorders, which are characterized by high variability in symptoms and slow responses that hinder DBS setting optimization. The objective of this work was to develop an in silico platform to examine the effects of electrical stimulation in regions neighboring a stimulated brain region. APPROACH: We used the Jansen-Rit neural mass model of single and coupled nodes to simulate the response to a train of electrical current pulses at different frequencies (10-160 Hz) of the local field potential recorded in the amygdala and cortical structures in human subjects and a non-human primate. RESULTS: We found that using a single node model, the evoked responses could be accurately modeled following a narrow range of stimulation frequencies. Including a second coupled node increased the range of stimulation frequencies whose evoked responses could be efficiently modeled. Furthermore, in a chronic recording from a non-human primate, features of the in vivo evoked response remained consistent for several weeks, suggesting that model re-parameterization for chronic stimulation protocols would be infrequent. SIGNIFICANCE: Using a model of neural population activity, we reproduced the evoked response to cortical and subcortical stimulation in human and non-human primate. This modeling framework provides an environment to explore, safely and rapidly, a wide range of stimulation settings not possible in human brain stimulation studies. The model can be trained on a limited dataset of stimulation responses to develop an optimal stimulation strategy for an individual patient.