Non-human primate (NHP) research has become an essential step in the translation of medical technologies from animal models to clinical trials. This is especially so in neural research, as there is a large discrepancy between rodent and human brains in both anatomy and size. For some techniques such as optogenetics, which requires viral transduction of neurons, traditional diffusion-based viral injection approaches are effective in rodent brains but are impractical for large NHP ones. Convection-enhanced delivery (CED), a large-scale injection approach, currently lacks a practical quantitative bench-side injection modeling method to guide neurosurgical preparation. We aim to develop a gel model of the NHP brain and replicate surgical injections of it in order to reduce the risks of directly injecting into a NHP without sufficient preparation. We are testing the validity of our model by monitoring the spread of the injection through the gel and comparing the data with those from MRI scans of the injections in NHP. Since CED can behave differently depending on the location of injection in the brain, we are testing bench-side injections at different depths to validate the versatility of our model. We are seeing that the injections in the gel model mirror that of the injections in NHP brains as expected. Our next steps are to test the effectiveness of smaller injection cannula sizes with our bench-side model to assess if injection results remain consistent. This would indicate that tissue damage could be minimized in surgeries while still achieving desired injection parameters.

Optogenetic stimulation is a technique that modulates the activity of genetically modified neurons with light of a particular wavelength. Optogenetic modulation has high temporal resolution and cell-type specificity that enables precise stimulation of cortical neurons and allows us to conduct artifact-free recording during stimulation. Using a large-scale optogenetic interface, we stimulated and recorded across the primary somatosensory (S1) and motor (M1) cortices of non-human primates (NHP). We conducted our investigation on NHPs because their cortical organization is particularly similar to that of humans. The goal of this study is to determine the effect of various spatial and temporal patterns of optogenetic stimulation on the neural response and network dynamics across the two cortical regions. Delivering stimulus pulses via two lasers placed on top of the cortical surface, we found that stimulation of one cortical region evoked neural responses across both S1 and M1, which we then classified into primary and secondary responses based on their delays. While our previous work has established that optogenetic stimulation strengthened functional connectivity between S1 and M1, we wanted to further investigate the distribution of primary and secondary neural responses after repeated stimulation. We examined two measures of neural responses, the temporal delay between the trough of evoked response and onset of light stimulation, and the distribution of power across cortical networks up to 50ms after the stimulation. Our preliminary results indicate that optogenetic stimulation changed the delay of the primary and secondary response. We also observed that different temporal patterns of paired laser pulses evoked distinct neural activity. Identifying different neural responses after complex spatiotemporal patterns of stimulation would help us predict network changes post cortical modulation and contribute significantly to the development of stimulation-based clinical therapies and rehabilitation strategies for neural disorders.

Non-human primate (NHP) research is a pivotal step in the progression of neuroscientific and neural engineering research from animal models to human trials. In most NHP neuroscience experiments, neurosurgery is required to implant devices such as head posts, recording arrays, and optical windows. Current practices for these surgeries use methods for surgical preparation that carry a degree of unavoidable uncertainty. This comes from an inability to visualize and test the physical compatibility of complex components and anatomy prior to neurosurgery. This project details methods for creating 3D printed models of a subject’s brain and skull, as well as an agarose gel model of the brain. These models can be obtained from magnetic resonance imaging (MRI) using brain extraction software for the brain model, and custom code for the skull. The preparation protocol takes advantage of state-of-the-art 3D printing technology to combine models of the brain and skull with neuroprosthesis. With the addition of a craniotomy using the custom code, the skull and brain models can visualize brain tissue inside the skull, enabling better preparation for surgeries. Using the methods outlined in the protocol, the accuracy of the 3D printed brain, skull, and craniotomy placement were successfully validated through a comparison to the original MRI scan. The gel brain was additionally used to visualize delivery of a mock viral vector through the craniotomy of a skull model. By preoperatively fitting a headpost to the physical model of the skull, we successfully shortened the implantation surgery time by 40% and greatly reduced the risk of operative complications. These methods are designed for surgeries involving neurological stimulation and recording as well as injection in NHPs, but the versatility of the system allows for future expansion of the protocol, extraction techniques, and models to a wider scope of surgeries.

Stroke, when the blood supply to the brain is reduced or disrupted, is a leading cause of disability among adults. Brain plasticity, also known as neural plasticity, can aid in the way that the brain recovers from a traumatic injury such as a stroke by creating newer, stronger synapses (connections) between neurons and thus increasing cell functionality. This literature review explores how brain plasticity informs new bioengineering solutions to stroke rehabilitation and asks, “What type of novel stroke treatments have been developed using the concept of brain plasticity?” Preliminary findings indicate that a breakthrough in this field is using optogenetics to trigger and control the neural connections that the brain can make through promoting motor function after ischemic stroke. Other innovations in this field include repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and epidural cortical stimulation, which have all been shown to make permanent changes in neural synaptic transmission. These methods partially restore brain function while being less invasive and more effective in comparison to older interventions. This literature review indicates that new bioengineering treatments informed by brain plasticity are promising and could promote better rehabilitation outcomes for those suffering from stroke and potentially other traumatic brain injuries.

 Stroke is the leading cause of long-term disability in the United States. Disabilities can range from a loss of sensory function like touch to motor functions like controlling arm movements due to the damage to the brain’s network. Despite the prevalence of stroke, the underlying network dynamics that lead to functional deficits are not well understood. Due to the physiological similarities between non-human primate (NHP) and human brains, an NHP model is essential for studying the effects of stroke and developing therapies. Here we used the photothrombotic (PT) stroke technique to study network dynamics in the NHP sensorimotor cortex following an ischemic lesion. Using the PT stroke technique, we induced a focal ischemic lesion on the NHP sensorimotor cortex. We collected local field potentials from both hemispheres using an electrocorticographic  array on the cortical surface. As a measure of neural activity, we calculated ipsilesional power in the low gamma band. Channels were then organized into three clusters based on their net change in power (increase, decrease, no change). As expected, the cluster with an overall decrease in power corresponded to the lesion's physical location. We also studied the network connectivity by calculating pair-wise coherence across different frequency bands: theta, beta, low gamma, and high gamma. Overall, we saw that low frequencies were associated with decreases in coherence, while higher frequencies were associated with increases following stroke. Preliminary results from the contralesional hemisphere show similar changes. In this study, we observed local neurophysiological changes up to three hours following an ischemic lesion. The observed increases in power in the perilesional region and coherence at high frequencies suggest compensatory mechanisms immediately following an injury. We can use this study's results to guide future developments in stimulation-based therapy to alleviate the functional deficits from a stroke.