The basal ganglia is an important brain structure that shapes our behavior and is implicated in a number of movement disorders (eg. Parkinson’s disease, PD) and various mood disorders (eg. depression, anxiety, etc.). This structure consists of a number of nuclei, from which the striatum serves as a major hub for integrating signals projected from across the brain. A distinctive aspect of the basal ganglia is its immersive engagement of the neurotransmitter, dopamine, which serves to modulate how the nuclei communicate with each other and the rest of the brain. The depletion of this neuroactive chemical is evidenced in PD and other neurological disorders. Nevertheless, the underlying pathophysiology of this depletion and the neural circuits and processes responsible for its regulation are not known. The ability to probe this structure is critical to not only elucidate its working mechanisms and functional connections with the rest of the brain, but also deliver therapeutic stimuli to regulate and ameliorate dysfunctional neural circuits.
Yet, the task is complicated by the deeply rooted placement of this structure inside the brain, necessitating the physical traversal and penetration of numerous overlying cortical and subcortical layers of brain tissue. In severe PD patients, deep brain stimulation (DBS) devices are chronically implanted into the brain to electrically stimulate large populations of neurons usually residing in the subthalamic nucleus (STN). These electrical currents usually act to excite dopaminergic neurons to replenish dopamine levels and restore normal motor functions. Despite its ability to treat PD symptoms, the side effects and complications associated with such a spatially diffuse field of stimulation modulating both targeted and non-targeted regions of the brain can be detrimental to the wellbeing and lifestyle of the affected individuals. By restricting the extent of the delivered stimulus to targeted cells responsible for the dysfunctional, the treatment would be more efficacious and safer.
The injectrode is capable of integrating a plurality of functions: electrical stimulation to electrically perturb neural activity, electrical recording to monitor neural activity, chemical delivery to channel pharmacological microdoses through two different lumens, and electrochemical recording to selectively measure chemical concentrations of dopamine or other neuroactive chemicals via voltammetric methods. All of this is manifested in a device diameter of < 200 µm, which may help reduce surgically induced trauma.
We have performed a number of experiments to demonstrate the injectrode’s biocompatibility, induced micromotion, physical rigidity to accurately penetrate and target defined brain areas, ability to channel spatially restricted (< 1 mm spherical diameter) chemical boluses, and functional efficacy in chemically modulating neural activity in the striatum. We are currently in the stage of translating the research towards elucidating neurochemical mechanisms in the striatum of non-human primates and ultimately endeavor towards realizing improved treatment of PD and many other neurological disorders in humans.
Figure 4. Fast Scan Cyclic Voltammetry (FSCV) used to measure current induced at specific potentials unique to individual chemicals (eg. DA redox potentials are Eox = 0.65 V & Ere = -0.25 V) in the primate striatum.
Publications
Upadhyay, U.M., Tyler, B., Patta, Y., Wicks R., Spencer, K., Scott, A., Masi, B., Hwang, L., Grossman, R., Cima, M., Brem, H., Langer, R. Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain. Proc Natl Acad Sci. 2013; 11(45):16071-76. DOI: 10.1073/pnas.1313420110
