Multi-scale, multi-modal analysis uncovers complex relationship at the brain tissue-implant neural interface: new emphasis on the biological interface

Abstract

To better understand the biological factors influencing neural activity, detailed cellular and molecular tissue responses were examined. Decreases in neural activity and blood oxygenation in the tissue surrounding the implant, shift in expression levels of vesicular transporter proteins and ion channels, axon and myelin injury, and interrupted blood flow in nearby capillaries can impact neural activity around implanted neural interfaces. Combined, these tissue changes highlight the need for more comprehensive, basic science research to elucidate the relationship between biology and chronic electrophysiology performance in order to advance neural technologies.

Calcium activation of cortical neurons by continuous electrical stimulation: Frequency dependence, temporal fidelity, and activation density

“…GCaMPs are genetically encoded intracellular calcium indicators that largely reflect action potential firing (Chen et al, ; Dana et al, ; Greenberg, Houweling, & Kerr, ; Kerr & Denk, ; Sato, Gray, Mainen, & Svoboda, ; Smetters, Majewska, & Yuste, ). Because quiescent neurons have low GCaMP fluorescence, capillary visualization using 0.1 mg of sulforhodamin101 (SR101) was employed to ensure the location of the electrode and visibility in the tissue with low laser power (<20 mW) as previously described (Figure b) (Eles et al, ; Kozai, Eles et al, ; Kozai, Jaquins‐gerstl et al, ; Kozai et al, ; Michelson et al, ; Wellman & Kozai, ). Although GCaMP6 is more sensitive compared to other calcium indicators, such as Oregon green BAPTA, it has a longer decay constant that did not impair detection of activity (Chen et al, ).…”

“…Anesthesia was induced with a mixture consisting of 75 mg/kg ketamine and 7 mg/kg xylazine administered intraperitoneally (IP) and updated with 40 mg/kg as needed. Rectangular craniotomies (~4 mm per side) were made over each somatosensory cortex and electrodes were implanted at a 30º angle as previously described (Eles et al, ; Kozai, Eles, Vazquez, & Cui, ; Kozai, Jaquins‐gerstl, Vazquez, Michael, & Cui, ; Kozai, Vazquez, Weaver, Kim, & Cui, ; Michelson et al, ; Wellman & Kozai, ). Electrical stimulation was conducted through a single‐shank 16‐channel Michigan style functional silicon probe with 703 µm 2 electrode sites (NeuroNexus Technologies, Ann Arbor, MI).…”

Alterations in Ion Channel Expression Surrounding Implanted Microelectrode Arrays in the Brain

“…Neuronal loss and glial encapsulation are traditionally used as metrics to assess the biocompatibility of devices for chronic neural interfacing 9,[44][45][46][47][48][49][50][51][52] . However, recent work indicates that these conventional methods are insufficient to explain long-term signal quality 53 , where inter-day variability and progressive signal loss burden chronic recording arrays 3,5,6,54,55 . Well-characterized alterations in ion channels and synapses following cortical injury 10,12,[22][23][24][25]35,56 and inflammation [14][15][16][17]37,57 suggest that similar alterations may accompany implanted devices.…”

In vivo microstimulation with cathodic and anodic asymmetric waveforms modulates spatiotemporal calcium dynamics in cortical neuropil and pyramidal neurons of male mice

“…Subjects (n = 5-6 biological replicates) were housed in 12h light/dark cycles with free access to food and water. Acute surgery and electrode implantation followed a protocol previously published [24,[40][41][42][43][44][45][46][47][48][49]. Mice were initially anesthetized with ketamine/xylazine (75mg/kg;7mg/kg) intraperitoneally (IP) and updated with ketamine (40 mg/kg) as needed (~ every hour).…”