Dynamic amplitude modulation of microstimulation evokes biomimetic onset and offset transients and reduces depression of evoked calcium responses in sensory cortices

Background: Intracortical microstimulation (ICMS) is an emerging approach to restore sensation to people with neurological injury or disease. Biomimetic microstimulation, or stimulus trains that mimic neural activity in the brain through encoding of onset and offset transients, could improve the utility of ICMS for brain-computer interface (BCI) applications, but how biomimetic microstimulation affects neural activation is not understood. Current "biomimetic" ICMS trains aim to reproduce the strong onset and offset transients evoked in the brain by sensory input through dynamic modulation of stimulus parameters. Stimulus induced depression of neural activity (decreases in evoked intensity over time) is also a potential barrier to clinical implementation of sensory feedback, and dynamic microstimulation may reduce this effect.Objective: We evaluated how bio-inspired ICMS trains with dynamic modulation of amplitude and/or frequency change the calcium response, spatial distribution, and depression of neurons in the somatosensory and visual cortices. Methods: Calcium responses of neurons were measured in Layer 2/3 of visual and somatosensory cortices of anesthetized GCaMP6s mice in response to ICMS trains with fixed amplitude and frequency (Fixed) and three dynamic ICMS trains that increased the stimulation intensity during the onset and offset of stimulation by modulating the amplitude (DynAmp), frequency (DynFreq), or amplitude and frequency (DynBoth). ICMS was provided for either 1-s with 4-s breaks (Short) or for 30-s with 15-s breaks (Long).Results: DynAmp and DynBoth trains evoked distinct onset and offset transients in recruited neural populations, while DynFreq trains evoked population activity similar to Fixed trains. Individual neurons had heterogeneous responses primarily based on how quickly they depressed to ICMS, where neurons farther from the electrode depressed faster and a small subpopulation (1-5%) were modulated by DynFreq trains. Neurons that depressed to Short trains were also more likely to depress to Long trains, but Long trains induced more depression overall due to the increased stimulation length. Increasing the amplitude during the hold phase resulted in an increase in recruitment and intensity which resulted in more depression and reduced offset responses. Dynamic amplitude modulation reduced stimulation induced depression by 14.6 & PLUSMN; 0.3% for Short and 36.1 & PLUSMN; 0.6% for Long trains. Ideal observers were 0.031 & PLUSMN; 0.009 s faster for onset detection and 1.33 & PLUSMN; 0.21 s faster for offset detection with dynamic amplitude encoding.Conclusions: Dynamic amplitude modulation evokes distinct onset and offset transients, reduces depression of neural calcium activity, and decreases total charge injection for sensory feedback in BCIs by lowering recruitment of neurons during long maintained periods of ICMS. In contrast, dynamic frequency modulation evokes distinct onset and offset transients in a small subpopulation of neurons but also reduces depression in recruited neurons by reducing the rate of activation.