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The temporal pattern of intracortical microstimulation pulses elicits distinct temporal and spatial recruitment of cortical neuropil and neurons.

ABSTRACT: Objective.The temporal spacing or distribution of stimulation pulses in therapeutic neurostimulation waveforms-referred to here as the Temporal Pattern (TP)-has emerged as an important parameter for tuning the response to deep-brain stimulation and intracortical microstimulation (ICMS). While it has long been assumed that modulating the TP of ICMS may be effective by altering the rate coding of the neural response, it is unclear how it alters the neural response at the network level. The present study is designed to elucidate the neural response to TP at the network level.Approach. We usein vivotwo-photon imaging of mice expressing the calcium sensorThy1-GCaMP or the glutamate sensorhSyn-iGluSnFr to examine the layer II/III neural response to ICMS with different TPs. We study the neuronal calcium and glutamate response to TPs with the same average frequency (10 Hz) and same total charge injection, but varying degrees of bursting. We also investigate one control pattern with an average frequency of 100 Hz and 10X the charge injection.Main Results. Stimulation trains with the same average frequency and same total charge injection but distinct TPs recruit distinct sets of neurons. More than half (60% of 309 cells) of neurons prefer one TP over the other. Despite their distinct spatial recruitment patterns, cells exhibit similar ability to follow 30 s trains of both TPs without failing, and they exhibit similar levels of glutamate release during stimulation. Both neuronal calcium and glutamate release entrain to the bursting TP pattern, with a ∼21-fold increase in relative power at the frequency of bursting. Bursting also results in a statistically significant elevation in the correlation between somatic calcium activity and neuropil activity, which we explore as a metric for inhibitory-excitatory tone. Interestingly, soma-neuropil correlation during the bursting pattern is a statistically significant predictor of cell preference for TP, which exposes a key link between TP and inhibitory-excitatory tone. Finally, using mesoscale imaging, we show that both TPs result in distal inhibition during stimulation, which reveals complex spatial and temporal interactions between TP and inhibitory-excitatory tone in ICMS.Significance. Our results may ultimately suggest that TP is a valuable parameter space to modulate inhibitory-excitatory tone and to recruit distinct network activity in ICMS. This presents a broader mechanism of action than rate coding, as previously thought. By implicating these additional mechanisms, TP may have broader utility in the clinic and should be pursued to expand the efficacy of ICMS therapies.

SUBMITTER: Eles JR

PROVIDER: S-EPMC8167825 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective. Neural prosthetics often use intracortical microstimulation (ICMS) for sensory restoration. To restore natural and functional feedback, we must first understand how stimulation parameters influence the recruitment of neural populations. ICMS waveform asymmetry modulates the spatial activation of neurons around an electrode at 10 Hz; however, it is unclear how asymmetry may differentially modulate population activity at frequencies typically employed in the clinic (e.g. 100 Hz). We hypothesized that stimulation waveform asymmetry would differentially modulate preferential activation of certain neural populations, and the differential population activity would be frequency-dependent.Approach. We quantified how asymmetric stimulation waveforms delivered at 10 or 100 Hz for 30 s modulated spatiotemporal activity of cortical layer II/III pyramidal neurons usingin vivotwo-photon and mesoscale calcium imaging in anesthetized mice. Asymmetry is defined in terms of the ratio of the duration of the leading phase to the duration of the return phase of charge-balanced cathodal- and anodal-first waveforms (i.e. longer leading phase relative to return has larger asymmetry).Main results. Neurons within 40-60µm of the electrode display stable stimulation-induced activity indicative of direct activation, which was independent of waveform asymmetry. The stability of 72% of activated neurons and the preferential activation of 20%-90% of neurons depended on waveform asymmetry. Additionally, this asymmetry-dependent activation of different neural populations was associated with differential progression of population activity. Specifically, neural activity tended to increase over time during 10 Hz stimulation for some waveforms, whereas activity remained at the same level throughout stimulation for other waveforms. During 100 Hz stimulation, neural activity decreased over time for all waveforms, but decreased more for the waveforms that resulted in increasing neural activity during 10 Hz stimulation.Significance.These data demonstrate that at frequencies commonly used for sensory restoration, stimulation waveform alters the pattern of activation of different but overlapping populations of excitatory neurons. The impact of these waveform specific responses on the activation of different subtypes of neurons as well as sensory perception merits further investigation.

Project description:ObjectiveIntracortical microelectrode implants can generate a tissue response hallmarked by glial scarring and neuron cell death within 100-150 μm of the biomaterial device. Many have proposed that any performance decline in intracortical microstimulation (ICMS) due to this foreign body tissue response could be offset by increasing the stimulation amplitude. The mechanisms of this approach are unclear, however, as there has not been consensus on how increasing amplitude affects the spatial and temporal recruitment patterns of ICMS.ApproachWe clarify these unknowns using in vivo two-photon imaging of mice transgenically expressing the calcium sensor GCaMP6s in Thy1 neurons or virally expressing the glutamate sensor iGluSnFr in neurons. Calcium and neurotransmitter activity are tracked in the neuronal somas and neuropil during long-train stimulation in Layer II/III of somatosensory cortex.Main resultsNeural calcium activity and glutamate release are dense and strongest within 20-40 μm around the electrode, falling off with distance from the electrode. Neuronal calcium increases with higher amplitude stimulations. During prolonged stimulation trains, a sub-population of somas fail to maintain calcium activity. Interestingly, neuropil calcium activity is 3-fold less correlated to somatic calcium activity for cells that drop-out during the long stimulation train compared to cells that sustain activity throughout the train. Glutamate release is apparent only within 20 μm of the electrode and is sustained for at least 10s after cessation of the 15 and 20 μA stimulation train, but not lower amplitudes.SignificanceThese results demonstrate that increasing amplitude can increase the radius and intensity of neural recruitment, but it also alters the temporal response of some neurons. Further, dense glutamate release is highest within the first 20 μm of the electrode site even at high amplitudes, suggesting that there may be spatial limitations to the amplitude parameter space. The glutamate elevation outlasts stimulation, suggesting that high-amplitude stimulation may affect neurotransmitter re-uptake. This ultimately suggests that increasing the amplitude of ICMS device stimulation may fundamentally alter the temporal neural response, which could have implications for using amplitude to improve the ICMS effect or "offset" the effects of glial scarring.

Project description:BackgroundCutaneous leishmaniasis (CL) is a vector-borne disease classified by the World Health Organization as one of the most neglected tropical diseases. Brazil has the highest incidence of CL in America and is one of the ten countries in the world with the highest number of cases. Understanding the spatiotemporal dynamics of CL is essential to provide guidelines for public health policies in Brazil. In the present study we used a spatial and temporal statistical approach to evaluate the dynamics of CL in Brazil.MethodsWe used data of cutaneous leishmaniasis cases provided by the Ministry of Health of Brazil from 2001 to 2017. We calculated incidence rates and used the Mann-Kendall trend test to evaluate the temporal trend of CL in each municipality. In addition, we used Kuldorff scan method to identify spatiotemporal clusters and emerging hotspots test to evaluate hotspot areas and their temporal trends.ResultsWe found a general decrease in the number of CL cases in Brazil (from 15.3 to 8.4 cases per 100 000 habitants), although 3.2% of municipalities still have an increasing tendency of CL incidence and 72.5% showed no tendency at all. The scan analysis identified a primary cluster in northern and central regions and 21 secondary clusters located mainly in south and southeast regions. The emerging hotspots analysis detected a high spatial and temporal variability of hotspots inside the main cluster area, diminishing hotspots in eastern Amazon and permanent, emerging, and new hotspots in the states of Amapá and parts of Pará, Roraima, Acre and Mato Grosso. The central coast the state of Bahia is one of the most critical areas due to the detection of a cluster of the highest rank in a secondary cluster, and because it is the only area identified as an intensifying hotspot.ConclusionsUsing a combination of statistical methods we were able to detect areas of higher incidence of CL and understand how it changed over time. We suggest that these areas, especially those identified as permanent, new, emerging and intensifying hotspots, should be targeted for future research, surveillance, and implementation of vector control measures.

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The temporal pattern of intracortical microstimulation pulses elicits distinct temporal and spatial recruitment of cortical neuropil and neurons.

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