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An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain.

ABSTRACT: Brain tissue injury is often accompanied by spreading depolarization (SD) events, marked by widespread cellular depolarization and cessation of neuronal firing. SD recruits viable tissue into the lesion, making it a focus for intervention. During SD, drastic fluctuations occur in ion gradients, extracellular neurotransmitter concentrations, cellular metabolism, and cerebral blood flow. Measuring SD requires a multimodal approach to capture the array of changes. However, the use of multiple sensors can inflict tissue damage. Here, we use carbon-fiber microelectrodes to characterize several aspects of SD with a single, minimally invasive sensor in the deep brain region of the nucleus accumbens. Fast-scan cyclic voltammetry detects large changes in oxygen, which reflect the balance between cerebral blood flow and energy consumption, and also supraphysiological release of electroactive neurotransmitters (i.e., dopamine). We verify waves of SD with concurrent single-unit or DC potential electrophysiological recordings. The single-unit recordings reveal bursts of action potentials followed by inactivity. The DC potentials exhibit a slow negative voltage shift in the extracellular space indicative of wide-spread cellular depolarization. Here, we characterize the multiple modalities of our sensor and demonstrate its utility for improved SD recordings.

SUBMITTER: Hobbs CN

PROVIDER: S-EPMC5595244 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain.

Hobbs Caddy N CN Johnson Justin A JA Verber Matthew D MD Mark Wightman R R

The Analyst 20170801 16

Brain tissue injury is often accompanied by spreading depolarization (SD) events, marked by widespread cellular depolarization and cessation of neuronal firing. SD recruits viable tissue into the lesion, making it a focus for intervention. During SD, drastic fluctuations occur in ion gradients, extracellular neurotransmitter concentrations, cellular metabolism, and cerebral blood flow. Measuring SD requires a multimodal approach to capture the array of changes. However, the use of multiple senso ...[more]

PMID: 28715004

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Project description:OBJECTIVERetrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODSTen patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTSSuccessful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99-1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337-43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139-16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068-9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565-2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ2 = 3.86, p = 0.42) was observed.CONCLUSIONSKetamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov).

Dataset Information

An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain.

Publications

An implantable multimodal sensor for oxygen, neurotransmitters, and electrophysiology during spreading depolarization in the deep brain.

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