Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit

Abstract

There are currently no therapies proven to promote early recovery of consciousness in patients with severe brain injuries in the intensive care unit (ICU). Early recovery of consciousness would benefit patients and families by reducing the likelihood of premature withdrawal of life-sustaining therapy and may decrease ICU complications related to immobility, facilitate self-expression, enable autonomous decision-making, and increase access to rehabilitative care. Here, we present the connectome-based clinical trial platform (CCTP), a new mechanistic paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. The scientific premise of the CCTP is that personalized brain connectome maps can be used to select patients for targeted therapies that promote recovery of consciousness. Structural and functional MRI connectome maps will identify circuits that may be amenable to neuromodulation. Patients will be selected for clinical trials in the CCTP paradigm based on connectomes that are likely to respond to targeted therapies. To demonstrate the utility of this precision approach, we describe STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based clinical trial in which intravenous methylphenidate will be used to promote early recovery of consciousness in the ICU (ClinicalTrials.gov NCT03814356). We propose that the CCTP has the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

Applications of Advanced MRI to Disorders of Consciousness

“…First, though both fMRI and dMRI have advantages, a multimodal approach that combines the two, and synthesizes them with other conventional tools, may lend even greater insights into DoC. 27 51 52 68 84 85 Second, there is an opportunity to optimize how advanced MRI data are collected, as ongoing research explores techniques to improve resolution, 86 87 eliminate sources of physiologic noise, 88 89 90 91 92 93 and minimize the effects of confounders. 71 72 73 74 75 76 77 Third, the most effective way of analyzing and interpreting the data acquired with advanced MRI remains an active topic of investigation.…”

“…97 98 99 Similarly, while pharmacologic stimulants have demonstrated modest efficacy in improving levels of consciousness, 96 efficacy may be higher in patients with intact arousal circuitry. 93…”

Pharmacologic Therapies to Promote Recovery of Consciousness

“…39 42 43 44 45 An ongoing phase 1 clinical trial is evaluating the safety of intravenous methylphenidate in patients with severe TBI complicated by DoC (NCT03814356). 46…”

The Curing Coma Campaign and the Future of Coma Research

“…Numerous recent studies have improved our understanding of coma and consciousness after acute brain injury and demonstrate important momentum. 18 19 20 21 Collaborative efforts to improve stroke care, vaccine development, or space exploration have succeeded by bringing together scientists, clinicians, and the public in a shared sense of opportunity and responsibility. While there may be a sense of grandiosity in an effort such as the CCC, the opportunity to bring together scientists and clinicians from the acute and post-acute phases of patient care and to include patients and families in the effort holds promise and hope.…”