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

An Invited Commentary to this article was published on 13 August 2020

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). For patients whose families face time-sensitive, life-or-death decisions, treatments that promote recovery of consciousness are needed to reduce the likelihood of premature withdrawal of life-sustaining therapy, facilitate autonomous self-expression, and increase access to rehabilitative care. Here, we present the Connectome-based Clinical Trial Platform (CCTP), a new paradigm for developing and testing targeted therapies that promote early recovery of consciousness in the ICU. We report the protocol for STIMPACT (Stimulant Therapy Targeted to Individualized Connectivity Maps to Promote ReACTivation of Consciousness), a CCTP-based trial in which intravenous methylphenidate will be used for targeted stimulation of dopaminergic circuits within the subcortical ascending arousal network (ClinicalTrials.gov NCT03814356). The scientific premise of the CCTP and the STIMPACT trial is that personalized brain network mapping in the ICU can identify patients whose connectomes are amenable to neuromodulation. Phase 1 of the STIMPACT trial is an open-label, safety and dose-finding study in 22 patients with disorders of consciousness caused by acute severe traumatic brain injury. Patients in Phase 1 will receive escalating daily doses (0.5–2.0 mg/kg) of intravenous methylphenidate over a 4-day period and will undergo resting-state functional magnetic resonance imaging and electroencephalography to evaluate the drug’s pharmacodynamic properties. The primary outcome measure for Phase 1 relates to safety: the number of drug-related adverse events at each dose. Secondary outcome measures pertain to pharmacokinetics and pharmacodynamics: (1) time to maximal serum concentration; (2) serum half-life; (3) effect of the highest tolerated dose on resting-state functional MRI biomarkers of connectivity; and (4) effect of each dose on EEG biomarkers of cerebral cortical function. Predetermined safety and pharmacodynamic criteria must be fulfilled in Phase 1 to proceed to Phase 2A. Pharmacokinetic data from Phase 1 will also inform the study design of Phase 2A, where we will test the hypothesis that personalized connectome maps predict therapeutic responses to intravenous methylphenidate. Likewise, findings from Phase 2A will inform the design of Phase 2B, where we plan to enroll patients based on their personalized connectome maps. By selecting patients for clinical trials based on a principled, mechanistic assessment of their neuroanatomic potential for a therapeutic response, the CCTP paradigm and the STIMPACT trial have the potential to transform the therapeutic landscape in the ICU and improve outcomes for patients with severe brain injuries.

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Acknowledgements

We thank the members of the Patient and Family Advisory Board of the Massachusetts General Hospital Laboratory for NeuroImaging of Coma and Consciousness for their feedback and insights regarding the ethical conduct of this clinical trial. We acknowledge Maryam Masood and Zora DiPucchio for their contributions to the regulatory oversight of the trial. We also thank Dr. David A. Schoenfeld for helpful statistical consultation.

Funding

The study was funded by the NIH Director’s Office (DP2HD101400), National Institute of Neurological Disorders and Stroke (K23NS094538, R21NS109627, RF1NS115268), American Academy of Neurology/American Brain Foundation, James S. McDonnell Foundation, Rappaport Foundation, and Tiny Blue Dot Foundation. We also acknowledge support from the National Institute of Neurological Disorders and Stroke Clinical Trial Methodology Course (R25NS088248). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health Award UL 1TR002541) and financial contributions from Harvard University and its affiliated academic healthcare centers. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic healthcare centers, or the National Institutes of Health.

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Contributions

BLE: study conception and design; data acquisition, processing, and analysis; data interpretation; drafting the article; final approval of the version to be published. MEB: design of treatment compounding and operating procedures and pharmacokinetic monitoring, critical review of manuscript, final approval of the version to be published. DWZ: design of EEG pharmacodynamic biomarker; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. ASF: design of statistical plan; critical review of manuscript, final approval of the version to be published. SBS: design of structural MRI predictive biomarker; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. ZDT: design of functional MRI pharmacodynamic biomarker; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. SC: design of dynamic functional connectivity-based pharmacodynamic analysis; critical review of manuscript, final approval of the version to be published. JEK: design of functional MRI sequence; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. SC: design of functional MRI physiologic monitoring; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. SLM: design of functional MRI physiologic monitoring; data acquisition, processing, and analysis; critical review of manuscript, final approval of the version to be published. TPB: study design; critical review of manuscript, final approval of the version to be published. JJF: study design, ethical guidance, final approval of the version to be published. JTG: study design; critical review of manuscript, final approval of the version to be published. LRH: study design; critical review of manuscript, final approval of the version to be published. KS: development of investigational therapy; study design; critical review of manuscript, final approval of the version to be published. ENB: development of investigational therapy; study design; critical review of manuscript, final approval of the version to be published. YGB: study conception and design; data acquisition, processing, and analysis; data interpretation; drafting the article; final approval of the version to be published.

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Correspondence to Brian L. Edlow.

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All biomarker data reported here were obtained with written informed consent provided by healthy control subjects or by surrogate decision-makers for patients with altered consciousness, as part of a separate Institutional Review Board-approved protocol.

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Edlow, B.L., Barra, M.E., Zhou, D.W. et al. Personalized Connectome Mapping to Guide Targeted Therapy and Promote Recovery of Consciousness in the Intensive Care Unit. Neurocrit Care 33, 364–375 (2020). https://doi.org/10.1007/s12028-020-01062-7

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Keywords

  • Coma
  • Consciousness
  • Brain injury
  • Connectome
  • Clinical trial
  • Biomarker