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). 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.

Keywords: Biomarker; Brain injury; Clinical trial; Coma; Connectome; Consciousness.

Figures

Figure 1:. Personalized Connectome Mapping in the ICU Reveals Preserved Ventral Tegmental Area (VTA) Connections.

VTA tracts are shown from a left lateral view in a 33-year-old healthy male control and a 29-year-old man with acute severe TBI. The patient was comatose on arrival to the hospital and in a minimally conscious state at the time of this scan on post-injury day 7, as determined by a Coma Recovery Scale-Revised assessment. Tractography analysis was performed using TrackVis, as previously described [26]. All tracts are color-coded by sites of VTA connectivity: turquoise with dorsal raphe (DR), blue with locus coeruleus (LC), green with median raphe (MR), and pink with cortex, thalamus (Th), hypothalamus (Hy), or basal forebrain (BF). Multiple VTA connections are preserved in the patient, including with the medial prefrontal cortex (MPFC), which is a node of the default mode network. The patient recovered consciousness and functional independence by 6 months. Even in a patient with acute severe traumatic brain injury, the VTA may be a hub through which multiple brainstem AAN nodes connect with the Th, Hy, BF and cerebral cortex.

Figure 2:. Ventral Tegmental Area (VTA) Axonal Connections are Spared in a Subset of Patients.

We analyzed VTA connectivity with the hypothalamus (Hy), thalamus (Th), and basal forebrain (BF) in 16 patients, as well as in 16 matched controls. We calculated a connectivity probability (CP) between the VTA and each target ascending arousal network (AAN) node using previously described methods [9, 48, 84]. On a group level, median CP values were lower between the VTA and each AAN node in patients compared with controls. However, there is significant variance in control-group CP values, and many patients fall within the control-group interquartile range (IQR). These results indicate relative sparing of VTA connections in a subset of patients with acute severe TBI. See the Supplementary Material for a detailed description of the CP calculation algorithm.

Figure 3:. Predictive and Pharmacodynamic Biomarkers.

Left Panel: This type of individualized ascending arousal network (AAN) connectome map will be used as a biomarker to predict patient responses to therapy. In this proposed model of a “connectogram,” brainstem nodes are shown on the outside, while hypothalamic, thalamic, and basal forebrain nodes are shown in the middle. Line thickness is proportional to the connectivity probability (CP; see Supplementary Material for how this value is measured) for each node-node pair. Nodal grey shading is proportional to the percentage of each node occupied by a traumatic lesion (bottom right bar). These structural connectivity data, along with structural connectivity measures between the VTA and default mode network (DMN), are used to calculate SVTA. Connectogram artwork by Kimberly Main Knoper. Right Panel: Resting-state functional MRI (rs-fMRI) maps illustrating concurrent recovery of consciousness and reactivation of the DMN. Hot colors indicate correlated activity within the DMN. Cool colors indicate regions anti-correlated with the DMN (inset). Functional connectivity between the VTA and DMN (ZVTA-DMN) is a rs-fMRI pharmacodynamic biomarker that will be used to determine the neurobiological effects of intravenous methylphenidate in patients with acute severe traumatic brain injury. Abbreviations: nucleus basalis of Meynert/substantia innominata (BNM/SI), diagonal band of Broca (DBB), dorsal raphe (DR), intralaminar nuclei of the thalamus (IL), lateral hypothalamic area (LHA), laterodorsal tegmental nucleus (LDTg), locus coeruleus (LC), median raphe (MnR), mesencephalic reticular formation (mRt), parabrachial complex (PBC), paraventricular nucleus of the thalamus (PV), pedunculotegmental nucleus (PTg), periaqueductal grey (PAG), pontis oralis (PnO), reticular nuclei of the thalamus (Ret), tuberomammillary nucleus of the hypothalamus (TMN), ventral tegmental area (VTA).

Figure 4:. STIMPACT Study Design Schematic.

Each patient in Phase 1 of the STIMPACT Trial will undergo five days of data acquisition, with predictive biomarker data and baseline pharmacodynamic biomarker data collected on Day 0, and treatment-related biomarker data collected on Days 1-4. Hence, each patient’s biomarker responses to IV MPH will be measured against his/her own baseline biomarker variance. Abbreviations: BP = blood pressure; CRS-R = Coma Recovery Scale-Revised; HR = heart rate; IV MPH = intravenous methylphenidate; SVTA = ventral tegmental area hub strength; ZVTA-DMN = functional connectivity between the ventral tegmental area and the default mode network.

Figure 5:. Functional Connectivity between the Ventral Tegmental Area (VTA) and Default Mode Network (DMN) Reemerges During Recovery.

Eight patients with acute severe TBI underwent resting-state functional MRI (rs-fMRI) in the ICU and at six-month follow-up, by which time all had recovered consciousness. Mean group-level VTA functional connectivity maps are shown, based on Fisher Z-transformed correlations in the BOLD signal (color bar). Correlations are adjusted for significance with p

Figure 6:. Wavelet transform coherence analysis of a representative control subject (upper panel) and a representative patient (lower panel).

Time series of respiratory variation and change in blood-oxygen level dependent (ΔBOLD) signal in the left ventral diencephalon are shown in the left column. The dynamic interaction between respiratory variation and ΔBOLD is demonstrated by the squared wavelet coherence map between the time series of respiratory variation and ΔBOLD shown in the middle column. The magnitude of coherence ranges between 0 and 1, where warmer color represents stronger coherence and cooler color represents weaker coherence. Significant coherence between respiratory variation and ΔBOLD occurs in the area defined by the thick contour of the unfaded region. The x-coordinate of the area provides information on the duration of the oscillating cycle when respiratory variation interacts with ΔBOLD, and the y-coordinate shows the time when this interaction occurs over the resting state fMRI scan. The simplified format of coherence between respiratory variation and ΔBOLD is shown in the right column, with the features of oscillations displayed in terms of frequency. While increased coherence is found between respiratory variation and ΔBOLD at the frequency range of 0.008-0.063Hz in the healthy subject, the coherence between respiratory variation and ΔBOLD in the same frequency range is diminished in the patient with acute severe TBI. Compared with the healthy subject, the resting state BOLD signal changes are less influenced by respiratory variation in the patient with acute severe TBI. A detailed interpretation of the wavelet coherence findings is included in Supplementary Material.

Figure 7:. Alpha-delta ratio as a biomarker of recovery of consciousness.

We computed the dynamic range of the resting-state alpha-delta ratio in EEG recordings of patients with severe traumatic brain injury and controls. The plots show comparisons of alpha-delta ratio measures in 12 ICU patients with acute severe traumatic brain injury (left), these same 12 patients at 6-month follow-up (middle), and 16 healthy controls (right). Each column represents a single subject. The three red lines within each subject’s alpha-delta ratio plot represent the interquartile range (outer red lines) and the median (middle red line). These results suggest that 1) alpha-delta ratio is generally lower in unconscious ICU patients (coma and vegetative state) than in conscious ICU patients (minimally conscious state and post-traumatic confusional state); 2) in ICU patients who recover consciousness by 6 months, alpha-delta ratio typically increases to values similar to those of controls; and 3) there is substantial intra-subject variance in alpha-delta ratio during a single EEG recording.