Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging

Abstract

Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = −16 ms; 95% confidence interval (CI): −28 to −3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change −19 ms; 95% CI: −23 to −7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.

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

“…https://doi.org/10.1101/19013987 doi: medRxiv preprint basal forebrain, and cortex (Figures 1, 2). Consistent with these observations, nuclear imaging studies show that signal transmission in dopaminergic circuits is variably altered by severe TBI [35][36][37]. These converging lines of evidence support the hypothesis that preserved VTA connections are a potential target for therapeutic modulation in ICU patients with severe TBI.…”

Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies

“…As evidence indicates that some pharmacological and electrophysiological therapies can reactivate arousal pathways in selected patients with subacute and chronic brain injuries 261 , 265 , 272 , biomarkers are urgently needed to identify patients whose brain networks might be amenable to therapeutic modulation 273 . Evidence from single-photon emission computed tomography 274 and PET 275 studies of dopaminergic neurotransmission suggests that alterations to dopaminergic signalling can be detected in vivo in patients with severe brain injuries. Dopaminergic tone is crucial to restoring firing rates within a deafferented striatum 275 .…”

Distinct dopaminergic abnormalities in traumatic brain injury and Parkinson’s disease

“…For example, cognitive enhancers are often used in patients with cognitive impairment and many act through the dopamine neurotransmitter system. We have recently shown that response to methylphenidate, which is widely used following TBI, can be predicted if a patient’s dopaminergic state is known, demonstrating the clinical value of this diagnostic information 23. From the perspective of patients with possible PD, it is also important to appreciate that DaT abnormalities may be due to a remote history of TBI, which may not previously have been thought relevant.…”