By Nicholas Schiff, MD
Associate Professor of Neurology and Neuroscience, Center for the Advanced Study of Brain Injury, Weill Cornell Medical College
Dr. Schiff reports that he is a consultant for EnspireDBS, Inc.
SYNOPSIS: Preserved habituation of the auditory startle response, performed at the bedside, indicates intact cortical structures and cortico-cortical white matter tract connections. Preservation of this reaction in patients with unresponsive wakefulness can help distinguish the vegetative state from minimally conscious state and may even predict eventual awakening.
SOURCE: Hermann B, Salah AB, Perlbarg V, et al. Habituation of the auditory startle reflex is a new sign of minimally conscious state. Brain 2020;143:2154-2172.
Identification of sometimes very subtle nonreflexive behaviors associated with minimally conscious state (MCS) has been shown to discriminate significant differences in outcome following severe brain injuries.1,2 Such detectable yet often overlooked points on the neurological examination can offer a powerful tool for the neurologist, particularly early in the recovery of severe traumatic brain injury where brief visual or auditory tracking of stimuli may be the only hint auguring an improved outlook in a patient already weeks into their recovery. In a new study returning to the foundations of bedside neurological examination, Hermann et al reported on the performance of a simple behavioral assessment measure, the habituation of the auditory (acoustic) startle reflex (hASR), in discriminating MCS patients from those in the vegetative state (VS) and predicting outcomes. The ASR is a brainstem-mediated reflex typically elicited by a sharp noise, such as a hand clap, that often remains unmodulated in severely brain-injured patients demonstrating VS- or MCS-level examinations. In such patients, a blink reflex, sometimes with additional motor outflow, remains in one-to-one correspondence with each stimulus; habituation of ASR results in an extinguishing of the response with repeated stimuli.
In addition to their assessment of hASR as a behavioral screening tool for separating VS and MCS, Hermann et al reported on the correlation of several direct measurements of brain structural and functional integrity known to augment clinical discriminations of VS vs. MCS.3,4 Several of these measures are found to have strong association with the capacity to habituate the ASR, including quantitative electroencephalography (qEEG), fluoro-deoxyglucose positron emission tomography (FDG-PET), and diffusion tensor imaging (DTI).
In their study, 96 patients (48 with VS, four with MCS) were assessed using the gold standard quantitative behavioral assessment tool, the Coma Recovery Scale-Revised (CRS-R). More than half of the patient sample (55%) demonstrated hASR, comprising a majority of MCS (75%) and a minority of VS (35%) patients. Notably, the presence of hASR in patients provided the same level of discrimination of MCS vs. VS as the best performing subscale score of the CRS-R and independently associated with a high probability of identifying MCS in patients who had a prior clinical diagnosis of VS. In addition, hASR showed strong correlation with qEEG measures previously demonstrated to associate with MCS,4 preserved cerebral metabolism obtained from FDG-PET measurements, and inferred cortical interregional connectivity measured by DTI. Collectively, these results support the value of the hASR as a clinical diagnostic assessment tool at the bedside for patients with disorders of consciousness. Most importantly, the presence of hASR predicted the emergence of command following at six months in those patients without command following on bedside examination at the time of the measurement. This latter correlation invites the inclusion of hASR in future larger population outcome studies, particularly in intensive care unit populations where measures of cerebral integrity using qEEG-based command-following techniques show marked correlation with improved outcomes at one year following injury.5
Beyond the value of bringing focus to this simple and easily elicited clinical examination technique in the assessment of disorders of consciousness, the Hermann et al study adds insight into underlying brain mechanisms of recovery. Patients with measurable hASR in this study demonstrated more preserved DTI and deep white matter integrity and evidence of fronto-parietal cortical functional integrity, establishing a link of preserved hASR to specific cortico-cortical systems: The presence of hASR correlated with increased regional cerebral metabolism measured by FDG-PET within the posterior cingulate cortex, anterior cingulate cortex, premotor cortex, and anterior prefrontal cortex. Thus, hASR appears to provide an early indicator of the functional integrity of the long-range cortico-cortical connections between posterior cortices of the default mode network and the anterior forebrain mesocircuit involving the anterior cingulate and pre-motor regions. Activity within both of these networks is demonstrated to correlate with recovery from disorders of consciousness in a wide range of studies.3 Overall, this is an elegant study providing a deep exploration of the biological underpinnings of a preserved hASR and demonstrating its immediate clinical effect for assessment of disorders of consciousness.
- Giacino JT, Kalmar K. The vegetative and minimally conscious states: A comparison of clinical features and functional outcome. J Head Trauma Rehabil 1997;12:36-51.
- Nakase-Richardson R, Whyte J, Giacino JT, et al. Longitudinal outcome of patients with disordered consciousness in the NIDRR TBI Model Systems Programs. J Neurotrauma 2012;29:59-65.
- Laureys S, Schiff ND. Coma and consciousness: Paradigms (re)framed by neuroimaging. Neuroimage 2012;61:478-491.
- Sitt JD, King J-R, El Karoui I, et al. Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state. Brain 2014;137(Pt 8):2258-2270.
- Claassen J, Doyle K, Matory A, et al. Detection of brain activation in unresponsive patients with acute brain injury. N Engl J Med 2019;380:2497-2505.