Habituation of auditory startle reflex is a new sign of minimally conscious state

Abstract

Neurological examination of non-communicating patients relies on a few decisive items that enable the crucial distinction between vegetative state (VS)-also coined unresponsive wakefulness syndrome (UWS)-and minimally conscious state. Over the past 10 years, this distinction has proven its diagnostic value as well as its important prognostic value on consciousness recovery. However, clinicians are currently limited by three factors: (i) the current behavioural repertoire of minimally conscious state items is limited and restricted to a few cognitive domains in the goldstandard revised version of the Coma Recovery Scale; (ii) a proportion of ∼15-20% clinically VS/UWS patients are actually in a richer state than VS/UWS as evidenced by functional brain imaging; and (iii) the neurophysiological and cognitive interpretation of each minimally conscious state item is still unclear and debated. In the current study we demonstrate that habituation of the auditory startle reflex (hASR) tested at bedside constitutes a novel, simple and powerful behavioural sign that can accurately distinguish minimally conscious state from VS/UWS. In addition to enlarging the minimally conscious state items repertoire, and therefore decreasing the low sensitivity of current behavioural measures, we also provide an original and rigorous description of the neurophysiological basis of hASR through a combination of functional (high density EEG and 18F-fluorodeoxyglucose PET imaging) and structural (diffusion tensor imaging MRI) measures. We show that preservation of hASR is associated with the functional and structural integrity of a brain-scale fronto-parietal network, including prefrontal regions related to control of action and inhibition, and meso-parietal areas associated with minimally conscious and conscious states. Lastly, we show that hASR predicts 6-month improvement of consciousness. Taken together, our results show that hASR is a cortically-mediated behaviour, and suggest that it could be a new clinical item to clearly and accurately identify non-communicating patients who are in the minimally conscious state.

Keywords: auditory startle reflex; cortically mediated state; disorders of consciousness; habituation; minimally conscious state.

Figure 1

The hASR response and CRS-R. Proportion of the type of response to auditory startle reflex (ASR), either extinguishable (EX, in blue) or inextinguishable (IN, in red), according to the clinical state of consciousness defined by the CRS-R showing that ASR-EX is more frequent in minimally conscious (MCS) patients than in vegetative (VS/UWS) patients and vice versa, χ²(1) = 13.6, P = 0.0002 (A). Proportions of ASR response according to CRS-R scores within each subscale (B).

Figure 2

Multivariate prediction of consciousness based on EEG markers. (A) Relationship between auditory startle reflex (ASR) habituation and the multivariate prediction of consciousness based on EEG markers. Predicted probability of being classified minimally conscious (MCS) was higher in extinguishable patients (EX) than in inextinguishable patients (IN), regardless of the clinical state of consciousness [vegetative (VS/UWS) or MCS] with a main effect of ASR habituation using a 2 × 2 analysis of variance (ANOVA), F(1,81) = 19.6, P ≤ 1 × 10⁻⁴. Post hoc testing revealed that EX patients had a significantly higher probability than IN patients in both VS and MCS populations (P < 0.05, uncorrected). (B) Scalp topographies of some univariate markers [raw theta (θ) and alpha (α) power spectral densities and weighted symbolic mutual information in the theta band (wSMI θ)] showed a significant difference between the two groups, P_cl = 0.0150, P_cl = 0.0235 and P_cl = 0.0077, respectively. A cluster-based approach was used for the statistical comparison, with the main effect of ASR response (independent of the state of consciousness) in an ANOVA as a first step statistic followed by a 10 000 permutations spatial clustering procedure. Channels included in the significant cluster are highlighted by white circles. (C) wSMI θ connectivity differences between ASR-EX and ASR-IN. Only pairs of electrodes exhibiting a significant main effect of the ASR habituation are represented (P < 0.005, uncorrected). P_cl = cluster P-value. *P < 0.05.

Figure 3

Local-global auditory oddball paradigm. (A) Local effect ERP over Fz-centred region of interest showing a significant cluster (black) only in vegetative (VS/UWS) and minimally conscious (MCS) patients with ASR extinguishable response, P_cl = 0.0181 and P_cl = 0.0195, respectively. Scalp representations of averaged voltage values over the time period of the cluster clearly show an anterior positivity compatible with a P3a component. (B) Similarly, a global effect over Pz-centred region of interest was only found in VS/UWS and MCS patients with ASR extinguishable response, with a centro-posterior positivity suggestive of a P3b in MCS, P_cl = 0.0297 and a negative and more lateralized topography in VS/UWS, P_cl = 0.0275. Only results surviving multiple comparisons through a temporal cluster-based permutation procedure with 10 000 permutations are presented. DVT = deviant; P_cl = cluster P-value; SEM = standard error of the mean; STD = standard.

Figure 4

Contingent negative variation. CNV elicited by the first four sounds of the local-global paradigm, with both scalp topographies on top (average values and cluster-based permutation statistics) and ERPs averaged over the Cz-centred region of interest. Coloured dashed lines indicate a significant CNV slope while grey lines indicate a non-significant slope. Only vegetative (VS/UWS) and minimally conscious (MCS) patients with extinguishable response exhibited a significant CNV in both methods, P_cl = 0.0079 and P_cl = 0.0216, respectively. Only results surviving multiple comparisons through a spatial cluster-based permutation procedure with 10 000 permutations are presented. P_cl = cluster P-value; SEM = standard error of the mean.

Figure 5

FDG-PET brain metabolism according to ASR habituation response. (A) Relationship between auditory startle reflex (ASR) habituation and the metabolic index of the best preserved hemisphere showing a higher index in patients with extinguishable response (EX) as compared to patients with inextinguishable response (IN), regardless of the clinical state of consciousness [vegetative (VS/UWS) or minimally conscious (MCS)], as demonstrated by an analysis of variance (ANOVA) main effect of ASR habituation, F(1,32) = 4.63, P = 0.0391. Post hoc testing revealed that EX patients had a significantly higher probability than IN patients in the MCS population (P < 0.05, uncorrected). (B) Whole-brain voxel-based analysis of the metabolic index showing higher values in EX patients than in IN patients in parietal and medial frontal regions (left), with significant differences mainly observed in precuneus/posterior cingulate, premotor area and anterior cingulate (right). (C) ANOVA showed an independent main effect of the ASR habituation in posterior and anterior cingulate and supplementary motor area. For voxel-wise analyses, both metabolic index and P-values (thresholded at P < 0.005 uncorrected with a minimum extent of 100 voxels per cluster) are shown superimposed coronal, sagittal and axial slices of the MNI 152 T₁ brain template with related y, x and MNI coordinates. L = left; R = right. *P < 0.05.

Figure 6

Deep white matter integrity according to ASR habituation response. Relationship between auditory startle reflex habituation (ASR) and the deep white matter integrity assessed by DTI imaging, showing a higher fractional anisotropy [FA_deep, left, main effect of ASR habituation, F(1,53) = 4.9, P = 0.0306] and lower mean diffusivity [MD_deep, right, F(1,53) = 3.4, P = 0.0693] in patients with extinguishable response (EX) compared to patients with inextinguishable response (IN). Post hoc testing revealed a significant effect (P < 0.05 uncorrected) only in vegetative (VS/UWS) patients. *P < 0.05.