Mismatch negativity predicts recovery from the vegetative state

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Abstract

Objective

Mismatch negativity (MMN) is an automatic event related brain response, well investigated in the acute phase after severe brain injury: the presence of a MMN is often found to predict the emergence from coma, and the exclusion of shifting into a vegetative state (VS). In the present study MMN was examined during recovery from VS.

Methods

Ten vegetative patients were repeatedly examined every 2 weeks for an average period of 3.5 months. Amplitudes and latencies were related to the patients’ recovery from VS to consciousness, and to a healthy norm group. In addition, MMN was examined on its prognostic value in VS patients, in predicting recovery to consciousness and long-term functional outcome.

Results

With recovery to consciousness MMN-amplitudes increased. A sudden increase was seen in MMN amplitude when patients started to show inconsistent behavioural responses to simple commands. At this level MMN resembled the MMN response as was seen in the norm group. In addition, the MMN-amplitude and latency during the first measurement predicted the patients’ outcome on recovery to consciousness.

Conclusions

With recovery from VS to consciousness the ability to process auditory stimulus deviance increases. A sudden enhancement in MMN-amplitude preceded overt communication with the environment. This might be indicative of the consolidation of neural networks underlying overt communication. Moreover, MMN can be helpful in identifying the ability to recover from VS.

Significance

MMN can be used to track recovery from the vegetative state in the post-acute phase after severe brain injury. In addition, MMN can be used to predict the ability to recover from the vegetative state.

Introduction

Severe brain injury results in high morbidity and mortality rates. The majority of patients experience long-term or lifelong disabilities, bringing along major costs for family and society. So far there has been limited research concerning the group of young adults, who have the highest risks (Jennett, 1996, Finfer and Cohen, 2001).

Many individuals who sustain severe acquired brain injury experience prolonged or permanent disorders of consciousness. Acute severe brain injury inevitably results in coma, a state of loss of consciousness with the eyes closed, with no sleep–wake cycle (Multi-Society Task Force on Persistent Vegetative State, 1994a). If not resulting in death within a period of 3 to 4 weeks, this coma will develop into a vegetative state (VS, Jennett and Plum, 1972), where the patient seems awake but not aware: uncommunicative and unresponsive to the environment. VS is defined as persistent (PVS) as presence for longer than a month (Bernat, 2006). If recovery continues, patients regain minimal responsiveness to external stimuli (minimally conscious state, MCS) (Giacino et al., 2002), that eventually may result in full recovery of consciousness and responsiveness. Otherwise, patients may remain for a long time, or even the rest of their life span, in a vegetative or minimally conscious state. In a later stage it may be considered permanent although on clinical rather than temporal considerations (Working Party of the Royal College of Physicians, 2003). Once this diagnosis has been made, ethical and legal issues around withdrawal of treatment may arise (Jennett, 2005). The current study focuses on patients who were in VS for at least a month.

In general, 1–14 percent of the traumatic, and 12 percent of the non-traumatic prolonged comatose patients shift into VS (Multi-Society Task Force on Persistent Vegetative State, 1994a, Multi-Society Task Force on Persistent Vegetative State, 1994b). Fifty-two percent of the traumatic and 15 percent of the non-traumatic vegetative patients do recover to consciousness (Multi-Society Task Force on Persistent Vegetative State, 1994b). Since recovery from VS to consciousness does occur and depends on residual brain capacities, longitudinal research in the post-acute phase within this group is of great importance to understand what underlies.

The diagnosis of VS and MCS is based on clinical observation of behavioural criteria mostly. Several uncertainties stick to this method. First, observational methods depend on the subjective interpretation of behavioural responses, while conscious experience often occurs without behavioural signs. Second, no initial behavioural differences exist between the patients who may recover to consciousness and those who remain permanently vegetative.

To obtain complementary objective information about the level of consciousness in non-responsive patients, the present study focuses on neurophysiological responses during the recovery from VS to consciousness. A longitudinal study was performed in which the Mismatch Negativity (MMN) (Näätänen et al., 1978) was examined.

MMN is generated by the brain’s automatic response to physical stimulus deviation from the preceding stimulus in repetitive auditory input, revealing that physical features of auditory stimuli are fully processed regardless whether they are attended to or not (Näätänen et al., 2004). Mismatch negativity has repeatedly shown to predict outcome after coma (Fischer et al., 1999, Fischer et al., 2004, Kane et al., 1993, Kane et al., 1996, Luauté et al., 2005, Morlet et al., 2000). Fischer et al., 1999, Fischer et al., 2004 demonstrated that in the acute phase the presence of MMN predicted the exclusion of shifting into PVS. Additionally, Luauté et al. (2005) showed that when MMN was present in comatose patients no patient turned to permanent VS 1 year after the brain insult. MMN responses have been found in VS and MCS patients, especially when complex tones or musical notes were used (Jones et al., 1994, Kotchoubey et al., 2003, Kotchoubey et al., 2005). Additionally, in the study of Kotchoubey et al. (2005) 6 months after the brain insult clinical improvement was observed more frequently in VS and MCS patients with a significant MMN than in those without the MMN. Up to now researchers have not longitudinally investigated MMN responses during the recovery from VS. The present study reports on longitudinal changes in MMN responses during recovery to consciousness, and on its prognostic value in VS patients.

Section snippets

Participants

Ten severely brain-injured patients (7 were male; age M = 17.3, SD = 4.4, 8–25 years), who were admitted to an Early Intensive Neurorehabilitation Programme (Eilander et al., 2005), took part in the study between November 2002 and January 2004. The duration of the patients’ participation in the programme ranged from 1.5 to 5.2 months (M = 3.5 months; SD = 1.03) (Table 1). Time since injury at admission ranged from 6.2 to 19.4 weeks (M = 11.6 weeks; SD = 3.6). All but two patients suffered from a traumatic

Behavioural indices of recovery

At admission, the patients’ averaged LoC score was 3.6 (±0.52). At the end of the programme the average LoC score had increased to 5.9 (±1.9). Five patients reached a conscious level (exit MCS: LoC 7 or 8), 2 patients were still in MCS (LoC 5 or 6), and 3 patients were still in VS (LoC 2–4) at the end of the programme (see Table 1 for LoCdischarge).

The long-term outcome scores on the DRS and GOSE could be obtained for 9 patients, and are shown in Table 1. Two to 3 years after the injury the

Discussion

MMN-amplitude predicted the level of consciousness, and functional outcome 2 years after the injury. All patients who ultimately recovered to consciousness already showed higher amplitudes and shorter latencies in VS (first measurement) in comparison to the patients who remained in VS or MCS. A less strong prognostic value was found for the long-term functional outcome. The DRS and GOSE scores reveal that most of the conscious patients were still severely disabled about 2 years after their

Acknowledgements

This study was financially supported by: Stichting Centraal Fonds RVVZ, Johanna Kinderfonds, CZ groep Zorgverzekeringen, Zorgverzekeraar VGZ, Zorg en Zekerheid, Stichting Bio Kinderrevalidatie, and Hersenstichting Nederland. We gratefully acknowledge the cooperation of the patients and their families on this study. We are grateful to all members (H. van Dall, P.L. Hoenderdaal, J.C.M. Lavrijsen, A.I.R. Maas, A.J.H. Prevo, H. Stroink, A.J.J.M. Vingerhoets and H. van der Vlugt) of the scientific

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