Activation of a residual cortical network during painful stimulation in long-term postanoxic vegetative state: a ¹⁵O–H₂O PET study

Abstract

Survivors of prolonged cerebral anoxia often remain in the persistent vegetative state (PVS). In this study, long-term PVS patients were investigated by ¹⁵O–H₂O PET to analyze their central processing of pain. The study was approved by the local Ethics Committee, the experiments were performed in accordance with the Helsinki Declaration of 2000. Seven patients remaining in PVS of anoxic origin for a mean of 1.6 years (range 0.25–4 years) were investigated. We performed functional PET of the brain using ¹⁵O-labelled water during electrical nociceptive stimulation. Additionally, a brain metabolism study using ¹⁸F–fluorodeoxyglucose (FDG) PET and multi-sequence MRI (including a 3-D data set) were acquired in all patients. PET data were analyzed by means of Statistical Parametric Mapping (SPM99) and coregistered to a study-specific brain template. MRI and FDG PET showed severe cortical impairment at the structural and the functional level, that is, general atrophy of various degrees and a widespread significant hypometabolism, respectively. Pain-induced activation (hyperperfusion) was found in the posterior insula/secondary somatosensory cortex (SII), postcentral gyrus/primary somatosensory cortex (SI), and the cingulate cortex contralateral to the stimulus and in the posterior insula ipsilateral to the stimulus (P<0.05, small-volume-corrected). No additional areas of the complex pain-processing matrix were significantly activated. In conclusion, the regional activity found at the cortical level indicates that a residual pain-related cerebral network remains active in long-term PVS patients.

Introduction

Patients in the vegetative state (VS) are thought to be incapable of conscious experience of themselves and of external world while arousal is preserved [1]. VS is mostly caused by traumatic or nontraumatic (e.g. anoxic) brain injury and can be diagnosed using established clinical criteria (see below). If VS is still present 1 month after the underlying insult, it is called persistent vegetative state (PVS).

Functional neuroimaging, especially positron emission tomography (PET), has proven to contribute new aspects to the understanding of VS/PVS. Most PET studies measured resting brain metabolism and demonstrated a global reduction in cerebral metabolic rate for glucose [2]. Laureys et al. [3], [4] could show that in VS patients, the metabolically most impaired areas were the frontal and parietal associative cortices, whereas the most spared regions were basal forebrain, brainstem, and posterior hypothalamus and that cortico-cortical connectivity was altered [5]. In contrast to resting metabolism investigations, the imaging analysis of cerebral responses to external stimuli potentially provides deeper insights into preserved central processing of the patients' interaction with the external world. After single case reports [6], [7], functional disconnection was demonstrated in a systematic investigation in VS patients: primary auditory cortices, but not higher order multimodal association areas were activated during auditory stimulation [8].

One of the most important issues in the interaction with patients in the PVS is their sensation of pain. From the practical point of view, relatives and caregivers have to know if the patients feel pain during daily care, and this is often difficult to conclude from their reactions or mimicry and physical expressions. From the theoretical point of view, pain is an unpleasant experience that involves the conscious awareness of noxious sensations and aversive feelings associated with actual or potential tissue damage [9], and so cannot be separated from higher brain functions regulating consciousness and attention. The central nociceptive system as studied by various imaging techniques in normal subjects comprises the primary (SI) and secondary (SII) somatosensory cortices, the insular cortex, the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (DLPFC), and the parietal cortex [10], [11], [12]. A recent PET study of noxious somatosensory stimulation in a group of patients in early stages of PVS (duration of about 1 month) described a partly functionally disconnected and dissociated central pain-related network [13]. In the present study, patients in considerably later stages of PVS were studied to investigate if correlates of cerebral nociceptive processing remain detectable in long-term PVS which is associated with severe brain atrophy.