Preserved Auditory Steady State Response and Envelope-Following Response in Severe Brainstem Dysfunction Highlight the Need for Cross-Checking.

OBJECTIVES: Commercially available auditory steady state response (ASSR) systems are widely used to obtain hearing thresholds in the pediatric population objectively. Children are often examined during natural or induced sleep so that the recorded ASSRs are of subcortical origin, the inferior colliculus being often designated as the main ASSR contributor in these conditions. This report presents data from a battery of auditory neurophysiological objective tests obtained in 3 cases of severe brainstem dysfunction in sleeping children. In addition to ASSRs, envelope-following response (EFR) recordings designed to distinguish peripheral (cochlear nerve) from central (brainstem) were recorded to document the effect of brainstem dysfunction on the two types of phase-locked responses. DESIGN: Results obtained in the 3 children with severe brainstem dysfunctions were compared with those of age-matched controls. The cases were identified as posterior fossa tumor, undiagnosed (UD), and Pelizaeus-Merzbacher-Like Disease. The standard audiological objective tests comprised tympanograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses (ABRs), and ASSRs. EFRs were recorded using horizontal (EFR-H) and vertical (EFR-V) channels and a stimulus phase rotation technique allowing isolation of the EFR waveforms in the time domain to obtain direct latency measurements. RESULTS: The brainstem dysfunctions of the 3 children were revealed as abnormal (weak, absent, or delayed) ABRs central waves with a normal wave I. In addition, they all presented a summating and cochlear microphonic potential in their ABRs, coupled with a normal wave I, which implies normal cochlear and cochlear nerve function. EFR-H and EFR-V waveforms were identified in the two cases in whom they were recorded. The EFR-Hs onset latencies, response durations, and phase-locking values did not differ from their respective age-matched control values, indicating normal cochlear nerve EFRs. In contrast, the EFR-V phase-locking value and onset latency varied from their control values. Both patients had abnormal but identifiable and significantly phase-locked brainstem EFRs, even in a case with severely distorted ABR central waves. ASSR objective audiograms were recorded in two cases. They showed normal or slightly elevated (explained by a slight transmission loss) thresholds that do not yield any clue about their brainstem dysfunction, revealing the method's lack of sensitivity to severe brainstem dysfunction. CONCLUSIONS: The present study, performed on 3 sleeping children with severe brainstem dysfunction but normal cochlear responses (cochlear microphonic potential, summating potential, and ABR wave I), revealed the differential sensitivity of three auditory electrophysiological techniques. Estimated thresholds obtained by standard ASSR recordings (cases UD and Pelizaeus-Merzbacher-Like Disease) provided no clue to the brainstem dysfunction clearly revealed by the click-evoked ABR. EFR recordings (cases posterior fossa tumor and UD) showed preserved central responses with abnormal latencies and low phase-locking values, whereas the peripheral EFR attributed to the cochlear nerve was normal. The one case (UD) for which the three techniques could be performed confirms this sensitivity gradient, emphasizing the need for applying the Cross-Check Principle by avoiding resorting to ASSR recording alone. The entirely normal EFR-H recordings observed in two cases further strengthen the hypothesis of its cochlear nerve origin in sleeping children.

A Rare Case of Unilateral Auditory Neuropathy Induced by Proton Therapy.

Hearing loss (HL) is one of the most common complications of the treatment in head and neck oncology. Most cases of HL are due to the ototoxicity of platinum-based chemotherapy (PBC) - resulting usually in a symmetric bilateral sensorineural hearing loss (SNHL) - or radiotherapy. Radiation-induced SNHL is progressive, permanent, and dose-dependent. Total dose and follow-up time are important factors affecting incidence rates. However, the hearing consequences of proton radiation therapy (PRT), a radiation-type therapy especially used in pediatric malignancies of the central nervous system (CNS), remains unclear and poorly documented. We report here a case of a four-year-old patient with unilateral auditory neuropathy spectrum disorder (ANSD) related to PRT. This case highlights the need for appropriate auditory monitoring in patients undergoing PRT for CNS or head and neck malignancies.

Vestibular and radiological characteristics of children affected by unilateral auditory neuropathy spectrum disorder.

OBJECTIVE: Auditory neuropathy spectrum disorders (ANSD) are defined by the association of a preserved outer hair cell function and an impaired auditory nerve neural response, and present mostly bilaterally. Unilateral ANSD are consequently only seldom described, and most frequently as isolated cases. This study aims to describe the audiological, vestibular and radiological characteristics of a population of children with unilateral ANSD. MATERIAL AND METHODS: We isolated 22 patients with unilateral ANSD, 12 boys and 10 girls from 0 to 95 months, in a database of auditory evoked potentials. We reviewed the audiological, radiological and vestibular assessments. The audiological assessment included tympanometry, otoacoustic emission recording and auditory evoked potential. Otolithic function was assessed by performing cervical vestibular evoked myogenic potential. The canal function was determined by video head impulse test and/or caloric test. The radiological evaluation consisted of an MRI of the internal auditory canal. RESULTS: Many patients with a type A tympanometry had no response to otoacoustic emission (53,8%), in the presence of a cochlear microphonic potential. Vestibular assessment was performed in 9 of the 22 patients. 4 children had impaired otolithic and/or canal function. MRI evaluation of the inner ear was performed in 18 patients. Aplasia or hypoplasia of the cochlear nerve was found in 17 of them. MRI showed additional vestibular or brainstem abnormalities in 7 of the 18 children. All children with impaired vestibular function had vestibular or brainstem radiological alterations in addition to cochlear branch aplasia or hypoplasia. CONCLUSIONS: Radiological and vestibular abnormalities are common in children with unilateral ANSD and suggest that a radiological and vestibular assessment is required.

Subcortical neural generators of the envelope-following response in sleeping children: A transfer function analysis.

Multiple auditory structures, from cochlea to cortex, phase-lock to the envelope of complex stimuli. The relative contributions of these structures to the human surface-recorded envelope-following response (EFR) are still uncertain. Identification of the active contributor(s) is complicated by the fact that even the simplest two-tone (f1&f2) stimulus, targeting its (f2-f1) envelope, evokes additional linear (f1&f2) and non-linear (2f1-f2) phase-locked components as well as a transient auditory brainstem response (ABR). Here, we took advantage of the generalized primary tone phase variation method to isolate each predictable component in the time domain, allowing direct measurements of onset latency, duration and phase discontinuity values from which the involved generators were inferred. Targeting several envelope frequencies (0.22-1 kHz), we derived the EFR transfer functions along a vertical vertex-to-neck and a horizontal earlobe-to-earlobe recording channels, yielding respectively EFR-V and EFR-H waveforms. Subjects (N= 30) were sleeping children with normal electrophysiological thresholds and normal oto-acoustic emissions. Both EFR-H and EFR-V phase-locking values (PLV) transfer functions had a low-pass profile, EFR-V showing a lower cut-off frequency than EFR-H. We also computed the frequency-latency relationships of both EFRs onset latencies. EFR-H data fitted a power-law function incorporating a frequency-dependent traveling wave delay and a fixed one amounting to 1.2 ms. The fitted function nicely fell within five published estimations of the latency-frequency function of the ABR wave-I, thus pointing to a cochlear nerve origin. The absence of phase discontinuity and overall response durations that were equal to that of the stimulus indicated no contribution from a later generator. The recording of an entirely similar EFR-H response in a patient who had severe brainstem encephalitis with a normal, isolated, ABR wave-I but complete absence of later waves, further substantiated a cochlear nerve origin. Modeling of the EFR-V latency-frequency functions indicated a fixed transport time of 2 ms with respect to EFR-H onset, suggesting a cochlear nucleus (CN) origin, here also, without indication for multiple generators. Other features of the EFR-V response pointing to the CN were, at least for the EFR frequency below the cut-off values of the transfer functions, higher PLVs coupled with increased harmonic distortion. Such a behavior has been described in the so-called highly-synchronized neurons of the ventral cochlear nucleus (VCN). The present study compellingly demonstrated the advantage of isolating the EFR in the temporal domain so as to extract detailed spectro-temporal parameters that, combined with orthogonal recording channels, shed new light on the involved neural generators.

Necroptotic neuronal cell death in amyotrophic lateral sclerosis: A relevant hypothesis with potential therapeutic implication?

Necroptosis is emerging among possible mechanisms underlying cell death in neurodegenerative diseases. In this line, we hypothesize that necroptosis might be implicated in neuronal cell death in amyotrophic lateral sclerosis (ALS). To support this hypothesis, we hereby provide pilot data as well as some findings from the literature about the expression of key markers of the necroptotic pathway in ALS. Our preliminary data indicate the upregulation of key markers of necroptosis activation in lower motor neurons of the spinal cord. These human-derived data combined with some clinical and preclinical findings support our hypothesis testing the involvement of necroptosis in lower motor neurons death in ALS patients. These results pave the way to deepen the role of necroptosis in ALS using both preclinical and clinical approaches. If confirmed, this hypothesis might raise new interventional strategies to alleviate neurodegenerative process in ALS.

Revealing Clothing Does Not Make the Object: ERP Evidences That Cognitive Objectification is Driven by Posture Suggestiveness, Not by Revealing Clothing.

Recent research found that sexualized bodies are visually processed similarly to objects. This article examines the effects of skin-to-clothing ratio and posture suggestiveness on cognitive objectification. Participants were presented images of upright versus inverted bodies while we recorded the N170. We used the N170 amplitude inversion effect (larger N170 amplitudes for inverted vs. upright stimuli) to assess cognitive objectification, with no N170 inversion effect indicating less configural processing and more cognitive objectification. Contrary to Hypothesis 1, skin-to-clothing ratio was not associated with cognitive objectification (Experiments 1-3). However, consistent with Hypothesis 2, we found that posture suggestiveness was the key driver of cognitive objectification (Experiment 2), even after controlling for body asymmetry (Experiment 3). This article showed that high (vs. low) posture suggestiveness caused cognitive objectification (regardless of body asymmetry), whereas high (vs. low) skin-to-clothing ratio did not. The implications for objectification and body perception literatures are discussed.

Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components.

The primary tone phase variation (PTPV) technique combines selective sub-averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f 1 and f 2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f 2 - f 1 from its harmonic distortion 2f 2 - 2f 1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7 ms could be detected in all (N = 12) awake adult normal subjects, but in none (N = 10) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications.

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia.

OBJECTIVES: In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs). METHODS: In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed. RESULTS: Most ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average. CONCLUSIONS: In FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. SIGNIFICANCE: This model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation.

Peripheral and central contribution to the difficulty of speech in noise perception in dyslexic children.

Noise typically induces both peripheral and central masking of an auditory target. Whereas the idea that a deficit of speech in noise perception is inherent to dyslexia is still debated, most studies have actually focused on the peripheral contribution to the dyslexics' difficulties of perceiving speech in noise. Here, we investigated the respective contribution of both peripheral and central noise in three groups of children: dyslexic, chronological age matched controls (CA), and reading-level matched controls (RL). In all noise conditions, dyslexics displayed significantly lower performance than CA controls. However, they performed similarly or even better than RL controls. Scrutinizing individual profiles failed to reveal a strong consistency in the speech perception difficulties experienced across all noise conditions, or across noise conditions and reading-related performances. Taken together, our results thus suggest that both peripheral and central interference contribute to the poorer speech in noise perception of dyslexic children, but that this difficulty is not a core deficit inherent to dyslexia.

Clonidine administration during intraoperative monitoring for pediatric scoliosis surgery: Effects on central and peripheral motor responses.

OBJECTIVE: To study the effect of clonidine administrated as a co-analgesic during scoliosis surgery, on the neuromonitoring of spinal motor pathways. METHODS: Using standardized intraoperative monitoring, we compared the time course of peripherally and transcranially electrically evoked motor potentials (TcEMEPs) before and after injection of a single bolus of clonidine in children under total intravenous anesthesia (TIVA). MEP data were obtained from 9 patients and somatosensory evoked potentials (SSEPs) were obtained from 2 patients. The potential effect of clonidine on mean blood pressure (BP) was controlled. RESULTS: TcEMEPs from upper and lower limbs rapidly showed significant drops in amplitude after the injection of clonidine. Amplitudes reached minimal values within five minutes and remained very weak for at least 10-20minutes during which monitoring of the central motor pathways was severely compromised. SSEPs were not altered during maximal amplitude depression of the TcEMEPS. CONCLUSIONS: This is the first report showing that clonidine severely interferes with neuromonitoring of the spinal cord motor pathways. The results are discussed in light of the literature describing the effects of dexmedetomidine, another α-2 adrenergic agonist. The experimental and literature data point to central mechanisms taking place at both the spinal and cerebral levels. Therefore, clonidine as well as other α-2 adrenergic agonists should be used with extreme caution in patients for whom neuromonitoring of the motor pathways is required during surgery.

When the body becomes no more than the sum of its parts: the neural correlates of scrambled versus intact sexualized bodies.

Recent research found that configural information is less important for the processing of sexualized bodies than for the processing of nonsexualized bodies. The present investigation aims to expand these findings by directly manipulating configural versus analytic processing of sexualized and nonsexualized bodies. We posited that disrupting first-order relational information through scrambling should be associated with larger N170 amplitudes (scrambling effect) for nonsexualized bodies, whereas the scrambling manipulation should not modulate N170 amplitudes associated with sexualized bodies and objects. We presented images of scrambled versus intact sexualized bodies, nonsexualized bodies, and objects while the N170 was recorded. Consistent with our hypothesis, we found that the scrambling manipulation was associated with larger N170 amplitudes for nonsexualized bodies (i.e. scrambling effect), whereas no scrambling effect emerged for sexualized bodies and objects. This research is the first to show that sexualized bodies are processed analytically at a neural level. Implications for the literature in body perception and objectification will be discussed.

Neuropsychological and neurophysiological benefits from white noise in children with and without ADHD.

BACKGROUND: Optimal stimulation theory and moderate brain arousal (MBA) model hypothesize that extra-task stimulation (e.g. white noise) could improve cognitive functions of children with attention-deficit/hyperactivity disorder (ADHD). We investigate benefits of white noise on attention and inhibition in children with and without ADHD (7-12 years old), both at behavioral and at neurophysiological levels. METHODS: Thirty children with and without ADHD performed a visual cued Go/Nogo task in two conditions (white noise or no-noise exposure), in which behavioral and P300 (mean amplitudes) data were analyzed. Spontaneous eye-blink rates were also recorded and participants went through neuropsychological assessment. Two separate analyses were conducted with each child separately assigned into two groups (1) ADHD or typically developing children (TDC), and (2) noise beneficiaries or non-beneficiaries according to the observed performance during the experiment. This latest categorization, based on a new index we called "Noise Benefits Index" (NBI), was proposed to determine a neuropsychological profile positively sensitive to noise. RESULTS: Noise exposure reduced omission rate in children with ADHD, who were no longer different from TDC. Eye-blink rate was higher in children with ADHD but was not modulated by white noise. NBI indicated a significant relationship between ADHD and noise benefit. Strong correlations were observed between noise benefit and neuropsychological weaknesses in vigilance and inhibition. Participants who benefited from noise had an increased Go P300 in the noise condition. CONCLUSION: The improvement of children with ADHD with white noise supports both optimal stimulation theory and MBA model. However, eye-blink rate results question the dopaminergic hypothesis in the latter. The NBI evidenced a profile positively sensitive to noise, related with ADHD, and associated with weaker cognitive control.

In-situ expression of Interleukin-18 and associated mediators in the human brain of sALS patients: Hypothesis for a role for immune-inflammatory mechanisms.

Recent studies reported over-expression of a cytokine (Interleukin (IL)-18) in the serum of sporadic amyotrophic lateral sclerosis (sALS) patients. Here, we report on the first-time detection of in-situ expression of activated IL-18 in the human brain in sALS patients. We also detected cerebral in-situ expression of key-molecules known to be closely related to the molecular network associated with the activation/secretion of IL-18 cytokine, namely, the receptor-interacting serine/threonine-protein kinase 3 (RIPK3 or RIP3), NOD-like receptor pyrin domain containing 3 (NLRP3)-inflammasome, and activated caspase-1. These findings suggest and allow to hypothesize that there might be a role for this cytokine network in molecular mechanisms associated with or implicated in the physiopathology of this neurodegenerative disorder.

Informational masking of speech in dyslexic children.

Studies evaluating speech perception in noise have reported inconsistent results regarding a potential deficit in dyslexic children. So far, most of them investigated energetic masking. The present study evaluated situations inducing mostly informational masking, which reflects cognitive interference induced by the masker. Dyslexic children were asked to identify a female target syllable presented in quiet, babble, unmodulated, and modulated speech-shaped noise. Whereas their performance was comparable to normal-reading children in quiet, it dropped significantly in all noisy conditions compared to age-, but not reading level-matched controls. Interestingly, noise affected similarly the reception of voicing, place, and manner of articulation in dyslexic and normal-reading children.

Safety of MR Imaging at 1.5 T in Fetuses: A Retrospective Case-Control Study of Birth Weights and the Effects of Acoustic Noise.

PURPOSE: To evaluate the effects of exposure to routine magnetic resonance (MR) imaging at 1.5 T during pregnancy on fetal growth and neonatal hearing function in relation to the dose and timing of in utero exposure in a group of newborns at low risk for congenital hearing impairment or deafness. MATERIALS AND METHODS: This retrospective case-control study was approved by the local ethics committee, and written informed consent was waived. Between January 2008 and December 2012, a group of 751 neonates exposed to MR imaging in utero and a group of control subjects comprising 10 042 nonexposed neonates, both groups with no risk factors for hearing impairment at birth, were included. Neonatal hearing screening was performed by means of otoacoustic emission testing and auditory brain stem response according to national guidelines, and the prevalence of hearing impairment in the two groups was compared by using a noninferiority test with Wilson score confidence intervals. The effect of MR exposure on birth weight percentile was examined between the singleton neonates in the exposed group and a randomly chosen subset of 1805 singleton newborns of the nonexposed group by performing an analysis of variance. RESULTS: The rate of hearing impairment or deafness was found to be 0% (0 of 751) in the neonates in the exposed group and was not inferior to that in the nonexposed group (34 of 10 042 [0.34%], P < .05). There was no between-group difference in birth weight percentiles (50.6% for exposed vs 48.4% for nonexposed; P = .22). CONCLUSION: This study showed no adverse effects of exposure to 1.5-T MR imaging in utero on neonatal hearing function or birth weight percentiles.

Isolating informational masking in both pure and complex tone sequences.

OBJECTIVES: Interference between a target and simultaneous maskers occurs both at the cochlear level through energetic masking and more centrally through informational masking (IM). Hence, quantifying the amount of IM requires a strict control of the energetic component. Presenting target and maskers on different sides (i.e., dichotically) reduces energetic masking but provides listeners with important lateralization cues that also drastically reduce IM. The main purpose of this study (Experiment 1) was to evaluate a "switch" manipulation aiming at restoring most of the IM despite dichotic listening. Experiment 2 was designed to investigate the source of the difficulty induced by this switching dichotic condition. DESIGN: In Experiment 1, the authors presented 60 normal-hearing young adults with a detection task in which a regularly repeating target was embedded in a randomly varying background masker. The authors evaluated spatial masking release induced by three different dichotic listening conditions in comparison with a diotic baseline. Dichotic stimuli were presented in either a nonswitching or a switching condition. In the latter case, the presentation sides of dichotic target and maskers alternated several times throughout 10 sec sequences. The impact of the number of switches on IM was investigated parametrically, with both pure and complex tone sequences. In Experiment 2, the authors compared performance of 13 young, normal-hearing listeners in a monotic and dichotic version of the rapidly switching condition, using pure-tone sequences. RESULTS: When target and maskers switched rapidly within sequences, IM was significantly stronger than in nonswitching dichotic sequences and was comparable with the masking effect induced by diotic sequences. Furthermore, Experiment 2 suggests that rapidly switching target and maskers prevent listeners from relying on lateralization cues inherent to the dichotic condition, hence preserving important amounts of IM. CONCLUSIONS: This paradigm thus provides an original tool to isolate IM in signal and maskers having overlapping spectra.

Informational masking of complex tones in dyslexic children.

In complex auditory scenes, perceiving a given target signal is often complicated by the presence of competing maskers. In addition to energetic masking (EM), which arises because of peripheral interferences between target and maskers at the cochlear level, informational masking (IM), which takes place at a more central level, is also responsible for the difficulties encountered in typical ecological auditory environments. While recent research has led to mixed results regarding a potential speech-perception-in-noise deficit in dyslexic children, most of them actually investigated EM situations. The current study aimed at evaluating dyslexic children's sensitivity to pure IM in complex auditory sequences. Performance of the control normally-reading children increased throughout the experiment, reaching a significantly better level than dyslexics' in the last blocks. Our results provide evidence for a general auditory deficit in noise in dyslexic children. Although due to central mechanisms, this deficit does not seem to stem from a mere auditory attention impairment. Further research is needed to examine the precise nature of the auditory difficulty, and its link with reading acquisition in dyslexic children.

Hearing loss and deafness in the pediatric population: causes, diagnosis, and rehabilitation.

With prevalence figures close to 0.2% at birth and rising to 0.35% during adolescence, hearing loss is the most frequent sensory impairment in childhood. This silent handicap has to be actively sought for without delay as it will seriously interfere with the development of speech, language, cognitive and socio-emotional behavior. Objective physiological techniques (evoked potentials, oto-acoustic emissions, tympanometry) combined according to the cross-check principle allow early diagnosis. Objective testing yields invaluable information about the mechanism of the loss and the contribution of disruption of the neural code to the handicap. Among the acquired causes, cytomegalovirus (CMV) infections plays a major role and may take elusive forms. Aminoglycoside ototoxicity has a genetic determinant. Meningitis can lead to rapid endocochlear ossification prompting for rapid cochlear implantation. Genetic causes account for more than 60% of congenital hearing loss, new genetic causes being discovered at an amazing rate. The high number of genetic entities and their huge heterogeneity among them requires guidelines for requesting genetic testing when desirable. Several syndromes prone to request neuropediatricians' attention as an early diagnosis followed by specific treatment can considerably limit the ensuing handicap. Whatever the type of assistive device fitted (amplifying hearing aid or cochlear implant) and the importance of associated handicaps, a multidisciplinary rehabilitation combined with educated parental commitment is necessary for optimal results.

Selective expression of a neuromodulatory cytokine (IL-2) in specific brainstem neurovegetative centers: a possible final common neuro-molecular pathway in dying patients.

Cytokines interact with neurotransmitters and modify neuronal and neuroimmune functions. Intense in situ neuronal IL-2 immunoreactivity was detected in vital human brainstem neuronal centers which are principally implicated in cardio-respiratory control mechanisms. These observations were made in critically-ill aging adult as well as in young infant patients dying from various clinico-pathological conditions. We suggested that this in situ cytokine over-expression might tip a delicate balance in molecular interactions in those vital neuro-vegetative centers, causing disturbed homeostatic control of cardio-respiratory functions and impaired arousal responses; we further hypothesized that this IL-2-induced neuro-molecular disequilibrium in the brainstem microenvironment might thus be part of a final common pathway leading to death.