A human anti-neuronal autoantibody against GABA B receptor induces experimental autoimmune agrypnia.

In the serum and cerebrospinal fluid of a patient with recurrent acute episodes of respiratory crises, autonomic symptoms and total insomnia (agrypnia), we identified a novel anti-neural complement fixing antibody directed against GABA(B) receptor (GABA(B)R). Patient purified IgG recognized a band of approximately 110 kDa on protein extracts of mouse cerebellum, cortex and brainstem and immunolabelled cultured Chinese hamster ovary (CHO) cells, transfected with human GABA(B)R1 and rat GABA(B)R2 receptors. Western blot analysis of transfected CHO homogenates showed the same band using both patient purified IgG and anti-GABA(B)R1 antibody. In order to verify the pathogenic role of these purified antibodies, we injected patient IgG intrathecally into cisterna magna of C57BL/6 mice pre-implanted with EEG electrodes and we observed severe ataxia followed by breathing depression and total suppression of slow wave sleep, as evidenced by EEG recording, in a dose-dependent manner. Immunohistochemistry on brain sections of mice injected with patient IgG showed the simultaneous presence of bound human IgG and C5b-9 deposits on Purkinje cells and cerebellar granular layer. After incubation with anti-GABA(B)R antibody, a marked reduction of receptor immunostaining was found with relative sparing of neuronal architecture. In conclusion we recognized an anti-neuronal autoantibody directed against GABA(B)R that is associated with autoimmune agrypnia and we showed that our patient purified IgG was able to induce in mice experimental autoimmune agrypnia characterized by a complex neurological syndrome affecting several CNS functions.

Obstructive sleep apnea in Costello syndrome.

Costello syndrome (CS) was initially described by Costello in 1971; it is caused by a germline mutation in HRAS proto-oncogene. The aim of the present study was to evaluate the respiratory activity during sleep in a group of subjects with CS. We studied 10 consecutive patients, 4 males and 6 females, aged 3-29 years, affected by CS. All patients underwent clinical, neurological, otholaryngologic and radiologic evaluation, and a full-night polysomnography in the sleep laboratory. Polysomnography showed that seven patients presented a relevant number of respiratory events of obstructive type during sleep. The apnea-hypopnea index (AHI) ranged from 0 to 19.2 events per hour (mean index = 7.5 +/- 6.9 events/hr). In one patient AHI was not evaluable because of tracheostomy. Apnea induced mild or moderate hemoglobin desaturations (mean of lowest SpO2 values = 85.4 +/- 5.5%). Only sporadic respiratory pauses of central type were observed (mean number of central apnea per study: 7.2 +/- 6.8 events/hr). Sleep structure was fragmented, with a high number of awakenings (mean number of awakenings was 13.2 +/- 8.1; of these, 4.8 +/- 2.5 lasted longer than 2 min). In all patients, otolaryngologic and radiologic observations revealed one or more sites of narrowing in the upper airways. Our results suggest that Costello patients have a high prevalence of obstructive sleep-related respiratory disorders, which need to be assessed by means of polysomnography.

Rhythmic tongue movements during sleep: a peculiar parasomnia in Costello syndrome.

We describe a peculiar parasomnia observed in four Costello infants, characterized by periodic rhythmic movements of the tongue. Ten Costello patients (4 male; age range 9 months to 29 years) underwent 1 full-night laboratory-based video polysomnography. The four youngest patients (2 male and 2 female; age range 9-31 months) presented during sleep repeated stereotyped movements of the tongue, producing a sucking-like or licking-like movement, mostly during non-rapid eye movement (NREM) sleep. Rhythmic tongue movements in Costello syndrome show the features of an NREM sleep parasomnia. Tongue movements during sleep probably originate from brainstem structures and could be facilitated by an impaired control of the oropharyngeal and tongue muscles.

Attentional load of the primary task influences the frontal but not the temporal generators of mismatch negativity.

According to the model hypothesized by Näätänen and Michie, the generation of the mismatch negativity (MMN) requires a mismatch detection, taking place in temporal areas, followed by the activation of frontal generators, underlying attention switching toward the deviant stimulus. We aimed at verifying whether the activation of temporal and frontal regions is dependent on the amount of attentional resources allocable toward the deviant stimulus. We recorded event-related potentials (ERPs) in nine healthy subjects while reading and during a demanding visual task (Multiple Features Target Cancellation, MFTC). Raw data were further evaluated by Brain Electrical Source Analysis (BESA). During the Reading condition, distraction toward the unattended auditory stimuli was reflected by the enhancement of the N1 response to frequent stimuli and by the elicitation of a P3a response to deviant ones. The MMN distribution was explained by bilateral temporal dipoles. During the MFTC condition, no P3a was detected, while source analysis showed the activation of a right frontal generator. Temporal dipoles showed no change between the two conditions: we thus conclude that the earlier mismatch detection is independent on the attentional load. By contrast, the activation of a right frontal subcomponent occurred only during the high-load task, independently on any actual attention shift reflected by the P3a component. We thus discuss the hypothesis whether the right frontal MMN generator, rather than subserving a simple attention switching toward the deviant stimulus, plays a role in modulating the auditory change detection system ("contrast enhancement" model).

Increase of brain-stem high-frequency SEP subcomponents during light sleep in seizure-free epileptic patients.

OBJECTIVE: Three hertz spike-and-wave (SW) occurrence is caused by the abnormal functioning of the same thalamo-cortical loop generating sleep spindles. In fact, SW preferably occurs during light sleep and transitional phases of the vigilance status. Since high-frequency somatosensory evoked potentials (HF-SEPs) are powerfully modulated by sleep and arousal, we verified whether they can reveal abnormalities of arousal-related structures in two patients having showed sporadic SW discharges during light sleep. METHODS: We recorded right median nerve SEPs in two adult patients who suffered since the infancy from childhood absence epilepsy (CAE). Sleep stage-related changes of HF-SEPs were compared to those observed in five healthy volunteers. RESULTS: HF-SEPs decreased during sleep in controls. By contrast, the amplitude of the subcortical component dramatically increased in CAE patients during phase II NREM sleep. Simultaneous EEG showed normally represented sleep spindles, but not SW discharges. CONCLUSIONS: HF-SEP increase probably reflects the hyperactivation of brain-stem arousal-related structures. During such a hyperactivation no EEG abnormalities were observed. SIGNIFICANCE: We hypothesize that HF-SEP increase might reflect a protective mechanism against seizure occurrence during light sleep.

Brain-stem components of high-frequency somatosensory evoked potentials are modulated by arousal changes: nasopharyngeal recordings in healthy humans.

OBJECTIVE: Until now, the demonstration that early components of high-frequency oscillations (HFOs) evoked by electrical upper limb stimulation are generated in the brain-stem has been based on the results of scalp recordings. To better define the contribution of brain-stem components to HFOs building, we recorded high-frequency somatosensory evoked potentials (SEPs) in 6 healthy volunteers by means of a nasopharyngeal (NP) electrode. Moreover, since HFOs are highly susceptible to arousal fluctuations, we investigated whether eyes opening can influence HFOs at this level. METHODS: We recorded right median nerve SEPs from the ventral surface of the medulla by means of a NP electrode as well as from the scalp, in 6 healthy volunteers under two different arousal states (eyes opened versus eyes closed). SEPs have been further analyzed after digital narrow bandpass filtering (400-800 Hz). RESULTS: NP recordings demonstrated in all subjects a well-defined burst, occurring in the same latency window of the low-frequency P13-P14 complex. Eyes opening induced a significant amplitude increase of the NP-recorded HFOs, whereas scalp-recorded HFOs as well as low-frequency SEPs remained unchanged. CONCLUSIONS: Our findings demonstrate that slight arousal variations induce significant changes in brain-stem components of HFOs. According to the hypothesis that HFOs reflect the activation of central mechanisms, which modulate sensory inputs depending on variations of arousal state, our data suggest that this modulation is already effective at brain-stem level.

Influence of modafinil on somatosensory input processing in the human brain-stem.

OBJECTIVE: Since high frequency oscillations (HFOs) evoked by upper limb stimulation are susceptible to arousal fluctuation, we verified whether administration of modafinil, a vigilance promoting drug, modifies such responses at different levels of the somatosensory system. METHODS: HFOs were obtained in 6 healthy volunteers by 500-700 Hz filtering of right median nerve somatosensory evoked potentials, before and 2 hours after the administration of 100 mg modafinil. Raw data were further submitted to brain electrical source analysis. RESULTS: Modafinil significantly increased subcortical HFOs, as well as the strength of a dipolar source at the base of the skull. CONCLUSIONS: Our data suggest that modafinil exerts its action also at the level of the brain-stem, where it interferes with the processing of somatosensory ascending inputs.

Abnormal gating of somatosensory inputs in essential tremor.

OBJECTIVE: To study whether sensorimotor cortical areas are involved in Essential Tremor (ET) generation. BACKGROUND: It has been suggested that sensorimotor cortical areas can play a role in ET generation. Therefore, we studied median nerve somatosensory evoked potentials (SEPs) in 10 patients with definite ET. METHODS: To distinguish SEP changes due to hand movements from those specifically related to central mechanisms of tremor, SEPs were recorded at rest, during postural tremor and during active and passive movement of the hand. Moreover, we recorded SEPs from 5 volunteers who mimicked hand tremor. The traces were further submitted to dipolar source analysis. RESULTS: Mimicked tremor in controls as well as active and passive hand movements in ET patients caused a marked attenuation of all scalp SEP components. These SEP changes can be explained by the interference between movement and somatosensory input ('gating' phenomenon). By contrast, SEPs during postural tremor in ET patients showed a reduction of N20, P22, N24 and P24 cortical SEP components, whereas the fronto-central N30 wave remained unaffected. CONCLUSIONS: Our findings suggest that in ET patients the physiological interference between movement and somatosensory input to the cortex is not effective on the N30 response. This finding thus indicates that a dysfunction of the cortical generator of the N30 response may play a role in the pathogenesis of ET.