Cortical hyper-excitability in healthy children: evidence from habituation and recovery cycle phenomena of somatosensory evoked potentials.

AIM: To compare neurophysiological parameters of central nervous system excitability in healthy children/adolescents with those of healthy adults. METHOD: Two experimental protocols were used in 19 healthy children/adolescents (10 males and 9 females, mean age 9y 11mo [SD 2y 9mo], range 5-15y) and 19 healthy adults (8 males and 11 females, mean age 36y 6mo [SD 7y 9mo], range 27-51y). First, we administered repetitive trains of innocuous electrical stimulation of the median nerve and analysed habituation (progressive attenuation) of the cervical and cortical responses. Second, we administered several blocks of two closely timed electrical innocuous stimuli of the median nerve (with interstimulus intervals set at 5, 10, and 20ms in each block) and analysed the recovery index (the percentage of the response to the second stimulus with respect to that to the first). RESULTS: Clear-cut neurophysiological signs of cortical hyper-excitability were found in children/adolescents but not in adults. In contrast with the adults, the children/adolescents did not attenuate cortical responses to repetitive stimulation, and presented with extremely shortened recovery cycle. At baseline, both groups presented with comparable cortical responses. INTERPRETATION: Healthy children/adolescents present cortical hyper-excitability compared with healthy adults. These findings agree with previous findings that show an overall imbalance of excitatory and inhibitory neuronal and neurochemical mechanisms in favour of excitatory ones, in the healthy developing cerebral cortex.

Patterns of habituation and clinical fluctuations in migraine.

BACKGROUND: Habituation deficit, suggesting a deregulation of cortical excitability, represents a typical hallmark of interictal stages of migraine. We previously demonstrated that several neurophysiological markers of altered cortical excitability are significantly correlated to spontaneous clinical fluctuations of migraine. We therefore aimed at verifying whether clinical fluctuations are correlated to specific patterns of somatosensory evoked potential (SEP) habituation. METHODS: We analyzed habituation after median nerve stimulation of both high-frequency oscillations (HFOs) and N20 SEP in 25 migraine patients and 18 healthy volunteers. Subjects underwent six consecutive series of 500 stimuli. RESULTS: Migraine patients as a whole showed a significant habituation deficit of the N20 response. Moreover, spontaneously worsening patients show a clear potentiation of this wave in the last block of stimuli, whereas in spontaneously improving patients the N20 amplitude remained stable. Presynaptic HFOs were smaller in worsening patients and larger in improving ones, but they did not undergo habituation in patients as well as in healthy subjects. CONCLUSIONS: Potentiation of the N20 response in spontaneously worsening migraineurs confirms that the reduction of the thalamocortical drive plays a major role in migraine pathogenesis. Moreover, the stable pattern we observed in spontaneously improving patients suggests that compensatory mechanisms can also play an important role. The normal response to repeated stimuli of HFOs in migraineurs might indicate that, although its initial amount depends on clinical conditions, high-frequency thalamocortical drive remains stable during the stimulation and probably reflects the activity of a buffer mechanism.

Different levels of cortical excitability reflect clinical fluctuations in migraine.

BACKGROUND: In a previous study we demonstrated that high-frequency oscillations (HFOs) elicited by median nerve stimulation are significantly correlated to clinical fluctuations of migraine. We aimed at verifying whether clinical fluctuations and HFO changes are correlated to N20 somatosensory evoked potential (SEP) recovery cycle, which is likely to reflect the functional refractoriness of primary somatosensory cortex neurons. METHODS: We analysed both HFOs and N20 SEP recovery cycle to paired stimulation in 21 migraine patients and 18 healthy volunteers. RESULTS: Shortened recovery cycle correlated with low-amplitude HFOs as well as with clinical worsening. By contrast, prolonged recovery cycle correlated with enhanced HFOs, as well as with spontaneous clinical improvement. CONCLUSIONS: In our migraine patients the strict relationship between presynaptic HFO amplitude and N20 recovery function suggests that changes of both parameters might be caused by modifications of the thalamo-cortical drive. Our findings suggest that the thalamo-cortical drive during interictal stages could fluctuate from abnormally high to abnormally low levels, depending on mechanisms which reduce cortical excitability in spontaneously improving patients, and increase cortical excitability in spontaneously worsening ones.

Somatosensory mismatch negativity in healthy children.

AIM: Event-related potentials (ERPs) obtained when focused attention is kept away from the stimulus (unnoticed stimulation) are possibly linked to automatic mismatch-detection mechanisms, and could be a useful tool to investigate sensory discrimination ability. By considering the high impact of impaired somatosensory integration on many neurological disturbances in children, we aimed to verify whether mismatch-related responses to somatosensory stimulation could be obtained in healthy children. METHOD: Eleven healthy participants (age range 6-11y, mean 8y 2mo, SD 1y 7mo; seven males, four females) underwent 'oddball' electrical stimulation of the right hand (80% frequent stimuli delivered to the thumb, 20% deviant stimuli delivered to the fifth finger). Data were compared with those obtained when the frequent stimuli to the thumb were omitted ('standard-omitted' protocol). ERPs were recorded at frontal, central, and parietal scalp locations. Children's overt attention was engaged by a demanding video game. RESULTS: In the oddball protocol, deviant stimulation elicited a left central negativity at about 160ms latency, followed by a left frontal negative response at about 220ms latency. Standard-omitted traces showed only a left parietal negative response spreading to right parietal regions. INTERPRETATION: Mismatch-related somatosensory responses can be reliably obtained in children, providing that appropriate technical contrivances are used. In clinical use, the frontal components, which are present only during the oddball protocol, could be a reliable and unequivocal neurophysiological marker of the automatic mismatch-detection mechanism.

Visual and vestibular functioning, and age and surgery effects on postural control in healthy children with vertical strabismus.

PURPOSE: To describe visual and vestibular functioning and the effects of age and surgery effects on postural control in healthy children with vertical strabismus. DESIGN: This is a comparative case series. METHODS: We evaluated participants at the Scientific Institute Eugenio Medea during routine clinical activities. We enrolled 30 consecutive children/adolescents (age range 4-13 years) with isolated vertical strabismus, with and without corrective surgery. Participants were split into four subgroups according to age (4-8 years versus 9-13 years) and ocular surgery (surgery versus no surgery). The clinical protocol included ophthalmological, orthoptic, neurological, physiatrical, otolaryngological, and vestibular evaluations, and the instrumental protocol included ocular cyclotorsions assessment, posturography, and vestibular myogenic-evoked potentials. Main outcome measures of the study were the prevalence of study-relevant orthopedic, ocular, vestibular, and posturographic abnormalities. RESULTS: Among the overall largely variable findings across patients' groups, we found some interesting trends: larger binocular vision and convergence disorders in younger children, smaller prevalence of asymmetric vestibular-evoked potentials in operated children, less posturographic abnormalities in younger children. No clear-cut beneficial effect of surgery was found on all clinical and instrumental parameters considered, despite good re-alignment of the eyes. CONCLUSION: The pathophysiology of postural control in vertical strabismus is extremely complex and above the potential of this study design and should be specifically addressed in deeper experimental studies.

High frequency oscillations after median nerve stimulations in healthy children and adolescents.

The aim of the present research was to address somatosensory high frequency oscillations (400-800Hz) in healthy children and adolescents in comparison with healthy adults. We recorded somatosensory evoked potentials following median nerve stimulation in nineteen resting healthy children/adolescents and in nineteen resting healthy adults with eyes closed. We administered six consecutive stimulation blocks (500 sweeps each). The presynaptic component of high frequency oscillations amplitudes was smaller in healthy children/adolescents than in healthy adults (no difference between groups was found as far as the postsynaptic component was concerned). Healthy children/adolescents had smaller presynaptic component than the postsynaptic one (the postsynaptic component amplitude was 145% of the presynaptic one), while healthy adults showed the opposite (reduction of the postsynaptic component to 80% of the presynaptic one). No habituation phenomena concerning high frequency oscillation amplitudes were registered in neither healthy children/adolescents nor healthy adults. These findings suggest that healthy children/adolescents present with significantly different pattern of somatosensory high frequency oscillations compared with healthy adults' ones. This different pattern is reasonably expression of higher cortical excitability of the developing brain cortex.

Somatosensory High Frequency Oscillations reflect clinical fluctuations in migraine.

OBJECTIVE: It has been demonstrated that the early part of 600 Hz High Frequency Oscillations (HFOs), probably generated in the terminal part of thalamo-cortical somatosensory radiations, are abnormally reduced between attacks in migraineurs. We aimed at verifying whether spontaneous clinical fluctuations in migraine are correlated to HFO changes. METHODS: We recorded somatosensory evoked potentials in 28 migraine patients. Clinical fluctuations (number of attacks in the 6 months preceding and following the test) were correlated to the HFOs' amplitudes. Moreover, eight out of 28 patients underwent a longer follow-up, including HFO control and clinical observation during the 12 months following the baseline recording. RESULTS: The amplitude of early presynaptic HFOs was significantly correlated to the clinical evolution, since spontaneous worsening was associated with reduced presynaptic HFOs, whereas spontaneous improvement was associated with enhanced presynaptic HFOs (correlation test, p<0.05). No correlation was found between the amplitude of postsynaptic HFOs and clinical fluctuations. Patients undergoing longer follow-up showed substantially unchanged HFOs, accordingly with their stable clinical condition. CONCLUSIONS: HFOs' enhancement in spontaneously improved patients can reflect the increased activity of brainstem arousal related structures, which in turn increases the thalamo-cortical drive and the cortical lateral inhibition mediated by GABAergic interneurons. SIGNIFICANCE: HFOs' recording could represent a useful tool in the functional assessment of migraine.

High-frequency oscillations after median-nerve stimulation do not undergo habituation: a new insight on their functional meaning?

OBJECTIVE: Amplitude decrease of cortical responses after repeated stimuli ('habituation') is a well-known phenomenon, the functional meaning of which is to prevent sensory overflow and to save resources for meaningful and novel stimuli. It is known that the primary low-frequency N20 somatosensory evoked potential (SEP) undergoes habituation in healthy subjects. By contrast, the presence of this phenomenon has never been tested in High Frequency Oscillations (HFOs), which probably reflect the activity of a somatosensory arousal system. METHODS: We recorded SEPs after right median nerve stimulation in 19 healthy volunteers. Six consecutive series of 500 sweeps were collected and averaged at a repetition rate of 5 Hz. SEPs were recorded by means of Erb'point-to-Fz, Cv6-to-AC and P3-to-F3 arrays. P3-to-F3 recording further underwent narrow-bandpass (400-800 Hz) digital filtering to selectively analyse high-frequency components. RESULTS: Statistical analysis revealed a significant amplitude decrease of the primary N20 LF-SEP between the first and sixth block of stimuli. By contrast, HFO amplitudes remained substantially unchanged throughout the whole procedure. CONCLUSIONS: Differently from the N20 LF-SEP, scalp-recorded HFOs do not undergo habituation. SIGNIFICANCE: Our findings reinforce the view that HFOs reflect the activity of an arousal somatosensory system, which is able to signal novel stimuli, the relevance of which points out high synaptic efficacy.