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High frequency oscillations after median nerve stimulations in healthy children and adolescents
International Journal of Developmental Neuroscience 61 (2017) 68–72
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International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
High frequency oscillations after median nerve stimulations in healthy children and adolescents
MARK
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Sergio Zaninia, , Ivana Del Pieroa, Lucia Martuccia, Domenico Restucciab a b
Scientific Institute Eugenio Medea, Via Cialdini 29, 33037 Pasian di Prato, Udine, Italy Department of Neurosciences, Catholic University of the Sacred Heart, Policlinico A. Gemelli, Largo A. Gemelli 8, 00168 Rome, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Somatosensory evoked potentials High frequency oscillations Children/adolescent Cortical excitability Developing brain
The aim of the present research was to address somatosensory high frequency oscillations (400–800 Hz) 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.
1. Introduction Electrical stimulation of the upper limb evokes, along with the lowfrequency somatosensory evoked potentials (LF-SEP), also oscillatory activity in the high-frequency range (400 Hz to 800 Hz) so called highfrequency oscillations (hereafter, HFOs). These are more evident on the frontal-parietal regions controlateral to the stimulated arm. In the last 15 years, somatosensory HFOs presented increasing interest as they show strict relationship with arousal. In fact, HFOs’ amplitude decreases during sleep (Halboni et al., 2000) and increases by the opening of the eyes (Gobbelé et al., 2000; Restuccia et al., 2004), contrary to the LF-SEPs’ amplitudes that do not change under these conditions. These findings suggested HFOs to represent a “somatosensory arousal system” (Halboni et al., 2000; Gobbelé et al., 2000). Moreover, HFOs evoked by lower limb stimulation do not change their amplitude during quiet stance, contrary to LF-SEPs’ ones that are significantly reduced (Restuccia et al., 2008). Further, HFOs’ amplitudes do not undergo habituation (Restuccia et al., 2011). These evidences suggest HFOs’ generators to play a general role in modulating somatosensory inputs related to rapid environmental changes. However, the unique perspective of arousal might be insufficient to
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fully understanding the neurophysiological meaning of somatosensory HFOs. In fact, somatosensory HFOs represent a neurophysiological marker of a cortical-thalamic bi-directional system that modulates somatosensory input to the cortex (Restuccia and Della Marca, 2015). The more this system works properly (the corresponding neurophysiological marker is represented by HFOs of higher amplitudes), the more the cortex receives phasic somatosensory input, and, eventually, the better is the somatosensory input processed. The experimental evidence suggesting this interpretation of somatosensory HFOs comes from several different papers: Restuccia and Coppola (2015) demonstrated that auditory stimulation enhances somatosensory HFOs (cross-sensory sensitization), and Götz et al. (2015) showed how somatosensory evoked responses are modulated by the overall information context (HFOs, the hallmark of this modulating system, change accordingly to the task-athand). This interpretation of somatosensory HFOs settles the potential interest for a developmental perspective. It is known that the very early stages of somatosensory processing reach an adult-like pattern very soon (around 2 years of age) (Pihko et al., 2009). However, it is extremely plausible that maturational gradients of the cortex can modify somatosensory HFOs responses across childhood/adolescence.
Corresponding author. E-mail addresses: [email protected] (S. Zanini), [email protected] (I. Del Piero), [email protected] (L. Martucci), [email protected] (D. Restuccia).
http://dx.doi.org/10.1016/j.ijdevneu.2017.06.008 Received 21 March 2017; Received in revised form 22 June 2017; Accepted 29 June 2017 Available online 06 July 2017 0736-5748/ © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.
International Journal of Developmental Neuroscience 61 (2017) 68–72
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To the best of our knowledge, only one paper by Nakano and Hashimoto (2000) explicitly addressed this issue. These authors compared low- and high-frequency somatosensory responses, following median nerve stimulation, between two groups of healthy subjects: children (6–12 years old) and young adults (19–32 years old). Authors found that children presented with generalized and overall larger both low- and high-frequency somatosensory responses: larger N20 and P27 amplitude and larger N20 and P27 duration (in agreement with previous findings (Tanosaki et al., 1999)), but also larger HFOs amplitude and duration (total HFO responses, pre-synaptic/early component HFOs – from the HFOs’ onset to the N20 peak –, and post-synaptic/late component of HFOs – from the N20 peak to the HFOs’ endpoint). It is worth recalling that Nakano and Hashimoto (2000) registered somatosensory responses in opened eyes subjects. This point will be discussed thoroughly later on. Unfortunately, authors did not spend much time in trying explaining the physiology of these findings. In a recent experiment addressing N13 and N20 habituation and recovery cycle in healthy children/adolescents compared with healthy adults (Zanini et al., 2016) we found no group difference as far as the N20 amplitude was concerned and we found clear-cut absence of N20 habituation across stimulation trials in children/adolescents and two to three times shortened recovery cycle on each interstimulus interval (5, 10, and 20 ms) in the same group compared with the adult one. These findings suggested cortical hyper-excitability/responsiveness in healthy children/adolescents compared with healthy adults. Therefore, the disagreeing findings concerning larger N20 amplitude in children/adolescents than in adults, between Tanosaki et al.’s (1999), Nakano and Hashimoto’s (2000) studies and our recent paper (Zanini et al., 2016) suggested us to extend to the same group of healthy children/adolescents and healthy adults that we included in the habituation and recovery cycle study, a somatosensory HFOs study. In fact, cortical hyper-excitability/responsiveness in children/adolescent might very likely impact on HFOs, and larger HFOs in children/adolescents still deserves physiological explanation.
Fig. 1. Wide bandpass and filtered traces in adult. SEPs obtained from one healthy adult. P3-to-F3 recordings. Top: wide bandpass traces. Bottom: narrow bandpass (400–800 Hz) traces. In this subject, HFO components, coincident in time with high-frequency wavelets in filtered traces, are clearly recognizable on the ascending slope of the N20 potential in unfiltered traces. Moreover, no high-frequency signal is recognizable on filtered traces, in correspondence of slow potentials following the N20 response. This should exclude that HFOs could merely be the result of a filter artefact.
(anterior cervical (AC)); in the supraclavicular fossa (Erb’s point), referenced to Fz. Subjects were asked to lie with eyes closed on a couch in a warm and half-lit room. Since high-frequency SEPs are largely influenced by drowsiness or sleep (Halboni et al., 2000) participants were asked to signal the occurrence of drowsiness, to temporarily stop the examination. However, this maneuver was never necessary. The analysis time was 50 ms, with a sampling rate of 20000 Hz. The amplifier bandpass was 10–30000 Hz (12 dB roll-off). An automatic artefact-rejection system excluded from the average all runs containing transients exceeding ± 65 μV at any recording channel. To ensure baseline stabilization, SEPs were filtered off-line by means of a digital filter within a bandpass of 3–3000 Hz. One may suspect that HFOs can result, at least in part, from a filter artifact. However, it is not uncommon to find, in some subject with quite high-amplitude HFOs, clear oscillations on the ascending slope of the N20 response in wide bandpass traces. Moreover, HFOs are typically absent in the 30–40 ms latency range, while wide bandpass SEPs usually shows large deflections at the same latencies. Both findings should exclude, in principle, that HFO are merely due to a filtering artifact (Fig. 1).
2. Materials and methods 2.1. Participants We enrolled 19 (10 males) healthy developing children/adolescents (mean age 9 years and 11 months, age range 5–15 years) whose parents signed written informed consent. Absence of any neurological or psychiatric disorder was certain, on the basis of a parents’ interview. We also enrolled 19 (8 males) healthy adults (mean age 36 years and 6 months, age range 27–51 years) who signed written informed consent. They were selected among employees of Scientific Institute Eugenio Medea, of the Udine University Hospital, or of the Catholic University of the Sacred Heart in Rome, Italy, for whom absence of any neurological or psychiatric disorder was certain, on the basis of a direct interview. Children/adolescent and adults were not relatives. All participants were those enrolled for our previous study (Zanini et al., 2016). The research project was approved by the Ethical Committee of the Scientific Institute Eugenio Medea.
2.3. Statistical analysis We first analyzed latency and amplitude of the LF-SEPs. We measured latency and amplitude of the primary N20 response on the P3-toF3 traces, of the spinal N13 response on the Cv6-to-AC traces and of the Erb’s point response on the Erb-to-Fz traces. The amplitude of the Erb’s point response was evaluated from the first positive peak to the negative peak; that of the spinal N13 was evaluated from the baseline; and that of the N20 amplitude was evaluated as peak amplitude from the baseline. For the present paper, no further analyses were done on LFSEP components as they were out of our main interest and already described (Zanini et al., 2016). P3-to-F3 traces underwent time-frequency analysis (continuous wavelet transformation (CWT); Morlet’s wavelet family) by means of an automated signal analysis software (Autosignal version 1.7). This allowed to recognize, within the 400–800 Hz window, two separate components with slightly different frequencies, the former centered on the rising slope of the LF N20, and the latter beginning just prior to the N20 peak and reaching its maxima in the N20 descending slope. Thus, each trace was digitally filtered with a bandpass of 400–800 Hz and then analyzed. As far as the evaluation of the HFO amplitude on the P3to-F3 trace was concerned, instead of fixing pre-established intervals,
2.2. Neurophysiological recordings SEP recording was performed using a commercially available fivechannel Medelec™ Synergy apparatus (Viasys Health Care). We administered electrical stimulation to the right-median nerve at the wrist using a constant current square wave pulse (0.2 ms width, cathode proximal) and a stimulus intensity set just above the motor threshold (approximately in a range between 4 and 8 mA). Six consecutive series of 500 sweeps were collected and averaged at a repetition rate of 5 Hz. Active electrodes were placed over the contralateral parietal area (P3) referenced to F3; on the sixth cervical spinous process (Cv6), referenced to an electrode located immediately above the thyroid cartilage 69
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that healthy adults had larger presynaptic then postsynaptic AUCs (p = 0.009). No difference was found between healthy children/adolescents and healthy adults as far as the postsynaptic AUCs components were concerned (p = 0.68). In details, healthy children/adolescents increased mean postsynaptic AUC to 145% of the presynaptic one. Conversely, healthy adults reduced mean postsynaptic AUC to 80% of the presynaptic one. Children/adolescents presented with mean presynaptic AUCs amplitude corresponding to the 62% of the healthy adults’ one. No statistical correlations were found between age and neither pre (p = 0.30) nor postsynaptic (p = 0.93) AUCs.
we determined the burst duration as follows (Restuccia et al., 2011). The beginning of the burst was detected in correspondence of the N20 onset in the corresponding LF-SEP trace, while the burst ending at the last wavelet presenting with amplitude 50% larger than the average noise. The burst recorded at the P3-to-F3 array was further divided into two subsequent segments, ending and beginning, respectively, in correspondence to the peak of the N20. Since the early burst is thought to be generated in the terminals of the thalamocortical radiations fibres, whereas the late burst is probably generated by post-synaptic contributions from intracortical neurons (Gobbelé et al., 1998), these bursts will be termed “presynaptic” and “postsynaptic” bursts, respectively, in the rest of the paper. Burst amplitudes were measured as the area under the rectified waveform (AUC). We firstly compared AUCs by means of an analysis of variance for repeated measures within a 2 (2 groups: healthy children/adolescents vs healthy adults) X 2 (2 bursts: presynaptic vs postsynaptic) model. Post-hoc analyses were performed by means of t-test for paired samples (comparing presynaptic and postsynaptic bursts AUCs in each group, separately) and by means of an ANOVA (comparing presynaptic AUCs and postsynaptic AUCs, separately, between groups). P values was regarded as being significant below the threshold value 0.0125, following Bonferroni’s correction for multiple comparisons. We also run Pearson correlation analysis between age and presynaptic and postsynaptic AUCs. Secondly, we addressed the issue of habituation of HFOs comparing their AUCs on the first, on the third, and on the sixth blocks, by means of an analysis of variance for repeated measures within a 2 (2 groups: healthy children/adolescents vs healthy adults) X 3 (3 blocks: the first, the third, the sixth) model, for each HFO component: the presynaptic and the postsynaptic ones. This was done in order to investigate the habituation phenomena of these responses. In previous papers we showed no habituation of HFOs-AUC but, conversely, of N20 amplitude, in healthy adults (Restuccia et al., 2011) and lack of habituation of N20 amplitude in healthy children/adolescents (Zanini et al., 2016).
3.2. HFO habituation Secondly, we addressed the issue of habituation of HFOs responses of both presynaptic and postsynaptic components in both groups. The main factor burst turned out to be statistically not significant on both the presynaptic and the postsynaptic components (p = 0.77, p = 0.75, respectively). The main factor group turned out to be statistically significant as far as the presynaptic component was concerned (p = 0.02) but not the postsynaptic one (p = 0.17). No interactions were statistically significant (p = 0.15 and p = 0.84) for presynaptic and postsynaptic components, respectively (Fig. 4). 4. Discussion In summary, the main findings of this study consist of smaller presynaptic HFOs amplitude in children/adolescents than in adults (no difference across groups as far as the post-synaptic component was concerned), smaller presynaptic HFOs amplitude than postsynaptic HFOs amplitude in children/adolescents, and the opposite pattern (larger postsynaptic HFOs amplitude than the pre-synaptic one) in adults. In addition, no HFOs habituation phenomena were registered in both children/adolescents and adults. Firstly, we will discuss the last findings. Somatosensory HFOs did not undergo habituation across stimulation trials in both children/ adolescents and adults. In a previous paper (Restuccia et al., 2011) we reported the same findings in a different group of healthy adults. Therefore, the maintenance of HFO amplitudes seems to be a robust phenomenon irrespectively of age and stimulation sites (see Restuccia et al., 2008, as far as the lower limbs are concerned). These findings perfectly agree with the hypothesis of somatosensory HFOs as a neurophysiological hallmark of a somatosensosory arousal system. Secondly, we found some different findings with respect to Nakano and Hashimoto’s (2000) study. These authors found larger HFOs amplitudes in children than in adults, both as far as the presynaptic and the postsynaptic components are concerned, while we found the opposite concerning the presynaptic component (and no difference between groups as far as the postsynaptic component was concerned). Moreover, we found that children/adolescents increased the mean postsynaptic HFOs amplitude to 145% of the mean presynaptic one, while adults decreased it to 80% of the presynaptic one. Nakano and Hashimoto (2000) did not provide the reader with statistical analyses but they reported that children presented mean presynaptic HFOs amplitude equal to 515 nV and mean post-synaptic HFOs amplitude equal to 376 nV (therefore, children seemed to decrease post-synaptic HFO amplitudes to the 74% of the presynaptic value) and that adults maintained the equal HFOs amplitudes across the presynaptic and the postsynaptic HFO components (177 nV and 154 nV, respectively). The first comment we might put forward concerns methodology. Nakano and Hashimoto (2000) registered somatosensory responses in opened eyes subjects. It is well known (Gobbelé et al., 2000; Restuccia et al., 2004) that maintaining eyes opened increases HFOs amplitudes. It is still a matter of debate whether eyes opening increases more the presynaptic amplitude component, the postsynaptic one, or both. Therefore, to avoid interfering phenomena due to eyes opening, it is
3. Results 3.1. HFO amplitudes Firstly, we compared presynaptic and postsynaptic bursts’ AUCs between healthy children/adolescents and healthy adults. Both main factors group and burst turned out to be statistically not significant (p = 0.27, p = 0.66, respectively) while the interaction group × burst was highly statistically significant (p = 0.001) (Figs. 2 and 3). Post-hoc analyses revealed that healthy children/adolescents had smaller presynaptic than postsynaptic AUCs (p = 0.012), that healthy children/ adolescents had smaller presynaptic AUCs that adults (p = 0.004), and
Fig 2. HFOs amplitude. Children/adolescents presented with smaller pre-synaptic than post-synaptic HFOs amplitudes, smaller pre-synaptic HFO amplitudes than adults; adults presented with larger pre-synaptic than post-synaptic HFO amplitudes. Note: stars refer to statistically significant differences; bars refer to standard deviation.
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Fig. 3. Wide bandpass and filtered traces in adult and children. SEPs obtained from one healthy adult (left) and one healthy child (right). The adult subject is the same shown in Fig. 1. P3-to-F3 recordings. Top: wide bandpass traces. Bottom: narrow bandpass (400–800 Hz) traces. In both subjects, narrow bandpass traces show a clear burst of wavelets, consisting in two successive bursts, the former (single asterisk) probably generated in the terminal tracts of thalamo-cortical radiations, the latter (double asterisk) probably generated in the somatosensory cortex. In the adult subject, thalamic HFOs are larger than cortical ones, whereas in the child the opposite trend is evident.
even if opposite findings had also been reported (Lai et al., 2011). One possible explanation of these contrasting results comes from the clinical stage of migraine (stable, worsening – increasing number of attacks –, or improving – reducing number of attacks) (see Restuccia et al., 2012). Healthy children’s and adolescents’ cerebral cortex is less pre-activated due to weaker thalamo-cortical drive with respect to healthy adults. In fact, healthy children have presyntaptic HFOs AUC that is equal to 61% of the adults’ one (0.17 microV × ms vs 0.28 microV × ms, respectively). This age-dependent differences in the system devoted to modulation of somatosensory input to the cortex might easily depend on the underlying age-dependent neurobiological changes in the developing brain. Somatosensory evoked potentials are known to undergo maturational changes and both serotonine and norepinephrine activities (neurotransmitters know to modulate the sensory input flow to the cerebral cortex (Hurley et al., 2004)) are significantly different in the human developing brain compared with the adult one (Murrin et al., 2007). Another, not necessarily alternative, reasonable interpretation might be based on cortical inhibitory mechanisms, still nowadays only partially described, that are, however, known to mature post-natally at different ages, in animals such as rats, as well as in humans. In particular, inhibitory systems mature more slowly than excitatory ones. This creates a functional imbalance between excitatory and inhibitory synaptic neurotransmitters in the brain. In the immature brain the effects of excitatory neurotransmitter systems predominate initially and then become less predominant as inhibitory systems gradually mature (Brooks-Kayal, 2005). We could bear in mind the case of γ-amino-butirric-acid (GABA), the main cortical inhibitory molecule. GABA plays excitatory role very early post-natally (benzodiazepines can act as excitatory drugs instead of inhibitory/depressant ones). It is only when
more appropriate to register HFOs somatosensory responses with eyes closed as we did, especially if differences between children/adolescent and adult are the focus of interest. In addition to this point, we might try to address these disagreeing findings between Nakano and Hashimoto’s (2000) and our present studies bearing in mind findings from our previous paper (Zanini et al., 2016) where we reported evidence of cortical hyper-excitability/responsiveness in children/adolescents (lack of N20 habituation phenomena and shorted recovery cycle) with respect to adults (the same children/adolescents and the same adults of the present study). Reduced presynaptic HFOs amplitude is known to be associated to conditions of reduced thalamo-cortical drive that leads to cortical hyperexcitability/responsiveness (see Coppola et al., 2005, 2012; Restuccia et al., 2012, for several studies in patients suffering from migraine – a pathophysiological paradigm of cortical hyper-responsiveness/excitability). These previous studies brought support to the hypothesis of somatosensory HFOs (especially, in their presynaptic component) as a neurophysiological marker of a somatosensory modality-specific arousal system: the higher the pre-synaptic HFOs’ activity (large presynaptic HFO amplitude), the higher the cortical phasic response (the phasic response to a specific stimulus). In summary, children/adolescents that present cortical hyper-responsiveness/excitability condition (lack of habituation of cortical responses – see N20 – and shortened recovery cycle (Zanini et al., 2016)) present with smaller presynaptic HFOs amplitude than adults and smaller presynaptic HFOs amplitude that the post-synaptic one. These findings remind those coming from studies with patients with migraine where quite consistent evidence of smaller presynaptic than postsynaptic HFOs amplitudes where found (Sakuma et al., 2004; Coppola et al., 2005, 2012; Restuccia et al., 2012)
Fig. 4. HFOs habituation. No habituation of HFO amplitudes across stimulation blocks was found in children/adolescent and adults groups as far as both the presynaptic and the post-synaptic HFO components were concerned. Bars refer to standard deviation.
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Acknowledgements
brain maturation occurs that GABA receptors change their pharmacodynamic profiles favouring inhibitory responses to benzodiazepines (Mulla, 2010). A theoretical interpretation of higher cortical excitability responsiveness in children than in adults is above the main interests of the present study. Hyper-excitability/responsiveness of the developing cortex seems robust phenomenon. A possible explanation might come from animal studies. Borgdorff et al. (2007) showed that repetitive whisker stimulation (that activates the barrel cortex – the mouse analogue of the human somatosensory cortex) did facilitate sensory responses (instead of determining a depression of sensory responses – a habituation phenomenon). In addition, they showed that sensory responses to a single whisker deflection was smaller in young mice. Authors suggest that facilitating sensory responses (lack of habituation following repetitive stimulation) in young animals could compensate for the weak responses observed after single whisker deflection and might, therefore, have a profound influence on the activity-dependent wiring of the cortex during early development.
The research did not receive any specific grant from founding agencies in the public, commercial, or not-for-profit sectors. We thank three anonymous reviewers for comments on a previous version of the manuscript. References Borgdorff, A.J., Poulet, J.F.A., Petersen, C.C.H., 2007. Facilitating sensory responses in developing mouse somatosensory barrel cortex. J. Neurophysiol. 97, 2992–3003. Brooks-Kayal, A.R., 2005. Rearranging receptors. Epilepsia 46 (Suppl), 29–38. Coppola, G., Vandenheede, M., Di Clemente, L., Ambrosini, A., Fumal, A., De Pasqua, V., et al., 2005. Somatosenosry evoked high-frequency oscillations reflecting thalamocortical activity are decreased in migraine patients between attacks. Brain 128, 98–103. Coppola, G., De Pasqua, V., Pierelli, F., Schoenen, J., 2012. Effects of repetitive transcranial magnetic stimulation on somatosensory evoked potentials and high frequency oscillations in migraine. Cephalalgia 32, 700–709. 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5. Conclusions A throughout physiological (in healthy subjects of different ages) and pathophysiological (in patients suffering from diseases characterised by cortical hyper-responsiveness/excitability) interpretation of all these neurophysiological phenomena still deserve further and deeper investigations. In our opinion, only pharmacological manipulations (the easier way) of all the neurochemical networks involved in these somatosensory systems and/or highly complex technological approaches (see Götz et al., 2015) might represent adequate tools to disentangle the underlying neurophysiological mechanisms and provide stronger perspectives of analysis. In addition, we suggest that better interpretations of somatosensory HFOs in both healthy and pathologic subjects might come from studies that include several measures of cortical excitability/responsiveness. The findings from the present paper have, in our opinion, potential interest for clinical neuropsychiatry. In fact, it is well known that several neuropsychiatric conditions are characterized by atypical processing of sensorial stimuli (e.g. hypersensitivity to touch in autism spectrum disorders). Therefore, it is conceivable to think about further research addressing better definition of pathophysiology of sensory processing in atypical (pathological) development to, eventually, set new potential therapeutic strategies, both pharmacological and rehabilitative. The present study have some limits. The first is represented by our group characteristics: further studies might be conducted in larger groups of children from the very birth époque to the post-adolescent years/young adulthood to draft a complete developmental trajectory of these cerebral parameters of excitability. The second is represented by the experimental set-up: we chose a 5 Hz stimulation rate and it has been already reported that especially the late (postsynaptic) HFOs component is sensitive to stimulation frequency in adults (increasing the stimulation rate determines reduction of HFOs amplitudes) (Klostermann et al., 1999). No studies addressing somatosensory HFOs relative to stimulation frequency in children/adolescents have been conducted so far. Addressing this point might help in interpreting our findings. The third is represented by our sampling procedure: we registered using single bipolar montage that, invariably, captured signal sources perpendicularly (the thalamo-cortical projections) and tangentially (the cortical – postsynaptic – responses) with different degrees of sensitivity (Gobbelé et al., 2000; Fedele et al., 2012). Clearly, the same procedure was applied to both groups (children/adolescents and adults) and, thus, the differences found are remarkable and likely depending on developmental variables of cortical excitability. However, the registering montage might represent a critical issue with respect of the age of the subject and represent an important topic to investigate in further research.
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International Journal of Developmental Neuroscience journal homepage: www.elsevier.com/locate/ijdevneu
High frequency oscillations after median nerve stimulations in healthy children and adolescents
MARK
⁎
Sergio Zaninia, , Ivana Del Pieroa, Lucia Martuccia, Domenico Restucciab a b
Scientific Institute Eugenio Medea, Via Cialdini 29, 33037 Pasian di Prato, Udine, Italy Department of Neurosciences, Catholic University of the Sacred Heart, Policlinico A. Gemelli, Largo A. Gemelli 8, 00168 Rome, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Somatosensory evoked potentials High frequency oscillations Children/adolescent Cortical excitability Developing brain
The aim of the present research was to address somatosensory high frequency oscillations (400–800 Hz) 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.
1. Introduction Electrical stimulation of the upper limb evokes, along with the lowfrequency somatosensory evoked potentials (LF-SEP), also oscillatory activity in the high-frequency range (400 Hz to 800 Hz) so called highfrequency oscillations (hereafter, HFOs). These are more evident on the frontal-parietal regions controlateral to the stimulated arm. In the last 15 years, somatosensory HFOs presented increasing interest as they show strict relationship with arousal. In fact, HFOs’ amplitude decreases during sleep (Halboni et al., 2000) and increases by the opening of the eyes (Gobbelé et al., 2000; Restuccia et al., 2004), contrary to the LF-SEPs’ amplitudes that do not change under these conditions. These findings suggested HFOs to represent a “somatosensory arousal system” (Halboni et al., 2000; Gobbelé et al., 2000). Moreover, HFOs evoked by lower limb stimulation do not change their amplitude during quiet stance, contrary to LF-SEPs’ ones that are significantly reduced (Restuccia et al., 2008). Further, HFOs’ amplitudes do not undergo habituation (Restuccia et al., 2011). These evidences suggest HFOs’ generators to play a general role in modulating somatosensory inputs related to rapid environmental changes. However, the unique perspective of arousal might be insufficient to
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fully understanding the neurophysiological meaning of somatosensory HFOs. In fact, somatosensory HFOs represent a neurophysiological marker of a cortical-thalamic bi-directional system that modulates somatosensory input to the cortex (Restuccia and Della Marca, 2015). The more this system works properly (the corresponding neurophysiological marker is represented by HFOs of higher amplitudes), the more the cortex receives phasic somatosensory input, and, eventually, the better is the somatosensory input processed. The experimental evidence suggesting this interpretation of somatosensory HFOs comes from several different papers: Restuccia and Coppola (2015) demonstrated that auditory stimulation enhances somatosensory HFOs (cross-sensory sensitization), and Götz et al. (2015) showed how somatosensory evoked responses are modulated by the overall information context (HFOs, the hallmark of this modulating system, change accordingly to the task-athand). This interpretation of somatosensory HFOs settles the potential interest for a developmental perspective. It is known that the very early stages of somatosensory processing reach an adult-like pattern very soon (around 2 years of age) (Pihko et al., 2009). However, it is extremely plausible that maturational gradients of the cortex can modify somatosensory HFOs responses across childhood/adolescence.
Corresponding author. E-mail addresses: [email protected] (S. Zanini), [email protected] (I. Del Piero), [email protected] (L. Martucci), [email protected] (D. Restuccia).
http://dx.doi.org/10.1016/j.ijdevneu.2017.06.008 Received 21 March 2017; Received in revised form 22 June 2017; Accepted 29 June 2017 Available online 06 July 2017 0736-5748/ © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.
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To the best of our knowledge, only one paper by Nakano and Hashimoto (2000) explicitly addressed this issue. These authors compared low- and high-frequency somatosensory responses, following median nerve stimulation, between two groups of healthy subjects: children (6–12 years old) and young adults (19–32 years old). Authors found that children presented with generalized and overall larger both low- and high-frequency somatosensory responses: larger N20 and P27 amplitude and larger N20 and P27 duration (in agreement with previous findings (Tanosaki et al., 1999)), but also larger HFOs amplitude and duration (total HFO responses, pre-synaptic/early component HFOs – from the HFOs’ onset to the N20 peak –, and post-synaptic/late component of HFOs – from the N20 peak to the HFOs’ endpoint). It is worth recalling that Nakano and Hashimoto (2000) registered somatosensory responses in opened eyes subjects. This point will be discussed thoroughly later on. Unfortunately, authors did not spend much time in trying explaining the physiology of these findings. In a recent experiment addressing N13 and N20 habituation and recovery cycle in healthy children/adolescents compared with healthy adults (Zanini et al., 2016) we found no group difference as far as the N20 amplitude was concerned and we found clear-cut absence of N20 habituation across stimulation trials in children/adolescents and two to three times shortened recovery cycle on each interstimulus interval (5, 10, and 20 ms) in the same group compared with the adult one. These findings suggested cortical hyper-excitability/responsiveness in healthy children/adolescents compared with healthy adults. Therefore, the disagreeing findings concerning larger N20 amplitude in children/adolescents than in adults, between Tanosaki et al.’s (1999), Nakano and Hashimoto’s (2000) studies and our recent paper (Zanini et al., 2016) suggested us to extend to the same group of healthy children/adolescents and healthy adults that we included in the habituation and recovery cycle study, a somatosensory HFOs study. In fact, cortical hyper-excitability/responsiveness in children/adolescent might very likely impact on HFOs, and larger HFOs in children/adolescents still deserves physiological explanation.
Fig. 1. Wide bandpass and filtered traces in adult. SEPs obtained from one healthy adult. P3-to-F3 recordings. Top: wide bandpass traces. Bottom: narrow bandpass (400–800 Hz) traces. In this subject, HFO components, coincident in time with high-frequency wavelets in filtered traces, are clearly recognizable on the ascending slope of the N20 potential in unfiltered traces. Moreover, no high-frequency signal is recognizable on filtered traces, in correspondence of slow potentials following the N20 response. This should exclude that HFOs could merely be the result of a filter artefact.
(anterior cervical (AC)); in the supraclavicular fossa (Erb’s point), referenced to Fz. Subjects were asked to lie with eyes closed on a couch in a warm and half-lit room. Since high-frequency SEPs are largely influenced by drowsiness or sleep (Halboni et al., 2000) participants were asked to signal the occurrence of drowsiness, to temporarily stop the examination. However, this maneuver was never necessary. The analysis time was 50 ms, with a sampling rate of 20000 Hz. The amplifier bandpass was 10–30000 Hz (12 dB roll-off). An automatic artefact-rejection system excluded from the average all runs containing transients exceeding ± 65 μV at any recording channel. To ensure baseline stabilization, SEPs were filtered off-line by means of a digital filter within a bandpass of 3–3000 Hz. One may suspect that HFOs can result, at least in part, from a filter artifact. However, it is not uncommon to find, in some subject with quite high-amplitude HFOs, clear oscillations on the ascending slope of the N20 response in wide bandpass traces. Moreover, HFOs are typically absent in the 30–40 ms latency range, while wide bandpass SEPs usually shows large deflections at the same latencies. Both findings should exclude, in principle, that HFO are merely due to a filtering artifact (Fig. 1).
2. Materials and methods 2.1. Participants We enrolled 19 (10 males) healthy developing children/adolescents (mean age 9 years and 11 months, age range 5–15 years) whose parents signed written informed consent. Absence of any neurological or psychiatric disorder was certain, on the basis of a parents’ interview. We also enrolled 19 (8 males) healthy adults (mean age 36 years and 6 months, age range 27–51 years) who signed written informed consent. They were selected among employees of Scientific Institute Eugenio Medea, of the Udine University Hospital, or of the Catholic University of the Sacred Heart in Rome, Italy, for whom absence of any neurological or psychiatric disorder was certain, on the basis of a direct interview. Children/adolescent and adults were not relatives. All participants were those enrolled for our previous study (Zanini et al., 2016). The research project was approved by the Ethical Committee of the Scientific Institute Eugenio Medea.
2.3. Statistical analysis We first analyzed latency and amplitude of the LF-SEPs. We measured latency and amplitude of the primary N20 response on the P3-toF3 traces, of the spinal N13 response on the Cv6-to-AC traces and of the Erb’s point response on the Erb-to-Fz traces. The amplitude of the Erb’s point response was evaluated from the first positive peak to the negative peak; that of the spinal N13 was evaluated from the baseline; and that of the N20 amplitude was evaluated as peak amplitude from the baseline. For the present paper, no further analyses were done on LFSEP components as they were out of our main interest and already described (Zanini et al., 2016). P3-to-F3 traces underwent time-frequency analysis (continuous wavelet transformation (CWT); Morlet’s wavelet family) by means of an automated signal analysis software (Autosignal version 1.7). This allowed to recognize, within the 400–800 Hz window, two separate components with slightly different frequencies, the former centered on the rising slope of the LF N20, and the latter beginning just prior to the N20 peak and reaching its maxima in the N20 descending slope. Thus, each trace was digitally filtered with a bandpass of 400–800 Hz and then analyzed. As far as the evaluation of the HFO amplitude on the P3to-F3 trace was concerned, instead of fixing pre-established intervals,
2.2. Neurophysiological recordings SEP recording was performed using a commercially available fivechannel Medelec™ Synergy apparatus (Viasys Health Care). We administered electrical stimulation to the right-median nerve at the wrist using a constant current square wave pulse (0.2 ms width, cathode proximal) and a stimulus intensity set just above the motor threshold (approximately in a range between 4 and 8 mA). Six consecutive series of 500 sweeps were collected and averaged at a repetition rate of 5 Hz. Active electrodes were placed over the contralateral parietal area (P3) referenced to F3; on the sixth cervical spinous process (Cv6), referenced to an electrode located immediately above the thyroid cartilage 69
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that healthy adults had larger presynaptic then postsynaptic AUCs (p = 0.009). No difference was found between healthy children/adolescents and healthy adults as far as the postsynaptic AUCs components were concerned (p = 0.68). In details, healthy children/adolescents increased mean postsynaptic AUC to 145% of the presynaptic one. Conversely, healthy adults reduced mean postsynaptic AUC to 80% of the presynaptic one. Children/adolescents presented with mean presynaptic AUCs amplitude corresponding to the 62% of the healthy adults’ one. No statistical correlations were found between age and neither pre (p = 0.30) nor postsynaptic (p = 0.93) AUCs.
we determined the burst duration as follows (Restuccia et al., 2011). The beginning of the burst was detected in correspondence of the N20 onset in the corresponding LF-SEP trace, while the burst ending at the last wavelet presenting with amplitude 50% larger than the average noise. The burst recorded at the P3-to-F3 array was further divided into two subsequent segments, ending and beginning, respectively, in correspondence to the peak of the N20. Since the early burst is thought to be generated in the terminals of the thalamocortical radiations fibres, whereas the late burst is probably generated by post-synaptic contributions from intracortical neurons (Gobbelé et al., 1998), these bursts will be termed “presynaptic” and “postsynaptic” bursts, respectively, in the rest of the paper. Burst amplitudes were measured as the area under the rectified waveform (AUC). We firstly compared AUCs by means of an analysis of variance for repeated measures within a 2 (2 groups: healthy children/adolescents vs healthy adults) X 2 (2 bursts: presynaptic vs postsynaptic) model. Post-hoc analyses were performed by means of t-test for paired samples (comparing presynaptic and postsynaptic bursts AUCs in each group, separately) and by means of an ANOVA (comparing presynaptic AUCs and postsynaptic AUCs, separately, between groups). P values was regarded as being significant below the threshold value 0.0125, following Bonferroni’s correction for multiple comparisons. We also run Pearson correlation analysis between age and presynaptic and postsynaptic AUCs. Secondly, we addressed the issue of habituation of HFOs comparing their AUCs on the first, on the third, and on the sixth blocks, by means of an analysis of variance for repeated measures within a 2 (2 groups: healthy children/adolescents vs healthy adults) X 3 (3 blocks: the first, the third, the sixth) model, for each HFO component: the presynaptic and the postsynaptic ones. This was done in order to investigate the habituation phenomena of these responses. In previous papers we showed no habituation of HFOs-AUC but, conversely, of N20 amplitude, in healthy adults (Restuccia et al., 2011) and lack of habituation of N20 amplitude in healthy children/adolescents (Zanini et al., 2016).
3.2. HFO habituation Secondly, we addressed the issue of habituation of HFOs responses of both presynaptic and postsynaptic components in both groups. The main factor burst turned out to be statistically not significant on both the presynaptic and the postsynaptic components (p = 0.77, p = 0.75, respectively). The main factor group turned out to be statistically significant as far as the presynaptic component was concerned (p = 0.02) but not the postsynaptic one (p = 0.17). No interactions were statistically significant (p = 0.15 and p = 0.84) for presynaptic and postsynaptic components, respectively (Fig. 4). 4. Discussion In summary, the main findings of this study consist of smaller presynaptic HFOs amplitude in children/adolescents than in adults (no difference across groups as far as the post-synaptic component was concerned), smaller presynaptic HFOs amplitude than postsynaptic HFOs amplitude in children/adolescents, and the opposite pattern (larger postsynaptic HFOs amplitude than the pre-synaptic one) in adults. In addition, no HFOs habituation phenomena were registered in both children/adolescents and adults. Firstly, we will discuss the last findings. Somatosensory HFOs did not undergo habituation across stimulation trials in both children/ adolescents and adults. In a previous paper (Restuccia et al., 2011) we reported the same findings in a different group of healthy adults. Therefore, the maintenance of HFO amplitudes seems to be a robust phenomenon irrespectively of age and stimulation sites (see Restuccia et al., 2008, as far as the lower limbs are concerned). These findings perfectly agree with the hypothesis of somatosensory HFOs as a neurophysiological hallmark of a somatosensosory arousal system. Secondly, we found some different findings with respect to Nakano and Hashimoto’s (2000) study. These authors found larger HFOs amplitudes in children than in adults, both as far as the presynaptic and the postsynaptic components are concerned, while we found the opposite concerning the presynaptic component (and no difference between groups as far as the postsynaptic component was concerned). Moreover, we found that children/adolescents increased the mean postsynaptic HFOs amplitude to 145% of the mean presynaptic one, while adults decreased it to 80% of the presynaptic one. Nakano and Hashimoto (2000) did not provide the reader with statistical analyses but they reported that children presented mean presynaptic HFOs amplitude equal to 515 nV and mean post-synaptic HFOs amplitude equal to 376 nV (therefore, children seemed to decrease post-synaptic HFO amplitudes to the 74% of the presynaptic value) and that adults maintained the equal HFOs amplitudes across the presynaptic and the postsynaptic HFO components (177 nV and 154 nV, respectively). The first comment we might put forward concerns methodology. Nakano and Hashimoto (2000) registered somatosensory responses in opened eyes subjects. It is well known (Gobbelé et al., 2000; Restuccia et al., 2004) that maintaining eyes opened increases HFOs amplitudes. It is still a matter of debate whether eyes opening increases more the presynaptic amplitude component, the postsynaptic one, or both. Therefore, to avoid interfering phenomena due to eyes opening, it is
3. Results 3.1. HFO amplitudes Firstly, we compared presynaptic and postsynaptic bursts’ AUCs between healthy children/adolescents and healthy adults. Both main factors group and burst turned out to be statistically not significant (p = 0.27, p = 0.66, respectively) while the interaction group × burst was highly statistically significant (p = 0.001) (Figs. 2 and 3). Post-hoc analyses revealed that healthy children/adolescents had smaller presynaptic than postsynaptic AUCs (p = 0.012), that healthy children/ adolescents had smaller presynaptic AUCs that adults (p = 0.004), and
Fig 2. HFOs amplitude. Children/adolescents presented with smaller pre-synaptic than post-synaptic HFOs amplitudes, smaller pre-synaptic HFO amplitudes than adults; adults presented with larger pre-synaptic than post-synaptic HFO amplitudes. Note: stars refer to statistically significant differences; bars refer to standard deviation.
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Fig. 3. Wide bandpass and filtered traces in adult and children. SEPs obtained from one healthy adult (left) and one healthy child (right). The adult subject is the same shown in Fig. 1. P3-to-F3 recordings. Top: wide bandpass traces. Bottom: narrow bandpass (400–800 Hz) traces. In both subjects, narrow bandpass traces show a clear burst of wavelets, consisting in two successive bursts, the former (single asterisk) probably generated in the terminal tracts of thalamo-cortical radiations, the latter (double asterisk) probably generated in the somatosensory cortex. In the adult subject, thalamic HFOs are larger than cortical ones, whereas in the child the opposite trend is evident.
even if opposite findings had also been reported (Lai et al., 2011). One possible explanation of these contrasting results comes from the clinical stage of migraine (stable, worsening – increasing number of attacks –, or improving – reducing number of attacks) (see Restuccia et al., 2012). Healthy children’s and adolescents’ cerebral cortex is less pre-activated due to weaker thalamo-cortical drive with respect to healthy adults. In fact, healthy children have presyntaptic HFOs AUC that is equal to 61% of the adults’ one (0.17 microV × ms vs 0.28 microV × ms, respectively). This age-dependent differences in the system devoted to modulation of somatosensory input to the cortex might easily depend on the underlying age-dependent neurobiological changes in the developing brain. Somatosensory evoked potentials are known to undergo maturational changes and both serotonine and norepinephrine activities (neurotransmitters know to modulate the sensory input flow to the cerebral cortex (Hurley et al., 2004)) are significantly different in the human developing brain compared with the adult one (Murrin et al., 2007). Another, not necessarily alternative, reasonable interpretation might be based on cortical inhibitory mechanisms, still nowadays only partially described, that are, however, known to mature post-natally at different ages, in animals such as rats, as well as in humans. In particular, inhibitory systems mature more slowly than excitatory ones. This creates a functional imbalance between excitatory and inhibitory synaptic neurotransmitters in the brain. In the immature brain the effects of excitatory neurotransmitter systems predominate initially and then become less predominant as inhibitory systems gradually mature (Brooks-Kayal, 2005). We could bear in mind the case of γ-amino-butirric-acid (GABA), the main cortical inhibitory molecule. GABA plays excitatory role very early post-natally (benzodiazepines can act as excitatory drugs instead of inhibitory/depressant ones). It is only when
more appropriate to register HFOs somatosensory responses with eyes closed as we did, especially if differences between children/adolescent and adult are the focus of interest. In addition to this point, we might try to address these disagreeing findings between Nakano and Hashimoto’s (2000) and our present studies bearing in mind findings from our previous paper (Zanini et al., 2016) where we reported evidence of cortical hyper-excitability/responsiveness in children/adolescents (lack of N20 habituation phenomena and shorted recovery cycle) with respect to adults (the same children/adolescents and the same adults of the present study). Reduced presynaptic HFOs amplitude is known to be associated to conditions of reduced thalamo-cortical drive that leads to cortical hyperexcitability/responsiveness (see Coppola et al., 2005, 2012; Restuccia et al., 2012, for several studies in patients suffering from migraine – a pathophysiological paradigm of cortical hyper-responsiveness/excitability). These previous studies brought support to the hypothesis of somatosensory HFOs (especially, in their presynaptic component) as a neurophysiological marker of a somatosensory modality-specific arousal system: the higher the pre-synaptic HFOs’ activity (large presynaptic HFO amplitude), the higher the cortical phasic response (the phasic response to a specific stimulus). In summary, children/adolescents that present cortical hyper-responsiveness/excitability condition (lack of habituation of cortical responses – see N20 – and shortened recovery cycle (Zanini et al., 2016)) present with smaller presynaptic HFOs amplitude than adults and smaller presynaptic HFOs amplitude that the post-synaptic one. These findings remind those coming from studies with patients with migraine where quite consistent evidence of smaller presynaptic than postsynaptic HFOs amplitudes where found (Sakuma et al., 2004; Coppola et al., 2005, 2012; Restuccia et al., 2012)
Fig. 4. HFOs habituation. No habituation of HFO amplitudes across stimulation blocks was found in children/adolescent and adults groups as far as both the presynaptic and the post-synaptic HFO components were concerned. Bars refer to standard deviation.
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Acknowledgements
brain maturation occurs that GABA receptors change their pharmacodynamic profiles favouring inhibitory responses to benzodiazepines (Mulla, 2010). A theoretical interpretation of higher cortical excitability responsiveness in children than in adults is above the main interests of the present study. Hyper-excitability/responsiveness of the developing cortex seems robust phenomenon. A possible explanation might come from animal studies. Borgdorff et al. (2007) showed that repetitive whisker stimulation (that activates the barrel cortex – the mouse analogue of the human somatosensory cortex) did facilitate sensory responses (instead of determining a depression of sensory responses – a habituation phenomenon). In addition, they showed that sensory responses to a single whisker deflection was smaller in young mice. Authors suggest that facilitating sensory responses (lack of habituation following repetitive stimulation) in young animals could compensate for the weak responses observed after single whisker deflection and might, therefore, have a profound influence on the activity-dependent wiring of the cortex during early development.
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5. Conclusions A throughout physiological (in healthy subjects of different ages) and pathophysiological (in patients suffering from diseases characterised by cortical hyper-responsiveness/excitability) interpretation of all these neurophysiological phenomena still deserve further and deeper investigations. In our opinion, only pharmacological manipulations (the easier way) of all the neurochemical networks involved in these somatosensory systems and/or highly complex technological approaches (see Götz et al., 2015) might represent adequate tools to disentangle the underlying neurophysiological mechanisms and provide stronger perspectives of analysis. In addition, we suggest that better interpretations of somatosensory HFOs in both healthy and pathologic subjects might come from studies that include several measures of cortical excitability/responsiveness. The findings from the present paper have, in our opinion, potential interest for clinical neuropsychiatry. In fact, it is well known that several neuropsychiatric conditions are characterized by atypical processing of sensorial stimuli (e.g. hypersensitivity to touch in autism spectrum disorders). Therefore, it is conceivable to think about further research addressing better definition of pathophysiology of sensory processing in atypical (pathological) development to, eventually, set new potential therapeutic strategies, both pharmacological and rehabilitative. The present study have some limits. The first is represented by our group characteristics: further studies might be conducted in larger groups of children from the very birth époque to the post-adolescent years/young adulthood to draft a complete developmental trajectory of these cerebral parameters of excitability. The second is represented by the experimental set-up: we chose a 5 Hz stimulation rate and it has been already reported that especially the late (postsynaptic) HFOs component is sensitive to stimulation frequency in adults (increasing the stimulation rate determines reduction of HFOs amplitudes) (Klostermann et al., 1999). No studies addressing somatosensory HFOs relative to stimulation frequency in children/adolescents have been conducted so far. Addressing this point might help in interpreting our findings. The third is represented by our sampling procedure: we registered using single bipolar montage that, invariably, captured signal sources perpendicularly (the thalamo-cortical projections) and tangentially (the cortical – postsynaptic – responses) with different degrees of sensitivity (Gobbelé et al., 2000; Fedele et al., 2012). Clearly, the same procedure was applied to both groups (children/adolescents and adults) and, thus, the differences found are remarkable and likely depending on developmental variables of cortical excitability. However, the registering montage might represent a critical issue with respect of the age of the subject and represent an important topic to investigate in further research.
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