Nonlinear interactions of high-frequency oscillations in the human somatosensory system

OBJECTIVE: The source of somatosensory evoked high-frequency activity at about 600 Hz is still not completely clear. Hence, we aimed to study the influence of double stimulation on the human somatosensory system by analyzing both the low-frequency activity and the high-frequency oscillations (HFOs) at about 600 Hz. METHODS: We used median nerve stimulation at seven interstimuli intervals (ISIs) with a high time resolution between 2.4 and 4.8 ms to investigate the N15, N20 and superimposed HFOs. Simultaneously, the electroencephalogram and the magnetoencephalogram of 12 healthy participants were recorded. Subsequently, the source analysis of precortical and cortical dipoles was performed. RESULTS: The difference computations of precortical dipole activation curves showed in both the low- and high-frequency range a correlation between the ISI and the latency of the second stimulus response. The cortical low-frequency response showed a similar behavior. Contrarily, in the second response of cortical HFOs this latency shift could not be confirmed. We found amplitude fluctuations that were dependent on the ISI in the low-frequency activity and the HFOs. These nonlinear interactions occurred at ISIs, which differ by one full HFO period (1.6 ms). CONCLUSIONS: Low-frequency activity and HFOs originate from different generators. Precortical and cortical HFOs are independently generated. The amplitude fluctuations dependent on ISI indicate nonlinear interference between successive stimuli. SIGNIFICANCE: Information processing in human somatosensory system includes nonlinearity.     

Effects of general anesthesia on high-frequency oscillations in somatosensory evoked potentials.

To determine the characteristics of high-frequency oscillations (HFOs) of cortical somatosensory evoked potentials (SEPs), the effect of general anesthesia on HFOs and low-frequency primary cortical responses was studied. The authors recorded SEPs elicited by median nerve stimulation directly from human brains of seven patients who underwent implantation of subdural electrodes before surgical treatment of intractable epilepsy. Recordings were made before and during general anesthesia. Changes in the number of HFOs and amplitude ratios of HFOs/primary cortical responses were analyzed. Under general anesthesia, the number of HFO peaks and the amplitude ratios were significantly decreased. General anesthesia induced remarkably decreased HFO activities when compared to low-frequency SEPs, suggesting that each of those originated from different generators. Possible relations between gamma-amino-butyric acid (GABA)ergic inhibitory interneurons and HFOs are discussed.     

Comparison of somatosensory evoked high-frequency oscillations after posterior tibial and median nerve stimulation.

OBJECTIVE: We compared the high-frequency oscillations (HFOs) evoked by posterior tibial nerve (PTN) and median nerve (MN) stimulation. METHODS: Somatosensory evoked potentials (SEPs) were recorded with a filter set at 10-2000 Hz to right PTN and to right MN stimulation in 10 healthy subjects. The HFOs were obtained by digitally filtering the wide-band SEPs with a band-pass of 300-900 Hz. RESULTS: HFOs were recorded in 8 of the 10 subjects for PTN, and in all subjects for MN stimulation. The HFOs after both PTN and MN stimulation started approximately at or after the onset of the primary cortical response (P37 and N20) and ended around the middle of the second slope. HFO amplitudes and area after PTN stimulation were significantly smaller than those after MN stimulation. HFO duration after PTN stimulation was markedly longer than that after MN stimulation. However, HFO interpeak latencies did not differ between the two nerves. CONCLUSIONS: The present findings suggest that the HFOs after PTN and MN stimulation reflect a neural mechanism common to the hand and foot somatosensory cortex.     

The effects of stimulus rates on high frequency oscillations of median nerve somatosensory-evoked potentials--direct recording study from the human cerebral cortex.

OBJECTIVES: To study the effects of different stimulus rates on high-frequency oscillations (HFOs) of somatosensory-evoked potentials (SEPs), we recorded median nerve SEPs directly from the human cerebral cortex. METHODS: SEPs were recorded from subdural electrodes in 5 patients with intractable epilepsy, under the conditions of low (3.3Hz) and high (12.3Hz) stimulus rates. RESULTS: Increased stimulus rates to the median nerve from 3.3 to 12.3Hz showed a pronounced amplitude reduction of HFOs when compared with the primary N20-P20, area 3b, and P25, area 1, responses. CONCLUSIONS: HFOs were more sensitive to a high stimulus rate than the primary cortical responses, suggesting that the post-synaptic intracortical activities may greatly contribute to the HFO generation.     

Hand somatosensory subcortical and cortical sources assessed by functional source separation: an EEG study

We propose a novel electroencephalographic application of a recently developed cerebral source extraction method (Functional Source Separation, FSS), which starts from extracranial signals and adds a functional constraint to the cost function of a basic independent component analysis model without requiring solutions to be independent. Five ad-hoc functional constraints were used to extract the activity reflecting the temporal sequence of sensory information processing along the somatosensory pathway in response to the separate left and right median nerve galvanic stimulation. Constraints required only the maximization of the responsiveness at specific latencies following sensory stimulation, without taking into account that any frequency or spatial information. After source extraction, the reliability of identified FS was assessed based on the position of single dipoles fitted on its retroprojected signals and on a discrepancy measure. The FS positions were consistent with previously reported data (two early subcortical sources localized in the brain stem and thalamus, the three later sources in cortical areas), leaving negligible residual activity at the corresponding latencies. The high-frequency component of the oscillatory activity (HFO) of the extracted component was analyzed. The integrity of the low amplitude HFOs was preserved for each FS. On the basis of our data, we suggest that FSS can be an effective tool to investigate the HFO behavior of the different neuronal pools, recruited at successive times after median nerve galvanic stimulation. As FSs are reconstructed along the entire experimental session, directional and dynamic HFO synchronization phenomena can be studied.     

High-frequency somatosensory thalamocortical oscillations and psychopathology in schizophrenia

Human cortical somatosensory evoked potentials (SEPs), which are presumably generated in afferent thalamocortical and early cortical fibers, reveal a burst of superimposed early (N20) high-frequency oscillations (HFOs), around 600 Hz. There is increasing evidence of an imbalance of thalamocortical systems in schizophrenic patients. In order to assess correlations between somatosensory evoked oscillations and symptoms of schizophrenia, we investigated median nerve SEPs in 20 inpatients and their age-matched and gender-matched healthy controls using a multichannel EEG. Dipole source analysis and wavelet transformation were performed before and after application of a 450-Hz high-pass filter. In schizophrenics, the maximum HFOs occurred with a significantly prolonged latency. There was also a higher amplitude (energy) in the low-frequency range of the N20 component compared with the controls. Importantly, amplitudes (energy) of HFOs were inversely correlated with symptoms of formal thought disorder and delusions. Alterations of the thalamocortical somatosensory signal processing in schizophrenia with absence of an early HFO - assumed to be of inhibitory nature - could indicate a dysfunctional thalamic inhibition with increased amplitudes of N20, paralleled by enhanced positive schizophrenic symptoms.     

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.     

Unmasking of presynaptic and postsynaptic high-frequency oscillations in epidural cervical somatosensory evoked potentials during voluntary movement.

OBJECTIVE: To investigate the effect of the voluntary movement on the amplitude of the somatosensory evoked potentials (SEPs) recorded by an epidural electrode at level of the cervical spinal cord (CSC). METHODS: Fourteen patients underwent an epidural electrode implant at CSC level for pain relief. After the median nerve stimulation, SEPs were recorded from the epidural electrode and from 4 surface electrodes (in frontal and parietal regions contralateral to the stimulated side, over the 6th cervical vertebra, and on the Erb's point). SEPs were recorded at rest and during a voluntary flexo-extension movement of the stimulated wrist. Beyond the low-frequency SEPs, also the high-frequency oscillations (HFOs) were analysed. RESULTS: The epidural electrode contacts recorded a triphasic potential (P1-N1-P2), whose negative peak showed the same latency as the cervical N13 response. The epidural potential amplitude was significantly decreased during the voluntary movement, as compared to the rest. Two main HFOs were identifiable: (1) the 1200 Hz HFO which was significantly lower in amplitude during movement than at rest, and (2) the 500 Hz HFO which was not modified by the voluntary movement. CONCLUSIONS: The low-frequency cervical SEP component is subtended by HFOs probably generated by: (1) postsynaptic potentials in the dorsal horn neurones (1200 Hz), and (2) presynaptic ascending somatosensory inputs (500 Hz). SIGNIFICANCE: Our findings show that the voluntary movement may affect the somatosensory input processing also at CSC level.     

Human hand and lip sensorimotor cortex as studied on electrocorticography.

We investigated functional topography of human hand and lip sensorimotor cortex using somatosensory evoked potentials (SEPs) from chronically indwelling subdural grid electrodes (ECoG) in 3 epilepsy patients during stimulation of median nerve, ulnar nerve, and lower lip. We used dipole modeling to determine the cortical location of each peripheral sensory field. The cortical locations were in the postcentral gyrus and showed a clear somatotopic organization from medial superior to lateral inferior in the order: ulnar nerve, median nerve, and lip. The source localizations agreed with the results of cortical stimulations and anatomical features on intraoperative photographs. The cortical regions of median and ulnar nerve each could be modeled by sequential tangential and radial dipoles. The cortical region of lip was different and could be explained mostly by tangential dipoles. These findings suggest a difference in the cortical organization of human lip and hand sensory cortex and are consistent with a larger representation of lip in the posterior bank of central fissure in area 3b than on the gyral surface in area 1, similar to findings in macaque. Further studies in a larger population of patients with ECoG or normal subjects with scalp-EEG and MEG are warranted to test this hypothesis.     

Neural mechanisms of the ultrafast activities.

A brief review of previous studies is presented on ultra-fast activities > 300 Hz (high frequency oscillations, HFOs) overlying the cortical response in the somatosensory evoked potential (SEP) or magnetic field (SEF). The characteristics of somatosensory HFOs are described in terms of reproducibility and origin (area 3b and 1) of the HFOs, changes during a wake-sleep cycle, effects of higher stimulus rate or tactile interference, etc. Also, several hypotheses on the neural mechanisms of the HFOs are introduced; the early HFO burst is probably generated from action potentials of thalamocortical fibers at the time when they arrive at the area 3b (and 1), since this component is resistant to higher stimulus rate > 10Hz or general anesthesia: by contrast, the late HFO burst is sensitive to higher stimulus rate, reflecting activities of a postsynaptic neural network in the somatosensory cortices, area 3b and 1. As to possible mechanisms of the late HFO burst genesis, an interneuron hypothesis, a fast inhibitory postsynaptic potential (IPSP) hypothesis of the pyramidal cell and a chattering cell hypothesis will be discussed on the basis of physiological and pathological features of the somatosensory HFOs.     

High-frequency oscillations change in parallel with short-interval intracortical inhibition after theta burst magnetic stimulation.

OBJECTIVE: Theta burst transcranial magnetic stimulation (TBS) causes changes in motor cortical excitability. In the present study, somatosensory-evoked potentials (SEPs) and high-frequency oscillations (HFOs) were recorded before and after TBS over the motor cortex to examine how TBS influenced the somatosensory cortex. METHODS: SEPs following electric median nerve stimulation were recorded, and amplitudes for the P14, N20, P25, and N33 components were measured and analyzed. HFOs were separated by 400-800 Hz band-pass filtering, and root-mean-square amplitudes were calculated from onset to offset. SEPs and HFOs were measured before and after application of either intermittent or continuous TBS (iTBS/cTBS; 600 total pulses at 80% active motor threshold) over the motor cortex. Motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) of the first dorsal interosseous muscle were examined before and after TBS. RESULTS: MEPs, SICI, and HFO amplitudes were increased and decreased significantly after iTBS and cTBS, respectively. Wide-band SEPs did not change significantly after TBS. CONCLUSIONS: TBS changed the cortical excitability of the sensorimotor cortices. Changes in HFOs after TBS were parallel to those in SICI. SIGNIFICANCE: The mechanisms of changes in HFOs after TBS may be the same as those in SICI.     

Focal cortical high-frequency oscillations trigger epileptic spasms: Confirmation by digital video subdural EEG

OBJECTIVE: To localize high-frequency oscillations (HFOs) on the cortex during epileptic spasms using video subdural EEG and Multiple Band Frequency Analysis (MBFA). METHODS: Using video subdural EEG sampled at 1 kHz, we studied a 14-year-old boy with asymmetric epileptic spasms of possible left frontal origin. We identified HFOs, then analyzed and localized their distributions by MBFA. We correlated HFO distribution to clinical spasm intensity. RESULTS: Ictal subdural EEG recorded HFOs at 60-150 Hz lasting 0.3-4 s. MBFA showed extensive but noncontiguous distribution of HFOs predominantly over the left frontal and temporal regions. HFOs began and became quasiperiodic before manifestation of clinical spasms. As clinical spasms intensified, HFOs persisted in regions where they initiated subclinically but were of higher frequency and greater power than HFOs in other regions. We performed cortical resections over the left frontal and temporal regions with predominant HFOs. Six months after surgery, the patient remained seizure free. CONCLUSIONS: HFOs were present over the ictal onset zone during epileptic spasms. Periodic spasms in this patient had the characteristics of partial seizures. SIGNIFICANCE: We show that HFOs occurred over the cerebral cortex during epileptic spasms, and we suggest that these focal cortical HFOs triggered the spasms.     

Movement interference attenuates somatosensory high-frequency oscillations: contribution of local axon collaterals of 3b pyramidal neurons.

OBJECTIVES: We examined the effects of movement interference on high-frequency oscillations (HFOs) and N20m in 10 healthy subjects.METHODS: For the movement interference condition, somatosensory evoked magnetic fields (SEFs) following electric median nerve stimulation were recorded during voluntary movement of the digits. For the control condition, the SEFs were recorded without interference. The N20m and HFOs were separated by 3-300Hz and 300-900Hz bandpass filtering. Then, the peak-to-peak amplitudes were measured.RESULTS: Both interference/control amplitude ratios for the N20m and HFOs were smaller than 100%. In contrast, the HFO/N20m amplitude index, which was calculated by dividing the interference/control amplitude ratio for the HFOs with that for the N20m, was significantly greater in the movement interference condition than in the control condition.CONCLUSIONS: Although the overall amplitude of the HFOs was decreased by movement, enhancement of the HFOs by the movement was revealed by the HFO/N20m amplitude index. Thus, we suggest that the HFOs represent activity of the inhibitory interneurons excited by both thalamocortical afferent impulses and excitatory synaptic inputs from pyramidal neurons in area 3b through their local axon collaterals, thereby reflecting both feed-forward and feedback inhibitory effects onto the post-synaptic pyramidal neurons.     

Origins of the somatic N20 and high-frequency oscillations evoked by trigeminal stimulation in the piglets.

OBJECTIVE: In humans, the somatic evoked potentials (SEPs) and magnetic fields (SEFs) elicited by peripheral nerve stimulation contain high-frequency oscillations (HFOs) around 600 Hz superimposed on the initial cortical response N20. Responses elicited by snout stimulation in the swine also contain similar HFOs during the rising phase of the porcine N20. This study examined the generators of the N20 and HFOs in the swine. METHODS: We recorded intracortical SEPs and multi-unit activities in the sulcal area of the primary somatosensory cortex (SI) simultaneously with SEFs. The laminar profiles of the potential and current-source-density (CSD) were analyzed. RESULTS: The CSD analysis revealed that the N20 was produced by two dipolar generators, both directed toward the cortical surface. After the arrival of the initial thalamocortical volley in layer IV, the sink of the first generator shifted toward shallower layers II-III with a velocity of 0.109+/-0.038 m/s (mean+/-SD). The sink of the second generator moved to layer V. The initial thalamocortical axonal component of the HFO was produced by repolarizing current with the sink in layer IV. The CSD laminar profile of the postsynaptic component was very similar to the profile of intracortical N20. The current sink within each cycle of HFO propagated upward with a velocity of 0.633+/-0.189 m/s, indicating backpropagation. CONCLUSIONS: We propose that the N20 is generated by two sets of excitatory neurons which also produce the HFOs. Although the loci of synaptic inputs are unknown, these neurons appear to fire initially in the soma and produce backpropagating spikes toward distal apical dendrites. SIGNIFICANCE: These conclusions relate the N20 to the HFO and provide a new explanation of how the current underlying the N20 is invariantly directed toward superficial layers across species.     

Peripheral and segmental spinal abnormalities of median and ulnar somatosensory evoked potentials in Hirayama's disease

OBJECTIVES: To investigate the origin of juvenile muscle atrophy of the upper limbs (Hirayama's disease, a type of cervical myelopathy of unknown origin). SUBJECTS: Eight male patients were studied; data from 10 normal men were used as control. METHODS: Median and ulnar nerve somatosensory evoked potentials (SEP) were recorded. Brachial plexus potentials at Erb's point (EP), dorsal horn responses (N13), and subcortical (P14) and cortical potentials (N20) were evaluated. Tibial nerve SEP and motor evoked potentials (MEP) were also recorded from scalp and spinal sites to assess posterior column and pyramidal tract conduction, respectively. RESULTS: The most important SEP findings were: a very substantial attenuation of both the EP potentials and the N13 spinal responses; normal amplitude of the scalp N20; and normal latency of the individual peaks (EP-N9-N13-P14-N20). Although both nerves were involved, abnormalities in response to median nerve stimulation were more significant than those in response to ulnar nerve stimulation. There was little correlation between the degree of alterations observed and the clinical state. Latencies of both spinal and cortical potentials were normal following tibial nerve stimulation. The mean latency of cervical MEP and the central conduction time from the thenar eminence were slightly but significantly longer in patients than in controls. CONCLUSIONS: The findings support the hypothesis that this disease, which is clinically defined as a focal spinal muscle atrophy of the upper limb, may also involve the sensory system; if traumatic injury caused by stretching plays a role in the pathogenesis, the damage cannot be confined to the anterior horn of the spinal cord.     

Human high frequency somatosensory evoked potential components are refractory to circadian modulations of tonic alertness.

The impact of vigilance states, such as sleep or arousal changes, on the high-frequency (600 Hz) components (HFOs) of somatosensory evoked potentials (SEPs) is known. The present study sought to characterize the effects of circadian fluctuations of tonic alertness on HFOs in awake humans. Median nerve SEPs were recorded at four times during a 24-hour waking period. In parallel to the SEP recordings, a reaction-time (RT) task was performed to assess tonic alertness. Additionally, the spontaneous EEG was monitored. The low-frequency SEP component N20 and the early and late HFO parts did not change across the measurement sessions. In contrast, RTs were clearly prolonged at night and on the second morning. EEG also showed increased delta power at night. HFOs are sensitive to pronounced vigilance changes, such as sleep, but are refractory to fluctuations of tonic alertness. Tonic alertness is regarded to be the top-down cognitive control mechanism of wakefulness, whereas sleep is mediated by overwhelming bottom-up regulation, which seems apparently more relevant for, at least in part, subcortically triggered high-frequency burst generation in the ascending somatosensory system.     

Is there training-dependent reorganization of digit representations in area 3b of string players?

OBJECTIVE: The digit representations in area 3b were studied to examine whether there is training-dependent reorganization in string players. METHODS: Somatosensory evoked magnetic fields were recorded following electrical stimulation of digits 1 (D1), 2 (D2) and 5 (D5) of both hands in 8 string players and of the left hand in 12 control subjects. The N20m and P30m responses, and high-frequency oscillations (HFOs) were separated by 3-300 Hz and 300-900 Hz bandpass filtering. RESULTS: The dipole locations on the coronal plane and strengths of D1, D2 and D5, and D1-D5 cortical distance estimated at the peak of N20m or P30m did not differ between left and right hand in string players or between left hand in string players and controls. On the other hand, the dipole locations of D2 estimated from N20m and P30m and of D1 from N20m were significantly anterior, the D2-D5 distance from P30m longer, and the number of HFO peaks larger for D5 in string players than controls. CONCLUSIONS/SIGNIFICANCE: With strong mutual competition among the fingering digits, the scale of reorganization should be much smaller as compared with the competition-free denervation-induced reorganizations. Taken together, the training-dependent reorganization of somatosensory cortex in string players is manifest not only in the enlarged cortical representation but also in the enhanced HFOs presumably representing activity of the fast-spiking interneurons.     

Somatosensory evoked high-frequency oscillations in migraine patients.

OBJECTIVE: To explore additional evidence concerning generators of somatosensory evoked high-frequency oscillations (HFOs). METHODS: We recorded HFOs in migraine patients. Subjects were 19 healthy normal subjects and 19 migraineurs. Electrical stimuli were delivered alternately to the right and left median nerves at their wrists. EEGs were recorded from C3'-Fz, C4'-Fz, Erb1-Erb2, Erb2-Erb1 and Cv6-Fz using a 0.3 Hz low-frequency filter and a 3000 Hz high-frequency filter. Responses to 5000 stimuli were averaged. For separation of HFOs from underlying N20, the digitized wide-band signals were digitally bandpass filtered (400-800 Hz) and averaged. RESULTS: There were no significant differences in peak latencies and amplitudes for N9, N13, N20 and P25 components between normal controls and migraineurs. Root-mean-square amplitudes for HFOs in migraineurs were significantly diminished compared with normal controls. CONCLUSIONS: A diminished inhibitory mechanism in the somatosensory system may exist in migraineurs. It remains to determine what cell populations contribute to generating HFOs. SIGNIFICANCE: This indicates that there is a dysfunction in cortical information processing in the somatosensory cortex of migraineurs.     

Enlarged high frequency oscillations of the median nerve somatosensory evoked potential and survival in amyotrophic lateral sclerosis

ObjectiveA large N20 and P25 of the median nerve somatosensory evoked potential (SEP) predicts short survival in amyotrophic lateral sclerosis (ALS). We investigated whether high frequency oscillations (HFOs) over N20 are enlarged and associated with survival in ALS.MethodsA total of 145 patients with ALS and 57 healthy subjects were studied. We recorded the median nerve SEP and measured the onset-to-peak amplitude of N20 (N20o-p), and peak-to-peak amplitude between N20 and P25 (N20p-P25p). We obtained early and late HFO potentials by filtering SEP between 500 and 1 kHz, and measured the peak-to-peak amplitude. We followed up patients until endpoints (death or tracheostomy) and analyzed the relationship between SEP or HFO amplitudes and survival using a Cox analysis.ResultsPatients showed larger N20o-p, N20p-P25p, and early and late HFO amplitudes than the control values. N20p-P25p was associated with survival periods (p = 0.0004), while early and late HFO amplitudes showed no significant association with survival (p = 0.4307, and p = 0.6858, respectively).ConclusionsThe HFO amplitude in ALS is increased, but does not predict survival.SignificanceThe enlarged HFOs in ALS might be a compensatory phenomenon to the hyperexcitability of the sensory cortex pyramidal neurons.     

Contribution of different somatosensory afferent input to subcortical somatosensory evoked potentials in humans

ObjectivesTo investigate the subcortical somatosensory evoked potentials (SEPs) to electrical stimulation of either muscle or cutaneous afferents.MethodsSEPs were recorded in 6 patients suffering from Parkinson’s disease (PD) who underwent electrode implantation in the pedunculopontine (PPTg) nucleus area. We compared SEPs recorded from the scalp and from the intracranial electrode contacts to electrical stimuli applied to: 1) median nerve at the wrist, 2) abductor pollicis brevis motor point, and 3) distal phalanx of the thumb. Also the high-frequency oscillations (HFOs) were analysed.ResultsAfter median nerve and pure cutaneous (distant phalanx of the thumb) stimulation, a P1-N1 complex was recorded by the intracranial lead, while the scalp electrodes recorded the short-latency far-field responses (P14 and N18). On the contrary, motor point stimulation did not evoke any low-frequency component in the PPTg traces, nor the N18 potential on the scalp. HFOs were recorded to stimulation of all modalities by the PPTg electrode contacts.ConclusionsStimulus processing within the cuneate nucleus depends on modality, since only the cutaneous input activates the complex intranuclear network possibly generating the scalp N18 potential.SignificanceOur results shed light on the subcortical processing of the somatosensory input of different modalities.