Sensorimotor integration within the primary motor cortex by selective nerve fascicle stimulation.

The integration of sensory inputs in the motor cortex is crucial for dexterous movement. We recently demonstrated that a closed-loop control based on the feedback provided through intraneural multichannel electrodes implanted in the median and ulnar nerves of a participant with upper limb amputation improved manipulation skills and increased prosthesis embodiment. Here we assessed, in the same participant, whether and how selective intraneural sensory stimulation also elicits a measurable cortical activation and affects sensorimotor cortical circuits. After estimating the activation of the primary somatosensory cortex evoked by intraneural stimulation, sensorimotor integration was investigated by testing the inhibition of primary motor cortex (M1) output to transcranial magnetic stimulation, after both intraneural and perineural stimulation. Selective sensory intraneural stimulation evoked a low-amplitude, 16 ms-latency, parietal response in the same area of the earliest component evoked by whole-nerve stimulation, compatible with fast-conducting afferent fibre activation. For the first time, we show that the same intraneural stimulation was also capable of decreasing M1 output, at the same time range of the short-latency afferent inhibition effect of whole-nerve superficial stimulation. The inhibition generated by the stimulation of channels activating only sensory fibres was stronger than that due to intraneural or perineural stimulation of channels activating mixed fibres. We demonstrate in a human subject that the cortical sensorimotor integration inhibiting M1 output previously described after the experimental whole-nerve stimulation is present also with a more ecological selective sensory fibre stimulation. KEY POINTS: Cortical integration of sensory inputs is crucial for dexterous movement. Short-latency somatosensory afferent inhibition of motor cortical output is typically produced by peripheral whole-nerve stimulation. We exploited intraneural multichannel electrodes used to provide sensory feedback for prosthesis control to assess whether and how selective intraneural sensory stimulation affects sensorimotor cortical circuits in humans. Activation of the primary somatosensory cortex (S1) was explored by recording scalp somatosensory evoked potentials. Sensorimotor integration was tested by measuring the inhibitory effect of the afferent stimulation on the output of the primary motor cortex (M1) generated by transcranial magnetic stimulation. We demonstrate in humans that selective intraneural sensory stimulation elicits a measurable activation of S1 and that it inhibits the output of M1 at the same time range of whole-nerve superficial stimulation.

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

OBJECTIVES: To investigate the subcortical somatosensory evoked potentials (SEPs) to electrical stimulation of either muscle or cutaneous afferents. METHODS: SEPs 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. RESULTS: After 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. CONCLUSIONS: Stimulus processing within the cuneate nucleus depends on modality, since only the cutaneous input activates the complex intranuclear network possibly generating the scalp N18 potential. SIGNIFICANCE: Our results shed light on the subcortical processing of the somatosensory input of different modalities.

Pedunculopontine tegmental Nucleus-evoked prepulse inhibition of the blink reflex in Parkinson's disease.

OBJECTIVE: To investigate the effects on the blink reflex (BR) of single stimuli applied to the pedunculopontine tegmental nucleus (PPTg). METHODS: The BR was evoked by stimulating the supraorbital nerve (SON) in fifteen patients suffering from idiopathic Parkinson's disease (PD) who had electrodes monolaterally or bilaterally implanted in the PPTg for deep brain stimulation (DBS). Single stimuli were delivered to the PPTg through externalized electrode connection wires 3-4 days following PPTg implantation. RESULTS: PPTg stimuli increased the latency and reduced duration, amplitude and area of the R2 component of the BR in comparison to the response recorded in the absence of PPTg stimulation. These effects were independent of the side of SON stimulation and were stable for interstimulus interval (ISI) between PPTg prepulse and SON stimulus from 0 to 110 ms. The PPTg-induced prepulse inhibition of the BR was bilaterally present in the brainstem. The R1 component was unaffected. CONCLUSIONS: The prepulse inhibition of the R2 component may be modulated by the PPTg. SIGNIFICANCE: These findings suggest that abnormalities of BR occurring in PD may be ascribed to a reduction of basal ganglia-mediated inhibition of brainstem excitability.

Effects of the noncompetitive AMPA receptor antagonist perampanel on thalamo-cortical excitability: A study of high-frequency oscillations in somatosensory evoked potentials.

OBJECTIVE: Wedesignedalongitudinalcohortstudyon People with Epilepsy (PwE) with the aimofassessingthe effect of Perampanel (PER) oncortico-subcortical networks, as measured by high-frequency oscillations of somatosensory evoked potentials (SEP-HFOs). SEP-HFOs measure the excitability of both thalamo-corticalprojections(early HFOs) and intracortical GABAergic synapses (late HFOs), thus they could be used to study the anti-glutamatergic action of PER, a selective antagonist of the AMPA receptor. METHODS: 15 PwE eligible for PER add-on therapy, were enrolled prospectively. Subjects underwent SEPs recording from the dominant hand at two times: PwET0 (baseline, before PER titration) and PwET1 (therapeutic dose of 4 mg). HFOs were obtained by filtering N20 scalp response in the 400-800 Hz range. Patients were compared with a normative population of 15 healthy controls (HC) matched for age and sex. RESULTS: We found a significant reduction ofTotal HFOs and mostly early HFOs area between PwET0 and PwET1 (p = 0.05 and p = 0.045 respectively) and between HC and PwET1 (p = 0.01). Furthermore, we found a significant reduction of P24/N24 Amplitude between PwET0 and HC and between PwET0 and PwET1 (p = 0.006 and p = 0.032, respectively). CONCLUSIONS: Introduction of PER as add-on therapy reduced the area of total HFOs, acting mainly on the early burst, related to thalamo-cortical pathways. Furthermore P24/N24 amplitude, which seems to reflect a form of cortico-subcortical integration, resulted increased in PwE at T0 and normalized at T1. SIGNIFICANCE: Our findings suggest that PER acts on cortico-subcortical excitability. This could explain the broad spectrum of PER and its success in forms of epilepsy characterized by thalamo-cortical hyperexcitability.

The effects of antiepileptic drugs on high-frequency oscillations in somatosensory evoked potentials.

OBJECTIVES: High frequency oscillations (HFOs) of Somatosensory evoked potentials (SEPs) reflect the activity of thalamo-cortical and cortical neurons from the sensory pathway. Antiepileptic-drugs (AEDs) reduce seizures acting on the balance between excitation and inhibition. We aimed to study the effect of AED mono and polytherapy on SEP-HFO's components. METHODS: Twenty-five patients with focal epilepsy were enrolled for the purpose of this study. Patients were divided in 3 groups according to the number of AEDs (1, 2 or 3 AEDs). Patients in group 1 underwent SEP-HFOs recording in drug naïve condition and at 1 month after AED titration. HFOs were compared in duration, amplitude and latency among the three groups. RESULTS: The amplitude and duration of late HFOs of the affected hemisphere (AH) are different between groups and inversely correlated with the number of AEDs. In naïve patients monotherapy reverts the asymmetry in totHFOs (total HFOs) duration. CONCLUSION: Our results demonstrate that SEP-HFOs are sensitive to the action of AEDs on cortical excitability. This effect seems to affect mainly the cortical component of HFOs in the AH and it is related to the number of AEDs taken. SIGNIFICANCE: SEP-HFOs might be a viable tool to probe cortical excitability changes induced by AEDs.

Thalamic and cortical hyperexcitability in juvenile myoclonic epilepsy.

OBJECTIVES: Juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy marked by cortical hyperexcitability. Recent neuroimaging data suggested also a thalamic role in sustaining epileptic propensity in JME. However, thalamic hyperexcitability was not demonstrated so far. Low-frequency (LF-SEPs) and high-frequency somatosensory evoked potentials (HF-SEPs) are very sensitive to thalamic (early HF-SEPs burst, eHFO) and cortical (late HF-SEPs burst, lHFO) excitability. The aim of our experiment was to explore and discern the role of thalamic and cortical excitability in epileptic susceptibility of JME through a LF-SEPs and HF-SEPs study. METHODS: Twenty-three subjects with JME (11 females, 30.2 ± 9.8-year-old) and 23 healthy control subjects (12 females, age: 34.7 ± 7.7-year-old) underwent right median LF-SEPs scalp recordings. Cp3'-Fz traces were filtered (400-800 Hz) to reveal HF-SEPs. All JME patients were on drug treatment and seizure free, except for sporadic myoclonus. RESULTS: N20 LF-SEPs amplitude (p < 0.009), areas of totHFO, eHFO and lHFO (all p < 0.005) and totHFO duration (p = 0.013) were increased in JME respect to healthy subjects. totHFO area was negatively correlated with the number of antiepileptic drugs (rho = -0.505, sig.: 0.027), while eHFO area was positively correlated with the myoclonus frequency (rho = 0.555, sig = 0.014). CONCLUSIONS: We demonstrated that in JME the thalamic hyperexcitability assists the cortical one in sustaining epileptic susceptibility. SIGNIFICANCE: Our results support the concept of JME as a network and genetic disorder.

Thalamo-cortical dysfunction contributes to fatigability in multiple sclerosis patients: A neurophysiological study.

BACKGROUND: Fatigue and fatigability are common symptoms reported by patients affected by Multiple Sclerosis (MS). The pathogenic mechanisms of such symptoms are currently unknown, but increasing evidence suggests that thalamus could play a key-role. High-frequency oscillations (HFOs) are a neurophysiological measure reflecting the activity of thalamo-cortical network. In particular, the early component is generated from thalamic axons while the late part results from neurons located in somatosensory cortex. OBJECTIVE: To investigate the effect of a fatigue-inducing exercise on HFOs and on strength performances in MS patients and healthy controls (HCs). METHODS: Fifteen patients and fifteen HCs participated in this study. We recorded HFOs from median nerve somatosensory evoked potentials and assessed strength performances, before and after a fatigue-inducing exercise of hand muscles. RESULTS: Compared to HCs, after repeated fatiguing tasks, patients showed a significant reduction of early component of HFOs area and a significant increase of late component of HFOs duration. Strength performance declined both in patients and in HCs but remained lower in patients at all time-points. CONCLUSIONS: HFOs, a neurophysiological marker of thalamo-cortical pathway, are significantly modified by fatiguing tasks in MS patients, in particular the early component that refers to the functionality of thalamic axons.

Thalamo-cortical network dysfunction in temporal lobe epilepsy.

OBJECTIVES: Imaging and neurophysiological data shows that the cortical disfunction caused by focal epilepsy is not limited to the epileptic focus, thus raising the modern vision of focal epilepsy as a network disorder. The involvement of deep thalamo-cortical projections in temporal lobe epilepsy is a clear example. We aimed at demonstrating the interictal functional impairment of thalamo-cortical network in drug-naïve TLE patients through the study of high frequency oscillations of somatosensory evoked potentials (HF-SEP). METHODS: Twelve healthy controls (HC; 8 females, 52.2 ± 17.3 years-old) and 12 drug-naïve TLE patients (8 females, 55.5 ± 21.5 years-old) underwent bilateral median HF-SEP, recorded by scalp electrodes. Cp3'-Fz and Cp4'-Fz traces were filtered (400-800 Hz) to evidence HF-SEP. RESULTS: HF-SEP duration in the affected hemisphere was significantly longer when compared to that of both the unaffected hemisphere and HC hemispheres. No significant inter-hemispheric differences were found in areas, powers and latencies of HF-SEP wavelets. CONCLUSION: Our results demonstrate that TLE induces early interictal functional impairments of the thalamo-cortical network. SIGNIFICANCE: Our data strongly corroborates the vision of focal epilepsy as a network disorder and offers a new neurophysiological tool to test pharmacological, surgical and neuromodulatory therapies.

Cortical inhibitory dysfunction in epilepsia partialis continua: A high frequency oscillation somatosensory evoked potential study.

OBJECTIVE: The pathophysiology of epilepsia partialis continua (EPC) is still unclear, a thalamo-cortical circuit dysfunction has been hypothesized. The aim of present study is the functional evaluation of the thalamo-cortical network in EPC by means of the study of low- and high-frequency somatosensory evoked potentials (LF-SEP and HF-SEP). METHODS: Median LF-SEP and HF-SEP were recorded in 3 patients with EPC and in 2 patients with rolandic lesions without EPC (non-EPC). Recording electrodes were placed on P3, C3, F3 and P4, C4, F4 of scalp regions. HF-SEP were obtained by an offline 400-800 Hz filtering of P3-F3 and P4-F4 traces. RESULTS: In EPC patients, we found a significant suppression of post-synaptic HF-SEP burst and an amplitude reduction of the P24 wave of the LF-SEPs. Both these components are related to cortical inhibitory interneuron activity. HF-SEP and LF-SEP were normal in non-EPC patients. CONCLUSION: The different results obtained in patients with a rolandic lesion with and without EPC supports the hypothesis that EPC might be correlated to a dysfunction of gabaergic interneurons of a cortical sensory-motor network. SIGNIFICANCE: Our results might contribute to the understanding of the physiological basis of the cortical dysfunction causing epilepsia partialis continua.

CM-Pf deep brain stimulation and the long term management of motor and psychiatric symptoms in a case of Tourette syndrome.

Tourette syndrome is a rare neuropsychiatric disorder affecting the cortico-striato-thalamo-cortical system. The disease manifests in childhood with tics and various psychiatric comorbidities. Cases of refractory Tourette syndrome are valuable candidates for functional neurosurgery. The thalamic centromedian-parafascicular complex is an experimental target that shows a promising role in Tourette syndrome deep brain stimulation, due to pathophysiologic evidences. We have shown on a long term follow-up, that thalamic deep brain stimulation, targeted on the centromedian-parafascicular complex, could modulate motor (i.e. tics) symptoms and owns a putative effect on various psychiatric aspects. Non-responding psychiatric symptoms could be due to the aberrant developmental environment of young Tourette patients more than disease itself. Centromedian-parafascicular complex is intriguingly embedded in motor, associative and limbic pathways and should be further investigated in his role for neuromodulation of human movement and behavior.

Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum.

The region of the pedunculopontine tegmental nucleus (PPTg) has been proposed as a novel target for deep brain stimulation (DBS) to treat levodopa resistant symptoms in motor disorders. Recently, the anatomical organization of the brainstem has been revised and four new distinct structures have been represented in the ventrolateral pontine tegmentum area in which the PPTg was previously identified. Given this anatomical reassessment, and considering the increasing of our experience, in this paper we revisit the value of DBS applied to that area. The reappraisal of clinical outcomes in the light of this revisitation may also help to understand the consequences of DBS applied to structures located in the ventrolateral pontine tegmentum, apart from the PPTg. The implantation of 39 leads in 32 patients suffering from Parkinson's disease (PD, 27 patients) and progressive supranuclear palsy (PSP, four patients) allowed us to reach two major conclusions. The first is that the results of the advancement of our technique in brainstem DBS matches the revision of brainstem anatomy. The second is that anatomical and functional aspects of our findings may help to explain how DBS acts when applied in the brainstem and to identify the differences when it is applied either in the brainstem or in the subthalamic nucleus. Finally, in this paper we discuss how the loss of neurons in brainstem nuclei occurring in both PD and PSP, the results of intraoperative recording of somatosensory evoked potentials, and the improvement of postural control during DBS point toward the potential role of ascending sensory pathways and/or other structures in mediating the effects of DBS applied in the ventrolateral pontine tegmentum region.

Low- and high-frequency subcortical SEP amplitude reduction during pure passive movement.

OBJECTIVES: To investigate the effect of pure passive movement on both cortical and subcortical somatosensory evoked potentials (SEPs). METHODS: Median nerve SEPs were recorded in 8 patients suffering from Parkinson's disease (PD) and two patients with essential tremor. PD patients underwent electrode implantation in the subthalamic (STN) nucleus (3 patients) and pedunculopontine (PPTg) nucleus (5 patients), while 2 patients with essential tremor were implanted in the ventral intermediate nucleus (VIM) of the thalamus. In anesthetized patients, SEPs were recorded at rest and during a passive movement of the thumb of the stimulated wrist from the intracranial electrode contacts and from the scalp. Also the high-frequency oscillations (HFOs) were analyzed. RESULTS: Amplitudes of both deep and scalp components were decreased during passive movement, but the reduction was higher at cortical than subcortical level. Also the HFOs were reduced by movement. CONCLUSION: The different amount of the movement-related decrease suggests that the cortical SEP gating is not only the result of a subcortical somatosensory volley attenuation, but a further mechanism acting at cortical level should be considered. SIGNIFICANCE: Our results are important for understanding the physiological mechanism of the sensory-motor interaction during passive movement.

Low and high-frequency somatosensory evoked potentials recorded from the human pedunculopontine nucleus.

OBJECTIVE: To investigate the generators of the somatosensory evoked potential (SEP) components recorded from the Pedunculopontine Tegmental nucleus (PPTg). METHODS: Twenty-two patients, suffering from Parkinson's disease (PD), underwent electrode implantation in the PPTg area for deep brain stimulation (DBS). SEPs were recorded from the DBS electrode contacts to median nerve stimulation. RESULTS: SEPs recorded from the PPTg electrode contacts could be classified in 3 types, according to their waveforms. (1) The biphasic potential showed a positive peak (P16) whose latency (16.05 ± 0.61 ms) shifted of 0.18 ± 0.07 ms from the lower to the upper contact of the electrode. (2) The triphasic potential showed an initial positive peak (P15) whose latency (15.4 ± 0.2 ms) did not change across the DBS electrode contacts. (3) In the last SEP configuration (mixed biphasic and triphasic waveform), the positive peak was bifid including both the P15 and P16 potentials. CONCLUSION: While the P16 potential is probably generated by the somatosensory volley travelling along the medial lemniscus, the P15 response represents a far-field potential probably generated at the cuneate nucleus level. SIGNIFICANCE: Our results show the physiological meaning of the somatosensory responses recorded from the PPTg nucleus area.

The clinical effects of deep brain stimulation of the pedunculopontine tegmental nucleus in movement disorders may not be related to the anatomical target, leads location, and setup of electrical stimulation.

BACKGROUND: The pedunculopontine tegmental nucleus (PPTg) is a novel target for deep brain stimulation (DBS) in movement disorders. OBJECTIVE: To clarify the relationships between the individual anatomic variations of the brainstem, the site in which the PPTg DBS is applied, and the clinical outcome in a relatively large number of patients affected by Parkinson disease or progressive supranuclear palsy. METHODS: Magnetic resonance images have been used to evaluate brainstem anatomy and the relationships between lead position and specific brainstem landmarks. All data were matched on atlas representations of the PPTg and were correlated with Unified Parkinson Disease Rating Scale III (UPDRS III), subitems 27 to 30 of UPDRS III and the Hoehn and Yahr evaluations. RESULTS: A high variance of brainstem parameters was evident, affecting the relationships between the position of the nucleus and lead contacts. According to the contacts giving the best clinical outcome, patients could be distinguished between those who required the use of 2 adjacent contacts and those who required stimulation through 2 nonadjacent contacts. Furthermore, in the former group the target coordinates were more lateral and deeper compared with the latter group. CONCLUSION: Individual PPTg-DBS planning is required to overcome the inconsistencies linked to the high variability in the brainstem anatomy of patients. The lack of correlations between lead position, contact setup, and clinical outcome indicate that the benefits of PPTg DBS may not be strictly linked to the site of stimulation within the PPTg area, and may not depend upon the neurons still surviving in this region in Parkinson disease or progressive supranuclear palsy.

Transcranial direct current stimulation effects on the excitability of corticospinal axons of the human cerebral cortex.

BACKGROUND: Transcranial direct current stimulation (tDCS) of the human cerebral cortex modulates cortical excitability non-invasively in a polarity-specific manner: anodal tDCS leads to lasting facilitation of motor cortex excitability. OBJECTIVE: To further elucidate the underlying physiological mechanisms of tDCS. METHODS: We recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation of the primary motor cortex before and after a 20 min period of anodal tDCS in a conscious patient who had electrode implanted in the cervical epidural space for the control of pain. We performed magnetic stimulation of the motor cortex using a direction of the induced current in the brain capable of activating both corticospinal axons, evoking D-wave activity, and cortico-cortical axons projecting upon corticospinal cells, evoking I-wave activity. RESULTS: Anodal tDCS increased the excitability of cortical circuits generating both D and I-wave activity, with a more prolonged effect on D-wave activity. The changes in motor evoked potential recorded from hand muscles produced by tDCS were in agreement with the effects produced on intracortical circuitry. CONCLUSIONS: Epidural recordings of corticospinal activity in our patient indicate that anodal tDCS develops its facilitatory effects by an increase in the excitability of corticospinal axons and by an increase of activity in cortico-cortical projections onto pyramidal tract neurones, modulating motor cortex excitability with both synaptic (I waves) and non-synaptic (D waves) mechanisms.

Targeting the pedunculopontine nucleus: a new neurophysiological method based on somatosensory evoked potentials to calculate the distance of the deep brain stimulation lead from the Obex.

BACKGROUND: Pedunculopontine tegmental nucleus (PPTg) deep brain stimulation (DBS) has been used in patients with Parkinson disease. OBJECTIVE: To verify the position of the DBS lead within the pons during PPTg targeting. METHODS: In 10 Parkinson disease patients undergoing electrode implantation in the PPTg, somatosensory evoked potentials were recorded after median nerve stimulation from the 4 DBS electrode contacts and from 2 scalp leads placed in the frontal and parietal regions. RESULTS: The DBS electrode recorded a P16 potential (latency at contact 0, 16.33 ± 0.76 ms). There was a P16 latency shift of 0.18 ± 0.07 ms from contact 0 (lower) to contact 3 (upper). The scalp electrodes recorded the P14 far-field response (latency, 15.44 ± 0.63 ms) and the cortical N20 potential (latency, 21.58 ± 1.42 ms). The P16 potentials recorded by the intracranial electrode contacts are generated by the volley traveling along the medial lemniscus, whereas the scalp P14 potential represents a far-field response generated at the Obex level. Considering that the distance between the electrode contacts 0 and 3 is 6 mm, the distance of the electrode contact 0 from the Obex (ΔObex) was calculated by the equation: ΔObex = 6 × Δlatency P14- PPTg0/Δlatency PPTg0-PPTg3. The Obex-to-brainstem electrode distance obtained by the neurophysiological method confirmed that the electrode was located within the pons in all patients. Moreover, this distance was very similar to that issued from the individual brain magnetic resonance imaging. CONCLUSION: Somatosensory evoked potentials may be a helpful tool for calculating the macroelectrode position within the pons during PPTg targeting.