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.

Comparison between Tail Suspension Swing Test and Standard Rotation Test in Revealing Early Motor Behavioral Changes and Neurodegeneration in 6-OHDA Hemiparkinsonian Rats.

The unilateral 6-hydroxydopamine (6-OHDA) model of Parkinson's disease (PD) is one of the most commonly used in rodents. The anatomical, metabolic, and behavioral changes that occur after severe and stable 6-OHDA lesions have been extensively studied. Here, we investigated whether early motor behavioral deficits can be observed in the first week after the injection of 6-OHDA into the right substantia nigra pars compacta (SNc), and if they were indicative of the severity of the dopaminergic (DAergic) lesion in the SNc and the striatum at different time-points (day 1, 3, 5, 7, 14, 21). With this aim, we used our newly modified tail suspension swing test (TSST), the standard rotation test (RT), and immunohistochemical staining for tyrosine hydroxylase (TH). The TSST, but not the standard RT, revealed a spontaneous motor bias for the 6-OHDA-lesioned rats from the day 1 post-surgery. Both tests detected the motor asymmetry induced by (single and repeated) apomorphine (APO) challenges that correlated, in the first week, with the DAergic neuronal degeneration. The described TSST is fast and easy to perform, and in the drug-free condition is useful for the functional assessment of early motor asymmetry appearing after the 6-OHDA-lesion in the SNc, without the confounding effect of APO challenges.

High Cervical Spinal Cord Stimulation: A One Year Follow-Up Study on Motor and Non-Motor Functions in Parkinson's Disease.

BACKGROUND: The present study investigated the effectiveness of stimulation applied at cervical levels on pain and Parkinson's disease (PD) symptoms using either tonic or burst stimulation mode. METHODS: Tonic high cervical spinal cord stimulation (T-HCSCS) was applied on six PD patients suffering from low back pain and failed back surgery syndrome, while burst HCSCS (B-HCSCS) was applied in twelve PD patients to treat primarily motor deficits. Stimulation was applied percutaneously with quadripolar or octapolar electrodes. Clinical evaluation was assessed by the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H&Y) scale. Pain was evaluated by a visual analog scale. Evaluations of gait and of performance in a cognitive motor task were performed in some patients subjected to B-HCSCS. One patient who also suffered from severe autonomic cardiovascular dysfunction was investigated to evaluate the effectiveness of B-HCSCS on autonomic functions. RESULTS: B-HCSCS was more effective and had more consistent effects than T-HCSCS in reducing pain. In addition, B-HCSCS improved UPDRS scores, including motor sub-items and tremor and H&Y score. Motor benefits appeared quickly after the beginning of B-HCSCS, in contrast to long latency improvements induced by T-HCSCS. A slight decrease of effectiveness was observed 12 months after implantation. B-HCSCS also improved gait and ability of patients to correctly perform a cognitive-motor task requiring inhibition of a prepared movement. Finally, B-HCSCS ameliorated autonomic control in the investigated patient. CONCLUSIONS: The results support a better usefulness of B-HCSCS compared to T-HCSCS in controlling pain and specific aspects of PD motor and non-motor deficits for at least one year.

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.

The Basal Ganglia: More than just a switching device.

The basal ganglia consist of a variety of subcortical nuclei engaged in motor control and executive functions, such as motor learning, behavioral control, and emotion. The striatum, a major basal ganglia component, is particularly useful for cognitive planning of purposive motor acts owing to its structural features and the neuronal circuitry established with the cerebral cortex. Recent data indicate emergent functions played by the striatum. Indeed, cortico-striatal circuits carrying motor information are paralleled by circuits originating from associative and limbic territories, which are functionally integrated in the striatum. Functional integration between brain areas is achieved through patterns of coherent activity. Coherence belonging to cortico-basal ganglia circuits is also present in Parkinson's disease patients. Excessive synchronization occurring in this pathology is reduced by dopaminergic therapies. The mechanisms through which the dopaminergic effects may be addressed are the object of several ongoing investigations. Overall, the bulk of data reported in recent years has provided new vistas concerning basal ganglia role in the organization and control of movement and behavior, both in physiological and pathological conditions. In this review, basal ganglia functions involved in the organization of main movement categories and behaviors are critically discussed. Comparatively, the multiplicity of Parkinson's disease symptomatology is also revised.

Frameless Stereotaxis for Subthalamic Nucleus Deep Brain Stimulation: An Innovative Method for the Direct Visualization of Electrode Implantation by Intraoperative X-ray Control.

The recent introduction of frameless devices has enabled stereotactic neurosurgery to reach a level of accuracy that is comparable to traditional frame-based methodologies. Among frameless devices, the Nexframe appears to be very useful in implanting electrodes into the subthalamic nucleus or other structures for deep brain stimulation in Parkinson's disease. However, frameless devices, including the Nexframe, limit the possibility of intraoperative visual control of the placement of electrodes in the brain. Utilizing intraoperative O-arm Computed tomography (CT) scan or high-field Magnetic Resonance Imaging (MRI) could overcome this limitation, but their high cost restricts their use. Thus, in this paper we propose an innovation in Nexframe surgical planning that allows the intraoperative use of a C-arm X-ray apparatus to establish: (1) the progression of the electrode guide tube and the electrode in the brain; (2) the accuracy of the electrode trajectory; and (3) the correct attainment of the target. The proposed frameless technique using the Nexframe has been developed and successfully applied in our practice. It was shown to be helpful in overcoming the major issues that are usually encountered when electrodes are placed in the brain with frameless neurosurgery and reduced the risk of having to re-operate on patients to reposition the electrodes.

Fluorescent light induces neurodegeneration in the rodent nigrostriatal system but near infrared LED light does not.

We investigated the effects of continuous artificial light exposure on the mouse substantia nigra (SN). A three month exposure of C57Bl/6J mice to white fluorescent light induced a 30% reduction in dopamine (DA) neurons in SN compared to controls, accompanied by a decrease of DA and its metabolites in the striatum. After six months of exposure, neurodegeneration progressed slightly, but the level of DA returned to the basal level, while the metabolites increased with respect to the control. Three month exposure to near infrared LED light (∼710nm) did not alter DA neurons in SN, nor did it decrease DA and its metabolites in the striatum. Furthermore mesencephalic cell viability, as tested by [3H]DA uptake, did not change. Finally, we observed that 710nm LED light, locally conveyed in the rat SN, could modulate the firing activity of extracellular-recorded DA neurons. These data suggest that light can be detrimental or beneficial to DA neurons in SN, depending on the source and wavelength.

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.

Continuous stimulation of the pedunculopontine tegmental nucleus at 40 Hz affects preparative and executive control in a delayed sensorimotor task and reduces rotational movements induced by apomorphine in the 6-OHDA parkinsonian rat.

The pedunculopontine tegmental nucleus (PPTg) relays basal ganglia signals to the thalamus, lower brainstem and spinal cord. Using the 6-hydroxydopamine (6-OHDA) rat model of parkinsonism, we investigated whether deep brain stimulation (DBS) of the PPTg (40 Hz, 60 µs, 200-400 µA) may influence the preparative and executive phases in a conditioned behavioural task, and the motor asymmetries induced by apomorphine. In the conditioned task, rats had to press two levers according to a fixed delay paradigm. The 6-OHDA lesion was placed in the right medial forebrain bundle, i.e. contralaterally to the preferred forepaw used by rats to press levers in the adopted task. The stimulating electrode was implanted in the right PPTg, i.e. contralateral to left side, which was expected to be most affected. The lesion significantly reduced correct responses from 63.4% to 16.6%. PPTg-DBS effects were episodic; however, when rats successfully performed in the task (18.9%), reaction time (468.8 ± 36.5 ms) was significantly increased (589.9 ± 45.9 ms), but not improved by PPTg-DBS (646.7 ± 33.8 ms). Movement time was significantly increased following the lesion (649.2 ± 42.6 ms vs. 810.9 ± 53.0 ms), but significantly reduced by PPTg-DBS (820.4 ± 39.4 ms) compared to sham PPTg-DBS (979.8 ± 47.6 ms). In a second group of lesioned rats, rotations induced by apomorphine were significantly reduced by PPTg-DBS compared to sham PPTg-DBS (12.2 ± 0.6 vs. 9.5 ± 0.4 mean turns/min). Thus, it appears that specific aspects of motor deficits in 6-OHDA-lesioned rats may be modulated by PPTg-DBS.

Eyes as gateways for environmental light to the substantia nigra: relevance in Parkinson's disease.

Recent data indicates that prolonged bright light exposure of rats induces production of neuromelanin and reduction of tyrosine hydroxylase positive neurons in the substantia nigra. This effect was the result of direct light reaching the substantia nigra and not due to alteration of circadian rhythms. Here, we measured the spectrum of light reaching the substantia nigra in rats and analysed the pathway that light may take to reach this deep brain structure in humans. Wavelength range and light intensity, emitted from a fluorescent tube, were measured, using a stereotaxically implanted optical fibre in the rat mesencephalon. The hypothetical path of environmental light from the eye to the substantia nigra in humans was investigated by computed tomography and magnetic resonance imaging. Light with wavelengths greater than 600 nm reached the rat substantia nigra, with a peak at 709 nm. Eyes appear to be the gateway for light to the mesencephalon since covering the eyes with aluminum foil reduced light intensity by half. Using computed tomography and magnetic resonance imaging of a human head, we identified the eye and the superior orbital fissure as possible gateways for environmental light to reach the mesencephalon.

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.

The temporal context of certainty-uncertainty modulates the subthalamic nucleus-mediated anticipatory responding.

Lesions of the subthalamic nucleus (STN) in the rat are known to induce anticipatory responses in the preparatory period preceding conditioned movements. This study aimed to investigate how the temporal context in which a stimulus is presented affects the anticipatory responding caused by a unilateral STN lesion. A reaction-time task was employed in which a trigger signal starting a bar-pressing movement was presented at either side of the head in two temporal contexts. In the first, the trigger was presented at a fixed delay (FD paradigm) of 1s following an instruction signal. In the second, the 1s delay was randomly distributed (RD paradigm) among other delays. Reaction time was faster in the FD paradigm with respect to the RD paradigm. An increased readiness to move was observed in animals engaged in the RD paradigm as the delay period shortened, and this function was not abolished by the STN lesion. Anticipatory responding in general was less pronounced than in other paradigms previously reported in the literature, and predominated in the RD paradigm with respect to the FD paradigm. The destruction of the STN worsened the anticipatory responding only in the FD paradigm. A major consequence of the STN lesion was an increase of unconditioned responses to the instruction signal starting each trial. This attention deficit was more pronounced in the RD paradigm with respect to the FD paradigm, and was subsequently worsened by the lesion in both paradigms. The results suggest that the anticipatory responding may depend on the level of uncertainty implicit in each behavioural paradigm whereas inappropriate responding to the behavioural cue starting a trial may be independent from this factor, and highlight the importance of the behavioural paradigms employed when dealing with STN functions.

Unilateral deep brain stimulation of the pedunculopontine tegmental nucleus improves oromotor movements in Parkinson's disease.

BACKGROUND: Jaw movements are severely affected in Parkinson's disease. Deep brain stimulation (DBS) of basal ganglia targets is known to ameliorate oromotor control. In this study, we examined the effects of DBS of the pedunculopontine tegmental nucleus (PPTg) on jaw movements in selected parkinsonian patients. METHODS: The effects of low-frequency (25 Hz) stimulation of the PPTg on jaw movements were investigated through electrognathographic analysis in parkinsonian patients who were selected for PPTg stimulation. Changes in jaw velocity and amplitude during voluntary opening and closing movements of the mouth, as well as the maximum frequency of self-paced sequences of opening and closing cycles, were analyzed. RESULTS: Low-frequency stimulation of the PPTg in the OFF-drugs condition significantly improved the opening and closing velocities, vertical amplitude and rhythm of voluntary movements. In some instances, movement parameters during stimulation were within the range of those recorded in healthy controls. DISCUSSION: This is the first study investigating the impact of PPTg DBS on oromotor control in parkinsonian patients. The results show that jaw movements may be restored under stimulation and suggest that the pedunculopontine nucleus may play a key role in controlling oromotor activity.