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.

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.

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.

The deep brain stimulation of the pedunculopontine tegmental nucleus: towards a new stereotactic neurosurgery.

The application of deep brain stimulation (DBS) to the pedunculopontine tegmental nucleus (PPTg) has required profound modifications of classic neurosurgical techniques and of the criteria for evaluation of clinical results. This review analyzes a novel method of targeting the PPTg, based on angio-computerized tomography (angio-CT) scans and the tridimensional reconstruction of nuclei and cerebral vessels, and considers the advantages of applying these methods in comparison to the more traditional approach based on reference points obtained through the evaluation of the bicommessural line. Validation of the results obtained following unilateral PPTg DBS through neurophysiological recordings and objective measurements of functional parameters suggests that the PPTg may be considered as an initial target for the treatment of motor symptoms in selected patients affected by idiopathic Parkinson's disease (PD), which, if required, could be followed by DBS of other target areas. Moreover, on the basis of the observations derived from stimulating the PPTg, the potential utility attributed up to date to intraoperative neurophysiological recordings for identifying neurosurgical targets should be revisited, and the need for changes in the intraoperative management of patients has arisen from the body of evidence accumulated over recent years. The results obtained by different groups following PPTg DBS in parkinsonian patients are not uniform, most likely due to a cautious acceptance of this methodology, the experience progressively acquired, the criteria for patient selection and to subtle differences in target location. Although the role of PPTg in PD and/or in other pathologies remains to be clarified, pursuing the traditional approach on classical basal ganglia targets may limit the perspective of DBS based on multiple implantations.

The pedunculopontine tegmental nucleus: implications for a role in modulating spinal cord motoneuron excitability.

There is evidence that deep brain stimulation (DBS) of the pedunculopontine tegmental nucleus (PPTg) improves parkinsonian motor signs. The mechanisms that mediate these effects and the modifications that occur in the PPTg in Parkinson's disease (PD) are not fully known and are the object of current debate. The aim of this paper was to critically review available data with respect to (1) the presence of PPTg neurons linked to reticulospinal projections, (2) the involvement of these neurons in modulating spinal reflexes, and (3) the participation of fibers close to or within the PPTg region in such modulation. The PPTg neurons are distributed in a large pontotegmental region, stimulation of which can evoke activity in hindlimb, shoulder and neck muscles, and potentiate motor responses evoked by stimulation of dorsal roots. This influence seems to be carried out by fast-conducting descending fibers, which likely run in the medial reticulospinal pathway. It is yet unclear which neurotransmitters are involved and on which elements of the gray matter of the spinal cord PPTg fibers synapse. The modulation of spinal cord activity which can be achieved by stimulating the PPTg region seems to be mediated not only by PPTg neurons, but also by tecto-reticular fibers which run in the pontotegmental area, and which likely are activated during PPTg-DBS. The importance of these fibers is discussed taking into account the degeneration of PPTg neurons in PD and the benefits in gait and postural control that PPTg-DBS exerts in PD. The potential usefulness of PPTg-DBS in other neurodegenerative disorders characterized by neuronal loss in the brainstem is also considered.

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.

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.

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.

Deep brain stimulation promotes excitation and inhibition in subthalamic nucleus in Parkinson's disease.

Subthalamic nucleus single-unit recordings were undertaken before and during pedunculopontine [corrected] nucleus-stimulation at clinically relevant frequency (25 Hz) in six patients with Parkinson's disease. Pedunculopontine [corrected] nucleus stimulation changed the firing activity of almost every subthalamic nucleus cell (44/48) by decreasing the ongoing discharge in bursting subthalamic nucleus neurons (-62.1%) and exciting irregular (+63.2%) and tonic/regular discharges (+20.1%). These conflicting data challenge the definition of pedunculopontine [corrected] nucleus as a new target area for Parkinson's disease. If the modulation of subthalamic nucleus bursting units may corroborate the pedunculopontine [corrected] nucleus therapeutic role, the simultaneous excitatory influence during nonbursty patterns might interfere with a favorable outcome on motor signs. As a result, the implantation of pedunculopontine [corrected] nucleus alone may be hazardous while the association of subthalamic nucleus plus pedunculopontine [corrected] nucleus seems to be reasonable.

Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson's disease.

Gait disturbances and akinesia are extremely disabling in advanced Parkinson's disease. It has been suggested that modulation of the activity of the pedunculopontine nucleus (PPN) may be beneficial in the treatment of these symptoms. We report the clinical affects of deep brain stimulation (DBS) in the PPN and subthalamic nucleus (STN). Six patients with unsatisfactory pharmacological control of axial signs such as gait and postural stability underwent bilateral implantation of DBS electrodes in the STN and PPN. Clinical effects were evaluated 2-6 months after surgery in the OFF- and ON-medication state, with both STN and PPN stimulation ON or OFF, or with only one target being stimulated. Bilateral PPN-DBS at 25 Hz in OFF-medication produced an immediate 45% amelioration of the motor Unified Parkinson's Disease Rating Scale (UPDRS) subscale score, followed by a decline to give a final improvement of 32% in the score after 3-6 months. In contrast, bilateral STN-DBS at 130-185 Hz led to about 54% improvement. PPN-DBS was particularly effective on gait and postural items. In ON-medication state, the association of STN and PPN-DBS provided a significant further improvement when compared to the specific benefit mediated by the activation of either single target. Moreover, the combined DBS of both targets promoted a substantial amelioration in the performance of daily living activities. These findings indicate that, in patients with advanced Parkinson's disease, PPN-DBS associated with standard STN-DBS may be useful in improving gait and in optimizing the dopamine-mediated ON-state, particularly in those whose response to STN only DBS has deteriorated over time. This combination of targets may also prove useful in extra-pyramidal disorders, such as progressive supranuclear palsy, for which treatments are currently elusive.

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.

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.

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.

Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease.

The peduncolopontine nucleus modulates locomotor activity and dysfunction in this nucleus may be responsible for the gait and postural impairments seen in Parkinson's disease and other movement disorders. We report the first surgical exploration and implantation of deep brain stimulating electrodes of the peduncolopontine nucleus area in two Parkinson's disease patients to examine the safety and the potential benefit of chronic electrical stimulation at this site. Under local anesthesia, the peduncolopontine nucleus was approached from a coronal burr hole using a trajectory that was 78-80 degrees and 62-64 degrees on the coronal and sagittal planes. Microrecordings helped to identify neurons in peduncolopontine nucleus and the adjacent substantia nigra pars reticulata. Chronic deep brain stimulating electrodes were implanted within the peduncolopontine nucleus in a manner similar to that practiced with deep brain stimulating surgery at other targets. Peduncolopontine nucleus neurons were characterized by small and broad multiunits (230 muV, 2.5 ms, 14.6 Hz). Caudal to this area, neurons firing at higher frequency, approximately 70 Hz, characteristic of nigral neuronal discharges, were encountered, followed by 2 mm of cells similar to those recorded in the dorsal peduncolopontine nucleus area. After deep brain stimulating electrodes implantation, acute intraoperative stimulation (up to 3 V) was performed with two stimulation frequencies in each session. Stimulation at 80 Hz has little discernable effect. On the other hand, stimulation at 10 Hz fostered a subjective feeling of 'well-being' and a time-locked amelioration of the clinical scores. These findings demonstrate that the stereotactic approach of peduncolopontine nucleus is safe. The target may reliably be identified by microrecordings. Low-frequency stimulation may produce acute improvements in motor function.