Pedunculopontine nucleus deep brain stimulation in Parkinson’s disease

Postural instability and gait difficulty (PIGD) are commonly observed in advanced Parkinson’s disease. The neuronal mechanism of PIGD is not fully understood. Dysfunction of the pedunculopontine nucleus (PPN) might be a possible cause of these symptoms. The autopsy studies of subjects with PIGD revealed a neurodegenerative process involving mainly PPN cholinergic neurons. The PPN participates in the locomotion processes by initiation, modulation and execution of stereotyped patterns of movement. The standard neurosurgical treatment of PD is subthalamic deep brain stimulation (STN DBS). Clinical results revealed low efficiency of STN DBS on PIGD. Preliminary results of simultaneous PPN and STN DBS are very promising. Only a few reports have been published until now; a significant improvement of PIGD was observed in both ON and OFF L-dopa states.     

Pedunculopontine nucleus microelectrode recordings in movement disorder patients

The pedunculopontine nucleus (PPN) lies within the brainstem reticular formation and is involved in the motor control of gait and posture. Interest has focused recently on the PPN as a target for implantation of chronic deep brain stimulation (DBS) electrodes for Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) therapy. The aim of this study was to examine the neurophysiology of the human PPN region and to identify neurophysiological landmarks that may aid the proper placement of DBS electrodes in the nucleus for the treatment of PD and PSP. Neuronal firing and local field potentials were recorded simultaneously from two independently driven microelectrodes during stereotactic neurosurgery for implantation of a unilateral DBS electrode in the PPN in five PD patients and two PSP patients. Within the PPN region, the majority (57%) of the neurons fired randomly while about 21% of the neurons exhibited ‘bursty’ firing. In addition, 21% of the neurons had a long action potential duration and significantly lower firing rate suggesting they were cholinergic neurons. A change in firing rate produced by passive and/or active contralateral limb movement was observed in 38% of the neurons that were tested in the PPN region. Interestingly, oscillatory local field potential activity in the beta frequency range (∼25 Hz) was also observed in the PPN region. These electrophysiological characteristics of the PPN region provide further support for the proposed role of this region in motor control. It remains to be seen to what extent the physiological characteristics of the neurons and the stimulation-evoked effects will permit reliable identification of PPN and determination of the optimal target for DBS therapy.     

电刺激大鼠黑质网状部对脚桥核神经元自发放电的影响

目的:观察电刺激大鼠黑质网状部(substantia nigra pars reticulata,SNr)对脚桥核(pedunculopontine nucleus,PPN)神经元自发放电活动的影响,进一步探讨脑内电刺激治疗帕金森病(Parkinson's disease,PD)的机制.方法:应用细胞外记录方法观察不同...     

Cerebellar nuclei are activated by high-frequency stimulation of the subthalamic nucleus

The cerebellum, primarily considered a pure motor structure, is increasingly considered to play a role in behaviour and cognition. In a similar manner, there is increasing evidence that the basal ganglia are involved in non-motor processes. Recently a direct connection between the cerebellum and the basal ganglia has been shown to exist. High-frequency stimulation (HFS) of the subthalamic nucleus (STN) has become an accepted treatment in advanced Parkinson's disease (PD). We performed HFS of the STN in rats to evaluate the neuronal activation in the deep cerebellar nuclei (DCbN) using c-Fos immunohistochemistry. We found an increased c-Fos expression in the DCbN. Previously, we have shown that STN HFS in rats leads to decreased impulsive behaviour and our findings now suggest a link with increased DCbN activity. This is in line with our previous work showing that decreased DCbN activity is accompanied by disruptive behaviour. We suggest that the DCbN play a role in the selection of relevant information on which a behavioural response is based. The connection between the cerebellum and the basal ganglia may imply a role for the cerebellum in behavioural aspects of disorders of the basal ganglia.     

Glutamate and GABA modulate dopamine in the pedunculopontine tegmental nucleus

The pedunculopontine tegmental nucleus (PPTg) has an important anatomical position connecting basal ganglia and limbic systems with motor execution structures in the pons and spinal cord. It receives glutamatergic and GABAergic input and has additional reciprocal connections with mesencephalic dopaminergic neurons, suggesting that the PPTg plays a key role in frontostriatal information processing. In vivo microdialysis in freely moving rats, in combination with behavioral analysis, was used in this study to investigate whether the dopaminergic input can be modulated at the level of the PPTg via N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) or GABA_B receptors. Stimulation of the GABA_B receptor decreased dopamine release in the PPTg while that of the AMPA and NMDA receptors increased it. A time-related comparison of the effects of NMDA (0.75 and 1 mM) and AMPA (50 and 25 μM) revealed a more long-lasting effect after AMPA stimulation than after NMDA. However, only the infusion of the GABA_B receptor agonist baclofen (100 and 200 μM) stimulated stereotyped behavior (e.g. sniffing, digging or head movements) and contralateral circling. This study clearly demonstrates that GABAergic as well as glutamatergic terminals in the PPTg are critically involved in the modulation of the dopamine system. Moreover, a decrease in PPTg dopamine via GABA_B receptor stimulation seems to be behaviorally relevant. Electronic Publication     

Resonant antidromic cortical circuit activation as a consequence of high-frequency subthalamic deep-brain stimulation

Deep brain stimulation (DBS) is an effective treatment of Parkinson's disease (PD) for many patients. The most effective stimulation consists of high-frequency biphasic stimulation pulses around 130 Hz delivered between two active sites of an implanted depth electrode to the subthalamic nucleus (STN-DBS). Multiple studies have shown that a key effect of STN-DBS that correlates well with clinical outcome is the reduction of synchronous and oscillatory activity in cortical and basal ganglia networks. We hypothesized that antidromic cortical activation may provide an underlying mechanism responsible for this effect, because stimulation is usually performed in proximity to cortical efferent pathways. We show with intracellular cortical recordings in rats that STN-DBS did in fact lead to antidromic spiking of deep layer cortical neurons. Furthermore, antidromic spikes triggered a dampened oscillation of local field potentials in cortex with a resonant frequency around 120 Hz. The amplitude of antidromic activation was significantly correlated with an observed suppression of slow wave and beta band activity during STN-DBS. These findings were seen in ketamine-xylazine or isoflurane anesthesia in both normal and 6-hydroxydopamine (6-OHDA)-lesioned rats. Thus antidromic resonant activation of cortical microcircuits may make an important contribution toward counteracting the overly synchronous and oscillatory activity characteristic of cortical activity in PD.     

Functional neuroimaging of the 6-OHDA lesion rat model of Parkinson's disease

We characterized the unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rat, a well-known acute model of Parkinson's disease (PD), with [(18)F]-fluoro-2-deoxy-d-glucose (FDG) small-animal positron emission tomography (PET), which we compared with a drug-induced rotation behavioral test. In the 6-OHDA model, significant glucose hypometabolism was present in the primary motor cortex, substantia nigra, and pedunculopontine tegmental nucleus on the ipsilateral side. In contrast, neuronal activations were observed in the primary somatosensory cortex and ventral caudate-putamen area after lesioning. Correlation analysis revealed a significant relationship between the behavioral results and the degree of glucose metabolism impairment in the primary motor cortex, substantia nigra, and pedunculopontine tegmental nucleus. In addition, the pedunculopontine tegmental nucleus correlated significantly with the primary somatosensory cortex, the ventral caudate-putamen, the substantia nigra, and the primary motor cortex. Furthermore, the primary motor cortex also showed significant correlations with the substantia nigra. In conclusion, In vivo cerebral mapping of the 6-OHDA-lesioned rats using [(18)F]-FDG PET showed correspondence at the functional levels to the cortico-subcortical network impairment observed in PD patients.     

Deep brain stimulation of the posterior hypothalamic nucleus reverses akinesia in bilaterally 6-hydroxydopamine—lesioned rats

Deep brain stimulation (DBS) of the basal ganglia motor circuitry is a highly effective treatment for the debilitating motor symptoms of Parkinson's disease (PD). However, recent findings have indicated promising potential for PD therapy with DBS in brain structures outside the basal ganglia. For example, high frequency stimulation of the posterior hypothalamic nucleus (PH) can reverse haloperidol-induced akinesia in rats [Jackson J, Young CK, Hu B, Bland BH (2008) High frequency stimulation of the posterior hypothalamic nucleus restores movement and reinstates hippocampal-striatal theta coherence following haloperidol-induced catalepsy. Exp Neurol 213:210–219]. In the current study, we used the bilateral 6-hydroxydopamine lesion model of Parkinsonian akinesia in male Long-Evans rats to further explore the efficacy of PH DBS. The application of PH DBS in lesioned animals reversed akinesia in an active avoidance paradigm with increased latency compared to pre-lesion performance. The dramatic reversal of akinesia in two models of rodent Parkinsonism by PH DBS warrants further exploration of its therapeutic potential.     

Divergent motor projections from the pedunculopontine nucleus are differentially regulated in Parkinsonism

The pedunculopontine nucleus (PPN) is composed of neurons with different connectivity patterns that express different neurochemical markers, display distinct firing characteristics and are topographically organized in functional domains across its rostro-caudal axis. Previous reports have shown that the caudal region of the PPN is interconnected with motor regions of both the basal ganglia and brainstem/medulla. The co-distribution of ascending and descending motor outputs raises the question as to whether the PPN provides a coordinated or differential modulation of its targets in the basal ganglia and the medulla. To address this, we retrogradely labeled neurons in the two main PPN pathways involved in motor control and determined whether they project to one or both structures, their neurochemical phenotype, and their activity in normal and dopamine depleted rats, as indicated by Egr-1 expression. We show that ascending and descending motor pathways from the PPN arise largely from separate neurons that intermingle in the same region of the PPN, but have a distinct neurochemical composition and are differentially regulated in the Parkinsonian state. Thus, neurons projecting to the subthalamic nucleus consist of cholinergic, calbindin- and calretinin-expressing neurons, and Egr-1 is upregulated following a 6-hydroxydopamine lesion. In contrast, a larger proportion of neurons projecting to the gigantocellular nucleus are cholinergic, none express calbindin and the expression of Egr-1 is not changed by the dopamine lesion. Our results suggest that ascending and descending motor connections of the PPN are largely mediated by different sets of neurons and there are cell type-specific changes in Parkinsonian rats.     

MC4R expression in pedunculopontine nucleus involved in the modulation of midbrain dopamine system

Background and objective: Separate studies have implicated the pedunculopontine tegmental nucleus (PPTg) in processing aversive stimuli to dopamine systems, and melanocortin-4 receptor (MC4R) are broadly expressed by the neurons in the PPTg, but the exact neurosubstrate underlying the regulation of dopamine systems by the central melanocortin pathway is poorly understood. Methods: In this study, the PPTg of 6 adult mice expressing green fluorescent protein (GFP) under the control of the MC4R promoter was detected by fluorescence immunohistochemistry. Results: A large number of GFP-positive neurons in the dissipated parts of PPTg (dpPPTg) were found, and approximately 50% of MC4R-GFP- positive neurons in the dpPPTg coexpressed tyrosine hydroxylase, a marker of dopamine neurons, indicating that they were dopaminergic. Conclusions: Our findings support the hypothesis that MC4R signaling in the dpPPTg may involve in the modulation of midbrain dopamine systems.     

Nucleus tegmenti pedunculopontinus: Efferent connections with special reference to the basal ganglia,studied in the rat by anterograde and retrograde transport of horseradish peroxidase

The efferent connections of the brain stem nucleus tegmenti pedunculopontinus were studied in the rat using the techniques of anterograde and retrograde transport of the enzyme horseradish peroxidase, laying particular emphasis on that part of pedunculopontinus which receives direct descending projections from the basal ganglia and related nuclei. In a preliminary series of experiments horseradish peroxidase was injected into either the entopeduncular nucleus or the subthalamic nucleus and, following anterograde transport of enzyme, terminal labelling was identified in nucleus tegmenti pedunculopontinus, surrounding the brachium conjunctivum in the caudal mesencephalon.In a subsequent series of experiments, horseradish peroxidase was injected into that region of nucleus tegmenti pedunculopontinus which receives entopeduncular and subthalamic efferents and its efferent projections were studied by anterograde transport of the enzyme. The results indicate that nucleus tegmenti pedunculopontinus gives rise to widely distributed efferent projections which terminate rostrally in mesencephalic, diencephalic and telencephalic structures and caudally in the pontine tegmentum. In the mesencephalon, terminal labelling was found in the pars compacta of the ipsilateral substantia nigra and sometimes in the adjoining ventral tegmental area. Labelling was also found in the ipsilateral half of the periaqueductal grey. In the diencephalon terminal labelling occurred bilaterally in the subthalamic nucleus and ipsilaterally in the intralaminar nuclei of the thalamus. Further rostrally, terminal labelling was particularly evident in the ipsilateral pallidal complex, especially in the caudal two-thirds of the entopeduncular nucleus and the ventral half of the caudal third of the globus pallidus. Caudal to pedunculopontine injection sites dense labelling was observed in the reticular formation of the pontine tegmentum.In a final series of experiments, confirmation of apparent pedunculopontine efferent projections was sought using the retrograde transport of horseradish peroxidase. Enzyme was injected into sites possibly receiving pedunculopontine efferents and the peribrachial area of the brain stem was examined for retrograde cell labelling. In this way, pedunculopontine projections were confirmed to the globus pallidus, entopeduncular nucleus, subthalamic nucleus, substantia nigra, parafascicular nucleus and pontine reticular formation. Injections into the globus pallidus or subthalamic nucleus gave rise to retrograde cell labelling bilaterally in pedunculopontinus. In addition, retrograde transport studies alone demonstrated projections from pedunculopontinus to the cerebral cortex and to the spinal cord.It is concluded that the nucleus tegmenti pedunculopontinus has reciprocal relationships with parts of the basal ganglia and some functionally related nuclei (in particular, the pallidal complex, subthalamic nucleus and substantia nigra). These connections support the view that nucleus tegmenti pedunculopontinus is likely to be involved in the subcortical regulation and mediation of basal ganglia influences upon the lower motor system. This suggests a potential role for pedunculopontine afferent and efferent pathways in the pathophysiology of basal ganglia related disorders of movement.     

Acetylcholinesterase activity in the brain of dystonia musculorum (Dst(dt-J)) mutant mice

The dystonia musculorum (Dst^dt-J) mutant mouse suffers from severe motor coordination deficits, characterized, among various symptoms, by a spastic ataxia and dystonic movements, indicating central defects in motor structures in addition to dystrophy of peripheral sensory tracts and partial degeneration of spinocerebellar tracts. Neurochemical alterations, notably in dopaminergic and noradrenergic systems, were previously observed in basal ganglia and cerebellum. A quantitative histochemical cartography of brain acetylcholinesterase activity in Dst^dt-J mutants, in comparison with controls, revealed increases in the neostriatum, the habenula-interpeduncular pathway, the cholinergic pedunculopontine nucleus and its target structures, the thalamus, major regions of the basal ganglia, such as substantia nigra, ventral tegmental area, globus pallidum, and subthalamic nucleus, as well as in associated extrapyramidal regions, such as red nucleus, brainstem reticular formation, and superior colliculus. These acetylcholinesterase changes may play a role in motor deficits, particularly the dystonic symptomatology observed in the mutation.     

Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease

Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia.     

Projections of striatopallidal structures to the pedunculopontine nucleus of the tegmentum of the midbrain in dogs

A method based on retrograde axonal transport of horseradish peroxidase was used to study the striatopallidal afferent projections of the pendunculopontine nucleus of the midbrain (PPN) in dogs. The major source of these projections was found to be the pallidum, as both the compact and diffuse zones of this nucleus received projections from all of its structures: the entopeduncular nucleus, the globus pallidus, and the ventral pallidum. The striatal complex, specifically the nucleus accumbens, showed only occasional labeled neurons, projecting exclusively to the compact part of the PPN. Since the distribution of projection fibers arising from the functionally diverse territories of the striatopallidum and directed to individual structural subdivisions of the PPN showed no topical elements, identification of functionally specific (motor and limbic) areas of the PPN was not possible on the basis of the present analysis. __________ Translated from Morfologiya, Vol. 130, No. 6, pp. 30–34, November–December, 2006.     

Structural basis of the involvement of the striopallidum and pedunculopontine tegmental nucleus in the organization of adaptive behavior

Retrograde axonal transport was used to study the organizational characteristics of the afferent and efferent projection systems of individual substructures of the pedunculopontine tegmental nucleus and the functionally diverse (motor, limbic) areas of structures in the striopallidum. The structural bases of the conduction of functionally diverse information and its integration in the basal ganglia system and tegmental area were evaluated. The morphological data obtained here aid our understanding of the morphofunctional bases of the interaction of these structures and their involvement in adaptive behavior. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 7, pp. 777–787, July, 2006.     

Induction of immediate early gene expression by high-frequency stimulation of the subthalamic nucleus in rats

Deep brain stimulation is associated with delayed improvement of parkinsonian symptoms, such as hypokinesia with subthalamic nucleus stimulation, or dystonia with globus pallidus internus stimulation. The latency observed is better explained by molecular alterations than immediate electrophysiological processes, and clinical improvement may involve adaptive gene expression. Here, we have studied immediate early gene expression as fast molecular response to subthalamic nucleus stimulation. Bipolar electrodes were implanted bilaterally into the subthalamic nucleus of anesthetized male Wistar rats. High-frequency stimulation (130 Hz or 80 Hz, 60 micros, 300 microA) or low-frequency stimulation (5 Hz, 60 micros, 300 microA) was performed with the right electrode for 15, 60, 120, and 240 min whereas the silent left electrode served as negative control. Brains were fixed by transcardial perfusion and frozen sections were stained with polyclonal antibodies directed against three immediate early gene-encoded proteins, c-Fos, c-Jun, and Krox-24 (NGFI-A, Egr-1, Zif268, Tis8, Zenk). After 120 and 240 h, c-Fos immunoreactivity was strongly upregulated in subthalamic nucleus neurons on the stimulated site. In contrast, no c-Fos immunoreactivity was detected on the non-stimulated site except for single positive cells located in close proximity to the electrode tracks. Furthermore, c-Fos immunoreactivity was induced in subthalamic nucleus projection areas, such as primary and secondary motor cortex, primary somatosensory and insular cortex, lateral and medial globus pallidus, suprageniculate thalamic nucleus, pontine nuclei, medial geniculate nucleus, and substantia nigra. Similarly, c-Jun and Krox-24 were induced at the site of stimulation and in projection areas following high-frequency subthalamic nucleus stimulation. Whereas high frequency stimulation with 80 Hz was similarly effective none of the three immediate early gene-encoded proteins was induced with low-frequency stimulation (5 Hz) for 4 h. This is in accordance with the therapeutic effects of deep brain stimulation which are only elicited with high frequency stimulation. Our data provide evidence that immediate early gene expression in the subthalamic nucleus is rapidly and substantially induced by high-frequency stimulation. The induction of immediate early genes in projection sites suggests ipsilateral transsynaptic modulation of neuronal activity.     

Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease

Multiple studies have shown bilateral improvement in motor symptoms in Parkinson disease (PD) following unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) and internal segment of the globus pallidus, yet the mechanism(s) underlying this phenomenon are poorly understood. We hypothesized that STN neuronal activity is altered by contralateral STN DBS. This hypothesis was tested intraoperatively in humans with advanced PD using microelectrode recordings of the STN during contralateral STN DBS. We demonstrate alterations in the discharge pattern of STN neurons in response to contralateral STN DBS including short latency, temporally precise, stimulation frequency-independent responses consistent with antidromic activation. Furthermore, the total discharge frequency during contralateral high frequency stimulation (160 Hz) was greater than during low frequency stimulation (30 Hz) and the resting state. These findings demonstrate complex responses to DBS and imply that output activation throughout the basal ganglia-thalamic-cortical network rather than local inhibition is a therapeutic mechanism of DBS.     

A Network Analysis of 15O-H2O PET Reveals Deep Brain Stimulation Effects on Brain Network of Parkinson's Disease

Purpose

As Parkinson''s disease (PD) can be considered a network abnormality, the effects of deep brain stimulation (DBS) need to be investigated in the aspect of networks. This study aimed to examine how DBS of the bilateral subthalamic nucleus (STN) affects the motor networks of patients with idiopathic PD during motor performance and to show the feasibility of the network analysis using cross-sectional positron emission tomography (PET) images in DBS studies.

Materials and Methods

We obtained [¹⁵O]H₂O PET images from ten patients with PD during a sequential finger-to-thumb opposition task and during the resting state, with DBS-On and DBS-Off at STN. To identify the alteration of motor networks in PD and their changes due to STN-DBS, we applied independent component analysis (ICA) to all the cross-sectional PET images. We analysed the strength of each component according to DBS effects, task effects and interaction effects.

Results

ICA blindly decomposed components of functionally associated distributed clusters, which were comparable to the results of univariate statistical parametric mapping. ICA further revealed that STN-DBS modifies usage-strengths of components corresponding to the basal ganglia-thalamo-cortical circuits in PD patients by increasing the hypoactive basal ganglia and by suppressing the hyperactive cortical motor areas, ventrolateral thalamus and cerebellum.

Conclusion

Our results suggest that STN-DBS may affect not only the abnormal local activity, but also alter brain networks in patients with PD. This study also demonstrated the usefulness of ICA for cross-sectional PET data to reveal network modifications due to DBS, which was not observable using the subtraction method.     

Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction

The present study is designed to elucidate how basal ganglia afferents from the substantia nigra pars reticulata (SNr) to the mesopontine tegmental area of the brainstem contribute to gait control and muscle-tone regulation. We used unanesthetized and acutely decerebrated cats (n=27) in which the striatum, thalamus and cerebral cortex were removed but the SNr was preserved. Repetitive stimulation (50 Hz, 10-60 microA, for 5-20 s) applied to a mesencephalic locomotor region (MLR), which corresponded to the cuneiform nucleus, and adjacent areas, evoked locomotor movements. On the other hand, stimulation of a muscle-tone inhibitory region in the pedunculopontine tegmental nucleus (PPN) suppressed postural muscle tone. An injection of either glutamatergic agonists (N-methyl-D-aspartic acid and kainic acid) or GABA antagonists (bicuculline and picrotoxin) into the MLR and PPN also induced locomotion and muscle-tone suppression, respectively. Repetitive electrical stimuli (50-100 Hz, 20-60 microA for 5-20 s) delivered to the SNr alone did not alter muscular activity. However stimulating the lateral part of the SNr attenuated and blocked PPN-induced muscle-tone suppression. Moreover, weaker stimulation of the medial part of the SNr reduced the number of step cycles and disturbed the rhythmic alternation of limb movements of MLR-induced locomotion. The onset of locomotion was delayed as the stimulus intensity was increased. At a higher strength SNr stimulation abolished the locomotion. An injection of bicuculline into either the PPN or the MLR diminished the SNr effects noted above. These results suggest that locomotion and postural muscle tone are subject to modulation by GABAergic nigrotegmental projections which have a partial functional topography: a lateral and medial SNr, for regulation of postural muscle tone and locomotion, respectively. We conclude that disorders of the basal ganglia may include dysfunction of the nigrotegmental (basal ganglia-brainstem) systems, which consequently leads to the production of abnormal muscle tone and gait disturbance.     

Brain tissue energy dependence of CaM kinase IV cascade activation during hypoxia in the cerebral cortex of newborn piglets

Using an anti-cue keypress task, we examined executive control in Parkinson's disease (PD) patients treated with deep brain stimulation (DBS) of the subthalamic nucleus (STN) and dopaminergic medication. Across sessions, we varied stimulation (on, off) and dopaminergic medication (on, off). Reaction time (RT) results of the PD patients and their age-matched controls showed a consistent pattern of RT costs and benefits generated by anti-cues with short and long preparation intervals, respectively. This pattern was evident in all sessions, except when DBS stimulation and medication were off. In this condition PD patients showed no RT benefits. These findings are discussed in terms of an executive control process that suppresses the automatic but inappropriate response activation generated by anti-cues. In PD this mechanism is severely compromised but it can be remediated by dopaminergic medication and DBS, suggesting an essential role of the basal ganglia in the selection and suppression of competing responses.