GM1 Gangliosidosis, Late Infantile Onset Dystonia, and T2 Hypointensity in the Globus Pallidus and Substantia Nigra

BACKGROUND: GM1 gangliosidosis is a rare disease due to mutations in the GLB1 gene and autosomal recessive deficiency of b-galactosidase. There is considerable overlap between classical phenotypes and clinical and imaging findings, which are often difficult to interpret. PATIENT: The patient in this study had dysmorphism, dysostosis, progressive dystonia, and T2 hypointensity in the basal ganglia. Partially similar clinical and radiologic findings were described previously in two reports. CONCLUSIONS: T2 hypointensity in the globus pallidus should, in the appropriate clinical setting, lead to consideration of thediagnosis of GM1 gangliosidosis.

Dopamine reverses reward insensitivity in apathy following globus pallidus lesions.

Apathy is a complex, behavioural disorder associated with reduced spontaneous initiation of actions. Although present in mild forms in some healthy people, it is a pathological state in conditions such as Alzheimer's and Parkinson's disease where it can have profoundly devastating effects. Understanding the mechanisms underlying apathy is therefore of urgent concern but this has proven difficult because widespread brain changes in neurodegenerative diseases make interpretation difficult and there is no good animal model. Here we present a very rare case with profound apathy following bilateral, focal lesions of the basal ganglia, with globus pallidus regions that connect with orbitofrontal (OFC) and ventromedial prefrontal cortex (VMPFC) particularly affected. Using two measures of oculomotor decision-making we show that apathy in this individual was associated with reward insensitivity. However, reward sensitivity could be established partially with levodopa and more effectively with a dopamine receptor agonist. Concomitantly, there was an improvement in the patient's clinical state, with reduced apathy, greater motivation and increased social interactions. These findings provide a model system to study a key neuropsychiatric disorder. They demonstrate that reward insensitivity associated with basal ganglia dysfunction might be an important component of apathy that can be reversed by dopaminergic modulation.

Contribution du globus pallidus lors de la locomotion sous guidage visuel.

Les nombreuses études cliniques sur les maladies affectant les noyaux gris centraux (NGC) ont montré l’importance des déficits moteurs engendrés par un dysfonctionnement de ces structures. La locomotion est particulièrement affectée chez ces patients, ce qui suggère un rôle important des NGC dans le contrôle de celle-ci. En revanche, très peu d’études fondamentales ont enregistré l’activité des neurones des NGC durant la locomotion chez des modèles intacts. Le globus pallidus, en tant qu’une des principales structures de sortie des NGC, constitue une cible idéale pour étudier le signal transmis par les NGC au thalamus et au tronc cérébral. L’objectif de notre étude est de mieux comprendre la contribution que joue le segment externe du globus pallidus (GPe) dans le contrôle de la locomotion sous guidage visuel. Cette étude constitue le premier rapport d’enregistrements de l’activité des neurones du GPe lors de modifications volontaires de la marche sous guidage visuel. Notre hypothèse générale est que le GPe contribue au contrôle de la locomotion, et particulièrement lors des modifications de la marche. Nous avons enregistré l’activité des neurones du GPe de chats au repos, puis marchant sur un tapis et enjambant des obstacles. Nos résultats ont révélé que la plupart des cellules montraient peu de changements lors de la locomotion non-obstruée par rapport au repos. En revanche, la moitié des neurones enregistrés présentaient une modulation significative de leur décharge durant l’enjambement de l’obstacle. Nous avons observé une majorité de ces cellules qui diminuaient leur fréquence et un tiers de neurones qui l’augmentaient pendant le pas modifié, suggérant que le GPe exerce sur le mouvement un contrôle dépendant du contexte, permettant sélectivement l’augmentation ou la diminution de l’activité motrice. De plus, presque toutes les cellules déchargeaient durant la totalité de la phase de balancement du membre antérieur controlatéral, ce qui semble indiquer une contribution du GPe dans le timing et la durée de cette phase. Finalement, la moitié des neurones présentaient un changement réciproque entre la condition de lead et la condition de trail. Ce résultat suggère que le GPe participerait à la sélection d’action du membre lors des modifications de la marche. Nos résultats illustrent la complexité de l’activité du GPe lors de la locomotion sous guidage visuel et ils sont compatibles avec une contribution plus générale au mouvement que celle exercée par le cortex moteur.

Deep brain stimulation of the globus pallidus internal improves symptoms of chorea-acanthocytosis

Chorea-acanthocytosis is a rare autosomal recessive disorder. To date, treatment is only symptomatic and supportive. Results from the few reports of chorea-acanthocytosis patients treated with deep brain stimulation (DBS) have been inconsistent. We present case reports for two patients with chorea-acanthocytosis who received DBS treatment and compare the outcomes with results from the literature. Both patients showed the typical clinical features of chorea-acanthocytosis with motor symptoms resistant to medical treatment. Chorea was significantly improved following low-frequency DBS treatment in both patients. However, dystonia was only mildly improved. Four chorea-acanthocytosis patients treated with DBS treatment have been reported in the literature. One patient had improvement with low-frequency DBS stimulation, while another two had improvement with higher-frequency DBS. One patient, however, did not improve with either low-frequency or high-frequency DBS. Bilateral DBS to the GPi can improve chorea and dystonia in some patients with intractable chorea-acanthocytosis. However, selection criteria for the most promising candidates must be defined, and the long-term benefits evaluated in clinical studies.

Chronic stimulation of the globus pallidus internus for treatment of non-dYT1 generalized dystonia and choreoathetosis: 2-year follow up

OBJECT: The authors studied the long-term efficacy of deep brain stimulation (DBS) of the posteroventral lateral globus pallidus internus up to 2 years postoperatively in patients with primary non-DYT1 generalized dystonia or choreoathetosis. The results are briefly compared with those reported for DBS in DYT1 dystonia (Oppenheim dystonia), which is caused by the DYT1 gene. METHODS: Enrollment in this prospective expanded pilot study was limited to adult patients with severely disabling, medically refractory non-DYT1 generalized dystonia or choreoathetosis. Six consecutive patients underwent follow-up examinations at defined intervals of 3 months, 1 year, and 2 years postsurgery. There were five women and one man, and their mean age at surgery was 45.5 years. Formal assessments included both the Burke-Fahn-Marsden dystonia scale and the recently developed Unified Dystonia Rating Scale. Two patients had primary generalized non-DYT1 dystonia, and four suffered from choreoathetosis secondary to infantile cerebral palsy. Bilateral quadripolar DBS electrodes were implanted in all instances, except in one patient with markedly asymmetrical symptoms. There were no adverse events related to surgery. The Burke-Fahn-Marsden scores in the two patients with generalized dystonia improved by 78 and 71% at 3 months, by 82 and 69% at 1 year, and by 78 and 70% at 2 years postoperatively. This was paralleled by marked amelioration of disability scores. The mean improvement in Burke-Fahn-Marsden scores in patients with choreoathetosis was 12% at 3 months, 29% at 1 year, and 23% at 2 years postoperatively, which was not significant. Two of these patients thought that they had achieved marked improvement at 2 years postoperatively, although results of objective evaluations were less impressive. In these two patients there was a minor but stable improvement in disability scores. All patients had an improvement in pain scores at the 2-year follow-up review. Medication was tapered off in both patients with generalized dystonia and reduced in two of the patients with choreoathetosis. All stimulation-induced side effects were reversible on adjustment of the DBS settings. Energy consumption of the batteries was considerably higher than in patients with Parkinson disease. CONCLUSIONS: Chronic pallidal DBS is a safe and effective procedure in generalized non-DYT1 dystonia, and it may become the procedure of choice in patients with medically refractory dystonia. Postoperative improvement of choreoathetosis is more modest and varied, and subjective ratings of outcome may exceed objective evaluations.

Functional presynaptic HCN channels in the rat globus pallidus

Hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels are expressed postsynaptically in the rodent globus pallidus (GP), where they play several important roles in controlling GP neuronal activity. To further elucidate the role of HCN channels in the GP, immunocytochemical and electrophysiological approaches were used to test the hypothesis that HCN channels are also expressed presynaptically on the local axon collaterals of GP neurons. At the electron microscopic level, immunoperoxidase labelling for HCN1 and HCN2 was localized in GP somata and dendritic processes, myelinated and unmyelinated axons, and axon terminals. One population of labelled terminals formed symmetric synapses with somata and proximal dendrites and were immunoreactive for parvalbumin, consistent with the axon collaterals of GABAergic GP projection neurons. In addition, labelling for HCN2 and, to a lesser degree, HCN1 was observed in axon terminals that formed asymmetric synapses and were immunoreactive for the vesicular glutamate transporter 2. Immunogold labelling demonstrated that HCN1 and HCN2 were located predominantly at extrasynaptic sites along the plasma membrane of both types of terminal. To determine the function of presynaptic HCN channels in the GP, we performed whole-cell recordings from GP neurons in vitro. Bath application of the HCN channel blocker ZD7288 resulted in an increase in the frequency of mIPSCs but had no effect on their amplitude, implying that HCN channels tonically regulate the release of GABA. Their presence, and predicted role in modulating transmitter release, represents a hitherto unidentified mechanism whereby HCN channels influence the activity of GP neurons. © The Authors (2007).

Functional interconnectivity between the globus pallidus and the subthalamic nucleus in the mouse brain slice

In accordance with its central role in basal ganglia circuitry, changes in the rate of action potential firing and pattern of activity in the globus pallidus (GP)-subthalamic nucleus (STN) network are apparent in movement disorders. In this study we have developed a mouse brain slice preparation that maintains the functional connectivity between the GP and STN in order to assess its role in shaping and modulating bursting activity promoted by pharmacological manipulations. Fibre-tract tracing studies indicated that a parasagittal slice cut 20 deg to the midline best preserved connectivity between the GP and the STN. IPSCs and EPSCs elicited by electrical stimulation confirmed connectivity from GP to STN in 44/59 slices and from STN to GP in 22/33 slices, respectively. In control slices, 74/76 (97%) of STN cells fired tonically at a rate of 10.3 ± 1.3 Hz. This rate and pattern of single spiking activity was unaffected by bath application of the GABAA antagonist picrotoxin (50 μM, n = 9) or the glutamate receptor antagonist (6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX) 10 μM, n = 8). Bursting activity in STN neurones could be induced pharmacologically by application of NMDA alone (20 μM, 3/18 cells, 17%) but was more robust if NMDA was applied in conjunction with apamin (20-100 nM, 34/77 cells, 44%). Once again, neither picrotoxin (50 μM, n = 5) nor CNQX (10 μM, n = 5) had any effect on the frequency or pattern of the STN neurone activity while paired STN and GP recordings of tonic and bursting activity show no evidence of coherent activity. Thus, in a mouse brain slice preparation where functional GP-STN connectivity is preserved, no regenerative synaptically mediated activity indicative of a dynamic network is evident, either in the resting state or when neuronal bursting in both the GP and STN is generated by application of NMDA/apamin. This difference from the brain in Parkinson's disease may be attributed either to insufficient preservation of cortico-striato-pallidal or cortico-subthalamic circuitry, and/or an essential requirement for adaptive changes resulting from dopamine depletion for the expression of network activity within this tissue complex. © The Physiological Society 2005.

Independent neuronal oscillators of the rat globus pallidus

In vivo, neurons of the globus pallidus (GP) and subthalamic nucleus (STN) resonate independently around 70 Hz. However, on the loss of dopamine as in Parkinson's disease, there is a switch to a lower frequency of firing with increased bursting and synchronization of activity. In vitro, type A neurons of the GP, identified by the presence of Ih and rebound depolarizations, fire at frequencies (≤80 Hz) in response to glutamate pressure ejection, designed to mimic STN input. The profile of this frequency response was unaltered by bath application of the GABAA antagonist bicuculline (10 μM), indicating the lack of involvement of a local GABA neuronal network, while cross-correlations of neuronal pairs revealed uncorrelated activity or phase-locked activity with a variable phase delay, consistent with each GP neuron acting as an independent oscillator. This autonomy of firing appears to arise due to the presence of intrinsic voltage- and sodium-dependent subthreshold membrane oscillations. GABAA inhibitory postsynaptic potentials are able to disrupt this tonic activity while promoting a rebound depolarization and action potential firing. This rebound is able to reset the phase of the intrinsic oscillation and provides a mechanism for promoting coherent firing activity in ensembles of GP neurons that may ultimately lead to abnormal and pathological disorders of movement.

Functional characterization of GABAergic pallidopallidal and striatopallidal synapses in the rat globus pallidus in vitro

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. Driven by intrinsic mechanisms and excitatory glutamatergic inputs from the subthalamic nucleus, GP neurons receive GABAergic inhibitory input from the striatum (Str-GP) and from local collaterals of neighbouring pallidal neurons (GP-GP). Here we provide electrophysiological evidence for functional differences between these two inhibitory inputs. The basic synaptic characteristics of GP-GP and Str-GP GABAergic synapses were studied using whole-cell recordings with paired-pulse and train stimulation protocols and variance-mean (VM) analysis. We found (i) IPSC kinetics are consistent with local collaterals innervating the soma and proximal dendrites of GP neurons whereas striatal inputs innervate more distal regions. (ii) Compared to GP-GP synapses Str-GP synapses have a greater paired-pulse ratio, indicative of a lower probability of release. This was confirmed using VM analysis. (iii) In response to 20 and 50 Hz train stimulation, GP-GP synapses are weakly facilitatory in 1 mm external calcium and depressant in 2.4 mm calcium. This is in contrast to Str-GP synapses which display facilitation under both conditions. This is the first quantitative study comparing the properties of GP-GP and Str-GP synapses. The results are consistent with the differential location of these inhibitory synapses and subtle differences in their release probability which underpin stable GP-GP responses and robust short-term facilitation of Str-GP responses. These fundamental differences may provide the physiological basis for functional specialization.

Effect of dopamine on synchronous neuronal oscillations in the globus pallidus-subthalamic nucleus network

Changes in the pattern of activity of neurones within the basal ganglia are relevant in the pathophysiology and symptoms of Parkinson’s disease. The globus pallidus (GP) – subthalamic nucleus (STN) network has been proposed to form a pacemaker driving regenerative synchronous bursting activity. In order to test whether this activity can be sustained in vitro a 20o parasagittal slice of mouse midbrain was developed which preserved functional connectivity between the STN and GP. Mouse STN and GP cells were characterised electrophysiologically by the presence or absence of a voltage sag in response to hyperpolarising current steps indicative of Ih and the presence of rebound depolarisations. The presence of evoked and spontaneous post-synaptic GABA and glutamatergic currents indicated functional connectivity between the STN and GP. In control slices, STN cells fired action potentials at a regular rate, activity which was unaffected by bath application of the GABAA receptor antagonist picrotoxin (50 μM) or the glutamate receptor antagonist CNQX (10 μM). Paired extracellular recordings of STN cells showed uncorrelated firing. Oscillatory burst activity was induced pharmacologically using the glutamate receptor agonist, NMDA (20 μM), in combination with the potassium channel blocker apamin (50 -100 nM). The burst activity was unaffected by bath application of picrotoxin or CNQX while paired STN recordings showed uncorrelated activity indicating that the activity is not produced by the neuronal network. Thus, no regenerative activity is evident in this mouse brain preparation, either in control slices or when bursting is pharmacologically induced, suggesting the requirement of other afferent inputs that are not present in the slice. Using single-unit extracellular recording, dopamine (30 μM) produced an excitation of STN cells. This excitation was independent of synaptic transmission and was mimicked by both the Dl-like receptor agonist SKF38393 (10 μM) and the D2-like receptor agonist quinpirole (10 μM). However, the excitation was partially reduced by the D1-like antagonist SCH23390 (2 μM) but not by the D2-like antagonists sulpiride (10 μM) and eticlopride (10 μM). Using whole-recordings, dopamine was shown to induce membrane depolarisation. This depolarisation was caused either by a D1-like receptor mediated increase in a conductance which reversed at -34 mV, consistent with a non-specific cation conductance, or a D2-like receptor mediated decrease in conductance which reversed around -100 mV, consistent with a potassium conductance. Bath application of dopamine altered the pattern of the burst-firing produced by NMDA an apamin towards a more regular pattern. This effect was associated with a decrease in amplitude and ll1crease in frequency of TTX-resistant plateau potentials which underlie the burst activity.

Neuropathology of Basal Ganglia and its role in the Parkinsonian syndromes with special reference to the Globus pallidus

The globus pallidus, together with the striatum (caudate nucleus and putamen), substantia nigra, nucleus accumbens, and subthalamic nucleus constitute the basal ganglia, a group of nuclei which act as a single functional unit. The basal ganglia have extensive connections to the cerebral cortex and thalamus and exert control over a variety of functions including voluntary motor control, procedural learning, and motivation. The action of the globus pallidus is primarily inhibitory and balances the excitatory influence of other areas of the brain such as the cerebral cortex and cerebellum. Neuropathological changes affecting the basal ganglia play a significant role in the clinical signs and symptoms observed in the ‘parkinsonian syndromes’ viz., Parkinson’s disease (PD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and corticobasal degeneration (CBD). There is increasing evidence that different regions of the basal ganglia are differentially affected in these disorders. Hence, in all parkinsonian disorders and especially PD, there is significant pathology affecting the substantia nigra and its dopamine projection to the striatum. However, in PSP and MSA, the globus pallidus is also frequently affected while in DLB and CBD, whereas the caudate nucleus and/or putamen are affected, the globus pallidus is often spared. This chapter reviews the functional pathways of the basal ganglia, with special reference to the globus pallidus, and the role that differential pathology in these regions may play in the movement disorders characteristic of the parkinsonian syndromes.

Redefining functional models of basal ganglia organisation: Role for the posteroventral pallidum in linguistic processing?

Traditionally the basal ganglia have been implicated in motor behavior, as they are involved in both the execution of automatic actions and the modification of ongoing actions in novel contexts. Corresponding to cognition, the role of the basal ganglia has not been defined as explicitly. Relative to linguistic processes, contemporary theories of subcortical participation in language have endorsed a role for the globus pallidus internus (GPi) in the control of lexical-semantic operations. However, attempts to empirically validate these postulates have been largely limited to neuropsychological investigations of verbal fluency abilities subsequent to pallidotomy. We evaluated the impact of bilateral posteroventral pallidotomy (BPVP) on language function across a range of general and high-level linguistic abilities, and validated/extended working theories of pallidal participation in language. Comprehensive linguistic profiles were compiled up to 1 month before and 3 months after BPVP in 6 subjects with Parkinson's disease (PD). Commensurate linguistic profiles were also gathered over a 3-month period for a nonsurgical control cohort of 16 subjects with PD and a group of 16 non-neurologically impaired controls (NC). Nonparametric between-groups comparisons were conducted and reliable change indices calculated, relative to baseline/3-month follow-up difference scores. Group-wise statistical comparisons between the three groups failed to reveal significant postoperative changes in language performance. Case-by-case data analysis relative to clinically consequential change indices revealed reliable alterations in performance across several language variables as a consequence of BPVP. These findings lend support to models of subcortical participation in language, which promote a role for the GPi in lexical-semantic manipulation mechanisms. Concomitant improvements and decrements in postoperative performance were interpreted within the context of additive and subtractive postlesional effects. Relative to parkinsonian cohorts, clinically reliable versus statistically significant changes on a case by case basis may provide the most accurate method of characterizing the way in which pathophysiologically divergent basal ganglia linguistic circuits respond to BPVP.

Sequence heterogeneity in Parkinsonian speech

Parkinson's disease (PD) is a neurodegenerative movement disorder primarily due to basal ganglia dysfunction. While much research has been conducted on Parkinsonian deficits in the traditional arena of musculoskeletal limb movement, research in other functional motor tasks is lacking. The present study examined articulation in PD with increasingly complex sequences of articulatory movement. Of interest was whether dysfunction would affect articulation in the same manner as in limb-movement impairment. In particular, since very Similar (homogeneous) articulatory sequences (the tongue twister effect) are more difficult for healthy individuals to achieve than dissimilar (heterogeneous) gestures, while the reverse may apply for skeletal movements in PD, we asked which factor would dominate when PD patients articulated various grades of artificial tongue twisters: the influence of disease or a possible difference between the two motor systems. Execution was especially impaired when articulation involved a sequence of motor program heterogeneous in terms of place of articulation. The results are suggestive of a hypokinesic tendency in complex sequential articulatory movement as in limb movement. It appears that PD patients do show abnormalities in articulatory movement which are similar to those of the musculoskeletal system. The present study suggests that an underlying disease effect modulates movement impairment across different functional motor systems. (C) 1998 Academic Press.

Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy

The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 mu l) and AP7 (10 or 20 nmol/0.5 mu l), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 20 or 30 nmol/0.5 mu l). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity. (C) 2010 Published by Elsevier B.V.

Impairments of movement kinematics in patients with Huntington's disease: A comparison with and without a concurrent task

This study aimed to quantify the efficiency and smoothness of voluntary movement in Huntington's disease (HD) by the use of a graphics tablet that permits analysis of movement profiles. In particular, we aimed to ascertain whether a concurrent task (digit span) would affect the kinematics of goal-directed movements. Twelve patients with HD and their matched controls performed 12 vertical zig-zag movements, with both left and right hands (with and without the concurrent task), to large or small circular targets over long or short extents. The concurrent task was associated with shorter movement times and reduced right-hand superiority. Patients with HD were overall slower, especially with long strokes, and had similar peak velocities for both small and large targets, so that controls could better accommodate differences in target size. Patients with HD spent more time decelerating, especially with small targets, whereas controls allocated more nearly equal proportions of time to the acceleration and deceleration phases of movement, especially with large targets. Short strokes were generally less force inefficient than were long strokes, especially so for either hand in either group in the absence of the concurrent task, and for the right hand in its presence. With the concurrent task, however, the left hand's behavior changed differentially for the two groups; for patients with HD, it became more force efficient with short strokes and even less efficient with long strokes, whereas for controls, it became more efficient with long strokes. Controls may be able to divert attention away from the inferior left hand, increasing its automaticity, whereas patients with HD, because of disease, may be forced to engage even further online visual control under the demands of a concurrent task. Patients with HD may perhaps become increasingly reliant on terminal visual guidance, which indicates an impairment in constructing and refining an internal representation of the movement necessary for its. effective execution. Basal ganglia dysfunction may impair the ability to use internally generated cues to guide movement.