Search

Objectives Deep brain stimulation (DBS) is the surgical procedure for patients with advanced Parkinson’s disease. Globus pallidus internus (GPi) and subthalamic nucleus (STN) are the most targeted locations for the procedure. To investigate the variable efficiencies for the two different locations, we conducted a meta-analysis to compare both stimulation sites. Materials and methods A systematic search was performed in PubMed, Embase, and the Cochrane Library databases. Randomized controlled trials comparing the efficacies of GPi and STN DBS were included. Clinical outcomes of motor function, nonmotor function, and quality of life (QOL) were collected for the meta-analysis. Results Ten eligible trials with 1,034 patients were included in the analysis. Unified Parkinson’s disease rating scale III (UPDRS-III) scores were collected at 6, 12, and 24 months postsurgery separately to assess the motor function of the patients. A statistically significant effect in favor of the GPi DBS was obtained in the off-medication/on-stimulation phase of UPDRS-III at 12 months (mean difference [MD] =6.87, 95% confidence interval [95% CI]: 3.00–10.74, P=0.57, I2=0%). However, GPi DBS showed an opposite result at 24 months (MD =−2.46, 95% CI: −4.91 to −0.02, P=0.05, I2=0%). In the on-medication/on-stimulation phase, GPi DBS obtained a worse outcome compared with STN DBS (MD =−2.90, 95% CI: −5.71 to −0.09, P=0.05, I2=0%). Compared with STN DBS, increased dosage of levodopa equivalent doses was needed in GPi DBS (standardized MD =0.60, 95% CI: 0.46–0.74, P

Purpose: The aim of this study is to assess the diagnostic value of diffusion tensor magnetic resonance imaging (MRI) in the detection of brain microstructural changes in patients having migraine without aura. Material and methods: Our prospective study included 33 patients having migraine without aura and 15 volunteers with matched age and sex, who underwent brain MRI with diffusion tensor imaging (DTI). The fractional anisotropy (FA) and mean diffusivity (MD) of selected grey and white matter regions on both sides were measured and correlated with the neurological clinical examination. Results: Significant differences were detected in MD values in the thalamus, globus pallidus, and hippocampus head on the right side of patients versus controls. Also, significant differences of the FA values were detected in the thalamus, globus pallidus, and hippocampus head on the right side of patients versus controls. Regarding the FA values of the same regions on the left side, a significant difference in the FA value was detected only in the hippocampus head. There was a statistically significant difference in the FA values on both sides of the white matter of the frontal lobes, posterior limbs of the internal capsules, and cerebellar hemispheres in patients compared to controls. There was a statistically significant difference in MD values in the white matter of both frontal lobes, posterior limb of the right internal capsule, and both cerebellar hemispheres in patients compared to controls. Conclusions: DTI can detect microstructural changes of the grey and white matter in patients having migraine without aura that could not be detected by conventional MRI.

The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum. The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases such as Parkinson's (PD) or Alzheimer's diseases (AD). Here we present the characterisation of the S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue. Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1, 2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages). Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra, hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91% decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD groups and controls. Conclusion: This work shows that 18F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (n = 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns. Electronic supplementary material The online version of this article (10.1007/s00401-020-02158-2) contains supplementary material, which is available to authorized users.

Patients with hypoglycemic coma show abnormal signals in the white matter on magnetic resonance imaging. However, the precise pathological changes in the white matter caused by hypoglycemic coma remain unclear in humans and experimental animals. This study aimed to reveal the distribution and time course of histopathological and immunohistochemical changes occurring in the white matter during the early stages of hypoglycemic coma in rats. Insulin-induced hypoglycemic coma of 15-30-min duration was induced in rats, followed by recovery using a glucose solution. Rat brains were collected after 6 and 24 hr and after 3, 5, 7, and 14 days. The brains were submitted for histological and immunohistochemical analysis for neurofilament 200 kDa (NF), myelin basic protein, olig-2, Iba-1, and glial fibrillary acidic protein (GFAP). Vacuolation was observed in the fiber bundles of the globus pallidus on days 1-14. Most of the vacuoles were located in GFAP-positive astrocytic processes or the extracellular space and appeared to be edematous. Additionally, myelin pallor and a decrease in NF-positive signals were observed on day 14. Microgliosis and astrogliosis were also detected. Observations similar to the globus pallidus, except for edema, were noted in the internal capsule. In the corpus callosum, a mild decrease in NF-positive signals, microgliosis, and astrogliosis were observed. These results suggest that after transient hypoglycemic coma, edema and/or degeneration occurred in the white matter, especially in the globus pallidus, internal capsule, and corpus callosum in the early stages.

Objectives: Wilson’s disease (WD) is characterized with the accumulation of copper in the liver and brain. The objective of this study is to quantitatively measure the susceptibility changes of basal ganglia and brain stem of pediatric patients with neurological WD using quantitative susceptibility mapping (QSM) in comparison to healthy controls. Methods: Eleven patients with neurological WD (mean age 15 ± 3.3 years, range 10–22 years) and 14 age-matched controls were prospectively recruited. Both groups were scanned on a 1.5 Tesla clinical scanner. In addition to T1- and T2-weighted MR images, a 3D multi-echo spoiled gradient echo (GRE) sequence was acquired and QSM images were derived offline. The quantitative measurement of susceptibility of corpus striatum, thalamus of each hemisphere, midbrain, and pons were assessed with the region of interest analysis on the QSM images. The susceptibility values for the patient and control groups were compared using two-sample t-test. Results: One patient with WD had T1 shortening in the bilateral globus pallidus. Another one had hyperintensity in the bilateral putamen, caudate nuclei, and substantia nigra on T2-weighted images. The rest of the patients with WD and all subjects of the control group had no signal abnormalities on conventional MR images. The susceptibility measures of right side of globus pallidus, putamen, thalamus, midbrain, and entire pons were significantly different in patients compared to controls (P < 0.05). Conclusion: QSM method exhibits increased susceptibility differences of basal ganglia and brain stem in patients with WD that have neurologic impairment even if no signal alteration is detected on T1- and T2-weighted MR images.

Purpose: The medial medullary lamina (MML) separates the medial globus pallidus (GPm) from the lateral. The aim of this study was to assess the changes in appearance of MML related to age using the phase difference-enhanced (PADRE) imaging and to determine whether PADRE can depict the MML in the patients with Parkinson’s disease (PD). Materials and Methods: We enrolled 20 patients with PD and 50 normal control subjects (NC). First, for the visualization of the MML in the NC, we compared the PADRE, susceptibility-weighted imaging (SWI)-like images and T2weighted imaging (WI) by using multiple comparison. The grading methods are as follows: grade 1; MML was not delineated, grade 2; less than half of MML was delineated, grade 3; more than half of MML was delineated and grade 4; whole MML was clearly delineated. We determined grade 3 and 4 as good depiction, delineating the GPm. Then, we evaluated patients with PD using the same method. Results: In NC, the delineation of MML was good in 84% of cases on PADRE, but only 34% of cases showed a good depiction on SWI-like images (average grading score 3.31 vs 2.11, P < 0.05). No MML was delineated in all cases on T2WI. Although younger subjects tended to show whole MML clearly, a part of MML tends to be obscured with age on PADRE. In patients with PD the depiction of MML on PADRE was also good in 90% of cases. Conclusion: The PADRE technique facilitates the depiction of the MML within globus pallidus (GP) on a broad range of age NC and patients with PD and it is superior to SWI-like images and T2WI.

BACKGROUND: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs. METHODS: We obtained T(1)-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a(2) = additive genetics; c(2) = common or shared environment; e(2) = unique or nonshared environment). We also assessed correlations with RRB severity. RESULTS: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a(2) = 0.56 to 0.87), except for ACC white matter volume (a(2) = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a(2) = 0.65 to 0.97), but the cortical thickness of the ACC (c(2) = 0.44, 95% CI 0.22 to 0.66) and OFC (c(2) = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated. Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors. CONCLUSION: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD.

Background Alcohol misuse often manifests in two different patterns of drinking; Binge Drinking (BD; ≥4 (women) or ≥ 5 (men) drinks/day, ≤12 days/month) or Heavy Drinking (HD; ≥3 (women) or ≥4 (men) drinks/day, ≥16 days/month). Although direct comparisons have not been made, structural MRI studies indicate that the two types of drinking behaviors might be associated with different neuromorphometric characteristics. Methods This study used a cross-sectional design to compare brain structure (using MRI derived subcortical volume and cortical thickness measures) between participants with histories of BD (N = 16), HD (N = 15), and Healthy Controls (HC; N = 21). Whole-brain analyses were used to quantify group differences in subcortical volume and cortical thickness. Resulting cortical thickness clusters were quantified for their areas of overlap with resting-state network parcellations. Results BD was associated with decreased volumes of the bilateral global pallidus and decreased cortical thickness within the left superior-parietal cluster (p, Graphical abstract Unlabelled Image, Highlights • Histories of Binge Drinking and Heavy Drinking patterns are associated with distinct neuromorphometric characteristics. • Binge Drinking related neuromorphometric alterations include the global pallidus and the left superior-parietal region. • Heavy Drinking related neuromorphometric alterations were found within the left medial occipito-parietal region.

Levodopa has been the mainstay of symptomatic therapy for Parkinson’s disease (PD) for the last five decades. However, it is associated with the development of motor fluctuations and dyskinesia, in particular after several years of treatment. The aim of this study was to shed light on the acute brain functional reorganization in response to a single levodopa dose. Functional magnetic resonance imaging (fMRI) was performed after an overnight withdrawal of dopaminergic treatment and 1 h after a single dose of 250 mg levodopa in a group of 24 PD patients. Eigenvector centrality was calculated in both treatment states using resting-state fMRI. This offers a new data-driven and parameter-free approach, similar to Google’s PageRank algorithm, revealing brain connectivity alterations due to the effect of levodopa treatment. In all PD patients, levodopa treatment led to an improvement of clinical symptoms as measured with the Unified Parkinson’s Disease Rating Scale motor score (UPDRS-III). This therapeutic effect was accompanied with a major connectivity increase between cerebellar brain regions and subcortical areas of the motor system such as the thalamus, putamen, globus pallidus, and brainstem. The degree of interconnectedness of cerebellar regions correlated with the improvement of clinical symptoms due to the administration of levodopa. We observed significant functional cerebellar connectivity reorganization immediately after a single levodopa dose in PD patients. Enhanced general connectivity (eigenvector centrality) was associated with better motor performance as assessed by UPDRS-III score. This underlines the importance of considering cerebellar networks as therapeutic targets in PD. Electronic supplementary material The online version of this article (10.1007/s12311-018-0981-y) contains supplementary material, which is available to authorized users.

Brief epochs of beta oscillations have been implicated in sensorimotor control in the basal ganglia of task-performing healthy animals. However, which neural processes underlie their generation and how they are affected by sensorimotor processing remains unclear. To determine the mechanisms underlying transient beta oscillations in the local field potential (LFP), we combined computational modeling of the subthalamo-pallidal network for the generation of beta oscillations with realistic stimulation patterns derived from single unit data. The single unit data were recorded from different basal ganglia subregions in rats performing a cued choice task. In the recordings we found distinct firing patterns in the striatum, globus pallidus and subthalamic nucleus related to sensory and motor events during the behavioral task. Using these firing patterns to generate realistic inputs to our network model lead to transient beta oscillations with the same time course as the rat LFP data. In addition, our model can account for further non-intuitive aspects of beta modulation, including beta phase resets following sensory cues and correlations with reaction time. Overall, our model can explain how the combination of temporally regulated sensory responses of the subthalamic nucleus, ramping activity of the subthalamic nucleus, and movement-related activity of the globus pallidus, leads to transient beta oscillations during behavior.Significance StatementTransient beta oscillations emerge in the normal functioning cortico-basal ganglia loop during behavior. In this work we employ a unique approach connecting a computational model closely with experimental data. In this way we achieve a simulation environment for our model that mimics natural input patterns in awake behaving animals. Using this approach we demonstrate that a computational model for beta oscillations in Parkinson’s disease can also account for complex patterns of transient beta oscillations in healthy animals. Therefore, we propose that transient beta oscillations in healthy animals share the same mechanism with pathological beta oscillations in Parkinson’s disease. This important result connects functional and pathological roles of beta oscillations in the basal ganglia.

Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates ( Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12–30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.

The ability to alter neuronal gene expression, either to affect levels of endogenous molecules or to express exogenous ones, is a powerful tool for linking brain and behavior. Scientists continue to finesse genetic manipulation in mice. Yet mice do not exhibit every behavior of interest. For example, Mus musculus do not readily imitate sounds, a trait known as vocal learning and a feature of speech. In contrast, thousands of bird species exhibit this ability. The circuits and underlying molecular mechanisms appear similar between disparate avian orders and are shared with humans. An advantage of studying vocal learning birds is that the neurons dedicated to this trait are nested within the surrounding brain regions, providing anatomical targets for relating brain and behavior. In songbirds, these nuclei are known as the song control system. Molecular function can be interrogated in non-traditional model organisms by exploiting the ability of viruses to insert genetic material into neurons to drive expression of experimenter-defined genes. To date, the use of viruses in the song control system is limited. Here, we review prior successes and test additional viruses for their capacity to transduce basal ganglia song control neurons. These findings provide a roadmap for troubleshooting the use of viruses in animal champions of fascinating behaviors-nowhere better featured than at the 12th International Congress!

Gender influence on the clinical manifestations of Wilson’s Disease (WD) has been suggested; however, brain MRI pathology based on sexual dimorphism in WD has not yet been examined. The aim of this study was to analyse the effect of gender on brain MRI pathology according to the predominant form of WD. We retrospectively analysed the brain MR images of 204 newly diagnosed and untreated WD patients. The predominant form of the disease was neuropsychiatric (n = 105), hepatic (n = 67) or presymptomatic (n = 32). Overall, neuroimaging pathologies were found in 64.2 % WD patients. The clinical form analysis revealed significant gender-related differences. In the neuropsychiatric form, men presented with cerebellar atrophy and cortical brain atrophy more often than women (25/58 vs. 11/47; p

To determine the effect of electrode contact location on efficacy of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for primary generalised dystonia (PGD).A consecutive series of 15 patients with PGD (10 females, mean age 42 years, seven DYT1) who underwent bilateral GPi DBS, were assessed using the Burke-Fahn-Marsden (BFM) dystonia scale before and 6 months after surgery. The position of the stimulated electrode contact(s) was determined from the postoperative stereotactic MRI. Contralateral limb and total axial BFM subscores were compared with the location of the stimulated contact(s) within the GPi.The mean total BFM score decreased from 38.9 preoperatively to 11.9 at 6 months, an improvement of 69.5% (p0.00001). Cluster analysis of the stimulated contact coordinates identified two groups, distributed along an anterodorsal to posteroventral axis. Clinical improvement was greater for posteroventral than anterodorsal stimulation for the arm (86% vs 52%; p0.05) and trunk (96% vs 65%; p0.05) and inversely correlated with the y coordinate. For the leg, posteroventral and anterodorsal stimulation were of equivalent efficacy. Overall clinical improvement was maximal with posteroventral stimulation (89% vs 67%; p0.05) and inversely correlated with the y (A-P) coordinate (r = -0.62, p0.05).GPi DBS is effective for PGD but outcome is dependent on contact location. Posteroventral GPi stimulation provides the best overall effect and is superior for the arm and trunk. These results may be explained by the functional anatomy of GPi and its outflow tracts.

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histol- ogy: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diVuse white matter gliosis (DWMG) (n = 17) without necrosis; and " Negative" group (n = 7) with no abnormalities. Neuronal loss was found almost exclusively in PVL, with signiW- cantly increased incidence and severity in the thalamus (38%), globus pallidus (33%), and cerebellar dentate nucleus (29%) compared to DWMG cases. The incidence of gliosis was signiWcantly increased in PVL compared to DWMG cases in the deep gray nuclei (thalamus/basal ganglia; 50-60% of PVL cases), and basis pontis (100% of PVL cases). Thalamic and basal ganglionic lesions occur almost exclusively in infants with PVL. Gray matter lesions occur in a third or more of PVL cases suggesting that white matter injury generally does not occur in isolation, and that the term "perinatal panencephalopathy" may better describe the scope of the neuropathology.

Abnormalities in cortico-basal ganglia (CBG) networks can cause a variety of movement disorders ranging from hypokinetic disorders, such as Parkinson's disease (PD), to hyperkinetic conditions, such as Tourette syndrome (TS). Each condition is characterized by distinct patterns of abnormal neural discharge (dysrhythmia) at both the local single-neuron level and the global network level. Despite divergent etiologies, behavioral phenotypes, and neurophysiological profiles, high-frequency deep brain stimulation (HF-DBS) in the basal ganglia has been shown to be effective for both hypo- and hyperkinetic disorders. The aim of this review is to compare and contrast the electrophysiological hallmarks of PD and TS phenotypes in nonhuman primates and discuss why the same treatment (HF-DBS targeted to the globus pallidus internus, GPi-DBS) is capable of ameliorating both symptom profiles. Recent studies have shown that therapeutic GPi-DBS entrains the spiking of neurons located in the vicinity of the stimulating electrode, resulting in strong stimulus-locked modulations in firing probability with minimal changes in the population-scale firing rate. This stimulus effect normalizes/suppresses the pathological firing patterns and dysrhythmia that underlie specific phenotypes in both the PD and TS models. We propose that the elimination of pathological states via stimulus-driven entrainment and suppression, while maintaining thalamocortical network excitability within a normal physiological range, provides a common therapeutic mechanism through which HF-DBS permits information transfer for purposive motor behavior through the CBG while ameliorating conditions with widely different symptom profiles.

High-frequency stimulation is known to entrain spike activity downstream and upstream of several clinical deep brain stimulation (DBS) targets, including the cerebellar-receiving area of thalamus (VPLo), subthalamic nucleus (STN), and globus pallidus (GP). Less understood are the fidelity of entrainment to each stimulus pulse, whether entrainment patterns are stationary over time, and how responses differ among DBS targets. In this study, three rhesus macaques were implanted with a single DBS lead in VPLo, STN, or GP. Single-unit spike activity was recorded in the resting state in motor cortex during VPLo DBS, in GP during STN DBS, and in STN and pallidal-receiving area of motor thalamus (VLo) during GP DBS. VPLo DBS induced time-locked spike activity in 25% ( n = 15/61) of motor cortex cells, with entrained cells following 7.5 ± 7.4% of delivered pulses. STN DBS entrained spike activity in 26% ( n = 8/27) of GP cells, which yielded time-locked spike activity for 8.7 ± 8.4% of stimulus pulses. GP DBS entrained 67% ( n = 14/21) of STN cells and 32% ( n = 19/59) of VLo cells, which showed a higher fraction of pulses effectively inhibiting spike activity (82.0 ± 9.6% and 86.1 ± 16.6%, respectively). Latency of phase-locked spike activity increased over time in motor cortex (58%, VPLo DBS) and to a lesser extent in GP (25%, STN DBS). In contrast, the initial inhibitory phase observed in VLo and STN during GP DBS remained stable following stimulation onset. Together, these data suggest that circuit-level entrainment is low-pass filtered during high-frequency stimulation, most notably for glutamatergic pathways. Moreover, phase entrainment is not stationary or consistent at the circuit level for all DBS targets.

Background: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. Objective: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. Methods: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). Results: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. Conclusion: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

Objective: To investigate the efficacy of chronic pallidal deep brain stimulation (DBS) on off period dystonia, cramps, and sensory symptoms in advanced Parkinson's disease (PD). Methods: 16 patients (6 women, 10 men; mean age at surgery 65 years) suffering from advanced PD were followed up prospectively for one year after implantation of a monopolar electrode in the posteroventral lateral globus pallidus internus. Unilateral DBS was performed in 9 patients. 10 patients had bilateral procedures (contemporaneous bilateral surgery in 7 and staged bilateral surgery in 3 instances). The decision whether to perform unilateral or bilateral surgery depended on the clinical presentation of the patient. Patients were formally assessed preoperatively, at 3–5 days, 3 months, and 12 months after surgery. Results: In patients who underwent unilateral surgery, pain was present in 7 (78%), off dystonia in 5 (56%), cramps in 6 (67%), and dysaesthesia in 4 (44%). In patients who underwent bilateral surgery, pain was present in 7 (70%), off dystonia in 6 (60%), cramps in 7 (70%), and dysaesthesia in 4 (40%). With unilateral DBS, contralateral off period dystonia was improved by 100% at 1 year postoperatively, pain by 74%, cramps by 88%, and dysaesthesia by 100%. There was less pronounced amelioration of ipsilateral off period dystonia and sensory symptoms. With bilateral DBS, total scores for dystonia were improved by 86%, for pain by 90%, for cramps by 90%, and for dysaesthesia by 88%. The benefit appeared early at the first evaluation 3–5 days after surgery and was stable throughout the follow up period. Conclusions: Pallidal DBS yields major improvement of off period dystonia, cramps, and sensory symptoms in patients with advanced PD.

OBJECTIVES—To interpret clinical features after unilateral lesions of the globus pallidus on the basis of physiology of the basal ganglia. METHODS—Four patients with unilateral lesions in the globus pallidus (GP) were clinically examined and the literature on patients with pallidal lesions was reviewed. RESULTS—Three patients presented with contralateral dystonia largely confined to one arm in one case and one leg in two cases. One patient had predominant contralateral hemiparkinsonism manifested mainly as micrographia and mild dystonia in one arm. The cause of the lesions was unknown in two patients. In the other two symptoms had developed after head trauma and after anoxia. All lesions involved the internal segment of the GP. Two patients, including the patient with hemiparkinsonism, had additional involvement of the external segment of the GP. In the literature reports on 26 patients with bilateral lesions restricted to the GP only two with unilateral lesions were found. The patients with bilateral pallidal lesions manifested with dystonia, parkinsonism, or abulia. One of the patients with unilateral GP lesions had contralateral hemidystonia, the other contralateral arm tremor. CONCLUSION—These cases emphasise the importance of the GP, particularly its internal segment, in the pathophysiology of dystonia.

OBJECTIVES—With the advent of new antiparkinsonian drug therapy and promising results from subthalamic and pallidal stimulation, this study evaluated the long term efficacy of unilateral pallidotomy, a technique which has gained popularity over the past decade for the management of advanced Parkinson's disease. METHODS—The 15 patients reported here are part of the original cohort of 24 patients who underwent posteroventral pallidotomy for motor fluctuations and disabling dyskinesias 3 years ago as part of a prospective study. Evaluation scales included the unified Parkinson's disease rating scale, the Goetz dyskinesia scale, and the Purdue pegboard test. RESULTS—When compared with the prepallidotomy scores, the reduction in the limb dyskinesias and off state tremor scores persisted on the side contralateral to pallidotomy at the end of 3 years (dyskinesias were reduced by 64% (p

Objective - To examine follow up results of unilateral ventral medial pallidotomy in 22 patients with advanced Parkinson's disease more than 1 year after the operation in comparison with their results (previously reported) at 3 months. Methods - Twenty patients who had undergone unilateral pallidotomy were assessed with the core assessment programme for intracerebral transplantation (CAPIT) protocol preoperatively, at 3 months postoperatively, and again after a median postoperative follow up of 14 months. Two further patients had only one evaluation 3 months postoperatively. Results - The reduction of contralateral dyskinesias (median 67%) at 3 months was slightly attenuated after 1 year to 55% (both p < 0.001 compared with baseline). A less pronounced effect on ipsilateral and axial dyskinesias decreased from 39% to 33% (p < 0.005 and p < 0.01), and from 50% to 12.5% (p < 0.001 and p < 0.01), respectively. However, there was no significant change between the 3 month and the follow up assessment. The modest improvement of the contralateral unified Parkinson's disease rating scale (UPDRS) motor score in the 'off' state remained improved compared with preoperative levels, but less significantly (26%, p < 0.001, and 18%, p < 0.01). The activities of daily living (ADL) subscore of the UPDRS in the off state remained improved with median changes of 23% and 22% at follow up (both p < 0.005). There was no significant improvement of 'on' state or ipsilateral off state motor scores. Median modified Hoehn and Yahr scores in off and on state were unchanged, as was the time spent off. Speech in off had significantly deteriorated by 1 year after the operation. Conclusions - The beneficial effects of unilateral pallidotomy persist for at least 12 months and, dyskinesias are most responsive to this procedure.

Objective—To establish the pathophysiological mechanisms of striatopallidal and thalamic dystonia. Methods—Five patients from among 26 who presented (between March 1987 and July 1996) with focal dystonia, segmental dystonia, or hemidystonia caused by a single localised vascular lesion, were selected. Patients with lesions with indefinite boundaries, and diVuse, or multiple, or large brain lesions were excluded. Three dimensional T1 weighted MRI (1.5 tesla) was performed to determine the topography of the lesions. The atlas of Hassler allowed the stereotactic localisation of the lesions to be specified exactly. Results—Three patients had dystonic spasms associated with striatopallidal lesions and one with a thalamic and striatopallidal lesion. One other patient presented with a myoclonic dystonia related to a thalamic lesion. The striatopallidal lesions were located in the sensorimotor area with a somatotopical distribution. The pure thalamic lesion involved the centromedian nucleus, the sensory nuclei, and the pulvinar whereas the thalamic and striatopallidal lesion was located in the pallidonigral thalamic territory, which receives pallidonigral inputs. Conclusion—The striatopallidal dystonia might be the consequence of the interruption of the cortico-striato-pallidothalamo-cortical loop induced by lesions located within the sensorimotor part of the striatopallidal complex. By contrast, it is suggested that thalamic dystonia might be caused by lesions located in the centromedian or the ventral intermediate nuclei, outside the pallidonigral territory, but leading also to a dysfunction of the cortico-striato-pallido-thalamo -cortical loop.J Neurol Neurosurg Psychiatry 1998;65:703‐708)

Objective—to assess postoperative eVects of unilateral posteroventral pallidotomy on the organisation of upper limb movement. Methods—A three dimensional kinematic system (ELITE, B?T?S? Italy) was used to record reach to grasp movements to objects of either small (0.7 cm) or large (8 cm) diameter placed at a reaching distance of either 20 or 30 cm. Four patients with Parkinson’s disease were assessed in “oV” (12 hours without medication) and “on” (1 hour after administration of medication) preoperatively and postoperatively. Results—Duration of the movement and the time spent in arm deceleration were significantly reduced after surgery. However, movement patterning according to object size was adversely aVected. Postoperatively, all four patients showed an abnormal pattern of a longer movement duration, and three showed a longer time of reaching arm deceleration, for reach to grasp movements to the large object than for those to the small object. Conclusion—Posteroventral pallidotomy seems to be beneficial in reducing bradykinesia of upper limb movements but may have “costs” to movement patterning, particularly for reach to grasp movements to objects of diVering sizes. This study raises interesting questions about the role of the globus pallidus interna in coordinating stimulus bound visual information with appropriate motor patterning. (J Neurol Neurosurg Psychiatry 1998;65:479‐487)

OBJECTIVES To analyse the clinical features induced by lenticular infarction found in 20 patients, and to analyse the radiological and clinical correlations. METHODS Eight women and 12 men, mean age 73 years, were included in this study, which was carried out from 1 January 1994 to 30 November 1996. They were characterised by the onset of a lenticular infarction, shown by CT and MRI. A complete neurological and neurocognitive examination, and photon emission computed tomography (SPECT), were performed in all the patients and there was a long clinical follow up. RESULTS Two distinct clinical syndromes were identified corresponding to the two anatomical areas of the lenticular nucleus: behavioural and cognitive disorders were associated with infarcts within the globus pallidus, whereas both motor disorders (dystonia) and cognitive disorders were associated with infarcts within the putamen. Outcome was excellent in all the patients for motor function, but slight cognitive disorders, problems with short term memory, and dysphasia persisted for several months. The size of the lesion did not explain these symptoms. By contrast, the slight reduction in cerebral blood flow found in the adjacent frontotemporal area may explain them by a deafferentation or a diaschisis phenomenon. CONCLUSION It is possible to identify the clinical symptoms of a single lesion in the pallidus nucleus and in the putaminal nucleus, in which behavioural, cognitive, and movements disorders are important. After an acute and spectacular onset, outcome is in general excellent. A disease of the small arteries must be involved.

Eight of the first 15 patients with advanced Parkinson's disease who underwent microelectrode guided posteroventral pallidotomy developed transient abnormal involuntary movements during thermolesion, four of whom also did so during high frequency macrostimulation. Abnormal involuntary movements found before thermolesion were choreic, ballistic, or choreoathetoid in nature, usually persisted less than 60 minutes, and were contralateral to the site of thermolesion in six and bilateral in two of them. The appearance of abnormal involuntary movements during macrostimulation or thermolesion of the internal globus pallidus correlated with better surgical outcome as measured by UPDRS motor items and CAPIT timed test, so that they seem to be of prognostic value.

Background: Iron neurotoxicity has been linked to delayed neuronal injury and edema formation after intracerebral hemorrhage (ICH). We have previously shown that serum ferritin, an indicator of body iron load, correlates with the relative perihematoma edema volume (RPHEV) on days 3–4 after ICH. We undertook this study to directly examine the relationship between in vivo brain and hematoma iron content, measured by MRI, and RPHEV. Methods: We retrospectively reviewed prospectively collected clinical and laboratory data from 36 consecutive patients with acute spontaneous lobar ICH who had MRI performed within 2–4 days of ICH onset. We measured hematoma and edema volumes, and the signal intensity on T2-weighted images (T2SI), as an estimate of iron content, in the hematoma and contralateral globus pallidus (GP). We calculated the RPHEV and T2SI in the hematoma and GP, relative to T2SI in the frontal deep white matter which contains negligible iron, to estimate the hematoma and brain iron load. We used Spearman correlation coefficient to determine the association of relative T2SI of the hematoma and GP with RPHEV. Results: We found a significant inverse correlation between the relative T2SI in the hematoma (r = –0.75, p < 0.001) and to a lesser extent in the GP (r = –0.34, p = 0.04) and the RPHEV. Conclusions: Our findings suggest that in vivo brain and hematoma iron content, as measured by MRI, is linked to perihematoma edema after ICH, and provide further support to existing preclinical evidence linking iron-mediated toxicity to delayed neuronal injury after ICH.

International audience; The dynamics of the subthalamo-pallidal complex in Parkinson's disease (PD) during deep brain stimulation (DBS) are studied using two models, a simple firing-rate model and a population based model. We extend a simple firing-rate model of the complex formed by the subthalamic nucleus (STN) and the external segment of the Globus Pallidus (GPe) to explore its dynamical regime during DBS. More specifically, the modulation of neuronal activity (i.e., pattern and amplitude) during DBS is studied. A similar approach is used with a population based model. Simulation results reveal a progressive decrease of bursting activity in STN cells when DBS frequency is increased. In addition, the contribution of the stimulation current type (monophasic or biphasic) on the results is also examined. The two models provide qualitatively similar results, but the population based model is more biologically realistic and appears more appropriate to explore DBS mechanims. Understanding the underlying mechanisms of DBS is a prerequisite to the development of new stimulation protocols.

Objective: Subthalamic nucleus (STN) stimulation for patients with medically refractory Parkinson disease (PD) is expanding. Reported experience has provided some indication of techniques, efficacy, and morbidity, but few centres have reported more than 50 patients. To expand this knowledge, we reviewed our experience with a large series of consecutive patients. Methods: From March 1999 to September 2003, 191 subthalamic stimulator devices (19 unilateral) were implanted in 100 patients with PD at New York Presbyterian Hospital/Columbia University Medical Center. Sixteen patients had undergone a prior surgery for PD (pallidotomy, thalamotomy, or fetal transplant). Microelectrode guided implantations were performed using techniques similar to those described previously. Electrode implantation occurred 1–2 weeks before outpatient pulse generator implantation. Results: Reductions of dyskinesias and off severity/duration were similar to prior published reports. Morbidity included: 7 device infections (3.7%), 1 cerebral infarct, 1 intracerebral haematoma, 1 subdural haematoma, 1 air embolism, 2 wound haematomas requiring drainage (1.0%), 2 skin erosions over implanted hardware (1.0%), 3 periprocedural seizures (1.6%), 6 brain electrode revisions (3.1%), postoperative confusion in 13 patients (6.8%), and 16 battery failures (8.4%). Of the 100 patients, there were no surgical deaths or permanent new neurological deficits. The average hospital stay for all 100 patients was 3.1 days. Conclusion: Subthalamic stimulator implantation in a large consecutive series of patients with PD produced significant clinical improvement without mortality or major neurological morbidity. Morbidity primarily involved device infections and hardware/wound revisions.

Objectives: The authors report the results of detailed investigations into the motor function of a patient who, after a heavy drinking binge and subsequent unconsciousness, respiratory acidosis, and initial recovery, developed parkinsonism characterised by hypophonic speech and palilalia, "fast micrographia", impaired postural reflexes, and brady/akinesia in proximal (but not distal) alternating upper limb movements. Methods: In addition to brain magnetic resonance imaging (MRI), different aspects of motor function were investigated using reaction time (RT) tasks, pegboard and finger tapping tasks, flex and squeeze tasks, movement related cortical potentials (MRCPs), and contingent negative variation (CNV). Cognitive function was also assessed. The results were compared to those previously reported in patients with Parkinson's disease (PD). Results: Brain MRI showed isolated and bilateral globus pallidus (GP) lesions covering mainly the external parts (GPe). These lesions were most probably secondary to respiratory acidosis, as other investigations failed to reveal an alternative cause. The results of the RT tasks showed that the patient had difficulties in preparing and maintaining preparation for a forthcoming movement. MRCP and CNV studies were in line with this, as the early component of the MRCP and CNV were absent prior to movement. The patient's performance on pegboard and finger tapping, and flex and squeeze tasks was normal when performed with one hand, but clearly deteriorated when using both hands simultaneously or sequentially. Conclusions: In general, the present results were similar to those reported previously in patients with PD. This provides further indirect evidence that the output of globus pallidus is of major importance in abnormal motor function in PD. The possible similarities of the functional status of GP in PD and our case are discussed.

Background: Evidence from previous volumetric magnetic resonance studies has revealed that patients with chronic temporal lobe epilepsy show atrophy of distinct subcortical nuclei, predominantly ipsilateral to the focus side. We were interested to find out if there is also selective subcortical atrophy in patients suffering from long standing extratemporal lobe epilepsy. Methods: Thirty one patients in whom pre-surgical evaluation unambiguously localised an extratemporal focus were included in this study. Using high resolution magnetic resonance imaging, the volumes of the caudate nuclei, putamen, pallidum, and thalamus were measured bilaterally in both hemispheres and compared with measurements obtained in 15 healthy volunteers. Results: No significant difference in volumes was found between the two subject groups, or in any subgroup of extratemporal lobe epilepsy patients, nor was there any relation to clinical variables such as age of onset, overall seizure frequency, or disease duration. However, patients who had no or only rare generalised tonic–clonic seizures seemed to differ from the other patients and controls in that they had smaller putamen volumes bilaterally (p

Clinical experience suggests an important role of the indirect basal ganglia pathway in the genesis of childhood onset generalised dystonia, but it has been difficult to reconcile the increased muscle activity in dystonia with the current model of basal ganglia function in which the indirect pathway is considered primarily inhibitory. The aim of this study was to present a modification of the direct–indirect pathway model, in which the indirect pathway is inverting rather than purely inhibitory, so that while high signals are inhibited, low signals are amplified. As the basal ganglia may be a feedback loop that modifies cortical activity, instability from excessive gain in this feedback loop could explain features of dystonia. A detailed mathematical model is provided, together with simulations of cortical cell population spiking behaviour when connected through a basal ganglia loop. The simulations show that increased gain in the indirect pathway relative to the direct pathway can lead to unstable uncontrolled synchronous oscillations in cortex and basal ganglia. This behaviour could result in dystonia. The model provides a consistent explanation for the association of dystonia with parkinsonism and disorders characterised by dopamine depletion, the ability to treat some dystonias with dopamine, the ability of neuroleptic drug treatment to cause an acute dystonic reaction treatable with anticholinergic drugs, and the ability of pallidotomy or deep brain stimulation of the internal pallidum to alleviate symptoms of generalised dystonia.

1. This study examined whether group III metabotropic glutamate (mGlu) receptor agonists injected into the globus pallidus (GP), substantia nigra pars reticulata (SNr) or intracerebroventricularly (i.c.v.) could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, cannulated above the GP, SNr or third ventricle, were rendered akinetic with reserpine (5 mg kg(-1) s.c.). 18 h later, behavioural effects of the group III mGlu receptor agonists L-serine-O-phosphate (L-SOP) or L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) were examined. 3. In reserpine-treated rats, unilateral injection of L-SOP (2000 and 2500 nmol in 2.5 microl) into the GP produced a significant increase in net contraversive rotations compared to vehicle, reaching a maximum of 83+/-21 rotations 120 min(-1) (n=8). Pretreatment with the group III mGlu receptor antagonist methyl-serine-O-phosphate (M-SOP; 250 nmol in 2.5 microl) inhibited the response to L-SOP (2000 nmol) by 77%. Unilateral injection of L-SOP (250-1000 nmol in 2.5 microl) into the SNr of reserpine-treated rats produced a dose-dependent increase in net contraversive rotations, reaching a maximum of 47+/-6 rotations 30 min(-1) (n=6). M-SOP (50 nmol in 2.5 microl) inhibited the response to L-SOP (500 nmol) by 78%. 4. Following i.c.v. injection, L-SOP (2000-2500 nmol in 2.5 microl) or L-AP4 (0.5-100 nmol in 2 microl) produced a dose-dependent reversal of akinesia, attaining a maximum of 45+/-17 (n=8) and 72+/-3 (n=9) arbitrary locomotor units 30 min(-1), respectively. 6. These studies indicate that injection of group III mGlu receptor agonists into the GP, SNr or cerebral ventricles reverses reserpine-induced akinesia, the mechanism for which remains to be established.

1. This study examined whether GABA(B) receptor agonists injected directly into the substantia nigra pars reticulata (SNr) and globus pallidus (GP), or given intracerebroventricularly, could reverse reserpine-induced akinesia in the rat. 2. Male Sprague-Dawley rats, stereotaxically cannulated above the SNr, GP or third ventricle, were rendered akinetic by injection of reserpine (5 mg kg(-1) s.c.). After 18 h, the locomotor effects of the GABA(B) receptor agonists, baclofen or SKF 97541 were examined. 3. Unilateral injection of baclofen (1-5 micro g in 0.5 micro l) into the GP failed to evoke any locomotor response (n=6). In contrast, unilateral intranigral injection of baclofen (0.08-1.6 micro g in 0.5 micro l) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 162+/-24 turns 90 min(-1) (n=6-8). Pretreatment with the selective GABA(B) receptor antagonist, CGP 46381 (2.4 micro g in 0.5 micro l), inhibited the effects of baclofen (0.8 micro g) by 68+/-9% (n=6). 4. Following intracerebroventricular injection, baclofen (0.8-4 micro g in 2 micro l) produced a dose-dependent increase in net arbitrary locomotor units (ALUs), reaching a maximum of 447+/-154 ALUs in 35 min (n=6-7). SKF 97541 (4-32 micro g in 2 micro l) similarly reversed akinesia, reaching 129+/-69 ALUs in 15 min (n=6). 5. These data show that activation of GABA(B) receptors within the SNr, but not the GP, reverses reserpine-induced akinesia. The success of intracerebroventricular injection of baclofen suggests a potential for systemically active GABA(B) receptor agonists in the treatment of akinesia in Parkinson's disease.

1. We previously reported a presynaptic facilitatory action of A(2A) receptors on GABAergic synaptic transmission in the rat globus pallidus (GP). In the present study we identify the intracellular signalling mechanisms responsible for this facilitatory action of A(2A) receptors, using biochemical and patch-clamp methods in rat GP slices. 2. The adenosine A(2A) receptor selective agonist CGS21680 (1, 10 microM) and the adenylyl cyclase activator forskolin (1, 10 microM) both significantly increased cyclic AMP accumulation in GP slices. The CGS21680 (1 microM)-mediated increase in cyclic AMP was inhibited by the A(2A) receptor selective antagonist KF17837 (10 microM). 3. In an analysis of miniature inhibitory postsynaptic currents (mIPSCs), forskolin (10 microM) increased the mIPSC frequency without affecting their amplitude distribution, a result similar to that previously reported with CGS21680. 4. The adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22,536, 300 microM) abolished the CGS21680-induced enhancement in the frequency of mIPSCs. 5. H-89 (10 microM), a selective inhibitor for cyclic AMP-dependent protein kinase (PKA), blocked the CGS21680-induced enhancement of the mIPSC frequency. 6. The calcium channel blocker CdCl(2) (100 microM) did not prevent CGS21680 from increasing the frequency of mIPSCs. 7. These results indicate that A(2A) receptor-mediated potentiation of mIPSCs in the GP involves the sequential activation of the A(2A) receptor, adenylyl cyclase, and then PKA, and that this facilitatory modulation could occur independently of presynaptic Ca(2+) influx.

Objectives: Hemichorea sometimes occurs after lesions that selectively involve the caudate nucleus, putamen, and globus pallidus. Some reports have hypothesised that the loss of subthalamic nucleus control on the internal segment of the globus pallidus, followed by the disinhibition of the thalamus may contribute to chorea. However, the pathophysiology is poorly understood. Therefore, clinicoradiological localisation was evaluated and a comparison of the haemodynamic status of the basal ganglia and thalamus was made. Methods: Six patients presenting with acute onset of hemichorea were assessed. Neuroimaging studies, including MRI and SPECT examinations in addition to detailed biochemical tests, were performed. A semiquantitative analysis was performed by comparing the ratio of blood flow between patients and normal controls. In addition, the ratio of perfusion asymmetry was calculated as the ratio between each area contralateral to the chorea and that homolateral to the chorea. The comparison was made with a two sample t test. Results: The causes of hemichorea found consisted of four cases of acute stroke, one non-ketotic hyperglycaemia, and one systemic lupus erythematosus. Brain MRI indicated lesion sites in the contralateral putamen, globus pallidus, caudate nucleus, and subthalamic nucleus. A significant decrease in the ratio of blood flow in the basal ganglia contralateral to the chorea and a significant increase in the thalamus was found when comparing the perfusion asymmetries, which were calculated as the ratio of cerebral blood flow (CBF) for each region to that in the homolateral occipital area (p Conclusion: An alteration in CBF in both the contralateral thalamus and basal ganglia reflect the loss of pallidal inhibitory input from the pallidum to the thalamus. This change in CBF may be one of epiphenomena, which implicates an occurrence of hemichorea in humans.

Objectives: Current models of basal ganglia dysfunction in Parkinson9s disease suggest a pivotal role of subthalamic nucleus (STN) hyperactivity. There is a direct excitatory output to the globus pallidus internus (GPi), which in turn hyperinhibits the motor thalamus and leads to a lack of cortical facilitation. The model, however, does not address the reciprocal influence of GPi on STN activity. Methods: Measurement of immediate changes in STN single cell activity after GPi deep brain stimulation (DBS). Results: An opposite effect of GPi DBS in the dorsal versus ventral STN was found. There was an almost exclusive reduction of firing rate in the dorsal region of the STN, whereas the cells in the ventral region exhibited facilitation similar to the recordings from the substantia nigra pars reticulata. Conclusion: Although these findings require confirmation, they suggest that the current theories of GPi DBS action, which do not include a GPi-STN modulation, are most likely incomplete.

Objectives: Surgical treatment of complex cervical dystonia and of cervical dyskinesias associated with cervical myelopathy is challenging. In this prospective study, the long term effect of chronic pallidal stimulation in cervical dystonia and on combining the technique with spinal surgery in patients with severe cervical dyskinesias and secondary cervical myelopathy is described. Methods: Eight patients with a history of chronic dystonia who did not achieve adequate benefit from medical treatment or botulinum toxin injection participated in the study. Five patients had complex cervical dystonia with tonic postures and phasic movements. Three patients had rapidly progressive cervical myelopathy secondary to severe cervical dyskinesias and dystonia in the context of a generalised movement disorder. Quadripolar electrodes were implanted in the posteroventral lateral globus pallidus internus with stereotactic CT and microelectrode guidance. In the three patients with secondary cervical myelopathy, spinal surgery was performed within a few weeks and included multilevel laminectomies and a four level cervical corporectomy with spinal stabilisation. Results: Improvement of the movement disorder was noted early after pallidal surgery, but the full benefit could be appreciated only with a delay of several months during chronic stimulation. Three months after surgery, patients with cervical dystonia had improved by 38% in the severity score, by 54% in the disability score, and by 38% in the pain score of a modified version of the Toronto western spasmodic torticollis rating scale. At a mean follow up of 20 months, the severity score had improved by 63%, the disability score by 69%, and the pain score by 50% compared with preoperatively. There was also sustained amelioration of cervical dyskinesias in the three patients who underwent spinal surgery. Lead fractures occurred in two patients. The mean amplitude needed for chronic deep brain stimulation was 3.8 V at a mean pulse width of 210 µs, which is higher than that used for pallidal stimulation in Parkinson's disease. Conclusions: Chronic pallidal stimualtion is effective for complex cervical dystonia and it is a useful adjunct in patients with cervical dyskinesias and secondary cervical myelopathy who undergo spinal surgery.

OBJECTIVE Posteroventral pallidotomy (PVP) has proved to be an effective method for the treatment of Parkinson9s disease. However, data on bilateral procedures are still limited. To assess the effects of bilateral globus pallidus (GPi) lesion and to compare it with a combination of unilateral GPi lesion plus contralateral GPi stimulation (PVP+PVS), an open blind randomised trial was designed. METHODS A prospective series of patients with severe Parkinson9s disease refractory to medical treatment, and severe drug induced dyskinesias, were randomised either to simultaneous bilateral PVP or simultaneous PVP+PVS. All patients were assessed with the core assessment programme for intracerebral transplantation (CAPIT), and a comprehensive neuropsychological and neuropsychiatric battery both before surgery and 3 months later. RESULTS The severe adverse effects found in the first three patients subjected to bilateral PVP led to discontinuation of the protocol. All three patients developed depression and apathy. Speech, salivation, and swallowing, as well as freezing, walking, and falling, dramatically worsened. By contrast, all three patients undergoing PVP+PVS had a significant motor improvement. CONCLUSION Bilateral simultaneous lesions within the GPi may produce severe motor and psychiatric complications. On the other hand, a combination of PVP+ PVS significantly improves parkinsonian symptoms not associated with the side effects elicited by bilateral lesions.

OBJECTIVES In a randomised trial to study the efficacy of unilateral pallidotomy in patients with advanced Parkinson9s disease, patients having pallidotomy within 1 month after randomisation were compared with patients having pallidotomy 6 months after the primary outcome assessment. Of the 37 patients enrolled 32 had a unilateral pallidotomy. The follow up study of these patients is presented to report (1) clinical outcome; (2) adverse effects; (3) cognitive and behavioural effects; (4) relation between lesion location and outcome; and (5) preoperative patient characteristics predictive for good outcome. METHODS Outcome measures were the motor section of the unified Parkinson9s disease rating scale (UPDRS), levodopa induced dyskinesias, disability, quality of life, and a comprehensive neuropsychological assessment. Multivariate logistic regression was used to identify preoperative patient characteristics independently associated with good outcome. RESULTS Off phase assessment showed a reduction in parkinsonism from 49 to 36.5 points on the UPDRS 6 months after surgery. Improvements were also demonstrated for activities of daily living and quality of life. In the on phase dyskinesias were reduced. All effects lasted up to 12 months after surgery. Three patients had major permanent adverse effects. Besides worsening of verbal fluency after left sided surgery, systematic cognitive deterioration was not detected. Patients taking less than 1000 levodopa equivalent units (LEU)/day were more likely to improve. CONCLUSIONS The positive effects of unilateral pallidotomy are stable up to 1 year after surgery. Patients taking less than 1000 LEU per day were most likely to improve.