Microlesion effect as a predictor of the effectiveness of subthalamic deep brain stimulation for Parkinson's disease.

BACKGROUND: Microlesion effect (MLE) is a commonly observed phenomenon after electrode insertion into the subthalamic nucleus (STN) for deep brain stimulation (DBS). OBJECTIVES: The aim of this study was to determine the presence of the MLE in the early postoperative period and the relationship between MLE and STN DBS. METHODS: 74 patients with Parkinson's disease were included in this study. Motor symptoms were evaluated preoperatively, within 48 h after electrode implantation and at 6 months with United Parkinson's Disease Rating Scale part III (UPDRS-III). According to the improvement level with MLE, all participants were stratified into three groups: (1) less than 20%; (2) 20-40%, and (3) more than 40% in OFF medication states. The degree of improvement in UPDRS-III with DBS ON for each MLE group was assessed at the 6-month follow-up. Regression analysis was applied for the evaluation of the relationship between MLE and improvement with DBS ON. RESULTS: Mean results in UPDRS-III with the MLE in ON and OFF medication states were 22.1 ± 10.5 and 42.1 ± 14 points, respectively. At the 6-month follow-up, with active stimulation, results tended to further ameliorate to 14.6 (59.4%) points in ON and 20.8 (55.3%) in OFF. Mean improvement in MLE groups were: 33.6% group 1, 47.5% group 2 and 61.4% group 3. Regression analysis revealed a positive correlation between the MLE and results at 6 months with DBS ON. CONCLUSION: Results proved the presence of MLE in the early postoperative period. Furthermore, a positive correlation between MLE and improvement degree with active stimulation was observed.

Micro lesion effect of the globus pallidus internus and outcome with deep brain stimulation in patients with Parkinson disease and dystonia.

To determine whether the immediate response to electrode implantation (micro lesion effect, MLE) in the internal segment of the globus pallidus (GPi) predicts symptom improvement with deep brain stimulation (DBS) at 6 months in patients with Parkinson's disease (PD) or generalized dystonia. Electrode implantation in the subthalamic nucleus (STN) prior to electrical stimulation has been reported to predict a beneficial effect of DBS in patients with PD, but whether this is also the case for the GPi in either PD or dystonia patients has not been established. We studied 20 patients (11 with PD and 9 with dystonia) who underwent electrode implantation in the GPi. Effects were assessed using standardized scales after 24 hours, weekly for 3 weeks prior to starting DBS, and after 6 months of DBS. 10 of 11 PD and 8 of 9 dystonia cases who benefited from electrode implantation also showed improvement in all motor and disability scores after 6 months of DBS of the GPi. One dystonia patient who did not show MLE benefited from DBS. The presence of MLE after electrode implantation in the GPi may help predict motor benefit from DBS in PD and generalized dystonia patients.

Effects of dorsal striatal infusions of R(-)-propylnorapomorphine on kappa-opioid-mediated locomotor activity in the young rat: possible role of the indirect pathway.

Stimulation of kappa-opioid receptors in the substantia nigra pars reticulata (SNPR) increases the locomotor activity of young rats: an effect blocked by systemic administration of a D2-like receptor agonist. Based on these initial findings, we proposed that: (a) D2-like receptors in the dorsal striatum are responsible for attenuating kappa-opioid-induced locomotor activity, and (b) the effects of D2-like receptor stimulation are mediated by the indirect pathway, which extends from the dorsal striatum to the SNPR via the globus pallidus (GP) and subthalamic nucleus (STN). To test the first hypothesis, young rats were given a systemic injection (i.p.) of saline or the kappa-opioid receptor agonist (+/-)-trans-U50,488 methanesulfonate salt (U50,488) on postnatal day (PD) 18. Later in the testing session, rats received bilateral infusions of vehicle or the D2-like receptor agonist R(-)-propylnorapomorphine (NPA) into the dorsal striatum, and the ability of NPA to block U50,488-induced locomotor activity was determined. To test the second hypothesis, rats were given sham or bilateral electrolytic lesions of the GP or STN on PD 16. Two days later, saline- and U50,488-induced locomotor activity was measured after systemic (i.p.) administration of vehicle or NPA. As predicted, dorsal striatal infusions of NPA attenuated the U50,488-induced locomotor activity of young rats. Contrary to our expectations, bilateral lesions of the GP or STN did not impair NPA's ability to block U50,488-induced locomotor activity. When considered together, these results suggest that: (a) stimulation of D2-like receptors in the dorsal striatum is sufficient to attenuate the kappa-opioid-mediated locomotor activity of young rats; and (b) the indirect pathway does not mediate the effects of D2-like receptor stimulation in this behavioral model.

Involvement of cholinergic neuronal systems in intravenous cocaine self-administration.

Recent studies suggest the participation of cholinergic neurons in the brain processes underlying reinforcement. The involvement of cholinergic neurons in cocaine self-administration has been recently demonstrated in studies using muscarinic and nicotinic agonists and antagonists, microdialysis, assessment of choline acetyltransferase activity and acetylcholine (ACh) turnover rates. The present experiment was initiated to identify subsets of cholinergic neurons involved in the brain processes that underlie cocaine self-administration by lesioning discrete populations with a selective neurotoxin. Rats were trained to self-administer cocaine and the cholinergic neurotoxin 192-IgG-saporin or vehicle was then bilaterally administered into the posterior nucleus accumbens (NAcc)-ventral pallidum (VP). The 192-IgG-saporin induced lesions resulted in a pattern of drug-intake consistent with either a shift in the dose intake relationship to the left or downward compared to sham-treated controls. A second experiment used a self-administration threshold procedure that demonstrated this lesion shifted the dose intake relationship to the left compared to the sham-vehicle treated rats. The magnitude and extent of the lesion was assessed by measuring the expression of p75 (the target for 192-IgG-saporin) and choline acetyltransferase (ChAT) in the NAcc, VP, caudate nucleus-putamen (CP) and vertical limb of the medial septal nucleus-diagonal band (MS-DB) of these rats using real time reverse transcriptase-polymerase chain reaction. Significant reductions in gene expression for p75 (a selective marker for basal forebrain cholinergic neurons) and ChAT were seen in the MS-DB and VP while only small decreases were seen in the NAcc and CP of the 192-IgG-saporin treated rats. These data indicate that the overall influence of cholinergic neurons in the MS-DB and VP are inhibitory to the processes underlying cocaine self-administration and suggest that agonists directed toward subclasses of cholinergic receptors may have efficacy as pharmacotherapeutic adjuncts for the treatment of cocaine abuse.

Effect of high-frequency stimulation of the subthalamic nucleus on the neuronal activities of the substantia nigra pars reticulata and ventrolateral nucleus of the thalamus in the rat.

Electrophysiological recordings were made in anaesthetized rats to investigate the mode of function of high-frequency stimulation of the subthalamic nucleus used as a therapeutic approach for Parkinson's disease. High-frequency electrical stimulation of the subthalamic nucleus (130 Hz) induced a net decrease in activity of all cells recorded around the site of stimulation in the subthalamic nucleus. It also caused an inhibition of the majority of neurons recorded in the substantia nigra pars reticulata in normal rats (94%) and in rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta (90%) or with ibotenic acid lesions of the globus pallidus (79.5%). The majority of cells recorded in the ventrolateral nucleus of the thalamus responded with an increase in their activity (84%). These results show that high-frequency stimulation of the subthalamic nucleus induces a reduction of the excitatory glutamatergic output from the subthalamic nucleus which results in deactivation of substantia nigra pars reticulata neurons. The reduction in tonic inhibitory drive of nigral neurons induces a disinhibition of activity in the ventrolateral motor thalamic nucleus, which should result in activation of the motor cortical system.

Distribution and binding parameters of GABAA receptors in the thalamic nuclei of Macaca mulatta and changes caused by lesioning in the globus pallidus and reticular thalamic nucleus.

Ascending output from the basal ganglia to the primate motor thalamus is carried by GABAergic nigro- and pallido-thalamic pathways, which interact with intrinsic thalamic GABAergic systems represented in primates by local circuit neurons and axons of the reticular thalamic nucleus. Disease-triggered pathological processes in the basal ganglia can compromise any of these pathways either directly or indirectly, yet the effects of basal ganglia lesioning on its thalamic afferent-receiving territories has not been studied in primates. Two GABA(A) receptor ligands, [(3)H]muscimol and [(3)H]flunitrazepam, were used to study the distribution and binding properties of the receptor in intact monkeys, those with kainic acid lesions in the globus pallidus, and those with ibotenic acid lesions in the reticular nucleus using quantitative autoradiographic technique on cryostat sections of fresh frozen brain tissue. In control monkeys the binding affinities for [(3)H]muscimol averaged 50 nM in the thalamic nuclei and 86 nM in the basal ganglia while the binding densities varied (maximum density of binding sites [Bmax] range of 99.4-1000.1 fmol/mg of tissue). Binding affinities and Bmax values for [(3)H]flunitrazepam averaged 2.02 nM and 81-113 fmol/mg of tissue, respectively. Addition of 100-microM GABA increased average affinity to 1.35 nM whereas Bmax values increased anywhere from 1-50% in different nuclei. Zolpidem (100 nM) decreased binding by 68-80%. Bmax values for both ligands were decreased at the two survival times in both medial and lateral globus pallidus implying involvement of both nuclei in the lesion. Statistically significant, 40% decrease (P=0.055) of Bmax for [(3)H]muscimol was observed in the ventral anterior nucleus pars densicellularis (VAdc, the main pallidal projection territory in the thalamus) 1 week after globus pallidus lesioning and a 36% decrease (P=0.017) 4 months post-lesioning. In contrast, [(3)H]flunitrazepam Bmax values in the VAdc of the same animals were increased by 23% (P=0.021) at 1 week and 28% (P=0.005) 4 months postlesion, respectively. One week after the reticular nucleus lesioning, the binding densities of [(3)H]muscimol and [(3)H]flunitrazepam were decreased in the thalamic nuclei receiving projections from the lesioned reticular nucleus sector by approximately 50% (P<0.05) and 10-33% (P<0.05), respectively. The results suggest that different GABA(A) receptor subtypes are associated with different GABAergic systems in the thalamus which react differently to deafferentation.

Bilateral morphological changes in the substantia nigra of the rat following unilateral damage of the striatum.

The effects of damage of the striatum and globus pallidus of one side on the size of cells in the pars reticulata and pars compacta of the substantia nigra on both sides and in the contralateral globus pallidus have been examined. Cellular cross-sectional areas have been compared with those for neurons in the same nuclei in normal age and sex matched littermate control animals. One week after removal of the left striatum and globus pallidus and overlying cortex, the cells in the ipsilateral pars compacta are significantly shrunken (15%). This decrease in size gets progressively more marked with longer survival times reaching 50% 112 days after operation, the longest survival time examined. The shrinkage is accompanied by marked cell loss. Neurons in the contralateral pars compacta show an initial significant hypertrophy of their cell bodies (20%) in the first week after the operation, and later show a shrinkage of 20% at 35 days. The degree of this contralateral shrinkage gradually declines to 12% at 112 days. The changes in the pars compacta are accompanied by a significant enlargement (33%) of the cells in the pars reticulata of the substantia nigra on the side of the damage. This hypertrophy is present by 35 days after operation and persists at least until 112 days. Similar hypertrophy occurs in the ipsilateral globus pallidus in the one case where this could be examined. There are no significant changes in the contralateral pars reticulata, but there is significant enlargement (23%) of the neurons in the contralateral globus pallidus.

Globus pallidus lesions inhibit the induction of c-Fos by haloperidol in the basal ganglia output nuclei in rats.

This study examined the induction of c-Fos expression in the substantia nigra pars reticulata (SNr) and entopeduncular nucleus (EP) in the rats with a globus pallidus (GP) lesion, following the administration of haloperidol. After a GP lesion was made unilaterally by stereotaxic administration of ibotenic acid, haloperidol was administered systemically, and the number of cells expressing c-Fos was quantitatively assessed. Haloperidol induced a high level of the expression of c-Fos in neurons of the SNr and EP, and the GP lesion significantly decreased the expression of c-Fos in the ipsilateral SNr and EP. Since it has been suggested that c-Fos expression in the SNr/EP is caused by increased excitatory inputs from the subthalamic nucleus (STN), the present results provide functional evidence indicating that neuronal activities of the basal ganglia output nuclei are not increased by GP ablation, unlike D2 receptor blockade, supporting the recently proposed hypothesis that overactivity of the STN resulting from dopamine depletion is not solely a result of disinhibition from inhibitory GP efferents.

Focal lesions within the ventral striato-pallidum abolish attraction for male chemosignals in female mice.

In rodents, socio-sexual behaviour is largely mediated by chemosensory cues, some of which are rewarding stimuli. Female mice display an innate attraction towards male chemosignals, dependent on the vomeronasal system. This behaviour likely reflects the hedonic value of sexual chemosignals. The anteromedial aspect of the olfactory tubercle, along with its associated islands of Calleja, receives vomeronasal inputs and sexually-dimorphic vasopressinergic innervation. Thus, we hypothesised that this portion of the ventral striato-pallidum, known to be involved in reward processing, might be important for sexual odorant-guided behaviours. In this study, we demonstrate that lesions of this region, but not of regions in the posterolateral striato-pallidum, abolish the attraction of female mice for male chemosignals, without affecting significantly their preference for a different natural reward (a sucrose solution). These results show that, at least in female mice, the integrity of the anterior aspect of the medioventral striato-pallidum, comprising a portion of the olfactory tubercle and associated islands of Calleja, is necessary for the attraction for male chemosignals. We suggest that this region contributes to the processing of the hedonic properties of biologically significant odorants.

Visual Wulst analyses "where" and entopallium analyses "what" in the zebra finch visual system.

Quite a lot of studies have tried to elucidate the differences in function of the two telencephalic targets of the avian visual system. We have tried to find out how the two systems are involved in orientation towards a food tray which is either marked by a special pattern or has to be identified by its relation to spatial cues. In this report, we compared in the zebra finch the effects of Wulst lesions on pattern discrimination with Wulst lesion effects on spatial discrimination, and we examined the effect of entopallium lesions on spatial discrimination. Birds with Wulst lesions showed deficits in spatial discrimination, but not in pattern discrimination. Entopallial lesions caused no deficits in spatial discrimination tasks. Combining the present results with a previous study revealing an impairment of pattern discrimination by such entopallial lesions [19], we are able to demonstrate a double dissociation: namely, an impairment of pattern discrimination by entopallial lesions and impairment of spatial discrimination by Wulst lesions, but no effects of the opposite pairing of task and lesion site. The entopallium is thus involved if the food source is identified by a pattern, and the Wulst if it has to be found by spatial cues.

Delayed-onset diurnal bruxism, psychic akinesia and depression after carbon monoxide poisoning: a case report.

Diagnosing the delayed neuropsychological sequelae of carbon monoxide (CO) poisoning is a clinical challenge because of its varied presentations. Pallidal lesions, the most common site of involvement in CO poisoning [Clin Radiol. 2000;55(4):273-80] can cause psychic akinesia [Mov Disord. 2001;16(5):810-4; J Neurol Neurosurg Psychiatry 1984;47(4):377-85]. We present a patient with diurnal bruxism, psychic akinesia and depression that were delayed manifestations of CO poisoning.

Analysis of five cases with neurogenic stuttering following brain injury in the basal ganglia.

UNLABELLED: This study examined stuttering patterns in five patients with basal ganglia injury. None of the patients had a history of developmental stuttering. Four patients were right-handed; one patient was ambidextrous. Stuttering tests administered to patients assessed sentence repetition, reading aloud, explanations of a comic strip, and conversation. Accessory behaviors such as facial grimaces, associated movements of the limbs, and avoidance behaviors were observed. The results of this study differ from those of previous studies of neurogenic stuttering in several respects: (1) blocks were frequently observed. (2) Adaptation was observed. (3) Almost all stuttering occurred at the initiation of words. (4) Across patients, stuttering frequency did not vary in a consistent manner with speaking task. New speech characteristics for neurogenic stuttering without aphasia following injury to the basal ganglia are described. EDUCATIONAL OBJECTIVES: After reading this text, the reader will be able to: (1) provide characteristics of neurogenic stuttering after the basal ganglia in patients without aphasia; (2) discuss the difference of the features and characteristics of stuttering between previously reported patients and present patients.

Lesions in monkey globus pallidus externus exacerbate parkinsonian symptoms.

To further define the role of the external segment of the globus pallidus (GPe) in the development of parkinsonian motor signs, two rhesus monkeys were made parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Behavioral assessments of bradykinesia and akinesia as well as single neuron recordings in the internal segment of the globus pallidus (GPi) were performed in both monkeys before and after ablating the sensorimotor portion of GPe. The effects of apomorphine on behavior and neuronal activity were also assessed in the parkinsonian monkeys before and after GPe ablation. We found that lesions in GPe exacerbated parkinsonian symptoms, altered neuronal activity in GPi, and reduced the therapeutic effects of apomorphine. These results support the hypothesis that GPe can influence GPi neuronal activity and is directly involved in parkinsonism. In addition, these data suggest that the inclusion of GPe in pallidotomy lesions for the treatment of Parkinson's disease can block the beneficial effects of antiparkinsonian medications and should be avoided.

Long-term functional consequences of quinolinic acid striatal lesions and their alteration following an addition of a globus pallidus lesion assessed using pharmacological magnetic resonance imaging.

The present study tested the hypothesis that lesion to the rat globus pallidus (GP) can "normalize" the functioning of the basal ganglia-thalamocortical circuits in striatal-lesioned rats by assessing the functional connectivity of these regions using functional magnetic resonance imaging (fMRI). Changes in brain activation following systemic administration of amphetamine were assessed in (1) rats sustaining a unilateral lesion to the striatum, (2) rats sustaining a combined striatal and pallidal lesion, and (3) control rats. Striatal-lesioned rats showed attenuated cortical activation following amphetamine administration and lower correlations between the responses to amphetamine in different brain regions compared to control rats. Although the addition of an excitotoxic GP lesion failed to prevent striatal lesion-induced attenuation of cortical activation by amphetamine, it was effective in "normalizing" the correlations between the responses to amphetamine in the different areas. These results suggest that, although the GP lesion is ineffective in correcting the global changes in activity caused by the striatal lesion, it may have the capacity to partially restore alterations in functional connectivity resulting from the striatal lesion. These results are further discussed in view of our previous demonstration that lesions to the GP can reverse several behavioral deficits produced by a striatal lesion.

Quantitative assessment of the effect of basal ganglia lesions on the stretch reflex in primates.

The effect of basal ganglia stereotactic lesions on motor tone in 3 primates was quantitated. The elastic and neurogenic forces generated with a controlled stretch of each animal's upper extremities were measured pre- and postlesion, and compared to previous studies. The techniques were sensitive to subtle changes in motor tone that were not clinically apparent. The results suggest that the basal ganglia, through the outflow path of the globus pallidus, is important in controlling the sensitivity of both flexors and extensors to stretch. These quantification techniques also have promise in evaluating treatment regimens for spasticity, rigidity, and other conditions with abnormal motor tone.

Production of generalized learning deficit and permanent growth stunting by bilateral brain stem lesions.

Bilateral lesions of the globus pallidus, ventrolateral thalamus, substantia nigra, or the median raphe produce a generalized learning deficit in rats. Bilateral lesions of the dorsomedial hypothalamic nuclei stunt growth in rats without significantly disturbing endocrine functions and without producing a generalized learning deficit. Globus pallidus, ventrolateral thalamus, substantia nigra, median raphe, and dorsomedial hypothalamic nuclei lesions were produced in weanling Sprague-Dawley rats to compare their effect on physical growth. At approximately 72 d of age, all lesions had resulted in reduced body wt, tail length, and tibial length. The differences lacked significance only in body wt after median raphe lesions and tail length after ventrolateral thalamus lesions. In rats with the generalized learning deficit, body size was most stunted after substantia nigra lesions. Tibial epiphyseal width was modestly increased in rats with the generalized learning deficit. Food intake/average body wt ratio in substantia nigra and dorsomedial hypothalamic nuclei rats did not differ significantly from control values. Decreases in brain, heart, liver, kidney, and testes tended to occur after all the lesions, but brain and testis organ wt/body wt ratios were either increased or unchanged. We conclude that brain lesions producing a generalized learning deficit in rats result in impaired physical growth. The results indicated that the stunted animals maintain adequate food intake and have normal growth hormone function. The anatomical substrate for generalized learning impairment may overlap with that of a set point for body size.