Nursing Management of a Patient With COVID-19 Receiving ECMO: A Case Report.

INTRODUCTION: Venovenous extracorporeal membrane oxygenation has been recommended as an effective rescue therapy for select critically ill patients with COVID-19. This case report describes a first experience caring for a patient with COVID-19 who received venovenous extracorporeal membrane oxygenation and expands the literature by discussing relevant nursing management and operational considerations. CLINICAL FINDINGS: A 46-year-old man presented to a hospital emergency department with pleuritic chest pain, dyspnea, anorexia, and chills. The patient was intubated for pneumonia-associated acute respiratory distress syndrome. DIAGNOSIS: A nasopharyngeal swab specimen was positive for SARS-CoV-2, and chest radiography confirmed a diagnosis of COVID-19 with acute respiratory distress syndrome. INTERVENTIONS: After no improvement with mechanical ventilation and prone positioning, the patient began receiving venovenous extracorporeal membrane oxygenation and was transferred to an extracorporeal membrane oxygenation center. Frontline critical care nurses played a vital role in coordinating patient care activities, monitoring changes in the patient's condition, and detecting complications early. OUTCOMES: The patient was decannulated on day 15 and extubated on day 17. The patient was successfully discharged home on hospital day 24. CONCLUSION: Caring for a patient with COVID-19 receiving venovenous extracorporeal membrane oxygenation posed unprecedented challenges that required deviations from standards of care to optimize infection control measures and staff safety while providing quality care. This case report may inform, prepare, and guide other critical care nurses who will be caring for similar patients during this pandemic.

Relative preservation of thalamic centromedian nucleus in parkinsonian patients with dystonia.

To determine whether variable thalamic degeneration in Parkinson's disease (PD) contributes to less drug responsive clinical features. Formalin-fixed thalami from longitudinally followed patients with PD and early dystonia (N = 6), early falls (N = 5) or no dystonia or falls (N = 6) and age-matched controls without neuropathology (N = 10) were serially sectioned, stained, and analyzed. Neurons in the centromedian parafascicular (CM-Pf) nucleus were quantified using the optical disector method and analysis of variance with post hoc testing used to determine variability in neurodegeneration between groups. Patients with PD were confirmed to have significant neurodegeneration in the CM-Pf complex, with no difference in the degree of neurodegeneration between patients with PD with early falls compared with patients with no history of falls or dystonia. In contrast, patients with PD with early dystonia had significantly less neurodegeneration of the CM but not the Pf than patients without this feature. Preservation of the CM in patients with PD with early dystonia would result in a relative increase in CM activity through the direct basal ganglia pathway and increased primary motor cortex activity. Overall this data provides evidence for pathway-specific neurodegeneration as an underlying feature of the clinical variability observed in patients with PD.

Sprouting of dopamine terminals and altered dopamine release and uptake in Parkinsonian dyskinaesia.

Failed storage capacity, leading to pulsatile delivery of dopamine (DA) in the striatum, is used to explain the emergence of 'wearing off' and dyskinaesia in Parkinson's disease. In this study, we show that surviving DA neurons in 6-OHDA lesioned rats sprout to re-innervate the striatum, and maintain terminal density until approximately 60% of neurons are lost. We demonstrate that DA terminal density correlates with baseline striatal DA concentration ([DA]). Electrochemical and synaptosome studies in 6-OHDA lesioned rats and primates suggest that impaired striatal DA re-uptake and increased DA release from medial forebrain bundle fibres contribute to maintaining striatal DA levels. In lesioned rats where terminal density fell by 60% or more, L-DOPA administration increased striatal DA levels markedly. The striatal [DA] produced by L-DOPA directly correlated with the extent of dyskinaesia, suggesting that dyskinaesia was related to high striatal [DA]. While sprouting and decreased dopamine uptake transporter function would be expected to contribute to the marked increase in L-DOPA induced [DA], the increased [DA] was most marked when DAergic fibres were >60% denervated, suggesting that other release sites, such as serotonergic fibres might be contributing. In conclusion, the extent of dyskinaesia was directly proportional to the extent of DA terminal denervation and levels of extra-synaptic striatal DA. We propose that sprouting of DA terminals and decreased dopamine uptake transporter function prevent the appearance of Parkinsonian symptoms until about 60% loss of nigral neurons, but also contribute to dysregulated striatal DA release that is responsible for the emergence of dyskinaesia and 'wearing off'.

Behavioural effects of trishomocubanes in rats with unilateral 6-hydroxydopamine lesions.

Whilst dopamine replacement improves cardinal features of Parkinson's disease, chronic levodopa administration is associated with dose-related side effects and not all symptoms are ameliorated, necessitating the development of new treatments. Studies of trishomocubanes, a novel group of sigma ligands, have shown enhanced amphetamine-stimulated striatal release of dopamine and a potentially neuroprotective action in vitro and reversal of reserpine-induced catalepsy in vivo. Such effects warrant investigation in animal models of parkinsonism. Our study therefore examines two novel trishomocubane compounds, N-(3'-fluorophenyl)methyl-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (1) and, N-(3'-fluorophenyl)ethyl-4-azahexacyclo[5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol (2) in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease. A variety of motor behaviours were studied in rats given 6-OHDA lesions. Groups of lesioned rats were given either (1) or (2) or vehicle solution i.p. Acute administration of 3 mg/kg (1) resulted in a decrease in locomotor activity. Twenty-five milligrams per kilogram (2) caused a decrease in locomotor activity at t=10 and t=20 min of the locomotor test but this was not found when (2) was co-administered with either apomorphine or amphetamine. The decreased locomotor activity indicates that (1) and (2) may have sedative/anxiolytic effect(s). However, elevated plus maze data failed to demonstrate anxiolysis with (2). Quantification of dopaminergic neurons did not demonstrate any significant difference in the magnitude of cell loss between drug-treated vs. vehicle treated rats so no neuroprotective effect was demonstrated in this model at the doses utilised.

Use of the narrow beam test in the rat, 6-hydroxydopamine model of Parkinson's disease.

Batteries of behavioural tests provide a method by which researchers may examine specific functional pathways. The narrow beam test examines the ability of a rat to cross a narrow, elevated beam of wood or other material. In order to determine the utility of the narrow beam test in the study of Parkinsonism, it was of interest to characterise the performance of animals at this task. Rats were placed at one end of a 105 cm long, elevated beam and both the time it took to begin crossing the beam, as well as the total time taken to cross the beam, were measured. The effects of training, time of day and 6-hydroxydopamine lesion on beam performance were examined. Rats reached maximal performance at the task within a single test session and time of day had no effect on beam performance. Parkinsonian rats demonstrated a four-fold increase in both the latency to initiate the task and the total time to cross the beam (p < 0.05).

Effect of ventrolateral thalamic nucleus lesions in the unilateral 6-hydroxydopamine rat model.

Whilst dysfunction of basal ganglia-thalamic circuitry is implicated in the genesis of parkinsonian symptomatology, few studies have examined the effects of lesioning the motor thalamus in the context of parkinsonism. Forty rats were therefore subdivided into four lesion groups each of 10 rats with lesions or sham surgery targeting (1) the medial forebrain bundle and/or (2) motor thalamus, resulting in: Sham/Sham, 6-OHDA/Sham, Sham/NMDA and 6-OHDA/NMDA groups. Behavioural testing was performed prior to any surgery and after each surgery including analysis of posture, drug-induced rotation, sensorimotor and autonomic deficits. As expected 6-OHDA lesions induced abnormalities in posture, locomotion, sensorimotor and pilomotor function, ipsilateral and contralateral rotational asymmetries after amphetamine and apomorphine, respectively. These behavioural changes reflect parkinsonism in this model. Additional thalamic lesions virtually abolished apomorphine-induced rotational asymmetry and improved sensorimotor response latency to tactile stimulation on the contralateral side. These data support the contribution of dysfunctional motor thalamic circuitry in rotational asymmetry and abnormal sensorimotor function in parkinsonian rats.

Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning.

Degeneration of cholinergic neurons is a well known characteristic of Alzheimer's disease (AD). Two radioligands were studied in a rat model of cholinergic degeneration to evaluate their potential efficacy for molecular imaging of AD. Following specific cholinergic-cell immunolesioning with 192 IgG-saporin (SAP), ex vivo autoradiography was performed with (123)IBVM, a radioligand which targets the vesicular acetylcholine transporter (VAChT). Following the decay of (123)I, the same animals had in vitro autoradiography performed with (125)I-A-85380, a marker for nicotinic acetylcholine receptors (nAChRs). As expected significant, widespread decreases in (123)IBVM uptake were observed in SAP treated animals. Moderate but significant reductions in (125)I-A-85380 binding in the hippocampus (Hip) and cerebellum (Cbm) were also observed following SAP immunolesioning. The results with (123)IBVM confirm and extend previous work investigating the uptake of radioiodinated IBVM in this animal model. The results with (125)I-A-85380 are unique and are in contrast with work performed in this animal model with other nAChR radioligands, indicating the favourable properties of this radioligand for molecular imaging.

Effects of pallidotomy on motor symptoms in an animal model of Parkinson's disease.

The present study was designed to evaluate the motor effects of lesioning the internal globus pallidus in an animal model of Parkinson's disease. Fourty rats were divided into four groups (each of 10 rats) which received either unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle (mfb) plus sham surgery to the pallidum, sham surgery of mfb plus N-methyl-D-aspartate (NMDA) induced pallidal lesions, combined 6-OHDA mfb + NMDA pallidal lesions or sham surgery to both structures. Animals with 6-OHDA lesions developed significant ipsilateral biases in head position, body axis and circling after amphetamine challenge (all P < 0.05). Prominent contralateral deficits were present in sensorimotor response latency and contralateral circling was induced by apomorphine challenge (both P < 0.05). The addition of an NMDA pallidal lesion, improved the head position and body axis biases, as well as dopamine-agonist induced rotation and contralateral reaction time in a sensorimotor task (all P < 0.05). There was, however, a slight worsening of sensorimotor response on the ipsilateral side (P < 0.05). Pallidal lesions in the absence of 6-OHDA lesions produced contralateral head position and body axis biases (both P < 0.05). These data indicate that pallidotomy improves some, but not all aspects of parkinsonian motor dysfunction in an animal model of Parkinson's disease (PD).

A comparison of degeneration in motor thalamus and cortex between progressive supranuclear palsy and Parkinson's disease.

Changes in motor cortical activation are associated with the major symptoms observed in both Parkinson's disease and progressive supranuclear palsy (PSP). While research has concentrated on basal ganglia abnormalities as central to these cortical changes, several studies in both disorders have shown pathology in the thalamus and motor cortices. In particular, we recently reported an 88% loss of corticocortical projection neurones in the pre-supplementary motor (pre-SMA) cortex in Parkinson's disease. Further analysis of the degree of neuronal loss and pathology in motor cortices and their thalamocortical relays in Parkinson's disease and PSP is warranted. Six cases with PSP, nine cases with Parkinson's disease and nine controls were selected from a prospectively studied brain donor cohort. alpha-Synuclein, ubiquitin and tau immunohistochemistry were used to identify pathological lesions. Unbiased stereological methods were used to analyse atrophy and neuronal loss in the motor thalamus [ventral anterior, ventrolateral anterior and ventrolateral posterior (VLp) nuclei] and motor cortices (primary motor, dorsolateral premotor and pre-SMA cortices). Analysis of variance and post hoc testing was used to determine differences between groups. In Parkinson's disease, the motor thalamus and motor cortices (apart from the pre-SMA) were preserved containing only rare alpha-synuclein-positive and ubiquitin-positive Lewy bodies. In contrast, patients with PSP had significant atrophy and neuronal loss in VLp (22 and 30%, respectively), pre-SMA (21 and 51%, respectively) and primary motor cortices (33 and 54%, respectively). In the primary motor cortex of PSP cases, neuronal loss was confined to inhibitory interneurones, whereas in the pre-SMA both interneurones (reduced by 26%) and corticocortical projection neurones (reduced by 82%) were affected. Tau-positive neurofibrillary and glial tangles were observed throughout the motor thalamus and motor cortices in PSP. These non-dopaminergic lesions in motor circuits are likely to contribute to the pathogenesis of both PSP and Parkinson's disease. The selective involvement of the VLp and primary motor cortex in PSP implicates these cerebellothalamocortical pathways as differentiating this disease, possibly contributing to the early falls.

Novel oral drug administration in an animal model of neuroleptic therapy.

A novel method of oral drug administration was used in a neuroleptic animal study. Seventy male Sprague-Dawley rats were randomly subdivided into four groups, which were treated with clozapine, haloperidol, diazepam or a vehicle solution (5% sucrose solution). Oral drug treatment was achieved by training the rats to drink the drug of choice mixed with five percent sucrose or vehicle solution from a syringe. Within 3-4 weeks the haloperidol group developed vacuous chewing movement, which did not disappear with discontinuation of the drug. Significant weight gain was observed for all drug groups in relation to the control group, whereas only the diazepam group showed a significant increase in response latency on the disengage test of sensorimotor function, which disappeared with drug withdrawal. A novel means of testing the motivational status showed that all drug-treated groups engaged in eating chocolate before grooming (t=11.69, p<0.001), whereas the control group showed no specific tendency towards either task. Furthermore, there was a significant delay in grooming for the haloperidol group compared to the other drug groups and controls. In conclusion, a novel method of oral drug administration with minimum stress was introduced that was sufficient to cause the described changes in behavioural parameters. Additionally, the combination of tests used provided an efficient discrimination between the behavioural effects of clozapine, haloperidol and diazepam in rodents.

Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys.

Current neurosurgical strategies target overactive brain regions including the subthalamic nucleus, globus pallidus and thalamus to control various symptoms of Parkinson's disease. Subthalamotomy improves akinesia and can induce postural deficits in both parkinsonian humans and animals, pallidotomy improves limb dyskinesia and more variably, distal bradykinesia whilst thalamotomy improves tremor. Because the SNr also becomes overactive in PD and there are few surgical studies in parkinsonian primates, we therefore evaluated the effects of lesioning the SNr in hemiparkinsonian marmosets to establish the effects on symptomatology. Nine monkeys received unilateral 6-hydroxydopamine (6-OHDA) lesions. Seven weeks later, four received kainic acid lesions of the SNr. Behavioural tests were performed prior to 6-OHDA surgery and then fortnightly for 14 weeks. Unilateral 6-OHDA lesions induced ipsilateral postural bias, ipsilateral rotation after amphetamine injection and bradykinesia. Whilst, SNr lesions significantly altered the direction of head position and amphetamine-induced rotation relative to 6-OHDA lesions, there was no improvement in 6-OHDA-induced reaching deficits or sensorimotor neglect. Unbiased quantitation of the nigral lesions showed on average 88% loss of dopaminergic neurons after 6-OHDA lesions and 77% loss of non-dopaminergic neurons after SNr lesions. Our results demonstrate that the SNr is important in body orientation changes in parkinsonism.

A pain in the throat: a 19-year history of symptoms relating to the carotid artery.

A 38-year-old man presented with a 19-year history of sore throat and an ache radiating from the centre of the anterior neck to the both ears and the occiput. Computed tomography angiography revealed a tortuous submucosal right internal carotid artery, which was causing tonsillar displacement. The diagnosis of carotidynia has a controversial history within the literature and is currently not accepted as a distinct pathological entity by the International Headache Society. In this patient, the clinical and imaging features, in addition to the absence of any other pathology confers support to the diagnosis of carotidynia.

Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuronal number for the output, internal relay, and striatal modulating nuclei.

This study compares the basal ganglia of rats, marmosets, macaques, baboons, and humans. It uses established protocols to estimate the volume and number of neurons within the output nuclei (internal globus pallidus, IGP; and nondopaminergic substantia nigra, SNND), two internal relay and modulating nuclei (subthalamic nucleus, STh; and external globus pallidus, EGP), and a modulator of the striatum (dopaminergic substantia nigra, SND). Nuclear boundaries were defined by using immunohistochemistry for striatal afferents. Total numbers of Nissl-stained and parvalbumin-immunoreactive neurons were calculated by using the fractionator technique. Comparisons between species were standardized relative to brain mass (rats < marmosets < macaques < baboons < humans). The EGP consistently had more neurons relative to the IGP, STh, and SND, which had similar neuronal numbers within each species. The SNND had proportionally more neurons in rats than in primates (especially humans). The distribution of SND neurons varied substantially between rats and primates (very few ventrally located neurons in rats) with humans containing fewer SND neurons than other primates. The reduction in SND neurons in humans suggests less dopaminergic regulation of the basal ganglia system compared with other species. The consistency in the number of IGP neurons across all species, combined with the reduction in SNND neurons in humans, suggests a greater emphasis on output pathways through the IGP and that there are proportionally more STh and EGP neurons in humans.

Convulsive and postural effects of lesioning the mid-substantia nigra pars reticulata in naïve and 6-hydroxydopamine lesioned rats.

The subthalamic nucleus is targeted for the treatment of Parkinson's disease. Unilateral lesions improve some aspects of parkinsonism but produce postural abnormalities in animal models but the exact pathways producing these effects remain to be defined. Using a battery of tests we evaluated the effects of lesioning one of the two major subthalamic targets, the substantia nigra pars reticulata in naïve and 6-OHDA lesioned rats. Lesions targeting the mid-substantia nigra pars reticulata resulted in acute tonic-clonic seizures and intense contralateral rotational asymmetry. During the first month after substantia nigra pars reticulata lesions there was normalisation of the ipsilateral head position bias induced by unilateral 6-OHDA lesions, significant contralateral body axis bias but no significant alteration of apomorphine induced rotation and sensorimotor neglect in 6-OHDA lesioned rats. Combined with our previous data, this suggests that subthalamic projections via the substantia nigra pars reticulata are important in seizures and postural behaviours. Therefore unilateral subthalamotomy probably induces postural deficits in hemiparkinsonian animals via projections involving the substantia nigra pars reticulata. This has implications for patients undergoing subthalamotomy for treatment of Parkinson's disease.

Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection.

Much recent work is investigating the role of oxidative stress and inflammatory mechanisms in the aetiology of neurodegeneration in Parkinson's disease. The present study evaluated whether the green tea constituent epigallocatechin gallate (EGCG) which has both anti-oxidant and anti-inflammatory properties, exerts neuroprotection and symptomatic effects when administered orally as a pre-treatment prior to 6-hydroxydopamine (6-OHDA) lesions. Groups of rats were given either 1mg/kg, 2mg/kg EGCG or vehicle solution for 14 days. Sham or 6-OHDA surgery was performed on day 11 of the drug administration protocol. Behavioural analysis was conducted before drugs/vehicle solution, again during the treatment period and then repeated at fortnightly intervals for 2 months post-operatively. Whilst some subtle behavioural improvements in postural abnormalities and ability to cross a narrow beam were observed in lesioned rats after EGCG (vs. vehicle) there was no evidence of neuroprotection on post-mortem quantification of degree of nigral dopaminergic neuronal loss when comparing the lesioned groups given the various treatments.

Regulation of beta-catenin trafficking to the membrane in living cells.

Beta-catenin is a key mediator of the Wnt signaling process and accumulates in the nucleus and at the membrane in response to Wnt-mediated inhibition of GSK-3beta. In this study we used live cell photobleaching experiments to determine the dynamics and rate of recruitment of beta-catenin at membrane adherens junctions (cell adhesion) and membrane ruffles (cell migration). First, we confirmed the nuclear-cytoplasmic shuttling of GFP-tagged beta-catenin, and found that a small mobile pool of beta-catenin can move from the nucleus to membrane ruffles in NIH 3T3 fibroblasts with a t(0.5) of approximately 30 s. Thus, beta-catenin can shuttle between the nucleus and plasma membrane. The localized recruitment of beta-catenin-GFP to membrane ruffles was more rapid, and the strong recovery observed after bleaching (mobile fraction 53%, t(0.5) approximately 5 s) is indicative of high turnover and transient association. In contrast, beta-catenin-GFP displayed poor recovery at adherens junctions in MDCK epithelial cells (mobile fraction 10%, t(0.5) approximately 8 s), indicating stable retention at these membrane structures. We previously identified IQGAP1 as an upstream regulator of beta-catenin at the membrane, and this is supported by photobleaching assays which now reveal IQGAP1 to be more stably anchored at membrane ruffles than beta-catenin. Further analysis showed that LiCl-mediated inactivation of the kinase GSK-3beta increased beta-catenin membrane ruffle staining; this correlated with a faster rate of recruitment and not increased membrane retention of beta-catenin. In summary, beta-catenin displays a high turnover rate at membrane ruffles consistent with its dynamic internalization and recycling at these sites by macropinocytosis.

Membrane localization of adenomatous polyposis coli protein at cellular protrusions: targeting sequences and regulation by beta-catenin.

Adenomatous polyposis coli protein (APC) translocates to, and stabilizes, the plus-ends of microtubules. In microtubule-dependent cellular protrusions, APC frequently accumulates in peripheral clusters at the basal membrane. APC targeting to membrane clusters is important for cell migration, but the localization mechanism is poorly understood. In this study, we performed deletion mapping and defined a minimal sequence (amino acids 1-2226) that efficiently targets APC to membrane clusters. This sequence lacks DLG-1 and EB1 binding sites, suggesting that these partners are not absolutely required for APC membrane targeting. A series of APC sequences were transiently expressed in cells and compared for their ability to compete endogenous APC at the membrane; potent inhibition of endogenous APC targeting was elicited by the Armadillo- (binds KAP3A, B56alpha, and ASEF) and beta-catenin-binding domains. The Armadillo domain was predicted to inhibit APC membrane localization through sequestration of the kinesin-KAP3A complex. The role of beta-catenin in APC membrane localization was unexpected but affirmed by overexpressing the APC binding sequence of beta-catenin, which similarly reduced APC membrane staining. Furthermore, we used RNA interference to show that loss of beta-catenin reduced APC at membrane clusters in migrating cells. In addition, we report that transiently expressed APC-yellow fluorescent protein co-localized with beta-catenin, KAP3A, EB1, and DLG-1 at membrane clusters, but only beta-catenin stimulated APC anchorage at the membrane. Our findings identify beta-catenin as a regulator of APC targeting to membrane clusters and link these two proteins to cell migration.

Melanized nigral neuronal numbers in Nigerian and British individuals.

The role of genetic and environmental factors in etiopathogenesis of Parkinson's disease (PD) is debated. The prevalence of PD is higher among white than nonwhite populations, yet it is five times higher in nonwhites living in the United States than in Nigeria. We compare counts of melanized nigral neurons between neurologically normal Nigerians and British brains. Neuronal counts were estimated in an age-matched sample of 23 Nigerian and 7 British brains from neurologically normal individuals who had no Lewy bodies and Lewy neurites on alpha-synuclein immunostaining. Two investigators blind to age and ethnicity performed counts of melanized neurons in a single 7-mum hemisections showing the substantia nigra pars compacta. No significant difference exits in the number of neurons between the Nigerian and the British subjects (P = 0.1, NS). Differences in melanized nigral neuronal numbers may not explain differences in the prevalence of PD between white and nonwhite populations, suggesting factors other than neuronal numbers contribute to differential susceptibility of black vs. white races to PD.

Experimental therapeutics of Parkinson's disease.

1. The loss of central dopamine, which characterises Parkinson's disease, led to the main pharmacological strategy for treatment, namely levodopa, a dopamine-replacement therapy. Several years after treatment, the majority of patients experience dose-limiting side-effects and loss of symptom control. There is a resurgence of interest in neurosurgery for treating the Parkinson's disease, particularly in new techniques targeting the subthalamic nucleus (STN), which is overactive in Parkinson's disease and contributes to symptom development. 2. We performed unilateral subthalamotomy (lesioning the subthalamic nucleus via the toxin N-methyl-d-aspartate) in marmosets and rats with experimentally induced parkinsonism (induced using the toxin 6-hydroxydopamine). A range of similar behaviours common to both rodents and primates were evaluated before and after each type of surgery. Post-mortem histology was used to confirm the lesions. We also provide details of a case with Parkinson's disease who underwent high-frequency bilateral stimulation of the STN and in whom we analysed the STN post-mortem. 3. Unilateral subthalamotomy improved akinesia in parkinsonian primates. However, both monkeys and rodents showed postural abnormalities. The patient who underwent bilateral high-frequency stimulation showed improvement of akinesia and other disease symptoms and no postural abnormalities. Post-mortem analysis did not demonstrate substantial damage of the STN as a result of the electrodes. 4. Although unilateral subthalamotomy improves some aspects of parkinsonism, it causes postural abnormalities in animal models of Parkinson's disease. Because bilateral high-frequency STN stimulation improves disease symptoms, is reversible and is not reported to induce postural side-effects, it may be a better surgical therapy for Parkinson's disease than lesioning the STN.

Clinical correlates of selective pathology in the amygdala of patients with Parkinson's disease.

The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.