Search

This article presents a comparative study on the anatomical assessment of the foramen magnum (FM) among the South Indian population using CT scans. The study found that the most common shape of the FM in both dry skulls and CT scan images was hexagonal. There were no significant differences in measurements between the two methods. The study provides valuable information for surgeons and medical professionals. The document is a list of references to various studies and articles related to the anatomical assessment of the foramen magnum and spinal cord, which can be useful for researchers studying these features in different populations. [Extracted from the article]

Introduction: Parkinson's disease (PD) is the most common neurodegenerative disease worldwide. Studies have shown that insulin-like growth factor-binding protein 5 (IGFBP5) may contribute to methamphetamine-induced neurotoxicity and neuronal apoptosis in PC-12 cells and rat striatum. Here, we studied the expression and role of IGFBP5 in the 6-OHDA-toxicant model of PD. Methods: PC-12 and SH-SY5Y cells were exposed to 50 μm 6-OHDA for 24 h. qRT-PCR, western blotting, CCK-8 assay, EdU staining, annexin V staining, and immunofluorescence were performed to study the effects of IGFBP5-specific siRNAs. The effects of IGFBP5 on a rat 6-OHDA model of PD were confirmed by performing behavioral tests, tyrosine hydroxylase (TH) immunofluorescence staining, and western blotting. Results: In the GSE7621 dataset, IGFBP5 was highly expressed in the substantia nigra tissues of PD patients compared to healthy controls. In PC-12 and SH-SY5Y cells, IGFBP5 was upregulated following 6-OHDA exposure in a dose-dependent manner. Silencing of IGFBP5 promoted PC-12 and SH-SY5Y proliferation and inhibited apoptosis under 6-OHDA stimulation. Silencing of IGFBP5 relieved 6-OHDA-induced TH-positive neuron loss. Hedgehog signaling pathway was predicted as a downstream signaling pathway of IGFBP5. Negative regulation between IGFBP5 and sonic hedgehog (SHH) signaling pathway was confirmed in vitro. The effects of IGFBP5 silencing on SH-SY5Y cells were partially reversed using cyclopamine, a direct inhibitor of the SHH signaling pathway. In addition, silencing of IGFBP5 attenuated motor deficits and neuronal damage in 6-OHDA-induced PD rats. Conclusion: Elevated IGFBP5 expression may be involved in 6-OHDA-induced neurotoxicity through regulation of the SHH signaling pathway. Highlights of the Study: IGFBP5 was highly expressed in a 6-OHDA-toxicant model of PD. Silencing of IGFBP5 promotes proliferation of 6-OHDA-treated neurons, alleviates apoptosis of 6-OHDA-treated neurons, and inhibits the loss of TH-positive neurons. Silencing of IGFBP5 is neuroprotective due to regulation of sonic hedgehog signaling pathway. [ABSTRACT FROM AUTHOR]

Epilepsy is a widespread neurological disorder. Many neurotransmitters, neuropeptides and neuromodulators have a significant role in the epileptic activity. Apelin-13 and cannabinoid CB1 receptor agonist and antagonist have an effect in the penicillin model of epilepsy. The relationship between apelin and epilepsy, and the apelin-cannabinoid relationship in epilepsy is still not well understood. Thus, this study focuses on the relationship between apelin-13 and CB1 receptor in experimental model of epilepsy. Penicillin injection was given intracortically (i.c.) for the development of epileptic seizures. Ninety-one male Wistar rats were divided into 13 groups. CB1 receptor agonist ACEA (7.5 µg, intracerebroventricularly, icv) and antagonist AM-251 (0.25 µg and 0.125 µg, icv) were administered to three different groups, two different doses of apelin-13 (5 µg and 15 µg, icv) were applied and the interactions between these five groups of substances were evaluated. Both apelin-13 (15 µg) and AM-251 (0.25 µg) raised the spike frequency of epileptiform activity separately. Application of apelin-13 + AM-251 also increased the spike frequency of epileptiform activity beginning in the 30 min after apelin-13 application. When the non-effective dose of AM-251 and the effective dose of apelin-13 were administered together, epileptic activity increased in the 20 min. ACEA reduced the epileptiform activity starting in the 50th min. apelin-13 and ACEA administration in effective doses decreased epileptiform activity. The non-effective doses of AM-251, apelin-13 and effective dose of ACEA decreased the epileptiform activity in the 50 min. Application of non-effective doses of apelin and AM-251 together does not induce any additional proconvulsant activity, and CB1 receptor agonist, ACEA reversed the proconvulsant activity of apelin-13. These results suggest that they utilize different receptors to begin their own effects by increasing intracellular Ca2+ in epilepsy. Considering that apelin-13 is an endogenous substance known for its neuroprotective properties, the proconvulsant effect of apelin-13 in the presented study is remarkable. [ABSTRACT FROM AUTHOR]

Experiments are described in which the benzodiazepine portion of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor and the muscarinic cholinergic receptor were investigated in Parkinson's disease and control brains. Tritiated flunitrazepam and tritiated quinuclidinyl benzilate (QNB) were used to locate and quantify the receptors by autoradiographic and homogenate binding techniques. Densitometric analysis of autoradiographs of the basal ganglia allowed comparison of receptor densities in the post-mortem control and parkinsonian tissue, while homogenate binding experiments gave information concerning receptor affinity and maximum binding capacity. The results indicate that: 1) Binding of flunitrazepam to the benzodiazepine receptor is reduced in the lateral segment of the globus pallidus in Parkinson's disease. This suggest that the GABA-ergic pathway from the putamen to the lateral pallidal segment is overactive in Parkinson's disease. 2) Binding of QNB to the cholinergic receptors of the medial pallidal segment is increased in Parkinson's disease. This finding suggests underactivity of the cholinergic pathway from the pedunculopontine nucleus of the medial pallidal segment. 3) Binding of these ligands in the caudate and putamen of Parkinson's disease is not significantly different from controls. We reviewed the literature concerning the activity of these projections in parkinsonian conditions assessed by different methods and discuss here their implications for the pathogenesis of parkinsonian symptoms.

The GABA/benzodiazepine receptor complex in the basal ganglia of primates treated with the neurotoxin n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied by semi-quantitative autoradiography with [3H]flunitrazepam ([3H]FNZ). Systemic treatment with MPTP produced a stable and lasting parkinsonian condition, with pronounced bradykinesia, akinesia and tremor. In the lateral segment of the globus pallidus (GPL) there was a significant reduction of [3H]FNZ binding compared with non-treated animals. There were no significant changes in the [3H]FNZ binding in the caudate nucleus, putamen and medial globus pallidus (GPM). This suggests that MPTP-treatment increases GABA release within the GPL exclusively. In view of the available evidence suggesting increased striatal output, and reduced unit activity within the GPL of the MPTP-treated primate, it seems likely that the striatal GABAergic output to the GPL is overactive in this model of Parkinson's disease. Furthermore, as there is no evidence for a change in GABA function within the GPM using this measure, the striatal neurones which innervate the GPM may be differentially affected by loss of dopamine innervation. In line with structural evidence and extrastriatal dopamine receptor distribution this suggests that the two striatopallidal systems are functionally heterogeneous. A hemi-parkinsonian primate model has also been used in this study. This model was produced by injection of MPTP directly into one carotid artery. The substantia nigra pars compacta (SNc) was destroyed on the injected side alone, and consequently the appearance of parkinsonian symptoms was confined to the contralateral side. [3H]FNZ binding in the GPL appears to be bilaterally reduced in this model, suggesting an interaction between the treated and non-treated side of the brain. In addition there is increased binding in the putamen and GPM with respect to the non-treated side of the brain. The increased [3H]FNZ binding in the GPM of the unilateral model may be due to the greater disruption of the nigropallidal and/or nigrostiatal dopamine neurones relative to the systemic model. The former would have the effect of uncoupling D1 dopamine receptors located on the terminals of striatal efferents from nigropallidal dopamine input, and as D1 dopamine receptors are implicated in the presynaptic control of GABA release from the terminals of striatal efferents, this would consequently reduce the level of GABA release in the GPM. The latter possibility would suggest that striatopallidal neurones projecting to GPM are more resistant to the effects of dopaminergic denervation than those projecting to GPL.

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from monkeys which had received unilateral intracarotid infusions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing loss of dopamine-containing neurones of the substantia nigra pars compacta. The monkeys developed hemi-parkinsonian symptoms (tremor, bradykinesia) in limbs contralateral to the side of the toxin infusion. Administration of apomorphine (0.05-0.25 mg/kg) caused contralateral rotational behaviour, and reversal of the parkinsonian symptoms. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A reduction in these sites of 97% (mean brain value) in the caudate nucleus, and 91% in the putamen, as compared with binding values from untreated control monkeys, was accompanied by a significant increase in the binding of [3H]sulpiride (D2) in these structures. In contrast, in the same animals there was no similar increase in [3H]SCH 23390 binding to D1 receptors in the denervated areas. These results suggest that in the parkinsonian brain, where the dopaminergic innervation of the caudate nucleus and putamen has been lost, D2 receptors may be more susceptible than D1 receptors to changes, revealed here as an increase in [3H]sulpiride binding sites.

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.

Administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primates induced a parkinsonian syndrome that could be reversed by levodopa treatment. Animals quickly developed an apparent restlessness ("akathisia") of the lower limbs after as little as five doses. After 4-10 weeks of regular levodopa therapy, animals developed "peak dose" choreiform movements in the lower limbs that spread, with time, to involve the upper limbs and orofacial musculature. With further treatment (5-21 months), animals developed "peak dose" dystonia that variably involved the limbs and orofacial musculature. These conditions represent novel models of levodopa-induced chorea and dystonia in humans. They depend on the same underlying neuropathology and treatment regimen as their human counterparts. It is to be anticipated that these models of dyskinesia will be useful in determining the mechanisms underlying chorea and dystonia in humans and are ideally suited for experimental evaluation of new treatment strategies.

Long-term treatment of human Parkinson's disease with levodopa or dopamine agonists is often complicated by the appearance of abnormal involuntary movements (dyskinesias) that are extremely difficult to control. Little is known of the cause, pathophysiological mechanisms, or possible strategies for amelioration of this manifestation of dyskinesia. A hypothesis is set forth on the neural mechanisms that mediate levodopa- or dopamine agonist-induced dyskinesia (in particular chorea) as a side effect of the treatment of parkinsonism. Evidence is drawn from both clinical observations and experimental studies in a spectrum of movement disorders ranging from ballism through chorea to parkinsonism. It is proposed that (a) All forms of chorea, whatever their origin, share a common underlying neural mechanism. (b) Disordered activity of the subthalamic nucleus is central to the generation of choreic movements. In levodopa- or dopamine agonist-induced dyskinesia, (c) The site of action of dopaminergic agents in causing chorea is the putamen. (d) The specific pathophysiological state conducive to the appearance of chorea is brought about by the long-term exposure of the dopamine-depleted (parkinsonian) putamen to exogenous dopaminergic agents. (e) Long-term exposure to dopaminergic agents causes (either directly or indirectly) preferential inhibition of the subpopulation of putaminal neurones that project specifically to the lateral segment of the globus pallidus. This causes disinhibition of lateral pallidal neurones, which become overactive and physiologically inhibit the subthalamic nucleus. (f) The hypothesis suggests a number of possible strategies that might be useful for the alleviation of levodopa-induced dyskinesia.

The neural mechanisms that mediate dystonia were investigated in a novel experimental primate model of dopamine agonist-induced dystonia. This condition was produced by long-term (15 months) dopamine agonist therapy of a macaque monkey that had been rendered hemiparkinsonian by unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into the right common carotid artery. The 2-deoxyglucose (2-DG) metabolic mapping technique was applied to the animal during the expression of active unilateral dystonia, and regional brain uptake of 2-DG was assessed autoradiographically. The results demonstrate that dystonia is associated with marked increases in 2-DG uptake in the constituent nuclei of the basal ganglia (caudate nucleus, putamen, medial and lateral segments of the globus pallidus) and in the subthalamic nucleus, but decreased uptake in the structures that receive output of the basal ganglia (ventral anterior/ventral lateral thalamic complex and lateral habenula). Based on these findings it is suggested that dystonia is characterized by increased activity in the putaminopallidal and pallidosubthalamic pathways, and decreased activity in the subthalamopallidal and pallidothalamic pathways.

Intracerebral injections of the broad spectrum excitatory amino acid antagonist kynurenic acid (50 ug) alleviated the symptoms of akinesia, tremor and rigidity in a severely parkinsonian monkey. Unilateral injection of kynurenic acid within the medial pallidal segment produced rotational behaviour away from the side of the injection, and the limbs on the contralateral side showed relief of the MPTP-induced parkinsonian symptoms. The subsequent bilateral injection of the excitatory amino acid antagonist allowed the monkey to move freely, unhindered by tremor or rigidity. In addition unilateral injections of the NMDA antagonist MK-801 (5, 25 and 50 ug) within the medial pallidum also produced dose-related rotational behaviour, with alleviation of parkinsonian symptoms in the contralateral limbs. Systemic administration of MK-801 (1 ng/kg - 1 ug/kg i.m.) was without effect.

Anecdotal references, preclinical, and non-randomized studies support the therapeutic potential of cannabinoids for movement disorders (MD). To create an evidenced-based point of view for patients and physicians, we performed a systematic review of randomized controlled trials (RCT) on the use of cannabinoids in MD. The seven RCTs found on PD used different cannabis formulations. No improvement of motor symptoms was shown in any of the two RCTs with this as primary outcome (PO), but in the nabilone group, an improvement in quality of life was documented. Of the three RCTs having levodopa-induced dyskinesia as PO, only one using nabilone showed a reduction. Anxiety and anxiety-induced tremor could be reduced in the cannabidiol group as well as anxiety and sleeping problems in the nabilone group in another RCT. In two RCTs with Tourette syndrome, an improvement in tics was revealed. From three RCTs on Huntington's disease only one found symptoms relief using nabilone. No reduction of dystonia could be shown in the two included RCTs. The limited number of available but small and inhomogeneous RCTs precludes reliable conclusions. Therefore, more and smartly designed RCTs are urgently needed., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson's disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction. [ABSTRACT FROM AUTHOR]

Background: The interaction between the auriculotemporal nerve and the middle meningeal artery within the infratemporal fossa is vital in the spread of perineural tumours. Knowledge of their morphological and morphometric variations is critical to surgeons approaching the infratemporal fossa. There is a paucity of literature on the relationship between the auriculotemporal nerve and middle meningeal artery in a South African population. Hence, the aim of this study was to document the morphology and morphometry of the auriculotemporal nerve and its relationship to the middle meningeal artery within a South African cohort. Materials and methods: The infratemporal fossae of 32 cadaveric specimens were dissected and the auriculotemporal nerves and middle meningeal arteries were analysed, together with their variations. Results: Nine out of 32 specimens displayed one-root, 14/32 two-root, 7/32 three-root, and 2/32 four-root auriculotemporal nerves. Eighteen auriculotemporal nerves originated from the mandibular nerve, while the rest had at least one communication to the inferior alveolar nerve. The mean distance between the first and second roots of the auriculotemporal nerve was 4.69 mm. There were V-shaped formations found in 23 auriculotemporal nerves. However, the middle meningeal artery only passed through 13/23 V-shapes. The maxillary artery was of a deep course in relation to the lateral pterygoid muscle in 19/32 and superficial in 13/32 of the sample. There were 15 accessory middle meningeal arteries present in 14/32 specimens. The accessory middle meningeal arteries often arose from the middle meningeal artery (46.67%). Conclusions: The results of this study show a high possibility of variations of the auriculotemporal nerve and middle meningeal artery in the South African population. The variations and interactions should be considered during surgical procedures. [ABSTRACT FROM AUTHOR]

This radiologic work aimed to display the alteration in the superior orbital fissure (SOF) morphology in the pediatric population with advancing age. This pediatric examination consisted of computed tomography images of 180 subjects (90 males/90 females) aged 1-18 years. The length (SOF-L) and width (SOF-W) of SOF were measured, and its shape was noted. SOF-L and SOF-W were measured as 16.04 ± 2.34 mm and 5.35 ± 1.01 mm, respectively. SOF-L was similar in infancy and early childhood periods, but then decreased up to postpubescent period. This measurement increased significantly in postpubescent period. SOF-W did not show important change from infancy period up to postpubescent period. After that, it increased significantly in postpubescent period. Seven configurations regarding SOF shape were observed: the straight type in 20.8% out of 360 SOFs, eight-shaped type in 12.2%, key-shaped type in 14%, racket-shaped type in 18.6%, narrow type in 7.2%, triangular type in 14.7%, and curved type in 12.5%. SOF shape was not affected by sex (p = 0.150) and side (p = 0.919). Linear functions were calculated as y = 16.310-0.028 × age for SOF-L, and as y = 4.886 + 0.048 × age for SOF-W. SOF-L showed an irregular pattern of first decreasing and then increasing, during the transition from 1 year to 18 years. SOF-W displayed an irregular pattern of increasing with advancing ages in children. Our linear functions representing the growth pattern of SOF in children may be useful to estimate SOF size., (© 2024. The Author(s), under exclusive licence to Japanese Association of Anatomists.)

Background: Unilateral subthalamic nucleus (STN) ablation using magnetic resonance-guided focused ultrasound (MRgFUS) is being explored as a new treatment for asymmetric Parkinson's disease (PD)., Objectives: The aims were to study the efficacy and safety of this treatment in asymmetric PD patients and to characterize the lesions., Methods: This prospective, single-center, open-label study evaluated asymmetric PD patients at 6 (n = 20) and 12 months (n = 12) after MRgFUS lesion of the STN. The primary outcome was the change in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), score in off medication on the treated side and the adverse events (AEs) at 6-month follow-up. We also evaluated cognitive-neuropsychological changes, self-assessment of clinical improvement, and the correlation of the lesion volume with the motor outcomes., Results: On the treated side, the MDS-UPDRS III score (mean difference = 13.8) and the scores in rigidity, bradykinesia, and tremor improved (P < 0.001) throughout the follow-up compared to baseline (at 6 months: rigidity mean difference = 2.8, improvement: 83.5%; bradykinesia mean difference = 6.0, improvement: 69.4%; tremor mean difference = 4.7, improvement: 91.5%). One patient had severe weakness in the treated hemibody, 1 had moderate dyskinesia, and 1 was in moderate confusional state that became mild (weakness) or completely resolved (dyskinesia and confusional state) at 6 months. The rest of the AEs were mild. We observed no clinically relevant changes in cognitive-neuropsychological tests. The percentage of ablation of the STN correlated with the improvement in the total MDS-UPDRS III and contralateral tremor scores (P < 0.05)., Conclusion: Unilateral MRgFUS lesion of the STN resulted in a significant motor improvement. We observed no persistent severe AEs, although mild, mostly transient AEs were frequent. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The integration of functional magnetic resonance imaging (fMRI) with advanced neuroscience technologies in experimental small animal models offers a unique path to interrogate the causal relationships between regional brain activity and brain-wide network measures-a goal challenging to accomplish in human subjects. This review traces the historical development of the neuromodulation techniques commonly used in rodents, such as electrical deep brain stimulation, optogenetics, and chemogenetics, and focuses on their application with fMRI. We discuss their advantageousness roles in uncovering the signaling architecture within the brain and the methodological considerations necessary when conducting these experiments. By presenting several rodent-based case studies, we aim to demonstrate the potential of the multimodal neuromodulation approach in shedding light on neurovascular coupling, the neural basis of brain network functions, and their connections to behaviors. Key findings highlight the cell-type and circuit-specific modulation of brain-wide activity patterns and their behavioral correlates. We also discuss several future directions and feature the use of mediation and moderation analytical models beyond the intuitive evoked response mapping, to better leverage the rich information available in fMRI data with neuromodulation. Using fMRI alongside neuromodulation techniques provide insights into the mesoscopic (relating to the intermediate scale between single neurons and large-scale brain networks) and macroscopic fMRI measures that correlate with specific neuronal events. This integration bridges the gap between different scales of neuroscience research, facilitating the exploration and testing of novel therapeutic strategies aimed at altering network-mediated behaviors. In conclusion, the combination of fMRI with neuromodulation techniques provides crucial insights into mesoscopic and macroscopic brain dynamics, advancing our understanding of brain function in health and disease. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1., (© 2024 International Society for Magnetic Resonance in Medicine.)

Tryptophan metabolism along the kynurenine pathway is of central importance for the immune function. It prevents hyperinflammation and induces long-term immune tolerance. Accumulating evidence also demonstrates cytoprotective and immunomodulatory properties of kynurenine pathway in conditions affecting either central or peripheral nervous system as well as other conditions such as inflammatory bowel disease (IBD). Although multilevel association exists between the inflammatory bowel disease (IBD) and various neurologic (e.g., neurodegenerative) disorders, it is believed that the kynurenine pathway plays a pivotal role in the development of both IBD and neurodegenerative disorders. In this setting, there is strong evidence linking the gut-brain axis with intestinal dysfunctions including IBD which is consistent with the fact that the risk of neurodegenerative diseases is higher in IBD patients. This review aims to highlight the role of kynurenine metabolic pathway in various neurologic and psychiatric diseases as well as relationship between IBD and neurodegenerative disorders in the light of the kynurenine metabolic pathway. [ABSTRACT FROM AUTHOR]

Background: It remains unclear whether changes in the venous circulation contribute to cognitive decline. Objective: This study aimed to clarify whether the spontaneous jugular vein reflux (JVR) is associated with cognitive impairment and incident dementia. Methods: Patients with any evidence of cerebral vessel disease on magnetic resonance imaging (MRI) were consecutively enrolled between October 2015 to July 2019. We employed carotid duplex sonography to measure the internal jugular vein (IJV). The subjects were classified into two groups based on the degree of JVR on either side: none, mild (JVR(–) group) and moderate, severe (JVR (+) group) JVR. They underwent both the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment-Japanese (MoCA-J) global tests. Their cognitive status was prospectively assessed until March 2023. Results: 302 patients with an MMSE score ≥24 underwent duplex sonography of the IJV. Among them, 91 had spontaneous JVR on either side. Both MMSE and MoCA-J were significantly lower in patients with JVR (+) group than in the JVR (–) group. After the adjustment for risk factors and MRI findings, intergroup differences in MoCA-J remained significant. Among the cognitive subdomains, median executive function and memory scores were significantly lower in the JVR (+) group than in the JVR (–) group. During the median 5.2-year follow-up, 11 patients with incident dementia were diagnosed. Patients with severe JVR were significantly more likely to be diagnosed with dementia (log-rank test, p = 0.031). Conclusions: Spontaneous IJV reflux especially severe JVR, was associated with global cognitive function, and potentially with incident dementia. [ABSTRACT FROM AUTHOR]

Purpose: Antagonising serotonin (5-HT) type 2A receptors (5-HT 2A R) is an effective strategy to alleviate both dyskinesia and psychosis in Parkinson's disease (PD). We have recently shown that activation of metabotropic glutamate 2 receptors (mGluR 2 ), via either orthosteric stimulation or positive allosteric modulation, enhances the anti-dyskinetic and anti-psychotic effects of 5-HT 2A R antagonism. Here, we investigated if greater therapeutic efficacy would be achieved by combining 5-HT 2A R antagonism with concurrent mGluR 2 orthosteric stimulation and mGluR 2 positive allosteric modulation., Methods: Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets exhibiting dyskinesia and psychosis-like behaviours (PLBs) were administered L-3,4-dihydroxyphenylalanine (L-DOPA) in combination with vehicle or the 5-HT 2A R antagonist EMD-281,014. EMD-281,014 was itself administered alone or with the mGluR 2 orthosteric agonist (OA) LY-354,740, the mGluR 2 positive allosteric modulator (PAM) LY-487,379 and combination thereof, after which the severity of dyskinesia, PLBs and parkinsonism was rated., Results: EMD-281,014 reduced dyskinesia and PLBs by up to 47% and 40%, respectively (both P < 0.001). The addition of LY-354,740, LY-487,379 and LY-354,740/LY-487,379 decreased dyskinesia by 56%, 65% and 77%, while PLBs were diminished by 55%, 63% and 71% (all P < 0.001). All treatment combinations provided anti-dyskinetic and anti-psychotic benefits significantly greater than those conferred by EMD-281,014 alone (all P < 0.05). The combination of EMD-281,014/LY-354,740/LY-487,379 resulted in anti-dyskinetic and anti-psychotic effects significantly greater than those conferred by EMD-281,014 with either LY-354,740 or LY-487,379 (both P < 0.05). No deleterious effects on L-DOPA anti-parkinsonian action were observed., Conclusion: Our results suggest that combining 5-HT 2A R antagonism with mGluR 2 activation results in greater reduction of L-DOPA-induced dyskinesia and PD psychosis. They also indicate that further additive effect can be achieved when a mGluR 2 OA and a mGluR 2 PAM are combined with a 5-HT 2A R antagonist than when a mGluR 2 OA or a mGluR 2 PAM are added to a 5-HT 2A R antagonist., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The nucleus accumbens (NAc) has been considered a key brain region for encoding reward/aversion and cue–outcome associations. These processes are encoded by medium spiny neurons that express either dopamine receptor D1 (D1‐MSNs) or D2 (D2‐MSNs). Despite the well‐established role of NAc neurons in encoding reward/aversion, the underlying processing by D1‐/D2‐MSNs remains largely unknown. Recent electrophysiological, optogenetic and calcium imaging studies provided insight on the complex role of D1‐ and D2‐MSNs in these behaviours and helped to clarify their involvement in associative learning. Here, we critically discuss findings supporting an intricate and complementary role of NAc D1‐ and D2‐MSNs in associative learning, emphasizing the need for additional studies in order to fully understand the role of these neurons in behaviour. [ABSTRACT FROM AUTHOR]

Purpose: The present study aimed to evaluate the insertion site of the tibialis anterior tendon three-dimensionally. Methods: Seventy lower limbs were dissected. The tibialis anterior tendon was dissected to verify the insertion site to the medial cuneiform and the base of the first metatarsal bone. The three-dimensional (3D) territory of the tibialis anterior tendon insertion on the medial cuneiform and the first metatarsal bones was measured on a reconstructed 3D model. Results: The insertion pattern of the tibialis anterior tendon was classified into three types, the most common being Type I: a single tibialis anterior tendon dividing into two equal-sized bands to the medial cuneiform and base of the first metatarsal bone (57.1%, 40/70 of cases). The 3D territory of the tibialis anterior tendon was larger in the plantar aspect than in the medial side of both the medial cuneiform and the base of the first metatarsal bone. The width of the tendon inserted into the medial cuneiform was wider than that inserted into the first metatarsal bone. Conclusion: The tibialis anterior tendon was more commonly attached to the plantar part than the medial part in both the medial cuneiform and the base of the first metatarsal bone. This anatomical information will help surgeons perform anatomical reconstruction of the tibialis anterior tendon, reduce further tendon damage in the first metatarsocuneiform joint area and also provide valuable knowledge to improve understanding of hallux valgus pathogenesis. [ABSTRACT FROM AUTHOR]

A pathological feature of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. DA is the neurotransmitter of dopaminergic neurons. Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. DA is unstable and can undergo oxidation and metabolism to produce multiple reactive and toxic by-products, including reactive oxygen species, DA quinones, and 3,4-dihydroxyphenylacetaldehyde. Here we summarize and highlight recent discoveries on DA-linked pathophysiologic pathways, and discuss the potential protective and therapeutic strategies to mitigate the complications associated with DA. [ABSTRACT FROM AUTHOR]

Safety issues caused by pharmaceuticals have frequently occurred worldwide, posing a tremendous threat to human health. As an essential part of drug development, the toxicological analysis and safety evaluation is of great significance. In addition, the risk of pharmaceuticals accumulation in the environment and the monitoring of the toxicity from natural medicines have also received ongoing concerns. Due to a lack of spatial distribution information provided by common analytical methods, analyses that provide spatial dimensions could serve as complementary safety evaluation methods for better prediction and evaluation of drug toxicity. With advances in technical solutions and software algorithms, mass spectrometry imaging (MSI) has received increasing attention as a popular analytical tool that enables the simultaneous implementation of qualitative, quantitative, and localization without complex sample pretreatment and labeling steps. In recent years, MSI has become more attractive, powerful, and sensitive and has been applied in several scientific fields that can meet the safety assessment requirements. This review aims to cover a detailed summary of the various MSI technologies utilized in the biomedical and pharmaceutical area, including technical principles, advantages, current status, and future trends. Representative applications and developments in the safety‐related issues of different pharmaceuticals and natural medicines are also described to provide a reference for pharmaceutical research, improve rational clinical medicine use, and ensure public safety. [ABSTRACT FROM AUTHOR]

Background: The year 2023 marks the 30th anniversary of deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD). This procedure prompted a universal interest in DBS for various brain disorders and resulted in a unique expansion of clinical and scientific collaboration between many disciplines, with impact on many aspects of society. Objective: To study the anthropology of DBS, that is, its ethno‐geographic origins, its evolution, its impact on clinicians and scientists, and its influence on society at large. Material and Methods: The authors scrutinized the geo‐ethnic origins of the pioneers of modern DBS, and they evaluated, based on the literature and on a long‐term praxis, the development of DBS and its impact on clinicians, on healthcare, and on society. Results: Scientists and clinicians from various geo‐ethnic origins pioneered modern DBS, leading to worldwide spread of this procedure and to the establishment of large multidisciplinary teams in many centers. Neurologists became actively involved in surgery and took on new laborious tasks of programming ever more complicated DBS systems. Publications sky‐rocketed and the global spread of DBS impacted positively on several aspects of society, including healthcare, awareness of neurological diseases, interdisciplinary relations, conferences, patient organizations, unemployment, industry, etc. Conclusions: STN DBS has boosted the field of deep brain electrotherapy for many neurological and psychiatric illnesses, and DBS has generated a global benefit on many aspects of society, well beyond its clinical benefits on symptoms of diseases. With the ever‐increasing indications for DBS, more positive global impact is expected. [ABSTRACT FROM AUTHOR]

Purpose: Measure out of the standard interval in the aorta diameter is a clue for aortic aneurysm or hypoplasia. Pediatric studies focusing specifically on the normal diameter of the abdominal aorta (AA) were limited in the literature. Therefore, the main goal of this work was to determine changes in the effective diameter of AA in healthy children aged 1-18 years for diagnosis of vascular diseases., Methods: This retrospective work focused on abdominopelvic computed tomography views of 180 children (sex: 90 males / 90 females, average age: 9.50 ± 5.20 years) without any abdominopelvic disease to measure diameters of AA, common iliac artery (CIA), external iliac artery (EIA), and first lumbar vertebra (L1)., Results: Vessel and vertebra diameters increased in pediatric subjects between 1 and 18 years (p < 0.001). Considering pediatric age periods, vessel diameters increased steadily, but L1 diameter showed an irregular growth pattern between age periods. All parameters were greater in males than females (p < 0.05), except from effective diameters of AA over the coeliac trunk (p = 0.084) and over the renal artery (p = 0.051). The ratios of diameters of vessels to L1 increased depending on ages between 1 and 18 years. Considering pediatric age periods, the ratios increased from infancy period to postpubescent period in irregular pattern; however, the ratios for right and left CIA, and AA over the aortic bifurcation did not alter after late childhood period. All ratios for males were similar to females (p > 0.05)., Conclusion: Our age-specific ratios may be beneficial for surgeons and radiologists for the diagnosis of vascular disorders such as aortic aneurysm., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Purpose: This examination aimed to display the size and topographic position of the Vidian canal (VC) in normal children., Methods: 180 pediatric subjects aged 1-18 years were included this computed tomography examination. The distances of VC to certain landmarks, and VC length were measured. The locations of VC according to the sphenoid sinus, and the medial plate of pterygoid process were classified as three types, separately., Results: The distances of VC to the vomerine crest, midsagittal plane, round foramen, and the superior wall of sphenoid sinus were measured as 12.68 ± 3.17 mm, 10.76 ± 2.52 mm, 8.62 ± 2.35 mm, and 14.16 ± 5.00 mm, respectively. The length and angle of VC were measured as 12.00 ± 2.52 mm, and 16.60 ± 9.76°, respectively. According to the sphenoid bone, VC location was identified as Type 1 in 113 sides (47.5%), as Type 2 in 70 sides (29.4%), and as Type 3 in 55 sides (23.1%). According to the medial plate of pterygoid process, VC location was identified as Type A in 274 sides (76.1%), as Type B in 55 sides (15.3%), and as Type C in 31 sides (8.6%). VC location types correlated with pediatric ages, but not sex or side., Conclusion: With advancing pediatric age, the protrusion of VC into the sphenoid sinus increases, and VC shifts from medial to lateral side of the medial plate of pterygoid process., (© 2024. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

This article explores the impact of therapeutic lesioning of the basal ganglia on patients with movement disorders. While lesioning can have clinical benefits, such as reducing akinesia and tremors, it can also lead to deficits in motor performance and impairments in learning new tasks. Non-motor symptoms like impulsivity and speech disturbances can also arise. The document emphasizes the role of the basal ganglia in motor function and discusses the effects of lesioning or blocking basal ganglia activity. It suggests that interrupting abnormal basal ganglia activity is preferable to allowing faulty signaling to disrupt the motor system. Additionally, the document provides a list of references to scientific articles on Parkinson's disease and the basal ganglia, offering valuable insights for researchers and healthcare professionals in the field. [Extracted from the article]

Background: While cannabis-based medicine is being commonly used in patients with movement disorders, there is a scarcity of publications regarding the effect of cannabis on dystonia. We aimed to describe medical cannabis use in patients with dystonia and related pain. Methods: We employed a structured interview to obtain data on the cannabis treatment regimen, perception of effectiveness and side effect profile. Eligible participants were patients diagnosed with dystonia from the movement disorders unit at the Tel-Aviv Medical Center who had used licensed medical cannabis between January 2019 and January 2021. Results: Twenty-three subjects were interviewed (11 women, mean age 52.7). The most common way of administration was smoking (n = 11). Following an average of 2.5 ± 2.9 years of use, those with widespread dystonia (generalized, hemi and multifocal, n = 11) self-reported on a numeric rating scale an average 63% (range 0%-100%) reduction in symptoms of dystonia, while those with more focal dystonia patterns reported a significantly lower treatment effect of 32%. Participants reported a positive impact in related pain and quality of life, with an average rating of 3.8 out of 5 (SD = 1.2, median = 4) and 3.6 out of 5 (SD = 1.15, median = 4), respectively. Most common side effects were dry mouth (65%), sedation (43%), dizziness (39%) and psychiatric disorders (26%). Three patients (13%) discontinued therapy. Conclusion: A subset of dystonia patients who use medical cannabis under clinical observation reported significant subjective improvement during 30 months of use in average. Further prospective randomized controlled trials are required to examine the effectiveness of cannabis in dystonia. [ABSTRACT FROM AUTHOR]

Priming and expression of L‐dopa‐induced dyskinesia (LID) is associated with maladaptive plasticity of striatal spiny projection neurons (SPNs) in the direct pathway of the basal ganglia. The L‐dopa dosage threshold for dyskinesia decreases immediately after dopaminergic denervation, then gradually after repeated L‐dopa treatment. Dopaminergic denervation induces D1 receptor hypersensitivity in the soma and axon terminals and diminishes negative feedback from GABAB receptors in the direct pathway SPNs, resulting in neuronal hypersensitivity. After dopaminergic denervation, serotonergic neurons metabolize L‐dopa. Serotonergic neurons do not have D2 receptors or dopamine transporters, resulting in a non‐regulated release of dopamine, with subsequent pulsatile dopamine receptor stimulation. L‐dopa treatment post‐dopaminergic denervation induces LID in rat models. Dyskinetic rats show a lack of depotentiation at their corticostriatal synapses and enlargement of their dendritic spines within direct pathway SPNs, both of which account for strengthened corticostriatal synaptic transmission in LID models. Intra‐SPN signal transduction is activated, resulting in the hypersynthesis of GABA. The volume of the internal segment of the globus pallidus (GPi) increases alongside the enlargement of axon terminals with many synaptic vesicles containing GABA from direct pathway SPNs. When the model expresses LID, excessive GABA is released into the GPi. LID priming involves excessive GABA storage in GPi axon terminals, with LID triggered by enhanced GABA release into the GPi. [ABSTRACT FROM AUTHOR]

The parkinsonian gait disorder and freezing of gait are therapeutically demanding symptoms with considerable impact on quality of life. The aim of this study was to assess the role of subthalamic and nigral neurons in the parkinsonian gait control using intraoperative microelectrode recordings of basal ganglia neurons during a supine stepping task. Twelve male patients (56 ± 7 years) suffering from moderate idiopathic Parkinson's disease (disease duration 10 ± 3 years, Hoehn and Yahr stage 2), undergoing awake neurosurgery for deep brain stimulation, participated in the study. After 10 s resting, stepping at self-paced speed for 35 s was followed by short intervals of stepping in response to random 'start' and 'stop' cues. Single- and multi-unit activity was analysed offline in relation to different aspects of the stepping task (attentional 'start' and 'stop' cues, heel strikes, stepping irregularities) in terms of firing frequency, firing pattern and oscillatory activity. Subthalamic nucleus and substantia nigra neurons responded to different aspects of the stepping task. Of the subthalamic nucleus neurons, 24% exhibited movement-related activity modulation as an increase of the firing rate, suggesting a predominant role of the subthalamic nucleus in motor aspects of the task, while 8% of subthalamic nucleus neurons showed a modulation in response to the attentional cues. In contrast, responsive substantia nigra neurons showed activity changes exclusively associated with attentional aspects of the stepping task (15%). The firing pattern of subthalamic nucleus neurons revealed gait-related firing regularization and a drop of beta oscillations during the stepping performance. During freezing episodes instead, there was a rise of beta oscillatory activity. This study shows for the first time specific, task-related subthalamic nucleus and substantia nigra single-unit activity changes during gait-like movements in humans with differential roles in motor and attentional control of gait. The emergence of perturbed firing patterns in the subthalamic nucleus indicates a disrupted information transfer within the gait network, resulting in freezing of gait. [ABSTRACT FROM AUTHOR]

Background: Acute appendicitis commonly causes emergency surgery. Clinical examination accuracy ranges from 71-97%; despite ultrasound diagnostic improvements, accuracy depends mainly on operator experience. This study uses a modified version of the Alvarado score, excluding one laboratory finding (shift to the left of neutrophil maturation). As differential count is not routinely undertaken in the study site (Erbil), patients were scored out of 9 rather than 10 points. This study compares the diagnostic accuracy of ultrasound and modified Alvarado score in the diagnosis of acute appendicitis, to reduce appendicitis mortality and morbidity, and reduce rates of negative appendicitis. Methodology: The study design was a prospective cross-sectional comparative study, which took place in the Surgery, Radiology and Histopathology Department of Rizgary Teaching Hospital and Rozhalat Emergency Hospital, Erbil, from January 2019 to December 2021. All patients who presented to the emergency room with signs and symptoms of acute appendicitis were clinically evaluated. Patients who had a modified Alvarado score > 8 were considered positive for modified Alvarado, and those scoring 6-7 were considered negative for modified Alvarado and were considered for ultrasound examination; among the latter, those with positive ultrasound results were included in the study. Results: Among the 468 patients, 257 (54.9%) were male and 211 (45.1%) were female (1.22:1 male: female ratio), with a mean age of 23.45 ± 2.1 years (ranging from 12 to 56 years). Modified ultrasonography has a sensitivity of 82% and an accuracy of 79.9%; the modified Alvarado score had a sensitivity of 95.2% and an accuracy of 87%. There was no association between the mean age of male and female patients with the histopathological results. The most commonly affected age group was the cohort 21-30 years (51.7% of all patients). The number of patients with positive histopathology was 411; negative histopathology was recorded for 57 patients, with no association between histopathological results and gender. There was a significant association between symptoms (cough signs, localized tenderness signs, and pointing signs) and positive histopathology findings. Conclusion: Modified Alvarado score has higher sensitivity than ultrasound, while ultrasound has a higher specificity. Neither tool is superior to the other, nor both need to be used together to reduce negative appendectomy rates. [ABSTRACT FROM AUTHOR]

Oral levodopa is the gold-standard therapy for treating Parkinson's disease (PD) but after a few years of treatment the therapeutic window narrows, and patients often experience various treatment-related complications. Patients in this advanced PD stage may benefit from alternative therapy, such as continuous intrajejunal delivery of levodopa-carbidopa intestinal gel (LCIG; or carbidopa-levodopa enteral suspension), continuous intrajejunal delivery of levodopa-carbidopa-entacapone intestinal gel, or continuous subcutaneous apomorphine infusion. Consideration and initiation of infusion therapies in advanced PD are suggested before the onset of major disability. The present review summarizes clinical evidence for infusion therapy in advanced PD management, discusses available screening tools for advanced PD, and provides considerations around optimal use of infusion therapy. [ABSTRACT FROM AUTHOR]

Somatoscopy is a systematic and cumulative visual examination of the morphological features of an individual. Physical anthropologists have classified humans into certain specific groups on the basis of specific morphoscopical features, and such variations have been widely studied. Fourteen somatoscopic traits of 800 adult (>25years) Ladakhi individuals, belonging to two Kargil (India) tribal groups (Brokpas and Purigpas) were examined; four hundred (N=400) healthy individuals from each tribe i.e., 221 males and 179 females of the Brokpa tribe and 210 males and 190 females of the Purigpa tribe, comprised the present study sample. Statistically significant differences were noticed between the Brokpas and the Purigpas with respect to the frequencies distribution of their skin colour, hair form, facial contour/profile, nasal types and presence/absence of epicanthic fold, prognathism, Darwin's tubercle, Adam's apple, scaphoid, attached ear lobe etc. The Brokpas exhibited significant sex differences in skin colour, eye colour, hair form, nasal septum, nasal tip, epicanthic fold, ear lobe, and Adam apple, whereas only skin colour, eye colour, ear lobe attachment, hair form, and prognathism were found significantly different in the two sexes of Purigpas. The morphological variation and sexual dimorphism in the human physical features of the two Ladakhi tribes will add to the existing knowledge regarding the anthropological characteristics of different ethnic groups of India. The differences in their morphological traits may be due to the differences in their genetic adaptations as the two tribal groups originated from two different ancient populations i.e., the Brokpas are of the European origin and the Purigpas are the descendants of the Tibeto-Mongoloids. The results of this study, however, need to be supplemented with a compressive investigation to confirm the heterogeneity in the morphological and genetic features of the two tribal groups of Ladakh (India) and the influence of differential ancestral migrations on the facial features of the individuals of the two tribal groups. [ABSTRACT FROM AUTHOR]

Lesioning and 2-deoxyglucose (2-DG) autoradiographic studies were applied to the hyperactivity induced in rats by intra-accumbens treatment with the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydro-naphthalene (ADTN). Lesions made in substantia innominata and rostro-ventral globus pallidus both attenuated the hyperactivity although no consistent changes in 2-DG uptake were recorded in these areas. Compared to normal rats, hyperactive rats showed greatly increased glucose utilization in the subthalamic nucleus and lateral habenula. Lesioning the subthalamic nucleus greatly reduced the hyperactivity, whereas a lateral habenula lesion was ineffective. Hyperactivity was associated with a discrete, bilateral area of increased 2-DG uptake in the reticular formation which corresponded to the description of the deep mesencephalic nucleus (DMN). Lesions made in the DMN greatly attenuated the hyperactivity response. The DMN may be a locomotor region in the rat.

The regional distribution of 5-hydroxytryptamine-1 receptors in the primate brain was studied by semi-quantitative autoradiographic analysis of tritiated ligand binding. Areas showing the highest density of 5-hydroxytryptamine-1 receptors (greater than 200 fmol [3H]5-hydroxytryptamine bound per mg tissue), included the cerebral cortex (laminae I-II), claustrum, posterior cell group of the basal nucleus of Meynert, the infracommissural part of the globus pallidus, cortical amygdaloid nucleus, hippocampal formation (CA1-subiculum region, the anterior CA2, CA3 and CA4 regions and the molecular layer of the dentate gyrus), thalamic nuclei (parafascicular, parataenial, paraventricular and superior central lateral nuclei), substantia nigra pars reticulata, dorsal raphe nucleus and choroid plexus. The distribution of 5-hydroxytryptamine-1 receptors is compared to the distribution of both 5-hydroxytryptamine receptors and terminal fields of serotonergic projections as previously described in subprimates.

The use of optical density ratios to describe changes in [14C]2-deoxyglucose uptake in neuroanatomical mapping experiments has recently been criticized. It has been argued that a fixed ratio of tissue isotope concentration does not yield a constant optical density ratio but is dependent on the exposure time and the absolute amounts of isotope used. Here it is demonstrated that such variations in optical density ratios are due to an artifact in calculating the optical density ratio, which can easily be corrected provided that the film is not approaching saturation and not due to the non-linearity of an exposure-density curve as has previously been suggested.

The 2-deoxyglucose metabolic mapping technique has been used to investigate the neural mechanisms which underlie the symptoms of Parkinsonism in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine primate model of Parkinson's disease. In six cynomolgus monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was either (a) administered intravenously to induce generalized Parkinsonism, or (b) infused into one carotid artery to induce unilateral Parkinsonism. Post-mortem examination revealed profound cell loss from the substantia nigra, pars compacta either bilaterally or unilaterally in the two groups, respectively. In addition, there was pathological involvement of the ventral tegmental area and locus coeruleus in animals receiving intravenous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 2-Deoxyglucose autoradiography revealed widespread changes in 2-deoxyglucose uptake in the brains of parkinsonian animals when compared to controls. Most of these changes were in basal ganglia and related structures and were qualitatively similar in the two groups of experimental animals. Prominent increases in 2-deoxyglucose uptake were observed in the lateral segment of the globus pallidus (24-27%), the ventral anterior and ventral lateral nuclei of the thalamus (14-22%) and the nucleus tegmenti pedunculopontinus of the caudal midbrain (17-69%). A profound decrease (17-26%) in 2-deoxyglucose uptake was observed in the subthalamic nucleus. We propose these data to indicate that in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism there is the following pattern of abnormal neuronal activity in basal ganglia circuitry: (i) increased activity in the projection from the putamen to the lateral segment of the globus pallidus; (ii) decreased activity in the projection from the putamen to the medial segment of the globus pallidus; (iii) decreased activity in the projection from the lateral segment of the globus pallidus to the subthalamic nucleus; (iv) increased activity in the projection from the subthalamic nucleus to the globus pallidus; and (v) increased activity in neurons of the medial segment of the globus pallidus projecting to the ventral anterior/ventral lateral thalamus and the pedunculopontine nucleus. These results are compared to the 2-deoxyglucose uptake findings in previous studies from this laboratory in hemiballism and hemichorea in the monkey. The central importance of the subthalamic nucleus in all three conditions is proposed, and supportive evidence for the excitatory nature of subthalamic efferent fibres is adduced.

Three monkeys received a chronic intravenous course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) so as to produce a permanent parkinsonian syndrome. One primate was electively commenced on chronic levodopa therapy 6 weeks after the cessation of MPTP treatment. Four months following the termination of MPTP administration, the response to oral doses of the novel D-2 dopamine agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was assessed in all animals using a clinical rating scale and automatic activity counters. PHNO was found to be a highly potent antiparkinsonian agent, completely reversing the symptoms of parkinsonism in a dose-dependent manner. Peak-dose dyskinesia was noted in 2 MPTP-treated animals during trials with PHNO, but was more severe in the animal receiving chronic levodopa therapy. Response fluctuations such as 'end-of-dose' deterioration and the 'on-off' phenomenon were common to all 3 parkinsonian animals following PHNO. The anti-parkinsonian effect and frequency of treatment-induced side-effects appeared to be similar with PHNO and levodopa. These results confirm the efficacy of PHNO as an anti-parkinsonian drug and link the production of dyskinesia with the D-2 dopamine receptor.

Hemichorea/hemiballismus was induced in monkeys by localized injections of a gamma-aminobutyric acid antagonist into the contralateral subthalamic nucleus. During active dyskinesia, [3H]-2-deoxyglucose was administered and, subsequently, regional cerebral metabolic activity was examined by autoradiographic exposure of brain sections. The results indicate that during dyskinesia there was an overall decrease in local cerebral glucose utilization in a number of structures on the side of the brain contralateral to the abnormal movements (ipsilateral to the drug injection). These structures included the injected subthalamic nucleus, both medial and lateral segments of the globus pallidus, the substantia nigra, and the ventral anterior and ventral lateral nuclei of the thalamus. On the basis of evidence that changes in the energy requirement of neurons are due mainly to changes in synaptic activity, the autoradiographic findings are interpreted as indicating that during experimental hemichorea/hemiballismus there was an overall decrease in synaptic activity of subthalamopallidal, subthalamonigral and pallidothalamic pathways on the side of the brain contralateral to the dyskinesia. This interpretation is discussed in relation to current theories of the pathophysiology of choreiform dyskinesias.

Neurones in the substantia nigra of the rat, anaesthetized with urethane, are inhibited both by electrical stimulation of the ipsilateral caudate nucleus and by iontophoretically applied gamma-aminobutyric acid (GABA). Iontophoretically applied picrotoxin reversibly blocks both of these inhibitory responses. These results are consistent with the hypothesis that GABA is the transmitter released by the inhibitory striato-nigral pathway.