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Background and Objectives : This study was performed for the purpose of assessing whether antiepileptic levetiracetam treatment produces a change in brain volumes in children with epilepsy. To that end, we compared the volumes of the basal ganglia (caudate nucleus, putamen, globus, hip-pocampus, and thalamus) at magnetic resonance imaging (MRI) before and after treatment (months 18-24) in pediatric epilepsy patients using levetiracetam. Materials and Methods : This retrospective study involved a volumetric comparison of patients presenting to the Balikesir University Medical Faculty pediatric neurology clinic between 01.08.2019 and 01.11.2023 and diagnosed with epilepsy, and who underwent cranial MRI before and 18-24 months after treatment at the radiology department. The demographic and clinical characteristics (age, sex, family history of epilepsy, type of epilepsy, and EEG features (normal, abnormal, epileptiform)) of the patients included in the study were recorded. Results: The comparison of basal ganglia volumes at cranial MRI before and at months 18-24 of treatment revealed significant differences in the left caudate nucleus, right putamen, left putamen, left globus pallidus, right thalamus, left thalamus, and right hippocampal regions. Conclusions: In conclusion, differing findings are encountered at cranial imaging in patients with epilepsy, depending on the seizure frequency, activity, and the type of antiepileptic drugs used. This study compared basal ganglia volumes on cranial MRIs taken before and 18-24 months after treatment in pediatric epilepsy patients using levetiracetam. A significant increase was observed in the volumes of basal ganglia (caudate nucleus, putamen, globus pallidus, hippocampus, and thalamus) on the MRIs of pediatric epilepsy patients using levetiracetam.

Objective: One proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in-vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown., Methods: We performed a double-blinded, cross-over, placebo-controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31 phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain., Results: In total, 20 (6 female) patients with Parkinson's disease and 22 sex- and age-matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high-energy phosphorus-containing metabolites in the basal ganglia (patients with Parkinson's disease: -40%; healthy controls: -39%) but not in the midbrain. There were no differences in high-energy phosphorus-containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response., Interpretation: Exogenously administered levodopa/benserazide strongly interferes with basal ganglia high-energy phosphorus-containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024;95:849-857., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration. Recent findings in animal models of PD propose tonic inhibition of the remaining DA neurons through GABA release from reactive glial cells. Movement dysfunctions could be ameliorated by promotion of activity in dormant DA cells. The endocannabinoid system (ECS) is extensively present in basal ganglia (BG) and is known as an indirect modulator of DAergic neurotransmission, thus drugs designed to target this system have shown promising therapeutic potential in PD patients. Interestingly, down/up-regulation of cannabinoid receptors (CBRs) varies across the different stages of PD, suggesting that some of the motor/ non-motor deficits may be related to changes in CBRs. Determination of the profile of changes of these receptors across the different stages of PD as well as their neural distribution within the BG could improve understanding of PD and identify pathways important in disease pathobiology. In this review, we focus on temporal and spatial alterations of CBRs during PD in the BG. At present, as inconclusive, but suggestive results have been obtained, future investigations should be conducted to extend preclinical studies examining CBRs changes within each stage in controlled clinical trials in order to determine the potential of targeting CBRs in management of PD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks., (© 2021. The Author(s).)

Objectives: The objective of this study is to describe the mechanism of damage to subcortical structures in chronic kidney disease (CKD) and to describe the range of movement disorders associated with CKD., Materials and Methods: We have reviewed the Medline literature up to January of 2020 using key words movement disorders and chronic kidney disease. The reviewed articles were studied for mechanisms of subcortical damage in CKD as well as type of the reported movements, their frequency and updated treatment., Results: The search revealed 183 articles most of them dealing with restless legs syndrome. The damage to basal ganglia in CKD resulted from several mechanisms including accumulation of nitro tyrosine caused by reactive oxygen species and action of uremic toxins leading to endothelial damage and dysfunction of blood-brain barrier. Involuntary movements in CKD include restless legs syndrome (RLS), myoclonus, asterixis, dystonia, chorea, tremor, and Parkinsonism., Conclusions: Chronic kidney disease can cause several abnormal involuntary movements via damaging basal ganglia and subcortical structures. The most common movement disorders in CKD are RLS, myoclonus and asterixis. Restless legs syndrome and myoclonus when severe, need and respond to treatment. Movement disorders in CKD improve with improvement of kidney function., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Parkinson's disease (PD) is a common neurological degenerative disease that cannot be completely cured, although drugs can improve or alleviate its symptoms. Optogenetic technology, which stimulates or inhibits neurons with excellent spatial and temporal resolution, provides a new idea and approach for the precise treatment of Parkinson's disease. However, the neural mechanism of photogenetic regulation remains unclear., Objective: In this paper, we want to study the nonlinear features of EEG signals in the striatum and globus pallidus through optogenetic stimulation of the substantia nigra compact part., Methods: Rotenone was injected stereotactically into the substantia nigra compact area and ventral tegmental area of SD rats to construct rotenone-treated rats. Then, for the optogenetic manipulation, we injected adeno-associated virus expressing channelrhodopsin to stimulate the globus pallidus and the striatum with a 1 mW blue light and collected LFP signals before, during, and after light stimulation. Finally, the collected LFP signals were analyzed by using nonlinear dynamic algorithms., Results: After observing the behavior and brain morphology, 16 models were finally determined to be successful. LFP results showed that approximate entropy and fractal dimension of rats in the control group were significantly greater than those in the experimental group after light treatment ( p < 0.05). The LFP nonlinear features in the globus pallidus and striatum of rotenone-treated rats showed significant statistical differences before and after light stimulation ( p < 0.05)., Conclusion: Optogenetic technology can regulate the characteristic value of LFP signals in rotenone-treated rats to a certain extent. Approximate entropy and fractal dimension algorithm can be used as an effective index to study LFP changes in rotenone-treated rats., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2021 Zongya Zhao et al.)

l-3,4-dihydroxyphenylalanine (l-DOPA) is an effective treatment for Parkinson's disease (PD); however, long-term treatment induces l-DOPA-induced dyskinesia (LID). To elucidate its pathophysiology, we developed a mouse model of LID by daily administration of l-DOPA to PD male ICR mice treated with 6-hydroxydopamine (6-OHDA), and recorded the spontaneous and cortically evoked neuronal activity in the external segment of the globus pallidus (GPe) and substantia nigra pars reticulata (SNr), the connecting and output nuclei of the basal ganglia, respectively, in awake conditions. Spontaneous firing rates of GPe neurons were decreased in the dyskinesia-off state (≥24 h after l-DOPA injection) and increased in the dyskinesia-on state (20-100 min after l-DOPA injection while showing dyskinesia), while those of SNr neurons showed no significant changes. GPe and SNr neurons showed bursting activity and low-frequency oscillation in the PD, dyskinesia-off, and dyskinesia-on states. In the GPe, cortically evoked late excitation was increased in the PD and dyskinesia-off states but decreased in the dyskinesia-on state. In the SNr, cortically evoked inhibition was largely suppressed, and monophasic excitation became dominant in the PD state. Chronic l-DOPA treatment partially recovered inhibition and suppressed late excitation in the dyskinesia-off state. In the dyskinesia-on state, inhibition was further enhanced, and late excitation was largely suppressed. Cortically evoked inhibition and late excitation in the SNr are mediated by the cortico-striato-SNr direct and cortico-striato-GPe-subthalamo-SNr indirect pathways, respectively. Thus, in the dyskinesia-on state, signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed, underlying LID. SIGNIFICANCE STATEMENT Parkinson's disease (PD) is caused by progressive loss of midbrain dopaminergic neurons, characterized by tremor, rigidity, and akinesia, and estimated to affect around six million people world-wide. Dopamine replacement therapy is the gold standard for PD treatment; however, control of symptoms using l-3,4-dihydroxyphenylalanine (l-DOPA) becomes difficult over time because of abnormal involuntary movements (AIMs) known as l-DOPA-induced dyskinesia (LID), one of the major issues for advanced PD. Our electrophysiological data suggest that dynamic changes in the basal ganglia circuitry underlie LID; signals through the direct pathway that release movements are enhanced, while signals through the indirect pathway that stop movements are suppressed. These results will provide the rationale for the development of more effective treatments for LID., (Copyright © 2021 the authors.)

Context: Investigate whether 123 I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning., Methods: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANT TM and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements., Results: Forty-two patients (mean age 46.3 ± 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume ( r  = 0.665; p  < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I ( p  < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH ( r  = 0.574; p  < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations ( p  < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness ( p  < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902; p  = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen., Conclusion: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.

Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities is an extremely rare autosomal recessive mitochondrial disease caused by biallelic mutations in MECR. Using whole-exome sequencing, we identified a novel homozygous MECR mutation (c.910G > T, p.Asp304Tyr) in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy. With lipoic acid treatment, the disease progression was under control, and neither visual impairment nor optic atrophy was observed. To our knowledge, this is the first study about MECR-related mitochondrial disease in a Chinese patient and the first to report that supplementation with lipoic acid is a possible effective therapeutic strategy for this disease., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Levodopa is considered the gold standard treatment of Parkinson's disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa's effect duration and to the appearance of motor complications. This evolution challenges the establishment of optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson's disease to evaluate motor function in response to levodopa treatment as the disease progresses. We combined a pharmacokinetic model of levodopa to a model of dopamine's kinetics and a neurocomputational model of basal ganglia. The parameter values were either measured directly or estimated from human and animal data. The concentrations and behaviors predicted by our model were compared to available information and data. Using this model, we were able to predict levodopa plasma concentration, its related dopamine concentration in the brain and the response performance of a motor task for different stages of disease.

The basal ganglia (BG) are involved in cognitive/motivational functions in addition to movement control. Thus, BG segregated circuits, the sensorimotor (SM) and medial prefrontal (mPF) circuits, process different functional domains, such as motor and cognitive/motivational behaviours, respectively. With a high presence in the BG, the CB1 cannabinoid receptor modulates BG circuits. Furthermore, dopamine (DA), one of the principal neurotransmitters in the BG, also plays a key role in circuit functionality. Taking into account the interaction between DA and the endocannabinoid system at the BG level, we investigated the functioning of BG circuits and their modulation by the CB1 receptor under DA-depleted conditions. We performed single-unit extracellular recordings of substantia nigra pars reticulata (SNr) neurons with simultaneous cortical stimulation in sham and 6-hydroxydopamine (6-OHDA)-lesioned rats, together with immunohistochemical assays. We showed that DA loss alters cortico-nigral information processing in both circuits, with a predominant transmission through the hyperdirect pathway in the SM circuit and an increased transmission through the direct pathway in the mPF circuit. Moreover, although DA denervation does not change CB1 receptor density, it impairs its functionality, leading to a lack of modulation. These data highlight an abnormal transfer of information through the associative/limbic domains after DA denervation that may be related to the non-motor symptoms manifested by Parkinson's disease patients., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Dopaminergic medication for Parkinson's disease is associated with troubling dystonia and dyskinesia and, in rodents, dopaminergic agonists likewise induce a variety of orofacial motor responses, certain of which are mimicked by serotonin2C (5-HT 2C ) receptor agonists. However, the neural substrates underlying these communalities and their interrelationship remain unclear. In Sprague-Dawley rats, the dopaminergic agonist, apomorphine (0.03-0.3 mg/kg) and the preferential D2/3 receptor agonist quinpirole (0.2-0.5 mg/kg), induced purposeless oral movements (chewing, jaw tremor, tongue darting). The 5-HT 2C receptor antagonist 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxyl]-5-pyridyl]carbamoyl]-6-trifluoromethylindone (SB 243213) (1 mg/kg) reduced the oral responses elicited by specific doses of both agonists (0.1 mg/kg apomorphine; 0.5 mg/kg quinpirole). After having confirmed that the oral bouts induced by quinpirole 0.5 mg/kg were blocked by another 5-HT 2C antagonist (6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridine-3-yl carbamoyl] indoline (SB 242084), 1 mg/kg), we mapped the changes in neuronal activity in numerous sub-territories of the basal ganglia using c-Fos expression. We found a marked increase of c-Fos expression in the subthalamic nucleus (STN) in combining quinpirole (0.5 mg/kg) with either SB 243213 or SB 242084. In a parallel set of electrophysiological experiments, the same combination of SB 243213/quinpirole produced an irregular pattern of discharge and an increase in the firing rate of STN neurons. Finally, it was shown that upon the electrical stimulation of the anterior cingulate cortex, quinpirole (0.5 mg/kg) increased the response of substantia nigra pars reticulata neurons corresponding to activation of the "hyperdirect" (cortico-subthalamonigral) pathway. This effect of quinpirole was abolished by the two 5-HT 2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT 2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

Whereas monoamine oxidase (MAO) type B inhibitors are used as adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in the treatment of Parkinson's disease (PD), the enzyme MAO type A (MAO-A) also participates in the metabolism of dopamine in the human and primate striatum. Here, we sought to assess the effect of the selective reversible MAO-A inhibitor moclobemide on L-DOPA anti-parkinsonian in the gold standard animal model of PD, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. We also assessed the effect of moclobemide on L-DOPA-induced dyskinesia and psychosis-like behaviours (PLBs). Experiments were performed in six MPTP-lesioned marmosets chronically treated with L-DOPA and exhibiting stable dyskinesia and PLBs upon each administration. In a randomised within-subject design, animals were administered a therapeutic dose of L-DOPA in combination with moclobemide (0.1, 1 and 10 mg/kg) or its vehicle, after which the severity of parkinsonism, dyskinesia, and PLBs was rated by an experienced blinded rater. Moclobemide significantly reduced the global parkinsonian disability (- 36% with 0.1 mg/kg, P < 0.05; - 38% with 1 mg/kg, P < 0.01; - 47% with 10 mg/kg, P < 0.01), when compared with its vehicle. This reduction of parkinsonism was not accompanied by an exacerbation of dyskinesia or PLBs. Reversible MAO-A inhibition with moclobemide appears as an effective way to increase the anti-parkinsonian action of L-DOPA, without negatively affecting dyskinesia or dopaminergic psychosis.

Monoamine oxidase (MAO) type B (MAO-B) inhibition was shown to confer anti-parkinsonian benefit as monotherapy and adjunct to L-3,4-dihydroxyphenylalanine (L-DOPA) in clinical trials. Here, we explore the anti-parkinsonian effect of MAO type A (MAO-A) inhibition as monotherapy, as the enzyme MAO-A is also encountered within the primate and human basal ganglia, where it metabolises dopamine, albeit to a lesser extent than MAO-B. In six 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmosets, we assessed the anti-parkinsonian effect of the reversible MAO-A inhibitor moclobemide (0.1 and 1 mg/kg) as monotherapy and compared it to that of L-DOPA and vehicle treatments. Moclobemide significantly reversed parkinsonism (by 39%, P < 0.01), while eliciting only mild dyskinesia and psychosis-like behaviours (PLBs). In contrast, L-DOPA anti-parkinsonian effect was accompanied by marked dyskinesia and PLBs. MAO-A inhibition with moclobemide may provide anti-parkinsonian benefit when administered without L-DOPA and might perhaps be considered as monotherapy for the treatment of Parkinson's disease in the early stages of the condition.

The claustrum is a small nucleus, exhibiting vast reciprocal connectivity with cortical, subcortical, and midbrain regions. Recent studies, including ours, implicate the claustrum in salience detection and attention. In the current study, we develop an iterative functional investigation of the claustrum, guided by quantitative spatial transcriptional analysis. Using this approach, we identify a circuit involving dopamine-receptor expressing claustral neurons projecting to frontal cortex necessary for context association of reward. We describe the recruitment of claustral neurons by cocaine and their role in drug sensitization. In order to characterize the circuit within which these neurons are embedded, we apply chemo- and opto-genetic manipulation of increasingly specified claustral subpopulations. This strategy resolves the role of a defined network of claustrum neurons expressing dopamine D1 receptors and projecting to frontal cortex in the acquisition of cocaine conditioned-place preference and real-time optogenetic conditioned-place preference. In sum, our results suggest a role for a claustrum-to-frontal cortex circuit in the attribution of incentive salience, allocating attention to reward-related contextual cues., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Basal ganglia lesions are typical findings on magnetic resonance imaging (MRI) of the brain in survivors of acute methanol poisoning. However, no data are available on the association between the magnitude of damaged brain regions, serum concentrations of markers of acute methanol toxicity, oxidative stress, neuroinflammation, and the rate of retinal nerve ganglion cell loss., Objectives: To investigate the association between MRI-based volumetry of the basal ganglia, retinal nerve fibre layer (RNFL) thickness and prognostic laboratory markers of outcomes in acute methanol poisoning., Methods: MRI-based volumetry of putamen, nucleus caudatus and globus pallidus was performed and compared with laboratory parameters of severity of poisoning and acute serum markers of oxidative damage of lipids (8-isoprostan, MDA, HHE, HNE), nucleic acids (8-OHdG, 8-OHG, 5-OHMU), proteins (o-Thyr, NO-Thyr, Cl-Thyr) and leukotrienes (LTC4, LTD4, LTE4, LTB4), as well as with the results of RNFL measurements by optic coherence tomography (OCT) in 16 patients with acute methanol poisoning (Group I) and in 28 survivors of poisoning two years after discharge with the same markers measured within the follow-up examination (Group II). The control group consisted of 28 healthy subjects without methanol poisoning., Results: The survivors of acute methanol poisoning had significantly lower volumes of basal ganglia than the controls. The patients with MRI signs of methanol-induced toxic brain damage had significantly lower volumes of basal ganglia than those without these signs. A positive correlation was found between the volume of putamen and arterial blood pH on admission (r = 0.45; p = 0.02 and r = 0.44; p = 0.02 for left and right putamen, correspondingly). A negative correlation was present between the volumes of putamen and acute serum lactate (r = -0.63; p < 0.001 and r = -0.59; p = 0.01), creatinine (r = -0.53; p = 0.01 and r = -0.47; p = 0.01) and glucose (r = -0.55; p < 0.001 and r = -0.50; p = 0.01) concentrations. The volume of basal ganglia positively correlated with acute concentrations of markers of lipoperoxidation (8-isoprostan: r = 0.61; p < 0.05 and r = 0.59; p < 0.05 for left and right putamen, correspondingly) and inflammation (leukotriene LTB4: r = 0.61; p < 0.05 and r = 0.61; p < 0.05 for left and right putamen, correspondingly). The higher the volume of the basal ganglia, the higher the thickness of the RNFL, with the strongest positive association between global RNFL and the volume of putamen bilaterally (all p < 0.01). In the follow-up markers of oxidative stress and inflammation, only o-Thyr concentration negatively correlated with the volume of putamen bilaterally (r = -0.39; p < 0.05 and r = -0.37; p < 0.05 for left and right putamen, correspondingly)., Conclusion: In survivors of acute methanol poisoning with signs of toxic brain damage, the magnitude of affected areas correlated with acute parameters of severity of poisoning, markers of oxidative stress and neuroinflammation. There was a positive association between the basal ganglia volume and the thickness of RNFL, making OCT an important screening test and MRI-based volumetry the confirmative diagnostic method for the detection of CNS sequelae of methanol poisoning., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Delta oscillations (0.5-4 Hz) are a robust feature of basal ganglia pathophysiology in patients with Parkinson's disease (PD) in relationship to tremor, but their relationship to other parkinsonian symptoms has not been investigated. While delta oscillations have been observed in mouse models of PD, they have only been investigated in anesthetized animals, suggesting that the oscillations may be an anesthesia artifact and limiting the ability to relate them to motor symptoms. Here, we establish a novel approach to detect spike oscillations embedded in noise to provide the first study of delta oscillations in awake, dopamine-depleted mice. We find that approximately half of neurons in the substantia nigra pars reticulata (SNr) exhibit delta oscillations in dopamine depletion and that these oscillations are a strong indicator of dopamine loss and akinesia, outperforming measures such as changes in firing rate, irregularity, bursting, and synchrony. These oscillations are typically weakened, but not ablated, during movement. We further establish that these oscillations are caused by the loss of D2-receptor activation and do not originate from motor cortex, contrary to previous findings in anesthetized animals. Instead, SNr oscillations precede those in M1 at a 100- to 300-ms lag, and these neurons' relationship to M1 oscillations can be used as the basis for a novel classification of SNr into two subpopulations. These results give insight into how dopamine loss leads to motor dysfunction and suggest a reappraisal of delta oscillations as a marker of akinetic symptoms in PD. NEW & NOTEWORTHY This work introduces a novel method to detect spike oscillations amidst neural noise. Using this method, we demonstrate that delta oscillations in the basal ganglia are a defining feature of awake, dopamine-depleted mice and are strongly correlated with dopamine loss and parkinsonian motor symptoms. These oscillations arise from a loss of D2-receptor activation and do not require motor cortex. Similar oscillations in human patients may be an underappreciated marker and target for Parkinson's disease (PD) treatment.

Despite its first description more than 75 years ago, effective treatment for "Allan-Herndon-Dudley-Syndrome (AHDS)", an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum , most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a "Trojan horse mechanism" by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Although pain is a prevalent nonmotor symptom in Parkinson's disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

The precise understanding of the dopaminergic (DA) system and its pharmacological modifications is crucial for diagnosis and treatment of neuropsychiatric disorders, as well as for understanding basic processes, such as motivation and reward. We probed the functional connectivity (FC) of subcortical nuclei related to the DA system according to seed regions defined according to an atlas of subcortical nuclei. We conducted a large pharmaco-fMRI study using a double-blind, placebo-controlled design, where we examined the effect of l -DOPA, a dopamine precursor, and amisulpride, a D2/D3-receptor antagonist on resting-state FC in 45 healthy young adults using a cross-over design. We examined the FC of subcortical nuclei with connection to the reward system and their reaction to opposing pharmacological probing. Amisulpride increased FC from the putamen to the precuneus and from ventral striatum to precentral gyrus. l -DOPA increased FC from the ventral tegmental area (VTA) to the insula/operculum and between ventral striatum and ventrolateral prefrontal cortex and it disrupted ventral striatal and dorsal caudate FC with the medial prefrontal cortex. In an exploratory analysis, we demonstrated that higher self-rated impulsivity goes together with a significant increase in VTA-mid-cingulate gyrus FC during l -DOPA-challenge. Therefore, our DA challenge modulated distinct large-scale subcortical connectivity networks. A dopamine-boost can increase midbrain DA nuclei connectivity to the cortex. The involvement of the VTA-cingulum connectivity in dependence of impulsivity has implications for diagnosis and therapy in disorders like ADHD., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

The motor thalamus (MTh) plays a crucial role in the basal ganglia (BG)-cortical loop in motor information codification. Despite this, there is limited evidence of MTh functionality in normal and Parkinsonian conditions. To shed light on the functional properties of the MTh, we examined the effects of acute and chronic dopamine (DA) depletion on the neuronal firing of MTh neurons, cortical/MTh interplay and MTh extracellular concentrations of glutamate (GLU) and gamma-aminobutyric acid (GABA) in two states of DA depletion: acute depletion induced by the tetrodotoxin (TTX) and chronic denervation obtained by 6-hydroxydopamine (6-OHDA), both infused into the medial forebrain bundle (MFB) in anesthetized rats. The acute TTX DA depletion caused a clear-cut reduction in MTh neuronal activity without changes in burst content, whereas the chronic 6-OHDA depletion did not modify the firing rate but increased the burst firing. The phase correlation analysis underscored that the 6-OHDA chronic DA depletion affected the MTh-cortical activity coupling compared to the acute TTX-induced DA depletion state. The TTX acute DA depletion caused a clear-cut increase of the MTh GABA concentration and no change of GLU levels. On the other hand, the 6-OHDA-induced chronic DA depletion led to a significant reduction of local GABA and an increase of GLU levels in the MTh. These data show that MTh is affected by DA depletion and support the hypothesis that a rebalancing of MTh in the chronic condition counterbalances the profound alteration arising after acute DA depletion state.

Parkinson's disease (PD) is a progressive neurodegenerative disease, which causes a tremendous socioeconomic burden. PD patients are suffering from debilitating motor and nonmotor symptoms. Cardinal motor symptoms of PD, including akinesia, bradykinesia, resting tremor, and rigidity, are caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta. In addition, decreased amounts of dopamine (DA) level in the basal ganglia induces numerous adaptive changes at the cellular and synaptic levels in the basal ganglia circuits. These cellular and synaptic adaptations are believed to underlie the emergence and propagation of correlated, rhythmic pattern of activity throughout the interconnected cortico-basal ganglia-thalamocortical network. The widespread pathological pattern of brain activity is closely linked to the devastating motor symptoms of PD. Accumulating evidence suggests that both dopaminergic degeneration and the associated abnormal cellular and circuit activity in the basal ganglia drive the motor symptoms of PD. In this short review I summarize the recent advances in our understanding of synaptic and cellular alterations in two basal ganglia nuclei (i.e. the striatum and the subthalamic nucleus) following a complete loss of DA, and in our conceptual understanding of the cellular and circuit bases for the pathological pattern of brain activity in parkinsonian state.

Parkinson disease (PD) is characterized by a clear beneficial motor response to levodopa (LD) treatment. However, with disease progression and longer LD exposure, drug-related motor fluctuations usually occur. Recognition of the individual relationship between LD concentration and its effect may be difficult, due to the complexity and variability of the mechanisms involved. This work proposes an innovative procedure for the automatic estimation of LD pharmacokinetics and pharmacodynamics parameters, by a biologically-inspired mathematical model. An original issue, compared with previous similar studies, is that the model comprises not only a compartmental description of LD pharmacokinetics in plasma and its effect on the striatal neurons, but also a neurocomputational model of basal ganglia action selection. Parameter estimation was achieved on 26 patients (13 with stable and 13 with fluctuating LD response) to mimic plasma LD concentration and alternate finger tapping frequency along four hours after LD administration, automatically minimizing a cost function of the difference between simulated and clinical data points. Results show that individual data can be satisfactorily simulated in all patients and that significant differences exist in the estimated parameters between the two groups. Specifically, the drug removal rate from the effect compartment, and the Hill coefficient of the concentration-effect relationship were significantly higher in the fluctuating than in the stable group. The model, with individualized parameters, may be used to reach a deeper comprehension of the PD mechanisms, mimic the effect of medication, and, based on the predicted neural responses, plan the correct management and design innovative therapeutic procedures., Competing Interests: The authors have declared that no competing interests exist.

Neuropsychiatric (NP) manifestations of systemic lupus erythematosus (SLE) are diverse, but involvement of basal ganglia is rare. We describe here a 28-year-old woman with NPSLE presenting aseptic meningitis accompanied by elevated interleukin-6 levels in the cerebrospinal fluid, who developed symmetrical basal ganglia lesions, containing a cytotoxic oedematous core, surrounded by vasogenic oedema upon magnetic resonance imaging. We were able to observe these lesions from a de novo appearance during the disease onset to its disappearance during immunosuppressive treatment. Reversibility upon immunosuppressive treatment indicated that autoimmune mediated mechanisms could contribute to the basal ganglia lesions in NPSLE.

Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson's disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder.

Tyrosine hydroxylase (TH) catalyzes the hydroxylation of L-tyrosine to L-DOPA. This is the rate-limiting step in the biosynthesis of the catecholamines - dopamine (DA), norepinephrine (NE), and epinephrine (EP). Catecholamines (CA) play a key role as neurotransmitters and hormones. Aberrant levels of CA are associated with multiple medical conditions, including Parkinson's disease. Palm Fruit Bioactives (PFB) significantly increased the levels of tyrosine hydroxylase in the brain of the Nile Grass rat (NGR), a novel and potentially significant finding, unique to PFB among known botanical sources. Increases were most pronounced in the basal ganglia, including the caudate-putamen, striatum and substantia nigra. The NGR represents an animal model of diet-induced Type 2 Diabetes Mellitus (T2DM), exhibiting hyperglycemia, hyperinsulinemia, and insulin resistance associated with hyperphagia and accelerated postweaning weight gain induced by a high-carbohydrate diet (hiCHO). The PFB-induced increase of TH in the basal ganglia of the NGR was documented by immuno-histochemical staining (IHC). This increase in TH occurred equally in both diabetes-susceptible and diabetes-resistant NGR fed a hiCHO. PFB also stimulated growth of the colon microbiota evidenced by an increase in cecal weight and altered microbiome.  The metabolites of colon microbiota, e.g. short-chain fatty acids, may influence the brain and behavior significantly.

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients., (Copyright © 2019. Published by Elsevier B.V.)

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies - including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites - markers of the brain's primary excitatory and inhibitory system - in both the 'typical' and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the 'shift' in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

[ 18 F]AV-1451 is one of the most widely used radiotracers for positron emission tomography (PET) imaging of tau protein aggregates in neurodegenerative disorders. While the radiotracer binds with high affinity to tau neurofibrillary tangles, extensive clinical studies have simultaneously revealed off-target tracer accumulation in areas of low tau burden such as the basal ganglia and choroid plexus. Though there are a number of possible reasons for this accumulation, it is often attributed to off-target binding to monoamine oxidase (MAO). In this paper, we investigate the association between [ 18 F]AV-1451 and MAO through (i) enzyme inhibition assays, (ii) autoradiography with postmortem tissue samples, and (iii) nonhuman primate PET imaging. We confirm that [ 18 F]AV-1451 is a weak inhibitor of MAO-A and -B and that MAO inhibitors can alter binding of [ 18 F]AV-1451 in autoradiography and in vivo PET imaging.

Background: Basal ganglia are particularly important for understanding the pathobiology of psychosis given their key roles in dopaminergic neurotransmission which are associated with psychotic symptoms and one of the target sites of antipsychotic drugs. Psychotic symptoms are prevalent in both schizophrenia (SZ) and bipolar disorder (BD). Although the components of basal ganglia are implicated in psychosis, comparative structural changes of components of the basal ganglia between SZ and BD are less clear after disentanglement of clinical effects of antipsychotic dose, duration and severity of illness., Methods: In this study, we examined the morphology of the basal ganglia in 326 subjects comprising of 45 patients of BD type I with psychotic symptoms, 97 first-episode SZ (FE-SZ) patients, 86 non-first-episode chronic SZ (NFE-SZ) patients, in comparison with 98 healthy controls (HC)., Results: Results showed increased volumes in subregions of caudate, putamen, and pallidum in chronic SZ patients compared with HC after controlling for age, gender, and total intracranial volume. No change was found between FE-SZ patients, psychotic BD patients, and HC. Furthermore, hierarchical regressions showed that the dosage of antipsychotics had a significant contribution to basal ganglia volumetric enlargement in NFE-SZ after controlling for the effects of age, gender, total intracranial volume, age at illness onset, as well as illness duration and severity., Limitations: Lack of information about the cumulative history of exposure to medication for all the three groups of patients is a major limitation in our study., Conclusions: There are distinct basal ganglia structural changes in SZ and psychotic BD. Basal ganglia are enlarged in chronic SZ but not in FE-SZ and BD and this enlargement is significantly associated with antipsychotic dosage over and beyond the effects of illness duration and severity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Oral contraceptive (OC) effects on the brain have gained increasing interest, but are highly controversial. Previous studies suggest that OC users have larger hippocampi, parahippocampi, fusiform gyri and Cerebelli. Preliminary evidence from one of those studies even suggests an effect of previous contraceptive use on the hippocampi of women who are not current users of OCs. Furthermore, more recent studies postulate an involvement of previous OC treatment in later development of mood disorders. To address the question whether previous OC treatment affects women's brain structure later in life, high resolution structural images were obtained from 131 naturally cycling women. Among them, 52 women had never used OC before, 52 had previously used one OC for a continuous time period and 27 had previously used multiple contraceptives. The groups did not differ in gray matter volumes. Since endogenous sex hormones modulate gray matter volumes of the hippocampus and basal ganglia along the menstrual cycle, we hypothesize effects of OC use on these areas. Specifically, we hypothesize that a longer duration of previous OC treatment is related to larger hippocampi and larger basal ganglia. Indeed we found the duration of previous OC use to be positively correlated to hippocampal and basal ganglia volumes bilaterally. For the hippocampus, but not for the basal ganglia, this association disappeared after controlling for the time since discontinuation. These results suggest that for the hippocampus, but not for the basal ganglia, effects of previous contraceptive treatment are reversed after a time period comparable to treatment duration. These data question the immediate reversibility of OC effects on brain structure. Accordingly, some changes in the brain due to long-term contraceptive use, while subtle, may be long-lasting.

Background and Purpose: In the sensorimotor (SM) and medial prefrontal (mPF) basal ganglia (BG) circuits, the cortical information is transferred to the substantia nigra pars reticulata (SNr) through the hyperdirect trans-subthalamic pathway and through the direct and indirect trans-striatal pathways. The cannabinoid CB 1 receptor, which is highly expressed in both BG circuits, may participate in the regulation of motor and motivational behaviours. Here, we investigated the modulation of cortico-nigral information transmission through the BG circuits by cannabinoids., Experimental Approach: We used single-unit recordings of SNr neurons along with simultaneous electrical stimulation of motor or mPF cortex in anaesthetized rats., Key Results: Cortical stimulation elicited a triphasic response in the SNr neurons from both SM and mPF-BG circuits, which consisted of an early excitation (hyperdirect transmission pathway), an inhibition (direct transmission pathway), and a late excitation (indirect transmission pathway). In the SM circuit, after Δ 9 -tetrahydrocannabinol or WIN 55,212-2 administration, the inhibition and the late excitation were decreased or completely lost, whereas the early excitation response remained unaltered. However, cannabinoid administration dramatically decreased all the responses in the mPF circuit. The CB 1 receptor antagonist AM251 (2 mg·kg -1 , i.v.) did not modify the triphasic response, but blocked the effects induced by cannabinoid agonists., Conclusions and Implications: CB 1 receptor activation modulates the SM information transmission through the trans-striatal pathways and profoundly decreases the cortico-BG transmission through the mPF circuit. These results may be relevant for elucidating the involvement of the cannabinoid system in motor performance and in decision making or goal-directed behaviour., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Parkinson's disease (PD) is a chronic, progressive condition affecting around 1% of the population older than 60 years. Upon long-term treatment with levodopa, the mainstay of treatment in PD, most patients, especially younger ones exposed to higher doses, will experience symptoms related to end-of-dose deterioration, peak-dose dyskinesias, and other motor fluctuations. Therapeutic strategies are grounded on modification of oral levodopa pharmacokinetics to extend levodopa benefit and development of new routes of drug delivery (e.g., levodopa/carbidopa intestinal gel infusion) or long-acting formulations of existing dopaminergic drugs to prolong the duration of striatal dopamine receptors stimulation. As our understanding of the pathophysiology of motor complications evolves, our therapeutic armamentarium is actively expanding and the focus of research is now actively pointing to the new non-dopaminergic agents acting both within the basal ganglia and in other brain regions (e.g., drugs acting on glutamate, GABA, serotonin, and calcium channels). Despite the fact that trials comparing the different therapeutic strategies are lacking, we aimed at devising practical evidence- and experience-guided suggestions for the clinical management of motor complications, emphasizing that this should always be an individualized endeavor. This review summarizes the pharmacological management of motor complications in PD, including new formulations and routes of delivery, and the newer released drugs such as istradefylline, opicapone, safinamide, and zonisamide. Advanced therapeutic strategies for selected cases such as treatment with apomorphine and surgical techniques (deep brain stimulation) are also discussed. A comprehensive knowledge of the available options and evidence is fundamental for the successful management of these challenging complications.

Background: PD is a common neurodegenerative disease primarily affecting the cortico-basal ganglia loop., Objective: To investigate whether chemogenetic-mediated neuromodulation of various nuclei and pathways can counterbalance basal ganglia network abnormalities and improve motor disability in experimental PD., Methods: Experimental PD was induced by stereotactic injection of 6-OHDA to the medial forebrain bundle. Designer receptors exclusively activated by designer drugs were expressed in different basal ganglia nuclei by stereotactic injections of adeno-associated viral vectors. We compared motor performance, monitored by the open-field and rotarod tests, after random and blinded application of either normal saline or the synthetic receptor activator, clozapine-N-oxide., Results: Motor performance, as measured by movement velocity, rotations, and rotarod scores, were significantly improved in PD mice by enhancing the activity of the GPe with Gq custom receptors and by reducing basal ganglia output activity, targeting the output nuclei GPi and SNr with Gi custom receptors., Conclusion: Our findings support the hypothesis that enhanced inhibitory output activity of the basal ganglia complex underlie motor signs in PD, and point to the therapeutic potential of chemogenetic based treatments in PD patients. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Neurotensin (NT) is a 13 amino acid neuropeptide that is expressed throughout the central nervous system and is implicated in the etiology of multiple diseases and disorders. Many primary investigations of NT-induced modulation of neuronal excitability at the level of the synapse have been conducted, but they have not been summarized in review form in nearly 30 years. Therefore, the goal of this review is to discuss the many actions of NT on neuronal excitability across brain regions as well as NT circuit architecture. In the basal ganglia as well as other brain nuclei, NT can act through diverse intracellular signaling cascades to enhance or depress neuronal activity by modulating activity of ion channels, ionotropic and metabotropic neurotransmitter receptors, and presynaptic release of neurotransmitters. Further, NT can produce indirect effects by evoking endocannabinoid release, and recently has itself been identified as a putative retrograde messenger. In the basal ganglia, the diverse actions and circuit architecture of NT signaling allow for input-specific control of reward-related behaviors., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

We propose a model that includes interactions between the cortex, the basal ganglia (BG), and the thalamus based on a dual competition. We hypothesize that the striatum, the subthalamic nucleus (STN), the internal globus pallidus (GPi), the thalamus, and the cortex are involved in closed feedback loops through the hyperdirect and direct pathways. These loops support a competition process that results in the ability of BG to make a cognitive decision followed by a motor one. Considering lateral cortical interactions, another competition takes place inside the cortex allowing the latter to make a cognitive and a motor decision. We show how this dual competition endows the model with two regimes. One is driven by reinforcement learning and the other by Hebbian learning. The final decision is made according to a combination of these two mechanisms with a gradual transfer from the former to the latter. We confirmed these theoretical results on primates ( Macaca mulatta ) using a novel paradigm predicted by the model.

Oculomotor abnormalities are fast becoming a proxy for disease diagnosis and progression. Saccades-ballistic eye movements-are known to be affected by dopaminergic cell loss in the basal ganglia, caused by Parkinson's disease. Pharmaceutical and neurosurgical interventions such as deep brain stimulation and functional neurosurgery have both been noted to have an effect on saccades. Comparing and contrasting these effects may yield insights into Parkinson's disease pathophysiology, and the mechanisms of pharmacological and neurosurgical treatments. Computational models of saccadic control, such as the LATER model, can help to interpret the distribution of saccadic latencies, providing a framework for objectively comparing the effects of pharmaceutical interventions and deep brain stimulation., (© 2019 Elsevier B.V. All rights reserved.)

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BP ND ) was assessed from PET data collected with [ 18 F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [ 18 F]PSS232 BP ND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [ 18 F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Management of levodopa-induced dyskinesias (LID) is one of the main challenges in the treatment of Parkinson's disease patients. Mechanisms involved in the appearance of these involuntary movements are not well known but modifications in the activity of different neurotransmitter pathways seem to play an important role. The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last levodopa dose (OFF levodopa). Biochemical analysis by real-time PCR for ECS elements was performed. CB 1 receptor expression was upregulated in the putamen, GPe and STN during the active phase of dyskinesia and downregulated in the same nuclei and in the SN when dyskinetic animals were OFF levodopa. Changes in the 2-arachidonoyl glycerol (2-AG) synthesizing/degrading enzymes affecting the pallidal-subthalamic projections in dyskinetic animals OFF levodopa would suggest that 2-AG may play a role in LID. Anandamide (AEA) synthesizing/degrading enzymes were altered specifically in the GPe of untreated parkinsonian monkeys, suggesting that increased AEA levels may be a compensatory mechanism. These results indicate that the expression of the ECS elements is influenced by alterations in dopaminergic neurotransmission. On one hand, changes in CB 1 receptor expression and in the 2-AG synthesizing/degrading enzymes suggest that they could be a therapeutic target for the active phase of LID. On the other hand, AEA metabolism could provide a non-dopaminergic target for symptomatic relief. However, further research is needed to unravel the mechanism of action of the ECS and how they could be modulated for a therapeutic purpose., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The basal ganglia (BG) include structures pivotal for motor and cognitive functions. Such structures are affected in neurodegenerative disorders and toxic or ischemic insults. The peculiar vulnerability of BG to toxic and ischemic damage has been the focus of preclinical research for all over the last century. This comprehensive review collects all evidences supporting a specific susceptibility of BG to energy deprivation, highlighting the pathways through which neuronal survival is jeopardized, and the consequent clinical correlates. In particular, we addressed intrinsic and extrinsic factors participating in BG neuronal vulnerability. The terminal blood supply, the main extrinsic factor, is crucial to the low threshold for hypoxic hazard. Specific, the lack of anastomoses between second and third order branches represents the frailty of an archaic terminal network, unable to guarantee collateral supply and resistance to oxygen deprivation. In addition, BG neurons survival is jeopardized by several intrinsic molecular factors. Among them, the subunit composition of ionotropic and metabotropic glutamate receptors, the impairment of mitochondria, the deficit in neurotransmitter clearance, the poor control of intracellular calcium homeostasis and the glutamatergic-dopaminergic pro-excitotoxic interplay, all play a significant role. Intrinsic and extrinsic factors represent two faces of the same coin, producing excitotoxic damage and poor ability to deal with energy deprivation. The clinical correlates of BG vulnerability are represented by ischemic lesions, such as striatocapsular infarcts and lacunar infarcts, and local toxic-induced damage, mainly associated with energy production impairment, due to carbon monoxide, cyanide and manganese., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including serotonin and adrenoceptors. We examined the long-term effects of multiple doses of iloperidone (0.5, 1.5, or 5 mg/kg) on serotonin (5-HT) 5-HT 1A , 5-HT 2A receptor subtypes, and adrenoceptors α 1 and α 2 subtypes. Rats received daily intraperitoneal injections of different doses of iloperiodone or vehicle for 4 weeks. Receptor autoradiography quantified the levels of 5-HT and adrenoceptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampal CA1 (HIP-CA1) and CA3 (HIP-CA3) regions. Four weeks of iloperidone treatment significantly and dose-dependently increased 5-HT 1A and decreased 5-HT 2A receptors in the MPC and DFC. Higher doses of iloperidone (1.5 and 5 mg/kg) increased 5-HT 1A and decreased 5-HT 2A receptors in HIP-CA1 and HIP-CA3 regions. In addition, repeated iloperidone treatment produced significant increases in α 1 - and α 2 -adrenoceptors in MPC, DFC, HIP-CA1, and HIP-CA3 regions. No changes in 5-HT and adrenoceptors were observed in other brain regions examined. These results suggest that long-term iloperidone treatment exerts region- and dose-specific effects on forebrain 5-HT and adrenoceptors, which may contribute to its therapeutic benefits in improving positive and negative symptoms of schizophrenia as well as maintaining a benign safety profile.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used as theranostic drug-carrier and MRI contrast agent. Their potential effects are still in blank while SPIONs are used for brain. The present study aims to investigate SPIONs' neurotoxicity in vitro and in vivo using stereotaxic technique. By co-incubating SPIONs with dopaminergic neuronal PC12 cells, we found that SPIONs had a dose-dependent cytotoxic in PC12 cells at 60-200 ug/mL but not at 10-50 ug/mL, it reduced cell viability, decreased the capacity of PC12 cells to extend neurites in response to nerve growth factor (NGF), induced a reduction of the tyrosine hydroxylase protein, while increasing PC12 cell apoptosis. Accordingly, the no-observed-adverse-effect level (NOAEL) of current SPIONs was 50 ug/mL in vitro, which would be useful for human health risk assessment. While directly injecting the SPIONs into the dorsal striatum or hippocampus, 7 and 14 days after surgery, nanoparticles decreased the TH + fiber density in both the dorsal striatum and the hippocampus. A behavioral evaluation demonstrated that SPIONs attenuated the animals' motor coordination and spatial memory, as evaluated by the rotarod test and the Morris water maze. We further examined mitogen-activated protein kinase (MAPK) activation and found that c-Jun N-terminal kinase (JNK) was activated after SPIONs treatment. It suggests that the SPIONs-induced neurotoxicity might be mediated through the JNK signaling pathway. SPIONs could possibly induce neurotoxic effects on the dorsal striatum and hippocampus., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive decline in motor functions, such as bradykinesia, caused by the pathological denervation of nigrostriatal dopaminergic neurons within the basal ganglia (BG). It is acknowledged that dopamine (DA) directly affects the modulatory role of BG towards the cortex. However, a growing body of literature is suggesting that DA-induced aberrant synaptic plasticity could play a role in the core symptoms of PD, thus recalling for a "reconceptualization" of the pathophysiology. The aim of this work was to investigate DA-driven aberrant learning as a concurrent cause of bradykinesia, using a comprehensive, biologically inspired neurocomputational model of action selection in the BG. The model includes the three main pathways operating in the BG circuitry, that is the direct, indirect and hyperdirect pathways, and use a two-term Hebb rule to train synapses in the striatum, based on previous history of rewards and punishments. Levodopa pharmacodynamics is also incorporated. Through model simulations of the Alternate Finger Tapping motor task, we assessed the role of aberrant learning on bradykinesia. The results show that training under drug medication (levodopa) provides not only immediate but also delayed benefit lasting in time. Conversely, if performed in conditions of vanishing levodopa efficacy, training may result in dysfunctional corticostriatal synaptic plasticity, further worsening motor performances in PD subjects. This suggests that bradykinesia may result from the concurrent effects of low DA levels and dysfunctional plasticity and that training can be exploited in medicated subjects to improve levodopa treatment., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

We investigated the effect of acute levodopa administration on movement-related cortical oscillations and movement velocity in Parkinson's disease (PD). Patients with PD on and off medication and age- and sex-matched healthy controls performed a ballistic upper limb flexion movement as fast and accurately as possible while cortical oscillations were recorded with high-density electroencephalography. Patients off medication were also studied using task-based functional magnetic resonance imaging (fMRI) using a force control paradigm. Percent signal change of functional activity during the force control task was calculated for the putamen and subthalamic nucleus (STN) contralateral to the hand tested. We found that patients with PD off medication had an exaggerated movement-related beta-band (13-30 Hz) desynchronization in the supplementary motor area (SMA) compared to controls. In PD, spectral power in the beta-band was correlated with movement velocity. Following an acute dose of levodopa, we observed that the beta-band desynchronization in the SMA was reduced in PD, and was associated with increased movement velocity and increased voltage of agonist muscle activity. Further, using fMRI we found that the functional activity in the putamen and STN in the off medication state, was related to how responsive that cortical oscillations in the SMA of PD were to levodopa. Collectively, these findings provide the first direct evaluation of how movement-related cortical oscillations relate to movement velocity during the ballistic phase of movement in PD and demonstrate that functional brain activity in the basal ganglia pathways relate to the effects of dopaminergic medication on cortical neuronal oscillations during movement.

Recently, the biased and highly selective 5-HT 1A agonists, NLX-112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico-basal ganglia-thalamic circuits following treatment with this novel group of 5-HT 1A agonists or the prototypical agonist, 8-OH-DPAT. Dyskinetic symptoms were consistently associated with 80 Hz oscillations, which were efficaciously suppressed by all 5-HT 1A agonists and reappeared upon co-administration of the antagonist, WAY100635. At the same time, the peak-frequency of fast 130 Hz gamma oscillations and their cross-frequency coupling to low-frequency delta oscillations were modified to a different extent by each of the 5-HT 1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80 Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non-motor symptoms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Brain arteriovenous malformations (AVMs) which associate with angiogenesis due to local hypertension, chronic cerebral ischaemia and tissue hypoxia usually lead to haemorrhage, however, the therapeutic medicine for the disease is still lacking. 2-methoxyestradiol (2-ME) has been shown effective in the anti-angiogenic treatment. This study was conducted to examine whether and how 2-ME could improve the vascular malformations. Intracranial venous hypertension (VH) model produced in adult male Sprague-Dawley rats and culture of human umbilical vein endothelial cells (HUVECs) at the anoxia condition were used to induce in vivo and in vitro angiogenesis, respectively. Lentiviral vectors of ID-1 and p53 genes and of their siRNA were intracranially injected into rats and transfected into HUVECs to overexpress and down-regulate these molecules. 2-ME treatment not only reduced the in vivo progression of brain tissue angiogenesis in the intracranial VH rats and the in vitro increases in microvasculature formation, cellular migration and HIF-1α expression induced by anoxia in HUVECs but also reversed the up-regulation of ID-1 and down-regulation of p53 in both the in vivo and in vitro angiogenesis models. All of the anti-angiogenesis effects of 2-ME observed in VH rats and anoxic HUVECs were abrogated by ID-1 overexpression and p53 knockdown. Our data collectively suggest that 2-ME treatment inhibits hypoxia/anoxia-induced angiogenesis dependently on ID-1 down-regulation and p53 up-regulation, providing a potential alternative medical treatment for un-ruptured AVM patients., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)