Parkinson's disease related alterations in cannabinoid transmission.

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.

Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations.

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.

Study on the Regulation Effect of Optogenetic Technology on LFP of the Basal Ganglia Nucleus in Rotenone-Treated Rats.

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.

Abnormal Cortico-Basal Ganglia Neurotransmission in a Mouse Model of l-DOPA-Induced Dyskinesia.

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.

Whole exome sequencing identifies a novel homozygous MECR mutation in a Chinese patient with childhood-onset dystonia and basal ganglia abnormalities, without optic atrophy.

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.

Dopaminergic denervation impairs cortical motor and associative/limbic information processing through the basal ganglia and its modulation by the CB1 receptor.

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.

Efficiency of 123I-ioflupane SPECT as the marker of basal ganglia damage in acute methanol poisoning: 6-year prospective study.

CONTEXT: Investigate whether 123I-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 DaTQUANTTM 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.

An integrative model of Parkinson's disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression.

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.

Movement Disorders in Chronic Kidney Disease - A Descriptive Review.

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.

A Subset of Purposeless Oral Movements Triggered by Dopaminergic Agonists Is Modulated by 5-HT2C Receptors in Rats: Implication of the Subthalamic Nucleus.

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-HT2C) 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-HT2C 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-HT2C 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-HT2C antagonists. Collectively, these results suggest that induction of orofacial motor responses by D2/3 receptor stimulation involves 5-HT2C receptor-mediated activation of the STN by recruitment of the hyperdirect (cortico-subthalamonigral) pathway.

Clinical presentation of a neuropsychiatric lupus patient with symmetrical basal ganglia lesions containing cytotoxic oedema cores surrounded by vasogenic oedema.

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.

Claustral Neurons Projecting to Frontal Cortex Mediate Contextual Association of Reward.

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.

Monoamine oxidase A inhibition with moclobemide enhances the anti-parkinsonian effect of L-DOPA in the MPTP-lesioned marmoset.

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 A inhibition as monotherapy reverses parkinsonism in the MPTP-lesioned marmoset.

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.

Delta oscillations are a robust biomarker of dopamine depletion severity and motor dysfunction in awake mice.

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.

MRI-based brain volumetry and retinal optical coherence tomography as the biomarkers of outcome in acute methanol poisoning.

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.

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice.

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.

Acute and Chronic Dopaminergic Depletion Differently Affect Motor Thalamic Function.

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.

Allan-Herndon-Dudley-Syndrome: Considerations about the Brain Phenotype with Implications for Treatment Strategies.

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.

Mathematical modeling and parameter estimation of levodopa motor response in patients with parkinson disease.

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.