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Background: Multiple system atrophy is an adult-onset, sporadic, neurodegenerative disorder with parkinsonian (MSA-P) and cerebellar (MSA-C) subtypes. Objective: We aimed to elucidate differences in prognostic factors between MSA subtypes. Methods: The study population comprised 45 probable MSA patients (MSA-P = 22; MSA-C = 23) and 45 healthy controls. Clinical parameters, heart rate variability (HRV), and conventional cardiac autonomic function testing (AFT) were the study tools. Results: Mean age of onset of MSA was 54.7 ± 9 years for MSA-P and 51.9 ± 7 years for MSA-C subgroups. Median disease duration was 2 years in both subgroups. A greater percentage of MSA-P patients (45.5%) had beneficial response to levodopa (P < 0.01). Patients in both subgroups reported significant autonomic disturbances, such as postural symptoms, bladder disturbances, and erectile dysfunction. MSA-P patients had a trend for a greater number of falls and bladder disturbances than MSA-C patients (P = 0.05). Cardiac AFT showed that in MSA-P, 22.2% had definitive and 77.7% had severe autonomic dysfunction, whereas in MSA-C, 9.5% had early, 28.5% had definitive, and 57.1% had severe autonomic dysfunction. HRV analysis showed significant reduction in overall HRV, sympathetic activity, and parasympathetic activity in MSA patients as compared with controls (P < 0.0001). The sympathetic limb was more severely affected in MSA-P patients as compared with MSA-C patients (P < 0.05). Conclusion: Autonomic dysfunction and postural instability, negative prognostic markers, were relatively more common in the MSA-P than in the MSA-C patients. This implies that MSA-P patients have poorer prognosis as compared with MSA-C. Dopaminergic medications can be beneficial in MSA-P patients. [ABSTRACT FROM AUTHOR]

Dopamine is involved in the pathophysiology of schizophrenia. Disrupted salience processing by the salience network (SN) may be a central link between dysregulated dopamine function and psychotic symptoms. However, dopaminergic influence on the SN and its presumed influence on psychotic and subpsychotic symptoms or psychotic-like experiences in healthy individuals remain unclear. Therefore, we investigated dopamine-induced changes in functional connectivity of the right anterior insula (rAI), a central SN hub, and their association with psychotic-like experiences. We enrolled 54 healthy, right-handed male subjects in a randomized, double-blind, cross-sectional placebo-controlled experiment. Psychotic-like experiences were assessed using the revised Exceptional Experiences Questionnaire (PAGE-R). They then received either placebo (n = 32) or 200 mg L-DOPA (n = 33), a dopamine precursor, orally and underwent resting-state functional magnetic resonance imaging. In a seed-to-voxel approach, we analyzed dopamine-induced changes in functional connectivity of the rAI and assessed the relationship between functional connectivity changes and PAGE-R score. L-DOPA reduced functional connectivity between the rAI and the left auditory cortex planum polare. In the placebo group, we found a strong negative correlation between PAGE-R score and rAI to planum polare functional connectivity; in the L-DOPA group, there was a strong positive correlation between PAGE-R score and functional connectivity between rAI and planum polare. The PAGE-R score explained about 30% of the functional connectivity variation between rAI and planum polare in the two groups. Our findings suggest that psychotic-like experiences are associated with dopamine-induced disruption of auditory input to the SN, which may lead to aberrant attribution of salience. [ABSTRACT FROM AUTHOR]

The neuropathological hallmarks of Parkinson's disease include preferential vulnerability of dopaminergic neurons of the substantia nigra pars compacta, and accumulation of intraneuronal protein inclusions known as Lewy bodies. These inclusions contain, among other proteins, aggregated alpha-synuclein and histone deacetylase 6 (HDAC6). In our study we found that selective inhibition of HDAC6 activity by Tubastatin A has protective effects in a rat model of Parkinson's disease. We provide evidence that this protection may be due to the activation of chaperone-mediated autophagy through the up-regulation of key members of this pathway. Moreover, Tubastatin A significantly inhibited the expression of a toxic form of alpha-synuclein that is phosphorylated at serine position 129. Tubastatin A treatment also permitted to partially modulate neuroinflammation. Taken together, our study highlights the neuroprotective effects of Tubastatin A in a rat model of Parkinson's disease and provides mechanistic insight in Tubastatin A-mediated protection against alpha-synuclein toxicity and substantia nigra degeneration. These findings are of potential therapeutic value in Parkinson's disease and other synucleinopathies. [ABSTRACT FROM AUTHOR]

BACKGROUND: The cardinal motor symptoms of Parkinson's disease (PD) include postural instability, bradykinesia, tremor and rigidity. The overall Unified Parkinson's Disease Rating Scale (UPDRS-III) indicates, the gold-standard treatment for PD (dopaminergic-therapy) is very effective in improving these symptoms. However, recent research indicated that 2 of the 4 cardinal symptoms of PD (balance and tremor) remain unimproved by dopaminergic-therapy. This prompts the investigation of other alternative and adjunct treatments such as exercise rehabilitation. Unfortunately, like drug studies, exercise studies often focus on overall symptom improvement yet fail to monitor changes to specific symptoms. This may be problematic for individuals with different symptomatic phenotypes. If tremor/balance were the main concern, then adjunct therapies may be critically important when these symptoms may be dopa-resistant. Thus, it is important for all therapies to examine individual symptomatic-improvement. Interestingly, recent studies show PDSAFEx™ (a sensory integration therapy) to have a significantly improve motor symptoms in comparison to traditional exercise (14). Yet, the effects of PDSAFEx™ on individual PD symptoms is unknown. OBJECTIVE: To explore the effects of PDSAFEx™ on PD symptoms in adjunct to medications. METHODS: UPDRS-III scores of 229 cases were retrospectively examined and analysed in SPSS using Wilcoxon pairs singed-rank test to evaluate specific symptom-improvements. RESULTS: PDSAFEx™ was confirmed to improve overall motor symptoms (p = 0.0001), but more importantly a significant improvement to tremor (p < 0.00001) and balance (p < 0.00001) were also identified. CONCLUSIONS: These findings suggest that PDSAFEx™ is an important adjunct to medications, since it is able to address all four cardinal symptoms of PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive, disabling, neurodegenerative disease that requires long term care and pharmaceutical treatment. Levodopa remains the gold standard treatment for PD globally, although it is largely unavailable and unaffordable for the majority of patients in many sub-Saharan African and other low-income countries (LICs). We suggest the potential for Mucuna pruriens (MP), a leguminous plant, to replace or supplement levodopa-based medicines in countries where levodopa is unaffordable and inaccessible due to its low costs of preparation and high natural availability. MP has been shown to induce a great improvement of motor symptoms with few adverse events in recent studies. However, caution is important until more robust data on the long-term safety of MP are available. We believe that MP could potentially be part of the answer to affordable, symptomatic treatment of PD in LICs worldwide. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study is to compare Parkinson's disease (PD) treatment practices by movement disorder (MD) specialists across a decade, and to determine the factors that influence drug choice for the motor symptoms of PD in newly diagnosed drug-naïve patients. Methods. This prospective temporal analysis included patients seen at the National Neuroscience Institute in Singapore and diagnosed with PD by MD specialists in the years 2007 and 2017. Primary outcomes were use of specific PD drugs and changes in drug-prescribing patterns. Descriptive analyses and multivariable logistic regression models determined the extent to which patient characteristics were associated with type of PD treatment. Results. Of 230 patients with PD (mean (SD) age, 66.7 (10.3) years), 131 (57.0%) were male. From 2007 to 2017, the use of ergot dopamine agonists and anticholinergics decreased from 19.3% to 2.0% (P < 0.001) and from 12.0% to 2.7% (P = 0.004), respectively. The use of monoamine oxidase B inhibitors (MAOBI) increased from 13.3% to 25.2% (P = 0.033). The use of levodopa (LD)-sparing strategies decreased nonsignificantly from 33.7% to 24.5% (P = 0.133). Overall, 196 (85.2%) patients were initiated on symptomatic monotherapy, with LD being the most commonly prescribed. MAOBI was the most common drug used in combination therapy. Age ≤70 (adjusted OR, 11.9; 95% CI, 4.5–31.5) and Hoehn and Yahr (HY) stage <2 (adjusted OR, 3.4; 95% CI, 1.5–7.7) were independent factors for LD-sparing strategies. Non-LD prescriptions (13 of 92; 14.1%) were more likely to be discontinued compared to LD ones (6 of 149; 4.0%) (P = 0.005). Conclusions. Drug-prescribing patterns in PD have changed significantly through the last decade, influenced by emerging evidence and reports of adverse drug effects. Choosing drugs based on the patient's age and disease severity remain sound guiding principles across the years. It is important that international and national guidelines for pharmacotherapy in PD be updated consistently throughout different socioeconomic settings to optimize care. [ABSTRACT FROM AUTHOR]

Stuttering is a DSM V psychiatric condition for which there are no FDA-approved medications for treatment. A growing body of evidence suggests that dopamine antagonist medications are effective in reducing the severity of stuttering symptoms. Stuttering shares many similarities to Tourette's Syndrome in that both begin in childhood, follow a similar male to female ratio of 4:1, respond to dopamine antagonists, and symptomatically worsen with dopamine agonists. In recent years, advances in the neurophysiology of stuttering have helped further guide pharmacological treatment. A newer medication with a novel mechanism of action, selective D1 antagonism, is currently being investigated in FDA trials for the treatment of stuttering. D1 antagonists possess different side-effect profiles than D2 antagonist medications and may provide a unique option for those who stutter. In addition, VMAT-2 inhibitors alter dopamine transmission in a unique mechanism of action that offers a promising treatment avenue in stuttering. This review seeks to highlight the different treatment options to help guide the practicing clinician in the treatment of stuttering. [ABSTRACT FROM AUTHOR]

A functional single-nucleotide polymorphism (SNP) in the catechol-O-methyltransferase (COMT) gene (rs4680) is a gene variant that has been shown to predict the ability to maintain cognitive agility during combat and competition. Critically, COMT Met (low-activity; high dopamine) allele carriers outperform Val (high-activity; low dopamine) homozygotes on a variety of cognitive tasks. However, the relationship between genotype and cognitive performance appears to reverse under stressful conditions. Stress increases pre-frontal cortex dopamine (PFC DA) levels, and Met allele carriers (with higher DA) show performance deficits relative to Val allele carriers. This pattern reflects the inverted U-shaped function of DA activity where too little (Val allele) or too much (Met allele carriers under stress) DA is associated with poor cognitive performance. The Val allele advantage for stress resiliency is referred to as the COMT "warrior/ worrier" model. In line with this model, we predicted that elite level mixed martial arts (MMA) fighters would be more likely than athlete controls to carry the GG (warrior) genotype compared to an athlete group and a non-athlete group. Based on findings in our previous studies, we also assessed the stress biomarkers cortisol and salivary alpha-amylase (sAA). There was an overall significant difference in genotype frequencies between groups (p =0.01) and the MMA group showed a significantly greater GG (warrior) genotype frequency than the non-athlete control group (p = 0.003). There was not a significant group x genotype interaction for the cortisol or sAA; however, the non-athlete GG group had significantly higher cortisol than the A/- group (p = 0.038). Combined, our findings suggest that the "warrior" genotype may play a participation role in combat sports. [ABSTRACT FROM AUTHOR]

Importance: Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease-like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease.Observations: Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off ("off periods"), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management.Conclusions and Relevance: Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias. [ABSTRACT FROM AUTHOR]

People with Parkinson's disease have been shown to have difficulty switching between movement plans. In the great majority of studies, the need to switch between tasks was made explicitly. Here, we tested whether people with Parkinson's disease, taking their normal medication, have difficulty switching between implicitly specified tasks. We further examined whether this switch is performed predictively or reactively. Twenty five people with Parkinson's disease continuously increased or decreased the frequency of their arm movements, inducing an abrupt–but unaware–switch between rhythmic movements (at high frequencies) and discrete movements (at low frequencies). We tested whether that precipitous change was performed reactively or predictively. We found that 56% of participants predictively switched between the two movement types. The ability of people with Parkinson's disease, taking their regular medication, to predictively control their movements on implicit tasks is thus preserved. [ABSTRACT FROM AUTHOR]

Objective: Cross-frequency coupling has been reported in the STN of patients with PD, but its significance and functional role are still not well understood. This study investigates pharmacological modulations of subthalamic oscillations and their nonlinear cross-frequency interactions across three consecutive cycles over unique 24-hour-long recordings.Background: Identifying neurobiomarkers for PD can drive the development of novel personalized treatments by providing objective assessment of impairment. In particular, distinct frequency bands in LFP recordings and their interaction with one another have been shown to modulate with dopaminergic medication and thus, proposed as such biomarkers.Methods: We recorded local field potentials 3 weeks postoperatively from externalized leads in 9 patients and correlated the neural patterns with improvements in motor signs over three medication intake cycles. We used two modalities to assess symptoms in the unmedicated OFF and the l-dopa-induced motor ON state: a subsection of the UPDRS and a keyboard tapping score measuring bradykinesia.Results: In the OFF state, the amplitude of high-frequency oscillations in the 200- to 300-Hz range was coupled with the phase of low-beta (13-22 Hz) in all patients. After transition to the ON state, three distinct coupling patterns were observed among subjects. Among these, patients showing ON coupling between high-beta (22-30 Hz) and high-frequency oscillations in the 300- to 400-Hz range had significantly greater improvement in bradykinesia, according to the keyboard scores.Conclusion: Observing diminished coupling in the ON state, previous studies have hypothesized that the sole existence of coupling in STN has an "impeding" effect on normal processes, and thus it was considered to be pathological. In contrast, our observation of ON state coupling at distinct frequencies associated with the improvements in motor features suggest that the underlying mechanism of coupling might have impeding or enhancing effects depending on the coupled frequencies. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The clinical presentation of repetitive choreiform involuntary movements of the anterior abdominal wall was first introduced as "belly dancer's dyskinesia." Etiologies of this rare condition include idiopathic causes, medication inducement, or post-abdominal surgery. We report a case of orobuccal stereotypic movements and abdominal wall dyskinesia secondary to prochlorperazine intake. The movements began 2 weeks after cessation of prochlorperazine. The patient took this dopamine receptor-blocking medication for 6 months to treat nausea due to chemotherapy. To our knowledge, abdominal wall dyskinesia as a tardive syndrome of prochlorperazine has not been previously reported. [ABSTRACT FROM AUTHOR]

Present-day drug therapies provide clear beneficial effects as many diseases can be driven into remission and the symptoms of others can be efficiently managed; however, the success of many drugs is limited due to both patient non-compliance and adverse off-target or toxicity-induced effects. There is emerging evidence that many of these side effects are caused by drug-induced impairment of mitochondrial function and eventual mitochondrial dysfunction. It is imperative to understand how and why drug-induced side effects occur and how mitochondrial function is affected. In an aging population, ageassociated drug toxicity is another key area of focus as the majority of patients on medication are older. Therefore, with an aging population possessing subtle or even more dramatic individual differences in mitochondrial function, there is a growing necessity to identify and understand early on potentially significant drug-associated off-target effects and toxicity issues. This will not only reduce the number of unwanted side effects linked to mitochondrial toxicity but also identify useful mitochondrial-modulating agents. Mechanistically, many successful drug classes including diabetic treatments, antibiotics, chemotherapies and antiviral agents have been linked to mitochondrial targeted effects. This is a growing area, with research to repurpose current medications affecting mitochondrial function being assessed in cancer, the immune system and neurodegenerative disorders including Parkinson's disease. Here, we review the effects that pharmacological agents have on mitochondrial function and explore the opportunities from these effects as potential disease treatments. Our focus will be on cancer treatment and immune modulation. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive disease due to dopaminergic cell loss in the substantia nigra and dopaminergic terminal lost in the striatum, which is the projection area of substantia nigra. It is characterized by resting tremor, bradykinesia, rigidity, and postural instability. In PD, non-motor symptoms such as cognitive impairment, anhedonia, apathy, and autonomic nervous system impairments affect quality of life as much as motor symptoms. PD may affect multiple systems and the underlying mechanisms are not known. However, developing new methods of treatment to slow or stop the rate of disease progression, to lessen or to cure the symptoms is crucial. The aim of this review was to discuss the alternative treatments that may be useful for both motor and non-motor symptoms. Symptomatic treatments with dopaminergic drugs aim to relieve motor symptoms and to increase the patient's life standards for a limited time. However, possible neuroprotective treatments that inhibit neuronal cell death can extend life span and provide higher quality of life. Lewy bodies, which are formed mainly from misfolded and native alpha-synuclein protein, is a pathologic hallmark of PD. Therefore, inhibiting the protein misfolding or clearing the aggregates could be a promising new therapeutic approach for the disease. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second neurodegenerative disease that lacks effective treatments. Buddlejasaponin IVb (BJP-IVb) is the main bioactive component of herbs in genus Clinopodium which display antioxidative, anti-inflammatory and neuroprotective activities. However, the role of BJP-IVb in PD still remains unknown. This study aimed to evaluate the effect of BJP-IVb on dopaminergic neurodegeneration in PD and clarified the underlying mechanisms from the aspect of iron overload-mediated ferroptosis. One-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models were established in this study. Behavioral tests, cell cytotoxicity assay, tyrosine hydroxylase (TH) and Nissl staining were performed to evaluate the antiparkinsonian effect of BJP-IVb. Cellular ultrastructure, iron content and lipid peroxidation were detected to evaluate iron overload-mediated dopaminergic neuron ferroptosis. Iron regulatory protein 2 (IRP2) and iron transport-related proteins were detected by immunofluorescence and Western blot to evaluated iron transport. Finally, plasmid vector-mediated IRP2 overexpression were performed to further clarify the molecular mechanism. BJP-IVb alleviated MPP+-induced neurotoxicity in vitro and improved MPTP-induced dopaminergic neuron loss and motor dysfunctions of PD mice, confirming an effect of BJP-IVb against dopaminergic neurodegeneration of PD. Further results revealed that BJP-IVb protected against PD by suppressing iron overload-mediated dopaminergic neuron ferroptosis, as evidenced by the attenuated lipid peroxidation, decreased iron content and changes in cellular ultrastructure. Finally, the decreased iron regulatory protein (IRP2) was confirmed to be responsible for BJP-IVb-mediated ferroptosis suppression by modulating iron transport-related proteins and alleviating iron overload. BJP-IVb suppressed iron overload-mediated dopaminergic neuron ferroptosis and improved motor dysfunctions in PD, which was achieved by inhibiting IRP2-mediated iron overload. This study provided a potential drug candidate for the treatment of PD. [Display omitted] • BJP-IVb alleviates MPP+-induced neurotoxicity in vitro. • BJP-IVb improves MPTP-induced motor dysfunctions and dopaminergic neuron loss in vivo. • BJP-IVb suppresses dopaminergic neurons ferroptosis by mitigating iron overload in PD models. • BJP-IVb suppresses iron overload by regulating iron transport in PD models. • BJP-IVb suppresses iron overload by suppressing IRP2-mediated iron transport in PD models. [ABSTRACT FROM AUTHOR]

Objetivo: Analizar el efecto del tratamiento dopaminérgico en el número y la función de las células T reguladoras. Antecedentes: La enfermedad de Parkinson (EP) cursa con alteraciones del sistema inmune, afectando las células T reguladoras (Tregs) y otras poblaciones celulares. Se ha reportado que las Tregs presentan disfunción y niveles disminuidos, tanto en modelos animales de EP como en pacientes (1). Se sospecha que el pramipexol, ampliamente prescito en la EP, tiene un efecto neuroprotector (3). Puesto que las Tregs expresan receptores a la dopamina, es fundamental determinar si el tratamiento dopaminérgico tiene efecto sobre la población de Tregs (2). Métodos: Tregs purificadas a partir de PBMCs de donantes sanos y pacientes con EP se co-cultivaron con células T efectoras en diferentes proporciones y se estimularon con CD3/CD28. Para el ensayo in vitro, las células se estimularon previamente con pramipexol (20 ng/ml y 200 ng/ml) durante 24 h. La proliferación de células T efectoras se determinó por citometría de flujo, por dilución del colorante de proliferación celular eFluor™ 670. Núm. de registro del protocolo: 145/19 Resultados: El pramipexol mejora la función de las células T reguladoras, porque aumentó los porcentajes de inhibición de la proliferación de las células tratadas in vitro y evitó la pérdida de función en las células T reguladoras de pacientes con EP, al mantener los porcentajes de inhibición similares a los controles. Conclusiones: El tratamiento dopaminérgico favorece la función supresora de las células T reguladoras en pacientes con EP. [ABSTRACT FROM AUTHOR]

Dopamine (DA) is a biomolecule that plays a critical part in the functioning of our brains by promoting motivation, maintaining focus, and altering mood. Excessive or low-level concentrations of DA in the human brain led to a dangerous neurological disorder. It is significantly important to trace the precise amount of DA to prevent such risky brain disease. Recently, heteroatoms-doped carbon dots (H-CDs) have attracted great attention for their capacity to detect biomolecules, metal ions, organic solvents, chemical dyes, etc. In this review, we have provided a comprehensive summary of the emerging trends in the heteroatom functional dopamine-doped carbon dots (DA-CDs), which are based on DA used as starting substances or functionalizing agents. Our analysis encompasses a detailed exploration of the synthetic methods, physical and chemical properties of carbon dots derived from dopamine, as well as their diverse range of applications. Additionally, we have also discussed the application of H-CDs in the dopmine detection by using various fluorescent, colorimetric, and electrochemical techniques. [Display omitted] • A comprehensive summary of heteroatoms-doped carbon dots based on dopamine as hybrid agents or detected substances. • The introduction of physicochemical properties and application for dopamine-synthesized or functionalized CDs.To discuss the application of heteroatoms-doped carbon dots (H-CDs) in dopamine detection. • To discuss the application of heteroatoms-doped carbon dots (H-CDs) in dopamine detection. [ABSTRACT FROM AUTHOR]

Dopamine is implicated in adaptive behavior through reward prediction error (RPE) signals that update value estimates. There is also accumulating evidence that animals in structured environments can use inference processes to facilitate behavioral flexibility. However, it is unclear how these two accounts of reward-guided decision-making should be integrated. Using a two-step task for mice, we show that dopamine reports RPEs using value information inferred from task structure knowledge, alongside information about reward rate and movement. Nonetheless, although rewards strongly influenced choices and dopamine activity, neither activating nor inhibiting dopamine neurons at trial outcome affected future choice. These data were recapitulated by a neural network model where cortex learned to track hidden task states by predicting observations, while basal ganglia learned values and actions via RPEs. This shows that the influence of rewards on choices can stem from dopamine-independent information they convey about the world's state, not the dopaminergic RPEs they produce., (© 2024. The Author(s).)

Biomarkers obtained from the neurophysiological signals of patients with Parkinson's disease (PD) have objective value in assessing their motor condition for effective diagnosis, monitoring, and clinical intervention. Prominent cortical biomarkers of PD have typically been derived from various β band wave features. This study approached the topic from an alternative perspective and attempted to estimate a recently suggested measure representing α band nonlinear autocorrelative memory from a publicly available EEG dataset that involves 15 patients with earlier-stage PD (dopaminergic medication OFF and ON states) and 16 age-matched healthy controls. The cortical nonlinearity was elevated for the PD ON state compared with the OFF state for bilateral sensorimotor channels C3 and C4 ( n = 26; P = 0.003). A similar statistical difference was also identified between PD OFF state and healthy subjects ( n = 26; P = 0.049). Analysis over all channels revealed that the α band nonlinearity induced upon medication was constrained to sensorimotor regions. The α nonlinearity measure was compared with a well-accepted cortical biomarker of β-γ phase-amplitude coupling (PAC). They were in moderate negative correlation ( r = -0.412; P = 0.036) for only healthy subjects, but not for the patients. The nonlinearity measure was found to be insusceptible to the nonstationary variations within the particular data. Our study provides further evidence that the α band nonlinearity measure can serve as a promising cortical biomarker of PD. The suggested measure can be estimated from a noninvasive low-resolution single scalp EEG channel of patients with relatively early-stage PD, who did not yet need to undergo deep brain stimulation operation. NEW & NOTEWORTHY This study suggests a nonlinearity measure that differentiates Parkinson's disease (PD) dopamine OFF-state scalp EEG data from those of dopamine ON-state patients and healthy subjects. Unlike typical PD cortical biomarkers based on β band activity, this metric shows elevation upon dopaminergic medication in the α band. We provide evidence supporting its potential as an early-stage promising PD biomarker that can be estimated from noninvasive EEG recordings with low resolution and SNR.

Methamphetamine treatment of mice rapidly and severely depleted levels of dopamine and its metabolites, homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the caudate nucleus. Exposure of mice to cigarette smoke by means of nose-only breathing apparatus for 20 min twice daily over 3 days prior to drug treatment significantly attenuated the neurotoxicity of methamphetamine as judged by a lesser depletion of dopamine, DOPAC and HVA. The lesser effect of methamphetamine upon content of serotonin level was unaltered by prior inhalation of smoke. Results suggest a specific protective effect of inhaled tobacco smoke upon the effects of methamphetamine upon dopaminergic circuitry.

Objectives: The evaluation of novel disease modifying drugs requires biomarkers that are simultaneously sensitive to disease state but resistant to the effects of background symptomatic treatment. Saccadic eye movement parameters have been proposed as a neurophysiological biomarker for Parkinson's disease (PD) and so it is important to know how they are affected by dopaminergic medication. Studies to date are conflicting: some have concluded that medication prolongs saccadic latencies while others suggest they are shortened. We aimed to characterise the effects of antiparkinsonian medication on prosaccadic and antisaccadic parameters in a large cohort of PD patients and age matched healthy controls and to survey the current literature in comparison to the study findings.Methods: We studied saccades both off and on medication in 38 PD patients and 34 healthy controls (HC). Latencies, amplitudes, velocities, and directional errors were evaluated, using a published standardised protocol. We then combined this study and previously published literature in a meta-analysis of the effects of antiparkinsonian medication on prosaccadic latency (PSL).Results: PSL is significantly prolonged by dopaminergic medication in PD, from a mean of 222.7 ms in the OFF medication state to a mean of 236.0 ms in the ON medication state (p = 0.028). This effect size is comparable to the difference between PD OFF medication and healthy control values. There was no statistically significant change in any other saccadic parameter with medication. Of particular note, antisaccadic latency was almost exactly the same on and off medication (means of 414.9 ms and 417.2 ms respectively, p = 0.97), while being almost 20% longer in PD patients compared to healthy controls (HC mean 357.2 ms; PD ON vs HC p = 0.015; PD OFF vs HC p = 0.0066).Conclusion: PSL is significantly affected by dopaminergic medication which may complicate its use as a biomarker in drug trials. Antisaccadic latency is particularly interesting in this regard because it shows a large disease effect with no medication effect. [ABSTRACT FROM AUTHOR]

Objectives: Communication processes play a key role in the patient-doctor relationship. Few studies have considered communicative processes in advanced Parkinson's disease (PD), and in particular in the phase of proposing complex therapies (CT). Therefore, we explored the role of communication and patient-doctor relationship in the transition phase to CT for advanced PD, analysing satisfaction, factors influencing the relationship and patients' unmet needs.Materials and Methods: Twenty-four PD patients (mean age 61.7 ± 8.8 years; mean disease duration 12 ± 4.8 years) eligible for deep brain stimulation or infusion therapies were submitted to a semi-structured interview aimed to investigate communication-related cognitions, feelings and behaviours concerning PD and the possible transition towards CT. The Patient-Doctor Relationship Questionnaire (PDRQ-9) was administered along with neuropsychological and behavioural screening tests.Results: All patients discussed the possible transition to CT with a neurologist. A high degree of satisfaction about the relationship with the neurologist was revealed (mean PDRQ-9 score 37.3 ± 7.3). The communication not only aroused feelings of fear (11/24 patients) and concern (15/24 patients), but also fostered the hope for motor improvement (15/24 patients). Half the patients (12/24) wanted to receive more information about CT after communication.Conclusions: This pilot study highlights the importance of doctor-patient communication in PD when facing the transition to CT. Trust in the physician emerged as a key point in favour of the therapeutic alliance. Neurologists should carefully consider patients' reactions and preferences for eliciting collaboration and treatment adherence, favouring a patient-centred standard of care. [ABSTRACT FROM AUTHOR]

Reduced levels of dopamine in Parkinson's disease contribute to changes in learning, resulting from the loss of midbrain neurons that transmit a dopaminergic teaching signal to the striatum. Dopamine medication used by patients with Parkinson's disease has previously been linked to behavioural changes during learning as well as to adjustments in value-based decision-making after learning. To date, however, little is known about the specific relationship between dopaminergic medication-driven differences during learning and subsequent changes in approach/avoidance tendencies in individual patients. Twenty-four Parkinson's disease patients ON and OFF dopaminergic medication and 24 healthy controls subjects underwent functional MRI while performing a probabilistic reinforcement learning experiment. During learning, dopaminergic medication reduced an overemphasis on negative outcomes. Medication reduced negative (but not positive) outcome learning rates, while concurrent striatal blood oxygen level-dependent responses showed reduced prediction error sensitivity. Medication-induced shifts in negative learning rates were predictive of changes in approach/avoidance choice patterns after learning, and these changes were accompanied by systematic striatal blood oxygen level-dependent response alterations. These findings elucidate the role of dopamine-driven learning differences in Parkinson's disease, and show how these changes during learning impact subsequent value-based decision-making. [ABSTRACT FROM AUTHOR]

An enteral suspension (ES)/intestinal gel formulation of levodopa/carbidopa (hereafter referred to as levodopa/carbidopa ES) [Duodopa® (EU); Duopa™ (USA)] has been developed to overcome the fluctuating plasma levodopa concentrations associated with oral levodopa/carbidopa formulations. In various countries, including those of the EU (under the Mutual Recognition Procedure), it is approved for the treatment of advanced levodopa-responsive Parkinson's disease (PD) with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. In several other countries, including the USA, it is approved for the treatment of motor fluctuations in patients with advanced PD. In adults with advanced PD, levodopa/carbidopa ES improved motor fluctuations, activities of daily living and health-related quality of life (HR-QOL) during short-term (12-week) treatment, with the beneficial effects on motor fluctuations largely sustained over the longer term (up to 7 years). Levodopa/carbidopa ES was generally well tolerated in this patient population, with adverse events (AEs) associated with aging, advanced PD-related comorbidities, the procedure/device or dopaminergic therapy. Its safety profile was comparable to that of oral levodopa/carbidopa with respect to non-procedure/device-associated AEs; most procedure/device-associated AEs were consistent in nature and incidence with medically recognised complications of the procedure in non-PD patients. Current evidence indicates that levodopa/carbidopa ES is an effective and generally well tolerated option for the treatment of motor fluctuations in patients with levodopa-responsive advanced PD who are not being effectively managed with non-invasive therapies. [ABSTRACT FROM AUTHOR]

Objectives: To explore the presence of dopamine dysregulation syndrome in non-Parkinson's disease patients receiving dopamine replacement therapy.Methods: Electronic searches were conducted of Medline, Embase, PsycINFO and PreMedline to capture articles related to dopamine misuse or factitious disorder combined with the presence of dopamine replacement therapy or a non-Parkinson's disease population. In total, 430 articles were reviewed and studies that addressed dopamine dysregulation syndrome in non-Parkinson's disease patients were included.Results: Nine case reports were identified.Conclusions: The pathophysiology underlying dopamine dysregulation syndrome has been thoroughly explored with numerous mechanisms posited. What remains unclear is whether dopamine dysregulation syndrome is a phenomenon specific to Parkinson's disease, as indicated in the proposed diagnostic criteria. A more useful predictor of susceptibility to dopamine dysregulation syndrome may be temperamental traits such as novelty seeking and impulsivity, which overlap with predisposing factors for an addiction disorder. [ABSTRACT FROM AUTHOR]

Restless legs syndrome (RLS) has a high prevalence in the elderly and can impact sleep quality and sleep quantity, reduce quality of life (QoL), and increase the risk of falls during episodes of night-time ambulation. In patients unable to verbalize their sensory symptoms, certain behavioral cues may help with the diagnosis. A state of brain iron deficiency could play a central role in the pathophysiology of RLS and be upstream to a series of dysfunctions that are not limited to the dopaminergic system. Management should initially emphasize lifestyle modifications and reduction of all possible iatrogenic contributors while maintaining a state of normal–high peripheral iron stores. Oral iron, in patients with ferritin levels < 75 μg/dL, appears to be effective, although iron infusions should be considered when more immediate benefit or oral iron have not been effective. When other attempts fail and patients continue to experience chronic RLS symptoms substantially interfering with QoL, pharmacological agents may present a favorable benefit versus risk profile. Such agents may include α-2-δ drugs or dopaminergic agents, after careful consideration of the risk of RLS augmentation with the latter class. In patients with established RLS augmentation from the use of dopaminergic drugs, the addition of α-2-δ agents or low-dose opioids, with subsequent slow tapering of dopaminergic agents, is recommended. With any of these agents, caution should be made with regard to the risk of drug–drug interactions and altered pharmacokinetics in this fragile population. Although showing excellent long-term safety data in non-elderly adults with RLS, studies are needed to ascertain that such treatments are effective and well tolerated in older adults. [ABSTRACT FROM AUTHOR]

Comparative analyses of the efficacies of dopaminergic agonists (pramipexole, ropinirole, and rotigotine patch) and α‐2‐δ ligands (gabapentin enacarbil and pregabalin) for treatment of primary restless leg syndrome (RLS) are lacking because of the few head‐to‐head clinical trials. A model‐based meta‐analysis approach was employed to quantitatively compare the efficacies of these 5 first‐line RLS drugs. Longitudinal efficacy data of RLS drugs were collected from published eligible literature. Mean changes in both the International Restless Leg Syndrome Study Group (IRLS) rating scale and Clinical Global Impression Improvement (CGI‐I) scale response rate were analyzed. A study‐level population pharmacodynamic model was used to fit the dose‐effect relationship and to describe the therapeutic effect over time for RLS drugs and placebo, and the typical efficacies of these drugs were compared. The onset of action was rapid for RLS drugs. In the placebo group, typical maximum IRLS reduction (Emax,IRLS) and CGI‐I response rate (Emax,CGI‐I) were –9.34 points and 48.2%, respectively. After deducting placebo effects, we found that the baseline IRLS score was significantly correlated with the Emax,IRLS of dopaminergic agonists. Typical Emax,IRLS of dopaminergic agonists was expressed as −7.7−0.682×(baseline IRLS score −24) points. Typical Emax,IRLS values of pregabalin and gabapentin enacarbil were –5.95 points and –4.00 points, respectively. The therapeutic effect of dopaminergic agonists was found to be associated with baseline symptom severity. In RLS patients with more severe symptoms, the therapeutic effect of dopaminergic agonists tended to be better than that of α‐2‐δ ligands. [ABSTRACT FROM AUTHOR]

Introduction: Clinical evidence suggests that Parkinson's Disease (PD) patients are risk averse. Dopaminergic therapy has been reported to increase risk tolerance, but the underlying mechanisms are unclear. Some studies have suggested an amplification of subjective reward value, consistent with the role of dopamine in reward value coding. Others have reported value-independent risk enhancement. We evaluated the value-dependence of the effects of PD and its therapy on risk using tasks designed to sensitively measure risk over a wide range of expected values.Method: 36 patients with idiopathic PD receiving levodopa monotherapy and 36 healthy matched controls performed two behavioural economic tasks aimed at quantifying 1) risk tolerance/aversion in the gain frame and 2) valuation of potential gains relative to losses. PD patients performed the tasks on and off their usual dose of levodopa in randomized order; controls performed the same tasks twice.Results: Relative to the controls, unmedicated PD patients showed significant value-independent risk aversion in the gain frame, which was normalized by levodopa. PD patients did not differ from controls in their valuation of gains relative to losses. However, across both tasks and regardless of medication, choices of the patients were more determined by expected values of the prospects than those of controls.Conclusion: Dopamine deficiency in PD was associated with risk aversion, and levodopa promoted riskier choice in a value-independent manner. PD patients also showed an increased sensitivity to expected value, which was independent of levodopa and does not appear to result directly from dopamine deficiency. [ABSTRACT FROM AUTHOR]

The Neurobiology of Adolescent Drinking in Adulthood (NADIA) Consortium has focused on the impact of adolescent binge drinking on brain development, particularly on effects that persist into adulthood. Adolescent binge drinking is common, and while many factors contribute to human brain development and alcohol use during adolescence, animal models are critical for understanding the specific consequences of alcohol exposure during this developmental period and the underlying mechanisms. Using adolescent intermittent ethanol (AIE) exposure models, NADIA investigators identified long‐lasting AIE‐induced changes in adult behavior that are consistent with observations in humans, such as increased alcohol drinking, increased anxiety (particularly social anxiety), increased impulsivity, reduced behavioral flexibility, impaired memory, disrupted sleep, and altered responses to alcohol. These behavioral changes are associated with multiple molecular, cellular, and physiological alterations in the brain that persist long after AIE exposure. At the molecular level, AIE results in long‐lasting changes in neuroimmune/trophic factor balance and epigenetic–microRNA (miRNA) signaling across glia and neurons. At the cellular level, AIE history is associated in adulthood with reduced expression of cholinergic, serotonergic, and dopaminergic neuron markers, attenuated cortical thickness, decreased neurogenesis, and altered dendritic spine and glial morphology. This constellation of molecular and cellular adaptations to AIE likely contributes to observed alterations in neurophysiology, measured by synaptic physiology, EEG patterns, and functional connectivity. Many of these AIE‐induced brain changes replicate findings seen in postmortem brains of humans with alcohol use disorder (AUD). NADIA researchers are now elucidating mechanisms of these adaptations. Emerging data demonstrate that exercise, antiinflammatory drugs, anticholinesterases, histone deacetylase inhibitors, and other pharmacological compounds are able to prevent (administered during AIE) and/or reverse (given after AIE) AIE‐induced pathology in adulthood. These studies support hypotheses that adolescent binge drinking increases risk of adult hazardous drinking and influences brain development, and may provide insight into novel therapeutic targets for AIE‐induced neuropathology and AUDs. [ABSTRACT FROM AUTHOR]

Introduction: Tardive syndrome (TS) is an often irreversible movement disorder caused by dopamine receptor‐blocking agents (DRBAs). Although TS are well recognized to occur with typical antipsychotics, less well appreciated is that atypical antipsychotics also carry a risk of TS. Methods: Case series. Results: We describe 4 patients who developed tardive dystonia, tardive akathisia, and drug‐induced parkinsonism with the use of the atypical antipsychotic, lurasidone, which was U.S. Food and Drug Administration approved in 2013 for use in bipolar disorder and schizophrenia. Conclusion: Movement disorders are reported as a rare side effect of lurasidone, and, as such, prescribers may perceive a false sense of security regarding this potential complication. Our cases indicate that this relatively new atypical antipsychotic may cause irreversible disabling TS as well as parkinsonism. Caution must be taken when prescribing lurasidone. View Supplementary Video 1 [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder with an increased morbidity and mortality. People with PD (PwP) may suffer from decreased quality of life due to various motor and nonmotor symptoms. To a huge proportion, PwP have written an advance directive (AD); however, the content of these forms in regard to PD-specific complications is unclear. The aim of this study was to qualitatively and quantitatively analyze ADs of PwP in Germany. ADs of PwP were analyzed in a German sample of members of the German PD patient association. Participants completed a questionnaire about their AD and sent a copy of their AD to the study center for detailed analyses. ADs were qualitatively and quantitatively analyzed for general and PD-specific aspects and usefulness concerning treatment decisions. 82 PwP were included in the study, and in 76, an AD could be analyzed. Family members, notaries, lawyers, and general physicians mainly counseled writing of the ADs. 4 PwP consulted a neurologist to establish a specific AD for PD. In the analysis, ADs displayed a good specificity for general aspects, but they were unspecific to PD in the vast majority of cases. PwP should be encouraged to create an AD early in their disease and adapt it in the course of the disease. PD-specific aspects for an AD could be details in relation to dopaminergic therapies at the end of life, management of non-oral advanced therapies, neuropsychiatric symptoms, dementia, and swallowing disturbances. [ABSTRACT FROM AUTHOR]

Background: Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established.Methods: To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study.Results: PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement.Conclusions: Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable. [ABSTRACT FROM AUTHOR]

Introduction: Dopa-responsive dystonia (DRD) related to GCH1 mutation is a biochemical disorder. DRD is majorly characterized by dystonia and/or parkinsonism. Although clinical disorders show a dramatic positive response to levodopa, there are controversies over the residual signs following treatment. This study was designed to investigate the residual signs following levodopa treatment in Korean DRD patients with GCH1 mutation.Methods: A structured questionnaire was prepared to obtain information about demographic factors, clinical characteristics, genetic data, neuroimaging data and residual signs following levodopa treatment of the patients, and was sent to movement specialists at tertiary hospitals. The data collected from the returned forms were analyzed using appropriate statistical methods such as Student's t-test, Mann-Whitney U test, Chi-square test or Fisher's exact test.Results: Thirty-nine DRD Korean patients with GCH1 mutation were recruited. One patient was presented with only parkinsonism. Dystonia was completely resolved in 32 out of 38 patients following treatment, while parkinsonism improved without residual signs in 8 out of 9 patients. The frequency of the residual signs in Korean patients (15.8% for dystonia and 11.1% for parkinsonism) is similar to that observed in Chinese patients, but lower in Western patients. Furthermore, these signs were more frequent in those patients with a delay in their diagnosis, and those who were relatively older at the time of diagnosis.Conclusions: Ethnic differences, age at diagnosis, and a temporal gap between the onset and diagnosis in Korean patients may influence the remaining neurologic abnormalities of DRD. [ABSTRACT FROM AUTHOR]

Introduction: Dopamine replacement via levodopa (LD) remains the most effective treatment for Parkinson's disease (PD), yet its use is often associated with motor complications within several years of continued use. The Accordion Pill® (AP-CD/LD) is a novel drug delivery system based on gastric retention of multilayer films containing immediate-release (IR) carbidopa (CD) and immediate- and controlled-release LD. The AP-CD/LD was designed to improve the consistency of LD in the bloodstream while offering patients with PD more consistent symptom management.Methods: This phase 2, multicenter, open-label, two-way randomized crossover study included 4 cohorts of participants with PD, each receiving AP-CD/LD (50/250 mg, 50/375 mg or 50/500 mg) twice daily in one treatment period and an active comparator in the other treatment period. Pharmacokinetics (PK) and efficacy were evaluated for AP-CD/LD vs IR-CD/LD. Treatment-emergent adverse events (TEAEs) and patient- and investigator-reported measures were also evaluated.Results: Compared with IR-CD/LD, treatment with either AP-CD/LD dose resulted in more stable LD plasma concentrations in both fluctuating and non-fluctuating PD patients, and significantly decreased Cmax (57.1% and 66.8% decreases among fluctuating and non-fluctuating patients, respectively). Both AP doses significantly improved standard measures of motor symptoms: (daily OFF time, total ON time, and good ON time), as well as patient- and investigator-assessed measures, versus IR-CD/LD. The safety and tolerability profile of AP-CD/LD was consistent with the known properties of IR-CD/LD.Conclusions: AP technology demonstrated effective controlled-release PK performance and reduced motor response fluctuations in advanced PD patients. A phase 3 randomized controlled trial is currently underway. [ABSTRACT FROM AUTHOR]

Key Points: Question: Are individuals with major depressive disorder who are not taking medication characterized by lower dopamine transporter levels within the brain reward system compared with psychiatrically healthy control participants? Findings: In this cross-sectional study that analyzed positron emission tomography in 25 individuals with major depressive disorder and 23 healthy controls and postmortem data in 15 individuals with major depressive disorder and 14 healthy controls, major depressive disorder was linked to lower dopamine transporter levels in the dorsal striatum. In the imaging data, this dysfunction was exacerbated by more episodes of depression. Meaning: Decreased dopamine transporter availability might represent a compensatory downregulation because of low dopaminergic signaling within mesolimbic pathways. Importance: Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive. Objective: Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide. Design, Setting, and Participants: This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered. Intervention: PET scan. Main Outcomes and Measures: Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots. Results: Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, −0.62 to −0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, −0.92 to −1.15). Conclusions and Relevance: Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways. This cross-sectional study explores dopamine transporter availability in individuals with major depressive disorder who were not taking medication and levels of dopamine transporter expression in postmortem tissues from donors with major depressive disorder who died by suicide. [ABSTRACT FROM AUTHOR]

OBJECTIVE To evaluate potential associations between preanesthetic administration of acepromazine or dexmedetomidine and development of arterial hypotension or bradycardia in isoflurane-anesthetized dogs undergoing ovariohysterectomy. ANIMALS 341 dogs. PROCEDURES Medical records were searched to identify dogs that underwent ovariohysterectomy between January 2009 and December 2010 and received hydromorphone with acepromazine or dexmedetomidine as preanesthetic agents. Demographic data, sedative and anesthetic drugs, duration of anesthesia, average vaporizer setting, positive pressure ventilation, occurrence of hypotension (mean arterial pressure < 60 mm Hg) or bradycardia (> 50% reduction in heart rate, compared with the preanesthetic value), time to first occurrence and duration of hypotension, and treatment with dopamine or anticholinergic agents were recorded. Data were compared between dogs that received acepromazine and dexmedetomidine. Logistic regression was used to investigate associations between the treatments of interest (and other putative risk factors) and development of hypotension or bradycardia. RESULTS For dogs that received acepromazine, the odds of developing hypotension were 2.61 times those for dogs that received dexmedetomidine. Hypotension occurred earlier and lasted longer in dogs that received acepromazine, and this group was treated with dopamine more frequently than the group that received dexmedetomidine. Lower body weight was associated with increased odds of hypotension. Odds of developing bradycardia were greater for dogs sedated with dexmedetomidine (vs acepromazine) and for dogs that underwent anesthetic induction with propofol or a ketamine-benzodiazepine combination (vs thiopental). CONCLUSIONS AND CLINICAL RELEVANCE Anesthetic complications differed between isoflurane-anesthetized dogs undergoing ovariohysterectomy after premedication with acepromazine or dexmedetomidine in this study; future prospective investigations are warranted to investigate these effects in other, less homogenous populations of dogs. [ABSTRACT FROM AUTHOR]

The article offers information on catatonia, a neuropsychiatric syndrome.The symptoms of catatonia include fever, dysautonomia and delirium. Neuroimaging and differential diagnosis have been to detect catatonia. The risk factors for the disease are enumerated, including dehydration, weight loss and cocaine use. The effectiveness of benzodiazepine and electroconvulsive therapy (ECT) in the treatment of catatonia is discussed.

Jinzhen oral liquid (JZ) is a classical traditional Chinese medicine formula used for the treatment of children lung disease. However, the effective substance of JZ is still unclear. In this study, we used lung injury rat model to study the protective effect of JZ, through UPLCQ- TOF/MS detection coupled with metabolic research and network pharmacology analysis. Fortunately, 31 absorbed prototype constituents and 41 metabolites were identified or tentatively characterized based on UPLC-Q-TOF/MS analysis, and the possible metabolic pathways were hydroxylation, sulfation and glucuronidation. We optimized the data screening in the early stage of network pharmacology by collecting targets based on adsorbed constituents, and further analyzed the main biological processes and pathways. 24 selected core targets were frequently involved in reactive oxygen species metabolic process, dopaminergic synapse pathway and so on, which might play important roles in the mechanisms of JZ for the treatment of lung injury. Overall, the absorbed constituents and their possible metabolic pathways, as well as the absorbed constituent-target-disease network provided insights into the mechanisms of JZ for the treatment of lung injury. Further studies are needed to validate the biological processes and effect pathways of JZ. [ABSTRACT FROM AUTHOR]

Background and Purpose: L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA.Experimental Approach: Adult C57BL6 mice were lesioned with 6-hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno-associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L-DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L-DOPA challenge.Key Results: Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation-induced dyskinesia [OID]) in 6-hydroxydopamine animals, but not in sham-lesioned animals. Additionally, chronic L-DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L-DOPA administration. Furthermore, L-DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID.Conclusion and Implications: This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID. [ABSTRACT FROM AUTHOR]

Background: CVT-301 (Inbrija) is a self-administered orally inhaled levodopa approved for the intermittent treatment of OFF episodes in patients with Parkinson's disease (PD) treated with carbidopa/levodopa. Prior studies only evaluated CVT-301 after the first ON of the day.Objective and Methods: The objective of this study was to evaluate the safety and tolerability of CVT-301 for early morning OFF. Using a randomized, double-blind, 2-way crossover design, eligible patients in the morning OFF state (having not received PD medication overnight) received a single dose of CVT-301 84 mg or placebo on 2 dosing days, immediately after their first morning oral carbidopa/levodopa dose. Safety assessments included treatment-emergent adverse events, vital signs, and patient- and examiner-reported dyskinesia. An exploratory efficacy assessment was examiner-rated time-to-ON with carbidopa/levodopa + CVT-301 vs carbidopa/levodopa + placebo.Results: Of the 36 patients (mean age 62.9 years) who enrolled and completed the study, 9 (25.0%) reported treatment-emergent adverse events following CVT-301 administration; 4 (11.1%) reported treatment-emergent adverse events following placebo. The most common adverse event was cough (4 [11.1%] for CVT-301 vs 1 [2.8%] for placebo), which was typically mild and transient. Incidence of asymptomatic orthostatic hypotension (CVT-301, 6; placebo, 7) and examiner-rated dyskinesia were similar for both (36-39% mild, 3-6% moderate, and 0% severe). Median time-to-ON was 25.0 min following carbidopa/levodopa + CVT-301 and 35.5 min following carbidopa/levodopa + placebo (P = 0.26). At 30 min, more patients had turned ON following carbidopa/levodopa + CVT-301 administration (66.7%), compared with carbidopa/levodopa + placebo (44.5%) (P = 0.040).Conclusion: Single doses of CVT-301 84 mg administered with oral carbidopa/levodopa for early morning OFF symptoms were well-tolerated, with no notable safety concerns. [ABSTRACT FROM AUTHOR]

Animal studies of effort-based choice behavior are being used to model effort-related motivational dysfunctions in humans. With these procedures, animals are offered a choice between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/low reward options. Several previous studies have shown that dopamine (DA) uptake inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040, can reverse the effort-related effects of the vesicular monoamine transport blocker tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport act as major stimulants that also release DA, and produce a number of undesirable side effects, there is a need to develop and characterize novel atypical DA transport inhibitors. (S) -CE-123 ((S) - 5 -((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil with the biochemical characteristics of an atypical DA transport blocker. The present paper describes the enantioselective synthesis and initial chemical characterization of (S) -CE-123, as well as behavioral experiments involving effort-based choice and microdialysis studies of extracellular DA. Rats were assessed using the fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior, decreasing lever pressing and increasing chow intake. (S) -CE-123 was coadministered at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that (S) -CE-123 significantly increased lever pressing on a progressive ratio/chow feeding choice task and that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core. In summary, (S) -CE-123 has the behavioral and neurochemical profile of a compound that can block DA transport, reverse the effort-related effects of tetrabenazine, and increase selection of high-effort progressive ratio responding. This suggests that (S) -CE-123 or a similar compound could be useful as a treatment for effort-related motivational dysfunction in humans. [ABSTRACT FROM AUTHOR]

Background: Prolonged dopaminergic replacement therapy in PD results in pulsatile dopamine receptors stimulation in both dorsal and ventral striatum causing wearing off, motor fluctuations, and nonmotor side effects such as behavioral addictions. Among impulse control disorders, binge eating can be easily modeled in laboratory animals.Objectives: We hypothesize that manipulation of dopamine levels in a 6-hydroxydopamine-lesioned rats, as a model of PD characterized by a different extent of dopamine denervation between dorsal and ventral striatum, would influence both synaptic plasticity of the nucleus accumbens and binge-like eating behavior.Methods: Food preference, food intake, and weight gain were monitored in sham-operated and unilaterally lesioned rats, subjected to a modified version of Corwin's limited access protocol, modelling binge eating disorder. Electrophysiological properties and long-term potentiation of GABAergic spiny projection neurons of the nucleus accumbens core were studied through ex vivo intracellular and patch-clamp recordings from corticostriatal slices of naïve and l-dopa-treated rats.Results: Sham-operated animals with intact nucleus accumbens core plasticity reliably developed food-addiction-like behavior when exposed to intermittent access to a highly palatable food. In contrast, parkinsonian rats were unresponsive to such restriction regimens, and also plasticity was lost in ventral spiny neurons. Chronic l-dopa reestablished long-term potentiation and compulsive eating, but with a different temporal dynamic that follows that of drug administration.Conclusions: Our data indicate that endogenous and exogenous dopamine drive binge-like consumption of a palatable food in healthy and parkinsonian rats with distinct temporal dynamics, providing new insights into the complexity of l-dopa effects on the mesolimbic dopaminergic system. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The experience of motherhood is most often emotionally positive and rewarding, but for many new mothers suffering from postpartum depression (PPD), this is not the case. Preclinical and clinical research has sought to uncover brain changes underlying PPD in order to gain a better understanding of how this disorder develops. This review focuses on the mesolimbic dopamine system, particularly the ventral tegmental area-nucleus accumbens pathway which has been implicated in the regulation of critical functions disrupted in PPD including mood, motivation, and mothering. Specifically, we discuss normative changes in the mesolimbic system during motherhood in both rodents and humans and how these are impacted in PPD. We also consider modulation of mesolimbic dopamine by the hypothalamic neuropeptide oxytocin and how oxytocin-dopamine interactions regulate mood and mothering during the postpartum period. In addition to providing an overview of reward mechanisms in PPD, our goal is to highlight open questions which warrant further research. [ABSTRACT FROM AUTHOR]

Parkinson's disease is a chronic multi-system disease that can cause motor and non-motor symptoms, cognitive changes and variably effective medications. Optimal management of the condition requires a multi-disciplinary team of healthcare professionals to work closely with the patient and their carers. The National Institute for Health and Care Excellence published updated guidelines on managing Parkinson's disease in adults in 2017. Here we discuss the implications of this guidance to current healthcare professionals involved in the care of people with Parkinson's disease. The guidance highlights the importance of clear communication with people with Parkinson's disease. We discuss examples of this, including providing a point of contact with specialist services for people with Parkinson's disease and ensuring information about the risks of impulse control disorders are given to people on dopaminergic therapy. The breadth of services required by people with Parkinson's disease is also described, including the need for access to physiotherapy, occupational therapy and speech and language therapy as well as treatment monitoring services for Clozapine. In addition, we emphasise the continued importance of ensuring people with Parkinson's disease receive their medications on time when in hospital or a care home. [ABSTRACT FROM AUTHOR]

Movement disorders differ in children to adults. First, neurodevelopmental movement disorders such as tics and stereotypies are more prevalent than parkinsonism, and second, there is a genomic revolution which is now explaining many early-onset dystonic syndromes. We outline an approach to children with movement disorders starting with defining the movement phenomenology, determining the level of functional impairment due to abnormal movements, and screening for comorbid psychiatric conditions and cognitive impairments which often contribute more to disability than the movements themselves. The rapid improvement in our understanding of the etiology of movement disorders has resulted in an increasing focus on precision medicine, targeting treatable conditions and defining modifiable disease processes. We profile some of the key disease-modifying therapies in metabolic, neurotransmitter, inflammatory, and autoimmune conditions and the increasing focus on gene or cellular therapies. When no disease-modifying therapies are possible, symptomatic therapies are often all that is available. These classically target dopaminergic, cholinergic, alpha-adrenergic, or GABAergic neurochemistry. Increasing interest in neuromodulation has highlighted that some clinical syndromes respond better to DBS, and further highlights the importance of "disease-specific" therapies with a future focus on individualized therapies according to the genomic findings or disease pathways that are disrupted. We summarize some pragmatic applications of symptomatic therapies, neuromodulation techniques, and some rehabilitative interventions and provide a contemporary overview of treatment in childhood-onset movement disorders. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Studies have shown that dual-task standing balance in Parkinson's disease (PD) is significantly diminished. Additionally, it is well accepted that dopaminergic medication improves dynamic balance (Berg Balance Scale, mini-BESTest), but standing balance (force platform posturography) may suffer. What remains unknown is how dopaminergic medication influences standing balance automaticity in PD.Research Question: Does dopaminergic medication improve standing balance automaticity during a phoneme monitoring dual-task in PD?Methods: This was a cross-sectional study. Sixteen subjects with PD completed single- and dual-task standing with eyes open and eyes closed for 3 min each in off and on medication states. 95% confidence ellipse area, anterior-posterior sway velocity, medial-lateral sway velocity, and integrated time to boundary were calculated. Data were analyzed with a repeated measures ANOVA.Results: Dopaminergic medication significantly increased ellipse area (p =  0.002) and decreased the performance on the secondary task (p =  0.004). Different eyes conditions (open vs. closed) significantly increased both sway velocities (anterior-posterior = p <  0.001, medial-lateral = p <  0.001), and increased integrated time to boundary (p <  0.001). There were also task by eyes condition interaction effects for anterior-posterior velocity and integrated time to boundary (p =  0.015 and p =  0.009, respectively). Increases in sway velocity and integrated time to boundary seen in the eyes condition and interaction effects are traditionally interpreted as poorer balance performance. However, in the context of stability/maneuverability tradeoff, the changes may indicate an increase in freedom of movement instead of a decrease in stability.Significance: The data did not support a medication-induced improvement in automaticity, as measured by significant medication by task interactions. An alternate interpretation for medication-induced balance changes in PD includes an increase in maneuverability without sacrificing stability after taking dopaminergic medication. [ABSTRACT FROM AUTHOR]

Introduction: There is lack of data on pattern of use of drugs in patients with chronic heart failure (CHF) from Nepalese population. This study was conducted to explore the trends of evidence based medications used for CHF in our population. Methods: This is a cross-sectional study on 200 consecutive patients with New York Heart Association (NYHA) class II to IV symptoms of CHF who attended cardiology clinic or admitted from September 2017 to August 2018 at Nobel Medical College Teaching Hospital, Biratnagar, Nepal. Results: Mean age of patients was 54 (range 15-90) years. Ischemic cardiomyopathy, rheumatic heart disease, dilated cardiomyopathy, hypertensive heart disease, peripartum cardiomyopathy were common etiologies of CHF. Analysis of drugs used in CHF revealed that 85% patients were prescribed diuretics, 58.5% angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 53% mineralocorticoid receptor antagonists (MRAs), 38% beta-blockers (BBs) and 24% digoxin. Digoxin was mainly used as add on therapy for patients with atrial fibrillation (24% of all patients). Antithrombotics (warfarin or aspirin), inotropic agents (dopamine, dobutamine or noradrenaline), antiarrhythmic agent (amiodarone) and nitrates (intravenous glyceryl trinitrate or oral isosorbide dinitrate) were prescribed for 48%, 28%, 5% and 6% patients respectively. All CHF patients with preserved or mid-range ejection fraction (25% of all patients) were prescribed diuretics along with antihypertensive drugs for hypertensive patients. Conclusion: CHF is associated with significant morbidity and mortality due to associated co-morbidities and underuse of proven therapy like BBs, ACEIs or ARBs and MRAs. Careful attention to optimization of different drugs therapy in patients with CHF may help to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders are frequent in Parkinson's disease (PD), but may be difficult to identify as they are closely related to other aspects of PD, such as motor impairment and non-motor fluctuations. While integral to PD treatment, dopaminergic therapies may contribute significantly to neuropsychiatric symptoms. Treatments in PD should be constantly reviewed and balanced, such as by adjusting doses appropriately, to minimize neuropsychiatric issues among other adverse events. [ABSTRACT FROM AUTHOR]