Striatal Dopaminergic Activity Research Articles

Scaling problem in Parkinson's disease patients with pain

IntroductionAlthough pain is common in Parkinson's disease (PD), the underlying mechanism remains unknown. Scaling function and dopaminergic hypofunction may contribute to pain development because increased pain sensitivity is observed in PD and is normalized after levodopa administration. We aimed to determine whether spatial discrimination (SD) and striatal dopaminergic activity (DA) differed between PD patients with and without pain. MethodsWe divided 90 patients with drug-naïve PD into two groups based on the presence or absence of pain and compared the SD threshold (SDT). We evaluated the correlation of the SDT with pain severity in PD with pain. We also compared the DA of 48 patients and analyzed the correlation with pain severity in PD patients with pain. ResultsThe SDTs did not differ between the two groups, but unmeasurable SDT was more frequent in PD with pain. There was a positive correlation of pain severity with the SDT of the more affected hand but no correlation with the SDT of the less affected hand. The DA did not differ between the groups. There was a negative trend of pain severity with the DA of the ventral striatum (VS) but no correlation with the other striatal subregions. ConclusionsPain in PD may be associated with scaling dysfunction in the sensory system. The abnormal scaling function would render the PD patient hypersensitive to even mild pain. The dopamine in the VS appears to be associated with pain severity; however, the relationship of striatal dopaminergic deficits with pain occurrence requires further investigation.

Cases Of Meige’s Syndrome Controlled Following Administration Of Low-Dose Botulinum Toxin Type-A: A Serial Case Series

Background: Meige syndrome is a form of cranial dystonia characterised by blepharospasm and oromandibular dystonia, with a twice-fold higher prevalence in women as compared to men. The definitive pathophysiology underlying Meige syndrome remains unknown, but some studies have postulated the role of striatal dopaminergic activity. Currently, no curative treatments are available for Meige syndrome, but non-specific modalities include oral agents such as anti-cholinergics, dopaminergics, and benzodiazepines. Botulinum toxin Type-A (BoNTA) constitutes an effective treatment option in cases of Meige syndrome refractory to oral management. Case summary: We report three cases of female patients, age 42, 57, and 61 years, presenting with complaints of blepharospasm and oromandibular dystonia. Low-dose BoNTA injections were administered, 10 units total weekly divided into the orbicularis oculi, corrugator supercilii, frontalis, procerus, nasalis, zygomaticus, mentalis, dan risorius, and orbicularis oris areas. Following repeated administrations of BoNTA injections, the three patients no longer experience symptoms up till now. Conclusion: The authors report that low-dose BoNTA injections are effective in ameliorating dystonic symptoms associated with Meige syndrome, with low incidences of side effects.

Restraint Stress Exacerbates Apoptosis in a 6-OHDA Animal Model of Parkinson Disease.

Activation of the apoptotic pathway has been associated with promoting neuronal cell death in the pathophysiology of Parkinson disease (PD). Nonetheless, the mechanisms by which it may occur remain unclear. It has been suggested that stress-induced oxidation and potential apoptosis may play a major role in the progression of PD. Thus, in this study, we aimed to investigate the effect of subchronic restraint stress on striatal dopaminergic activity, iron, p53, caspase-3, and plasmatic acetylcholinesterase (AChE) levels in male Wistar rat model of PD induced by administration of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB). The obtained results showed that restraint stress exacerbates motor coordination deficits and anxiety in animals treated with 6-OHDA in comparison to animals receiving saline, and it had no effect on object recognition memory. On another hand, 6-OHDA decreased dopamine (DA) levels, increased iron accumulation, and induced overexpression of the pro-apoptotic factors caspase-3, p53, and AChE. More interestingly, post-lesion restraint stress exacerbated the expression of caspase-3 and AChE without affecting p53 expression. These findings suggest that subchronic stress may accentuate apoptosis and may contribute to DA neuronal loss in the striatal regions and possibly exacerbate the progression of PD.

Striatal Dopamine Transporter Availability is Associated with Sleep Disturbance among Patients with Bipolar I Disorder: A Single-photon Emission Computed Tomography Study Using [99mTc] TRODAT-1.

Bipolar disorder (BD) is characterized by the poor sleep quality. Whether the striatal dopamine transporter (DAT) availability is related to sleep quality among patients with BD is unclear. Fifty-three euthymic patients with BD (24 BD-I and 29 BD-II) and sixty-eight healthy controls were enrolled. The Chinese Version of the Pittsburgh Sleep Quality Index (PSQI) was used, and the availability of DAT was assessed by single-photon emission computed tomography (SPECT) using [99mTc] TRODAT-1. The sleep disturbance component of the PSQI was significantly associated with the level of DAT availability among patients with BD. The striatal dopaminergic activity that contributes to resilience to adversity was associated with sleep pattern among patients with BD.

Studying cognitive function in patients with a long-standing diagnosis of SWEDD

IntroductionThe cognitive profile of patients with longstanding clinical Parkinsonism possessing scans without evidence of dopaminergic deficit (SWEDD) remains unclear from previous studies. MethodsWe studied 47 patients recruited in the Parkinson's Progression Markers Initiative with SWEDD as baseline diagnosis. They were subdivided by final clinical diagnoses after a 2-year follow-up period into 25 patients with either clinical evidence of Parkinson's Disease (PD) or unclassified parkinsonism and normal SPECT imaging (“true SWEDDs”), 6 patients with a psychogenic illness exhibiting Parkinsonism, 6 patients who had phenoconverted to PD based on reduced striatal dopaminergic activity on imaging, and 10 patients with another tremulous condition. Cognitive symptoms were compared between these subgroups, as well as with 62 PD patients and 195 healthy controls (HCs), at baseline and follow-ups. ResultsA significant difference in working memory was found between true SWEDDs and HCs (P = 0.009), but not true SWEDDs and PD patients (P = 0.432), nor PD patients and HCs (P = 0.154). The prevalence of attentional impairment was also significantly different between the three groups (P < 0.001). SWEDD subgroups possessed similar cognitive symptoms irrespective of their final clinical diagnosis. Psychogenic, phenoconverted and tremulous SWEDDs also possessed stable cognitive symptoms over the 2-year period whilst true SWEDDs, PD patients and HCs experienced significant changes in working memory. ConclusionsOur results, particularly relating to working memory and attention, add to the knowledge of other true SWEDD non-motor symptoms to facilitate earlier diagnosis and improved management strategies for these patients.

The Lack of Dopamine Transporter Is Associated With Conditional Associative Learning Impairments and Striatal Proteomic Changes.

Dopamine (DA) is critically involved in different functions of the central nervous system (CNS) including control of voluntary movement, affect, reward, sleep, and cognition. One of the key components of DA neurotransmission is DA reuptake by the DA transporter (DAT), ensuring rapid clearance of DA from the synaptic cleft. Thus, lack of DAT leads to persistent high extracellular DA levels. While there is strong evidence for a role of striatal dopaminergic activity in learning and memory processes, little is known about the contribution of DAT deficiency to conditional learning impairments and underlying molecular processes. DAT-knockout (DAT-KO) rats were tested in a set of behavioral experiments evaluating conditional associative learning, which requires unaltered striatal function. In parallel, a large-scale proteomic analysis of the striatum was performed to identify molecular factors probably underlying behavioral patterns. DAT-KO rats were incapable to acquire a new operant skill in Pavlovian/instrumental autoshaping, although the conditional stimulus–unconditional stimulus (CS-US) association seems to be unaffected. These findings suggest that DAT directly or indirectly contributes to the reduction of transference of incentive salience from the reward to the CS. We propose that specific impairment of conditional learning might be caused by molecular adaptations to the hyperdopaminergic state, presumably by dopamine receptor 1 (DRD1) hypofunction, as proposed by proteomic analysis. Whether DRD1 downregulation can cause cognitive deficits in the hyperdopaminergic state is the subject of discussion, and further studies are needed to answer this question. This study may be useful for the interpretation of previous and the design of future studies in the dopamine field.

Correlations with REM sleep behavior disorder severity in isolated rapid eye movement sleep behavior disorders patients

Objectives The pathogenesis of isolated rapid eye movement sleep behavior disorders (iRBD) is poorly understood. The severity of RBD may reflect its pathogenesis. Methods We compared motor function and non-motor symptoms (NMSs) between iRBD patients and healthy volunteers. We correlated motor function, NMSs, and striatal dopaminergic activity with RBD severity using video-polysomnography. Results Twenty-one iRBD patients and 17 controls participated. The Unified Parkinson’s Disease Rating Scale part III scores were higher in patients compared to controls (p < 0.001). There was no difference in upper extremity function between patients and controls (right, p = 0.220; left, p = 0.209), but gait was slower in iRBD patients (walking time, p < 0.001; number of steps, p < 0.001). The mean value of the Korean version of the Mini-Mental State Exam and Clinical Dementia Rating were lower in patients (p = 0.006, p = 0.003, respectively). Patients with were also more depressed (p = 0.002), had decreased olfactory function (p < 0.001), reported more frequent sleep/fatigue episodes (p < 0.001), worse attention/memory capacity (p < 0.001), gastrointestinal problems (p = 0.009), urinary problems (p = 0.007), and pain (p = 0.083). Further, iRBD patients reported more frequent sleep-related disturbances (p = 0.004), but no difference in daytime sleepiness (p = 0.663). Disease severity was correlated with pain (r = 0.686, p = 0.002) and visuospatial function (r= −0.507, p = 0.038). There were no correlations between RBD severity and striatal dopaminergic activities (p > 0.09). Conclusions iRBD is a multisystem neurodegenerative disorder, and gait abnormalities may be a disease characteristic, possibly related to the akinetic-rigid phenotype of Parkinson’s disease. The correlation between pain/visuospatial dysfunction and RBD severity may be related to its pathogenesis.

Differential effects of chronic voluntary wheel-running on morphine induced brain stimulation reward, motor activity and striatal dopaminergic activity

Physical exercise could be a protective factor against the development of substance use disorders; however, a number of preclinical studies report reward-enhancing effects of exercise for various drugs of abuse. We examined the effects of chronic wheel-running on brain reward sensitivity, reaction to novelty, reward-facilitating and locomotor-stimulating effects of morphine, using the intracranial self-stimulation (ICSS) and the open field test (OFT). Male Sprague-Dawley rats were randomly assigned to a sedentary or exercised group. For the ICSS procedure, rats were implanted with electrodes and trained to respond for electrical stimulation. Several indices were recorded in the training phase to estimate brain reward sensitivity. Once responding was stable, the animals of both groups received systemic injections of morphine and their ICSS thresholds were measured with the curve-shift paradigm. Employing the OFT, basal and morphine-induced locomotor activity was measured. Finally, basal and morphine-evoked tissue levels of dopamine and its metabolites were determined in the striatum using gas chromatography/mass spectrometry. Chronic wheel-running decreased brain reward sensitivity and subsequently increased the reward-facilitating effect of morphine. Exercised animals demonstrated a decreased reaction to novelty and reduced morphine-induced locomotion. Lastly, dopaminergic activity was decreased in the striatum of exercised animals under basal conditions, whereas morphine administration led to an increase in dopamine turnover. These findings indicate that chronic voluntary exercise exerts divergent effects on reward function, psychomotor activity and the reward-facilitating and locomotor-activating effects of opioids during adulthood. Our results provide insights into the increased non-medical use of opioids among young athletes reported in the literature.

Frontal\u2013striatal connectivity and positive symptoms of schizophrenia: implications for the mechanistic basis of prefrontal rTMS

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)—increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal–striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal ‘brake’. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

S9. NEUROIMAGING AND NEUROPHYSIOLOGY BIOMARKERS OF SCHIZOTYPAL PERSONALITY DISORDER: A SYSTEMATIC REVIEW

BackgroundSchizotypal personality disorder (SPD) is a cluster A personality disorder affecting 1.0% of general population, characterised by disturbances in cognition and reality testing dimensions, affect regulation, and interpersonal function. SPD shares similar but attenuated phenomenological, genetic, and neurobiological abnormalities with schizophrenia (SCZ) and is described as part of the continuum of schizophrenia spectrum disorders. Neuroimaging and neurophysiology are the main non-invasive techniques for the investigation of brain structure and function, so they play a crucial role in psychiatric research and for their applications into clinical practice. The present review aims to systematically identify the major neuroimaging and neurophysiology biomarkers of SPD.MethodsThe present review has been conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. The protocol was prospectively registered in PROSPERO - International prospective register of systematic reviews. The systematic review was performed to summarise the most comprehensive and updated evidence on functional neuroimaging and neurophysiology findings obtained through different techniques (DW-MRI, DTI, PET, SPECT, fMRI, MRS, EEG) in subjects with SPD.ResultsThe search initially yielded 218 records. After study selection and reference screening, the final set comprised 52 studies. Of the 52 studies included in this review, 9 were on DW-MRI and DTI, 11 were on PET and SPECT, 11 were on fMRI and MRS, and 21 were on EEG. Although it was complex to synthesise all the functional abnormalities found in the included studies into a single, unified, pathogenetic pathway, a common theme that emerged was the dysfunction of brain circuits including striatal, frontal, temporal, limbic regions, and their networks. This dysfunction may be the result of a dysregulation along the dopaminergic pathways and lead to deficits or defects in processes that organise a person’s cognitive-perceptual evaluation of the environment and the relatedness to him/herself. As for the limitations, a quantitative data synthesis was not planned for this work, therefore no meta-analytical integrations are presented in this review. The results of individual neuroimaging studies, in fact, are not comparable due to small and heterogeneous samples, analytical flexibility, or differences in imaging modalities and behavioral tasks.DiscussionBrain abnormalities in SPD are similar, but less marked, than those found in SCZ, and they do not mirror each other. In fact, different patterns of functional abnormalities in SPD and SCZ have been found in this systematic review, suggesting the ‘presence’ of possible compensatory factors, protecting subjects with SPD from frank psychosis and providing diagnostic specificity. Specifically, SPD differentiates from SCZ by showing: (a) milder frontal-striatal-temporal white matter dysconnectivity in DTI studies, (b) lesser frontal and striatal dysfunction and a decreased striatal dopaminergic activity in PET and SPECT studies, respectively, (c) different patterns of dysfunctional activation of frontal-striatal-thalamic circuitry during attentional processing in fMRI studies, and (d) milder alterations in EEG sensory gating and no evidence of alterations in EEG auditory or visual processing.

Neural and dopaminergic correlates of fatigue in Parkinson's disease.

Fatigue is one of the most common non-motor symptoms in Parkinson's disease (PD). Despite its clinical importance, there are few studies on the cause or mechanism of fatigue. Our aim was to find brain areas related to fatigue and to explore the association between striatal dopaminergic dysfunction and fatigue. We consecutively screened forty-seven patients with de novo PD from 2012 to 2017 and enrolled 32 patients. The gray matter volumes, white matter tracts, and striatal dopaminergic activity between PD without fatigue and with fatigue were compared. The correlation between fatigue and striatal dopaminergic activity was also analyzed. Our data did not show any significant difference in gray matter volume between PD without fatigue and with fatigue (familywise error [FWE] corrected p > 0.05) but revealed significantly higher mean fractional anisotropy (FA) values for all analyzed white matter tracts in PD with fatigue (false discovery rate [FDR] corrected p < 0.05), except left cingulum-hippocampus (CH), right superior longitudinal fasciculus, and right longitudinal fasciculus temporal part (FDR corrected p > 0.06); lower mean diffusivity (MD) values for all analyzed white matter tracts in PD with fatigue (FDR corrected p < 0.05), except in the left CH and uncinate fasciculus (FDR corrected p > 0.05). The mean radial diffusivity (RD) values, except for the left CH (FDR corrected p = 0.0576), were also significantly lower (FDR corrected p < 0.05). There was no difference in dopaminergic deficits between PD without fatigue and PD with fatigue (p > 0.50). The alteration of the white matter tract may reflect the degree of fatigue in PD. This is not true of the gray matter and striatal dopaminergic activity. These results show the possibility that white matter changes can be used as a biomarker for fatigue.

Human Brain Imaging Links Dopaminergic Systems to Impulsivity.

Molecular and functional imaging techniques have been used and combined with pharmacological probes to evaluate the role of dopamine in impulsivity. Overall, strong evidence links striatal dopaminergic function with impulsivity, measured by self-reports and laboratory tests of cognitive control and reward-based decision-making. The combination of molecular imaging using positron emission tomography (PET) with functional magnetic resonance imaging (fMRI) specifically implicates striatal D2-type dopamine receptors (i.e., D2 and D3) and corticostriatal connectivity in cognitive control. Low levels of striatal and midbrain D2-type receptor availability correlate with self-reported impulsivity, whereas striatal D2-type receptor availability shows positive correlation with motor response inhibition and cognitive flexibility. Impulsive choice on reward-based decision-making tasks also is related to deficits in striatal D2-type dopamine receptor availability, and there is evidence for an inverted U-shaped function in this relationship, reflecting an optimum of striatal dopaminergic activity. Findings from studies of clinical populations that present striatal dopamine D2-type receptor deficits as well as healthy control research participants identify D2-type receptors as therapeutic targets to improve cognitive control.

Presynaptic dopamine function measured with [18F]fluorodopa and L-DOPA effects on impulsive choice

We previously reported that L-DOPA effects on reward-based decision-making in a randomized, placebo-controlled, double-blind, crossover study were consistent with an inverted U-shaped function whereby both low and high extremes of dopamine signaling are associated with high-impulsive choice. To test this hypothesis, we performed [18F]DOPA positron emission tomography in 60 of the 87 participants in that study, and measured the effective distribution volume ratio (EDVR) of [18F]DOPA influx rate to [18F]dopamine washout rate, an index of presynaptic dopaminergic function. Participants with higher baseline EDVR self-reported lower impulsivity, and discounted rewards as a function of delay more strongly after receiving L-DOPA, whereas the opposite was detected for those with lower baseline EDVR. Our findings support a relationship of striatal dopaminergic activity to trait impulsivity, and the view that there is a non-linear, possibly inverted U-shaped relationship of striatal dopaminergic function with delay discounting. Individuals with optimal dopamine signaling would become more impulsive when receiving dopamine-enhancing drugs, whereas those with suboptimal dopaminergic signaling would benefit and exhibit less impulsive choice. Consideration of differences in endogenous dopamine signaling and possibly also other neurotransmitter activity may be crucial to advance understanding of the neurobiochemical mechanisms of impulsive decision-making and related mental disorders.

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study

Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations.

Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease.

To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-β-carboxymethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.

Cannabis induced increase in striatal glutamate associated with loss of functional corticostriatal connectivity

Cannabis is the most commonly used illicit drug and is known to alter state of consciousness and impair neurocognitive function. However, the mechanisms underlying these effects have yet to be fully elucidated. Rodent studies suggest that Δ9-tetrahydrocannabinol (THC) activates dopaminergic neurons in the limbic system, subsequently enhancing dopamine, which is implicated in the rewarding effects of cannabis. Additional evidence suggests that THC may act indirectly on dopamine firing by modulating GABA and glutamate release. This double-blind, placebo-controlled study assessed the acute influence of two doses of THC on brain kinetics of glutamate, GABA, and dopamine, in relation to behavioral outcomes, by using magnetic resonance spectroscopy and functional magnetic resonance imaging. Twenty occasional cannabis users received acute doses of cannabis (300 µg/kg THC) and placebo, in one of two dose regimes (full dose and divided dose), during two separate testing days. Administration of THC increased striatal glutamate concentrations, and dopamine as indicated by a reduction in functional connectivity (FC) between the nucleus accumbens (NAc) and cortical areas. Alterations in glutamate and FC were dose dependent and evident in the full dose group where THC serum concentrations exceeded 2 ng/ml at T-max. Average glutamate changes correlated strongly with FC alterations. Additionally, THC induced changes in FC correlated with feelings of subjective high and decreased performance on an attention task. Taken together, this suggests that THC elicits subjective and cognitive alterations via increased striatal dopaminergic activity and loss of corticostriatal connectivity, which is associated with an increase in striatal glutamate.

S156. FRONTO-STRIATAL FUNCTIONAL CONNECTIVITY AND STRIATAL DOPAMINE CAPACITY IN TREATMENT-RESPONSIVE AND REFRACTORY SCHIZOPHRENIA

BackgroundSchizophrenia is thought to be a heterogeneous disorder and evidences reflect categorically distinct subtypes according to the antipsychotic treatment response. Altered frontostriatal functional connectivity (FC) in schizophrenia and its correlation with antipsychotic treatment response also suggests divergence of underlying pathophysiologic mechanism. Meanwhile, the observations that prefrontal activity correlates with striatal dopaminergic function, leads to the hypothesis that the disrupted frontostriatal FC would be related with altered dopaminergic pathway in schizophrenia. The aim of this study was to investigate the relationship between frontostriatal FC and striatal dopaminergic activity in patients with schizophrenia according to the responsiveness to first-line antipsychotic drug.Methods24 symptomatically stable schizophrenia patients were recruited from Seoul National University Hospital, 12 of which responded to first-line antipsychotic drugs (first-line AP group) and 12 stable under clozapine (clozapine group), along with 12 matched health controls. All participants underwent resting-state functional MRI and [F18]DOPA positron emission tomography.ResultsThere were no significant difference in the total PANSS score between the first-line AP group and the clozapine group (mean difference=0.67, s.e.=3.21, df=33, p=1.000). Voxel-based analysis found significant negative correlation between frontal FC to the left associative striatum and the kicer in the corresponding region was found in first-line AP group but not in clozapine group or healthy control. Additional region of interest analysis confirmed the result (control group: R2=0.032, p=0.572; first-line AP group: R2=0.551, p=0.005; clozapine group: R2=0.108, p=0.297).DiscussionDifferent patterns of relationship between striatal dopamine capacity and frontostriatal FC observed in this study indicates different pathophysiology underlying schizophrenia according to antipsychotics treatment-responsiveness. Results should be reconfirmed in prospective manner with larger sample size in future studies.

Weight loss is associated with rapid striatal dopaminergic degeneration in Parkinson's disease

IntroductionWeight loss in Parkinson's disease (PD) is associated with poorer clinical outcomes and rapid disease progression. However, it is unclear whether a longitudinal association between weight loss and striatal dopaminergic degeneration exists. MethodsUsing data from 171 PD patients in the Parkinson's Progression Markers Initiative (PPMI) cohort, we investigated longitudinal associations of change in body mass index (BMI) with striatal dopaminergic activity on 123I-N-3-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane (123I-FP-CIT) single positron emission computed tomography (SPECT). We defined BMI loss as a reduction in BMI value > 5% of baseline, and categorized the PD patients into 2 subgroups (patients with and without BMI loss). Linear mixed model (LMM) analysis was employed to compare the progression of striatal dopaminergic degeneration. ResultsIn LMM analyses, BMI values in PD patients were not correlated with clinical severities of parkinsonian motor deficits, cognitive impairment and depressive mood. However, BMI values were positively associated with changes in striatal 123I-FP-CIT binding over 24 months (caudate nucleus, estimate = 9.37 × 10−3, p = 0.009; putamen, estimate = 7.04 × 10−3, p = 0.031). Patients with BMI loss exhibited greater deterioration of striatal dopaminergic activity than those without (caudate nucleus, estimate = 3.35 × 10−3, p = 0.008; putamen, estimate = 2.34 × 10−3, p = 0.025). ConclusionOur findings suggest a potential association between striatal dopaminergic activity with body weight or impairment in energy homeostasis. Body weight and its change may be a clinical biomarker reflecting striatal dopaminergic dysfunction in PD.

Ivermectin reduces motor coordination, serum testosterone, and central neurotransmitter levels but does not affect sexual motivation in male rats

Ivermectin (IVM) is a macrocyclic lactone used for the treatment of parasitic infections and widely used in veterinary medicine as endectocide. In mammals, evidence indicates that IVM interacts with γ-aminobutyric acid (GABA)-mediated chloride channels. GABAergic system is involved in the manifestation of sexual behavior. We previously found that IVM at therapeutic doses did not alter sexual behavior in male rats, but at a higher dose, the appetitive phase of sexual behavior was impaired. Thus, we investigated whether the reduction of sexual behavior that was previously observed was a consequence of motor or motivational deficits that are induced by IVM. Data showed significant decrease in striatal dopaminergic system activity and lower testosterone levels but no effects on sexual motivation or penile erection. These findings suggest IVM may activate the GABAergic system and reduce testosterone levels, resulting in a reduction of motor coordination as consequence of the inhibition of striatal dopamine release.

Tracking Real-Time Changes in Working Memory Updating and Gating with the Event-Based Eye-Blink Rate

Effective working memory (WM) functioning depends on the gating process that regulates the balance between maintenance and updating of WM. The present study used the event-based eye-blink rate (ebEBR), which presumably reflects phasic striatal dopamine activity, to examine how the cognitive processes of gating and updating separately facilitate flexible updating of WM contents and the potential involvement of dopamine in these processes. Real-time changes in eye blinks were tracked during performance on the reference-back task, in which demands on these two processes were independently manipulated. In all three experiments, trials that required WM updating and trials that required gate switching were both associated with increased ebEBR. These results may support the prefrontal cortex basal ganglia WM model (PBWM) by linking updating and gating to striatal dopaminergic activity. In Experiment 3, the ebEBR was used to determine what triggers gate switching. We found that switching to an updating mode (gate opening) was more stimulus driven and retroactive than switching to a maintenance mode, which was more context driven. Together, these findings show that the ebEBR – an inexpensive, non-invasive, easy-to-use measure – can be used to track changes in WM demands during task performance and, hence, possibly striatal dopamine activity.