Striatal Function Research Articles

17.3 EFFECT OF CANNABIDIOL ON SYMPTOMS, DISTRESS AND NEUROPHYSIOLOGICAL ABNORMALITIES IN CLINICAL HIGH-RISK FOR PSYCHOSIS PATIENTS: A PLACEBO-CONTROLLED STUDY

BackgroundThere has been growing interest in the therapeutic potential of Cannabidiol (CBD) stemming from independent evidence that CBD has antipsychotic and anxiolytic properties in patients with mental health disorders. CBD has been found to be non-inferior to antipsychotic medication in a 4-week clinical trial in acute schizophrenia (Leweke et al 2012) and also has been found to reduce anxiety symptoms in social phobia and following public speaking. Human data also suggest that it attenuates the cognitive impairments associated with use of the main psychoactive ingredient in cannabis. However, whether CBD may be useful in relieving symptoms and distress in patients at clinical high-risk of psychosis (CHR) has never been tested. Furthermore, how the beneficial effect of CBD on psychotic and anxiety symptoms may be mediated in the brain remains unclear.The aim of the present study was to investigate whether short-term treatment with CBD was associated with preliminary evidence of therapeutic benefit and understand the neurocognitive mechanisms.MethodsWe investigated the effects of short-term (21 days) treatment with CBD on psychotic and anxiety symptoms in 33 CHR patients, using a placebo-controlled, double-blind, parallel-arm design (CBD arm- 16; placebo arm- 17).In the subjects who received 21 days of treatment, we used fMRI in conjunction with a verbal memory task to assess the effect of CBD relative to placebo treatment on medial temporal and striatal function.ResultsOf the 33 CHR patients recruited into the trial, 31 completed treatment for 21 days. Following 21-day treatment (intention-to-treat, last observation carried forward analysis), CBD-treated (n=16) CHR patients showed a significantly greater reduction in anxiety (p=0.02) and in distress associated with psychotic symptoms (p=0.03) and a trend (p=0.14) toward greater reduction in the severity of psychotic symptoms compared to those treated with placebo (n=17) CHR patients (Figure 4). In addition, CBD was tolerated as well as placebo.Consistent with our predictions, treatment with CBD (n=15) attenuated the engagement during verbal encoding of the parahippocampal cortex, but increased activation in the putamen in CHR patients. A similar pattern of activation was evident during verbal recall, with CBD treatment associated with increased engagement in the putamen.DiscussionResults from our proof-of-concept study suggest that 3-week treatment with CBD has beneficial effects on anxiety, attenuated psychotic symptoms and the distress associated with psychotic symptoms. They also suggest that short-term treatment with CBD modulates both medial temporal and striatal function in CHR patients, regions that are critically implicated in the CHR state. Coupled with the absence of significant adverse effects associated with CBD, a particularly important issue in relation to the treatment of CHR individuals, not all of whom develop a full-blown psychotic disorder, these data indicate that long-term treatment with CBD is likely to be efficacious in CHR patients.

S145. ANTIPSYCHOTIC DISCONTINUATION IN FIRST EPISODE PSYCHOSIS: [18F]DOPA AND [11C]RACLOPRIDE PET STUDY

BackgroundRecent meta-analysis revealed that elevated presynaptic striatal dopaminergic function is a robust feature of psychosis like schizophrenia. Considering increased dopaminergic capacity in psychotic disorders, it is not surprising that antipsychotic drugs, which primarily block dopaminergic neurotransmission, are mostly effective in the treatment of psychosis.However, it remains obscure what would happen to presynaptic dopaminergic function with antipsychotic treatment. This is an important issue addressing whether the current antipsychotic drugs are correcting the primary dopaminergic abnormality or not. In addition, the issue can give a clue regarding the mechanism of relapse in psychotic disorders.MethodsWe measured presynaptic dopamine capacity using [18F]DOPA PET before and after the antipsychotic discontinuation in first episode psychosis. The binding potentials of [11C]raclopride were also measured after the discontinuation. Healthy controls had [18F]DOPA and [11C]raclopride scans at the corresponding date.First episode psychosis patients were carefully monitored in the aspects of symptomatic aggravations.ResultsThe presynaptic dopamine capacity and the density of dopamine receptors showed significant group effect and the interaction between group and time (p<0.005)DiscussionDopaminergic function seems to play a critical role in relapse of first episode psychosis.

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.

Patterns of dopamine transporter imaging in subtypes of multiple system atrophy.

To investigate the differences in the pattern of striatal (caudate and putamen) dopamine transporter (DAT) loss in a multiple system atrophy (MSA) cohort, based on the clinical variants parkinsonian subtype (MSA-P) and cerebellar subtype (MSA-C) via (11)C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11 C-CFT) positron emission tomography (PET) imaging. One hundred and six subjects (forty-one patients with probable MSA-P; forty patients with probable MSA-C; twenty-five healthy controls) underwent 11 C-CFT PET. Subregional 11 C-CFT uptake of bilateral caudate, anterior putamen, and posterior putamen was calculated respectively to measure the striatal dopaminergic function. Significant decrease in DAT binding in striatum was revealed in patients with MSA-C and MSA-P compared to normal controls (all regions, MSA-C vs controls, P<.0001; MSA-P vs controls, P<.0001). DAT reduction was more pronounced in MSA-P patients than that in MSA-C patients (all regions, P<.0001). Eleven of forty MSA-C patients displayed no DAT loss, whereas striatal DAT loss was evident in all MSA-P patients. MSA-P subtype showed a more obvious anteroposterior gradient of DAT loss and more asymmetric dopaminergic dysfunction compared to MSA-C patients. The subtypes of MSA studied here show significantly different spatial/anatomic patterns of striatonigral degeneration which may provide insights into their disease pathophysiology. Specifically, MSA-P patients exhibit an uneven and much greater pronounced loss of dopamine innervation, while a relatively uniform pattern is revealed in patients with the MSA-C. Furthermore, the typical reduction in DAT 11 C-CFT binding in striatum is not present in all MSA-C patients, with a minority of cases showing normal DAT binding.

Meta-analytic evidence for altered mesolimbic responses to reward in schizophrenia.

Dysfunction of reward-related neural circuitry in schizophrenia (SCZ) has been widely reported, and may provide insight into the motivational and cognitive disturbances that characterize the disorder. Although previous meta-analyses of reward learning paradigms in SCZ have been performed, a meta-analysis of whole-brain coordinate maps in SCZ alone has not been conducted. In this study, we performed an activation likelihood estimate (ALE) meta-analysis, and performed a follow-up analysis of functional connectivity and functional decoding of identified regions. We report several salient findings that extend prior work in this area. First, an alteration in reward-related activation was observed in the right ventral striatum, but this was not solely driven by hypoactivation in the SCZ group compared to healthy controls. Second, the region was characterized by functional connectivity primarily with the lateral prefrontal cortex and pre-supplementary motor area (preSMA), as well as subcortical regions such as the thalamus which show structural deficits in SCZ. Finally, although the meta-analysis showed no regions outside the ventral striatum to be significantly altered, regions with higher functional connectivity with the ventral striatum showed a greater number of subthreshold foci. Together, these findings confirm the alteration of ventral striatal function in SCZ, but suggest that a network-based approach may assist future analysis of the functional underpinnings of the disorder.

Dopamine D2 agonist affects visuospatial working memory distractor interference depending on individual differences in baseline working memory span.

The interplay of dopaminergic striatal D1-D2 circuits is thought to support working memory (WM) by selectively filtering information that is to be remembered versus information to be ignored. To test this theory, we conducted an experiment in which healthy participants performed a visuospatial working memory (VSWM) task after ingesting the D2-receptor agonist cabergoline (or placebo), in a randomized, double-blinded, crossover design. Results showed greater interference from distractors under cabergoline, particularly for individuals with higher baseline dopamine (indicated by WM span). These findings support computational theories of striatal D1-D2 function during WM encoding and distractor-filtering, and provide new evidence for interactive cortico-striatal systems that support VSWM capacity and their dependence on WM span.

Muscarinic Acetylcholine Receptors Inhibit Fyn Activity in the Rat Striatum In Vivo.

The Src family kinase (SFK) is a subfamily of non-receptor tyrosine kinases. SFK members, Src and especially Fyn, are expressed in the striatum. These SFK members are involved in the regulation of neuronal and synaptic activities and are linked to the pathogenesis of a variety of neuropsychiatric and neurodegenerative disorders. Given the fact that muscarinic acetylcholine (mACh) receptors are highly expressed in striatal neurons and are critical for the regulation of striatal function, we investigated the role of mACh receptors in the regulation of SFKs in the adult rat striatum in vivo. We found that pharmacological blockade of mACh receptors by systemic administration of the mACh antagonist scopolamine induced a marked increase in phosphorylation of SFKs in the striatum of male and female rats. This scopolamine-induced increase in SFK phosphorylation occurred in the two subdivisions of the striatum (caudate putamen and nucleus accumbens) and was time-dependent and reversible. Another mACh antagonist atropine was also effective in stimulating SFK phosphorylation. Coadministration of subthreshold doses of scopolamine and a dopamine D1 receptor agonist SKF81297 enhanced striatal SFK phosphorylation. Between Fyn and Src proteins immunoprecipitated from striatal tissue, scopolamine selectively increased phosphorylation of Fyn. The increase in Fyn phosphorylation was accompanied by an increase in Fyn kinase activity in response to scopolamine. These results reveal a significant role of mACh receptors in the regulation of SFKs (mainly Fyn) in striatal neurons. Under normal conditions, endogenous mACh receptors appear to exert an inhibitory effect on Fyn activity.

Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption.

The striatum controls food-related actions and consumption and is linked to feeding disorders, including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons and indirect pathway medium spiny neurons. The selective contribution of direct pathway medium spiny neurons and indirect pathway medium spiny neurons to food-related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets. While electrophysiology revealed complex task-related dynamics across neurons, population calcium was enhanced during approach and inhibited during consumption in both pathways. We also observed ramping changes in activity that preceded both pellet-directed actions and spontaneous movements. These signals were heterogeneous in the spiking units, with neurons exhibiting either increasing or decreasing ramps. In contrast, the population calcium signals were homogeneous, with both pathways having increasing ramps of activity for several seconds before actions were initiated. An analysis comparing population firing rates to population calcium signals also revealed stronger ramping dynamics in the calcium signals than in the spiking data. In a second experiment, we trained the mice to perform an action sequence to evaluate when the ramping signals terminated. We found that the ramping signals terminated at the beginning of the action sequence, suggesting they may reflect upcoming actions and not preconsumption activity. Plasticity of such mechanisms may underlie disorders that alter action selection, such as drug addiction or obesity.SIGNIFICANCE STATEMENT Alterations in striatal function have been linked to pathological consumption in disorders, such as obesity and drug addiction. We recorded spiking and population calcium activity from the dorsal striatum during ad libitum feeding and an operant task that resulted in mice obtaining food pellets. Dorsal striatal neurons exhibited long ramps in activity that preceded actions by several seconds, and may reflect upcoming actions. Understanding how the striatum controls the preparation and generation of actions may lead to improved therapies for disorders, such as drug addiction or obesity.

Transient developmental hearing loss leads to disruption of striatal function in adults

Transient hearing loss during development can lead to deficits in the auditory perceptual abilities of children. These deficits arise from both peripheral ear and central neural dysfunction along the auditory neuraxis. Even if hearing loss resolves or is treated, persistent learning deficits and language impairments can occur. This suggests that regions downstream of the primary auditory neuraxis can be disrupted by brief auditory deprivation. One such region, which is highly involved in language development, is the auditory striatum. Thus I asked how the development of cellular properties in the auditory striatum are affected by hearing loss, and how these changes affect the learning of an auditory task. I used the gerbil and a brain slice preparation to assess how the expression of long term potentiation (LTP), which is a biomarker of learning, correlated with behavioral performance in adult animals that had undergone developmental hearing loss. I found that the cellular expression of LTP corresponded with the rapid acquisition of the behavioral task, and that developmental hearing loss delayed both the expression of LTP and the correlated behavioral acquisition. This suggests that striatal dysfunction could play a role in language acquisition impairments in children with hearing loss.

The striatal cholinergic system in L-dopa-induced dyskinesias.

Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions. Consequently, an imbalance between these systems is associated with basal ganglia disorders. Here, we provide an overview of how striatal cholinergic interneurons modulate striatal activity under normal and pathological conditions. Numerous studies show that nigrostriatal damage such as that occurs with Parkinson's disease affects cholinergic receptor-mediated striatal activity. This altered cholinergic signaling is an important contributor to Parkinson's disease as well as to the dyskinesias that develop with L-dopa therapy, the gold standard for treatment. Indeed, multiple preclinical studies show that cholinergic receptor drugs may be beneficial for the treatment of L-dopa-induced dyskinesias. In this review, we discuss the evidence indicating that therapeutic modulation of the cholinergic system, particularly targeting of nicotinic cholinergic receptors, may offer a novel approach to manage this debilitating side effect of dopamine replacement therapy for Parkinson's disease.

Basal Ganglia Neuromodulation Over Multiple Temporal and Structural Scales-Simulations of Direct Pathway MSNs Investigate the Fast Onset of Dopaminergic Effects and Predict the Role of Kv4.2.

The basal ganglia are involved in the motivational and habitual control of motor and cognitive behaviors. Striatum, the largest basal ganglia input stage, integrates cortical and thalamic inputs in functionally segregated cortico-basal ganglia-thalamic loops, and in addition the basal ganglia output nuclei control targets in the brainstem. Striatal function depends on the balance between the direct pathway medium spiny neurons (D1-MSNs) that express D1 dopamine receptors and the indirect pathway MSNs that express D2 dopamine receptors. The striatal microstructure is also divided into striosomes and matrix compartments, based on the differential expression of several proteins. Dopaminergic afferents from the midbrain and local cholinergic interneurons play crucial roles for basal ganglia function, and striatal signaling via the striosomes in turn regulates the midbrain dopaminergic system directly and via the lateral habenula. Consequently, abnormal functions of the basal ganglia neuromodulatory system underlie many neurological and psychiatric disorders. Neuromodulation acts on multiple structural levels, ranging from the subcellular level to behavior, both in health and disease. For example, neuromodulation affects membrane excitability and controls synaptic plasticity and thus learning in the basal ganglia. However, it is not clear on what time scales these different effects are implemented. Phosphorylation of ion channels and the resulting membrane effects are typically studied over minutes while it has been shown that neuromodulation can affect behavior within a few hundred milliseconds. So how do these seemingly contradictory effects fit together? Here we first briefly review neuromodulation of the basal ganglia, with a focus on dopamine. We furthermore use biophysically detailed multi-compartmental models to integrate experimental data regarding dopaminergic effects on individual membrane conductances with the aim to explain the resulting cellular level dopaminergic effects. In particular we predict dopaminergic effects on Kv4.2 in D1-MSNs. Finally, we also explore dynamical aspects of the onset of neuromodulation effects in multi-scale computational models combining biochemical signaling cascades and multi-compartmental neuron models.

Anterior cingulate cortex glutamate and its association with striatal functioning during cognitive control

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by structural, functional and neurochemical alterations of the fronto-striatal circuits and by deficits in cognitive control. In particular, ADHD has been associated with impairments in top-down fronto-striatal glutamate-signalling. However, it is unknown whether fronto-striatal glutamate is related to cognitive control dysfunction. Here we explored whether and how anterior cingulate cortex (ACC) glutamate relates to striatal BOLD-responses during cognitive control. We used proton magnetic resonance spectroscopy to evaluate glutamate-to-creatine ratios in 62 participants (probands with ADHD n=19, unaffected siblings n=24 and typical controls n=19, mean age=20.4). Spectra were collected from the ACC and the dorsal striatum and glutamate-to-creatine ratios were extracted. Thirty-two participants additionally took part in a functional magnetic resonance imaging (fMRI) Stroop task to investigate neural responses during cognitive control. Given small sample sizes we report all effects with p<0.10 along with effect sizes. ADHD subjects showed decreased glutamate-to-creatine ratios in the ACC (F=3.81, p=0.059, ηp2=0.104; medium to large effect-size) compared with controls. Importantly, decreased ACC glutamate-to-creatine ratios were associated with increased striatal BOLD-responses during cognitive control (rho=−0.41, p=0.019; medium effect-size), independent of diagnosis. Increased striatal responses tended to be associated with more errors during the task and more hyperactivity/impulsivity symptoms (rho=0.34, p=0.058 and rho=0.33, p=0.068, respectively); the latter two being correlated too (rho=0.37, p=0.037), all with medium effect sizes. Our results suggest that ACC glutamate in ADHD might be associated with striatal (dys)functioning during the Stroop task, supporting the role of fronto-striatal glutamate in cognitive control.

MDPV induces a rapid up-regulation of striatal dopamine transporter function. A comparative study with cocaine

MDPV induces a rapid up-regulation of striatal dopamine transporter function. A comparative study with cocaine

Adenosine A2A-dopamine D2 receptor heteromers operate striatal function: impact on Parkinson's disease pharmacotherapeutics.

Adenosine A2A-dopamine D2 receptor heteromers operate striatal function: impact on Parkinson's disease pharmacotherapeutics.

Defining the Locus of Dopaminergic Dysfunction in Schizophrenia: A Meta-analysis and Test of the Mesolimbic Hypothesis.

BackgroundStudies using positron emission tomography to image striatal dopamine function, have demonstrated that individuals with schizophrenia display increases in presynaptic function. Mesolimbic dysfunction specifically, has previously been suggested to underlie psychotic symptoms. This has not been directly tested in vivo, and the precise anatomical locus of dopamine dysfunction within the striatum remains unclear. The current article investigates the magnitude of dopaminergic abnormalities in individuals with schizophrenia, and determines how the magnitude of abnormality varies across functional subdivisions of the striatum.MethodsEMBASE, PsychINFO, and MEDLINE were searched from January 1, 1960, to December 1, 2016. Inclusion criteria were molecular imaging studies that had measured presynaptic striatal dopamine functioning. Effects sizes for whole striatum and functional subdivisions were calculated separately. The magnitude of difference between functional subdivisions in patients and controls was meta-analyzed.ResultsTwenty-one eligible studies were identified, including 269 patients and 313 controls. Individuals with schizophrenia (Hedges’ g = 0.68, P < .001) demonstrated elevated presynaptic dopamine functioning compared to controls. Seven studies examined functional subdivisions. These demonstrated significant increases in patients compared to controls in associative (g = 0.73, P = .002) and sensorimotor (g = 0.54, P = .005) regions, but not limbic (g = 0.29, P = .09). The magnitude of the difference between associative and limbic subdivisions was significantly greater in patients compared to controls (g = 0.39, P = .003).ConclusionIn individuals with schizophrenia dopaminergic dysfunction is greater in dorsal compared to limbic subdivisions of the striatum. This is inconsistent with the mesolimbic hypothesis and identifies the dorsal striatum as a target for novel treatment development.

Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses.

Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered the study of the functions of these striatal compartments. Here we used 2-photon calcium imaging in neuronal birthdate-labeled Mash1-CreER;Ai14 mice to image simultaneously the activity of striosomal and matrix neurons as mice performed an auditory conditioning task. With this method, we identified circumscribed zones of tdTomato-labeled neuropil that correspond to striosomes as verified immunohistochemically. Neurons in both striosomes and matrix responded to reward-predicting cues and were active during or after consummatory licking. However, we found quantitative differences in response strength: striosomal neurons fired more to reward-predicting cues and encoded more information about expected outcome as mice learned the task, whereas matrix neurons were more strongly modulated by recent reward history. These findings open the possibility of harnessing in vivo imaging to determine the contributions of striosomes and matrix to striatal circuit function.

Striatal dopamine in Parkinson disease: A meta-analysis of imaging studies.

A meta-analysis of 142 positron emission tomography and single photon emission computed tomography studies that have investigated striatal presynaptic dopamine function in Parkinson disease (PD) was performed. Subregional estimates of striatal dopamine metabolism are presented. The aromatic L-amino-acid decarboxylase (AADC) defect appears to be consistently smaller than the dopamine transporter and vesicular monoamine transporter 2 defects, suggesting upregulation of AADC function in PD. The correlation between disease severity and dopamine loss appears linear, but the majority of longitudinal studies point to a negative exponential progression pattern of dopamine loss in PD. Ann Neurol 2017;82:873-882.

The direct basal ganglia pathway is hyperfunctional in focal dystonia.

See Fujita and Eidelberg (doi:10.1093/brain/awx305) for a scientific commentary on this article. Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

Is burning mouth syndrome a neuropathic pain condition?

Primary burning mouth syndrome (BMS) is defined as an "intraoral burning or dysaesthetic sensation, recurring daily… more than 3 months, without clinically evident causative lesions" (IHS 2013). In addition to pain, taste alterations are frequent (dysgeusia, xerostomia). Although lacking clinical signs of neuropathy, more accurate diagnostic methods have shown neuropathic involvement at various levels of the neuraxis in BMS: peripheral small fiber damage (thermal quantitative sensory testing, electrogustatometry, epithelial nerve fiber density), trigeminal system lesions in the periphery or the brainstem (brainstem reflex recordings, trigeminal neurography, evoked potentials), or signs of decreased inhibition within the central nervous system (deficient brainstem reflex habituation, positive signs in quantitative sensory testing, neurotransmitter-positron emission tomography findings indicative of deficient striatal dopamine function). Abnormalities in electrogustatometry indicate the involvement of the small Aδ taste afferents, in addition to somatosensory small fibers. According to these findings, the clinical entity of BMS can be divided into 2 main subtypes compatible with either peripheral or central neuropathic pain, which may overlap in individual patients. The central type does not respond to local treatments and associates often with psychiatric comorbidity (depression or anxiety), whereas the peripheral type responds to peripheral lidocaine blocks and topical clonazepam. Burning mouth syndrome is most prevalent in postmenopausal women, having led to a hypothesis that BMS is triggered as a consequence of nervous system damage caused by neurotoxic factors affecting especially vulnerable small fibers and basal ganglia in a setting of decrease in neuroprotective gonadal hormones and increase in stress hormone levels, typical for menopause.

Pramipexole reduces soluble mutant huntingtin and protects striatal neurons through dopamine D3 receptors in a genetic model of Huntington's disease

Huntington's disease (HD) is a neurodegenerative disorder caused by abnormal expansion of the polyglutamine tract in the huntingtin protein (HTT). The toxicity of mutant HTT (mHTT) is associated with intermediate mHTT soluble oligomers that subsequently form intranuclear inclusions. Thus, interventions promoting the clearance of soluble mHTT are regarded as neuroprotective. Striatal neurons are particularly vulnerable in HD. Their degeneration underlies motor symptoms and striatal atrophy, the anatomical hallmark of HD. Recent studies indicate that autophagy may be activated by dopamine D2 and D3 receptor (D2R/D3R) agonists. Since autophagy plays a central role in the degradation of misfolded proteins, and striatal neurons express D2R and D3R, D2R/D3R agonists may promote the clearance of mHTT in striatal neurons. Here, this hypothesis was tested by treating 8-week old R6/1 mice with the D2R/D3R agonist pramipexole for 4weeks. Pramipexole reduced striatal levels of soluble mHTT and increased the size of intranuclear inclusions in R6/1 mice. Furthermore, striatal DARPP-32 levels and motor functions were recovered. These effects were accompanied by an increase in LC3-II and a decrease in p62 in the striatum. Tollip, a selective adaptor of ubiquitinated polyQ proteins to LC3, was also reduced in the striata of R6/1mice but not in their wild-type littermates. No changes were detected in the cerebral cortex where D3R expression is very low, and behavioral and biochemical effects in the striatum were prevented by a D3R antagonist. The findings indicate that PPX protects striatal neurons by promoting the clearance of soluble mHTT through a D3R-mediated mechanism. The evidence of autophagy markers suggests that autophagy is activated, although it is not efficient at removing all mHTT recruited by the autophagic machinery as indicated by the increase in the size of intranuclear inclusions.