Dorsal Caudate Research Articles

Vitamin D’s Capacity to Increase Amphetamine-Induced Dopamine Release in Healthy Humans: A Clinical Translational [11C]-PHNO Positron Emission Tomography Study

BackgroundDopaminergic tone and phasic release have transdiagnostic relevance. Preclinical research suggests that the active form of vitamin D, calcitriol, increases subcortical tyrosine hydroxylase, D2/3 receptors, and amphetamine-stimulated dopamine release in rodents. Comparable studies have not been conducted in humans. MethodsHealthy, vitamin-D-sufficient adults (N=18; 32.8 ±6.6 years; 33% female) participated in a randomized, double-blind, placebo-controlled within-subjects study involving four total scans over two visits consisting of same-day pre-amphetamine and post-amphetamine (0.3 mg/kg) 11C-PHNO positron emission tomography (PET) scanning to examine D2/3 receptor availability (BPND) following active calcitriol (1.5 μg night before experimental day and 1.5 μg morning of experimental day) or placebo at least six days apart. Parametric images of 11C-PHNO PET BPND were computed using a simplified reference tissue model with the cerebellum as reference. Blood samples were acquired to measure serum calcitriol, amphetamine, and calcium levels. Regions of interest examined were the dorsal caudate, dorsal putamen, ventral striatum, globus pallidus, and substantia nigra. ResultsFor pre-amphetamine scans, there was a medication-by-region-of-interest interaction (F4,153=2.59, p=0.039) and a main effect of medication (F1,153=4.88, p=0.029) on BPND, with higher BPND values on calcitriol in the ventral striatum (t=2.89, p=0.004) and dorsal putamen (t=2.15, p=0.033). There was a main effect of medication on post-amphetamine change in BPND (F4,153=5.93, p=0.016), with greater decreases on calcitriol in the ventral striatum (t=3.00, p=0.003), substantia nigra (t=2.49, p=0.014), and dorsal caudate (t=2.29, p=0.023). ConclusionsResults provide translational support for vitamin D to target dopaminergic tone, with implications for clinical disorders involving dysregulated dopamine function. Clinical Trial RegistrationVitamin D as a Therapeutic Adjunct in the Stimulant Treatment of ADHD; https://clinicaltrials.gov/study/NCT03103750; ClinicalTrials.gov ID: NCT03103750

Cross-species striatal hubs: Linking anatomy to resting-state connectivity

Corticostriatal connections are essential for motivation, cognition, and behavioral flexibility. There is broad interest in using resting-state functional magnetic resonance imaging (rs-fMRI) to link circuit dysfunction in these connections with neuropsychiatric disorders. In this paper, we used tract-tracing data from non-human primates (NHPs) to assess the likelihood of monosynaptic connections being represented in rs-fMRI data of NHPs and humans. We also demonstrated that existing hub locations in the anatomical data can be identified in the rs-fMRI data from both species. To characterize this in detail, we mapped the complete striatal projection zones from 27 tract-tracer injections located in the orbitofrontal cortex (OFC), dorsal anterior cingulate cortex (dACC), ventromedial prefrontal cortex (vmPFC), ventrolateral PFC (vlPFC), and dorsal PFC (dPFC) of macaque monkeys. Rs-fMRI seeds at the same regions of NHP and homologous regions of human brains showed connectivity maps in the striatum mostly consistent with those observed in the tracer data. We then examined the location of overlap in striatal projection zones. The medial rostral dorsal caudate connected with all five frontocortical regions evaluated in this study in both modalities (tract-tracing and rs-fMRI) and species (NHP and human). Other locations in the caudate also presented an overlap of four frontocortical regions, suggesting the existence of different locations with lower levels of input diversity. Small retrograde tracer injections and rs-fMRI seeds in the striatum confirmed these cortical input patterns. This study sets the ground for future studies evaluating rs-fMRI in clinical samples to measure anatomical corticostriatal circuit dysfunction and identify connectional hubs to provide more specific treatment targets for neurological and psychiatric disorders.

Effects of a 5-HT4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT4 receptor (5-HT4R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT4R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT4R in the dCDh. We then examined the effects of a specific 5-HT4R antagonist infused into the dCDh. Blockade of 5-HT4R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT4R blockade because saline controls showed no such effect. The results demonstrate that 5-HT4Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT4R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.

Illness-related variables and abnormalities of resting-state brain activity in schizophrenia.

The development of neuroimaging biomarkers in patients with schizophrenia (SCZ) requires a refined clinical characterization. A limitation of the neuroimaging literature is the partial uptake of progress in characterizing disease-related features, particularly negative symptoms (NS) and cognitive impairment (CI). In the present study, we assessed NS and CI using up-to-date instruments and investigated the associations of abnormalities in brain resting-state (rs)-activity with disease-related features. Sixty-two community-dwelling SCZ subjects participated in the study. Multiple regression analyses were performed with the rs-activity of nine regions of interest as dependent variables and disease-related features as explanatory variables. Attention/vigilance deficits were negatively associated with dorsal anterior cingulate rs-activity and, together with depression, were positively associated with right dorsolateral prefrontal cortex rs-activity. These deficits and impairment of Reasoning/problem-solving, together with conceptual disorganization, were associated with right inferior parietal lobule and temporal parietal junction rs-activity. Independent of other features, the NS Expressive Deficit domain was associated with the left ventral caudate, while the Motivational Deficit was associated with the dorsal caudate rs-activity. Neurocognitive deficits and the two negative symptom domains are associated with different neural markers. Replications of these findings could foster the identification of clinically actionable biomarkers of poor functional outcomes.

Age and gender effects on striatal dopamine transporter density and cerebral perfusion in individuals with non-degenerative parkinsonism: a dual-phase 18F-FP-CIT PET study

BackgroundDual-phase fluorine-18 labeled N-3-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) positron emission tomography (PET) scans could be used to support disorders like Parkinson’s disease (PD). Dopamine transporter (DAT) binding and cerebral perfusion are associated with ageing and gender. We investigated the effects of age and gender on non-degenerative parkinsonism, using automated quantification in striatum: specific binding ratios (SBRs) for DAT binding in delayed phase PET (dCIT) and standardized-uptake-value ratios (SUVRs) for cerebral perfusion in early phase PET (eCIT). We also examined the correlations between SBR and SUVR.MethodsThis retrospective study analyzed subjects with dual-phase 18F-FP-CIT PET scans. The eCIT images were acquired immediately post-injection, and dCIT images were taken 120 min later. With Brightonix software, automated quantification of SBRs for dCIT and SUVRs for eCIT were acquired from visually normal scans. The effects of aging and gender were assessed by regressing SBRs and SUVRs on age for both genders. The correlations between SUVRs and SBRs were evaluated.ResultsWe studied 79 subjects (34 males and 45 females). An age-related reduction in SBRs was observed in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for both genders. SUVRs were found to negatively correlate with age in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for males and in the dorsal striatum and caudate nucleus for females. Positive correlations between SBRs and SUVRs in the dorsal striatum, ventral striatum, caudate nucleus, and putamen for male and in the dorsal striatum, caudate nucleus, and putamen for females.ConclusionsUsing quantified values from dual-phase 18F-FP-CIT PET with a single injection, we demonstrate a negative impact of age on SBRs (DAT binding) in the striatum for both genders and SUVRs (cerebral perfusion) in the dorsal striatum and caudate nucleus for both genders and in the ventral striatum and putamen for males. Additionally, we found positive associations between SBR and SUVR values in the dorsal striatum, caudate nucleus, and putamen for both genders and in the ventral striatum for males.

Processing Language Partly Shares Neural Genetic Basis with Processing Tools and Body Parts.

Language is an evolutionarily salient faculty for humans that relies on a distributed brain network spanning across frontal, temporal, parietal, and subcortical regions. To understand whether the complex language network shares common or distinct genetic mechanisms, we examined the relationships between the genetic effects underlying the brain responses to language and a set of object domains that have been suggested to coevolve with language: tools, faces (indicating social), and body parts (indicating social and gesturing). Analyzing the twin datasets released by the Human Connectome Project that had functional magnetic resonance imaging data from human twin subjects (monozygotic and dizygotic) undergoing language and working memory tasks contrasting multiple object domains (198 females and 144 males for the language task; 192 females and 142 males for the working memory task), we identified a set of cortical regions in the frontal and temporal cortices and subcortical regions whose activity to language was significantly genetically influenced. The heterogeneity of the genetic effects among these language clusters was corroborated by significant differences of the human gene expression profiles (Allen Human Brain Atlas dataset). Among them, the bilateral basal ganglia (mainly dorsal caudate) exhibited a common genetic basis for language, tool, and body part processing, and the right superior temporal gyrus exhibited a common genetic basis for language and tool processing across multiple types of analyses. These results uncovered the heterogeneous genetic patterns of language neural processes, shedding light on the evolution of language and its shared origins with tools and bodily functions.

Evaluation of the Glymphatic System in Schizophrenia Spectrum Disorder Using Proton Magnetic Resonance Spectroscopy Measurement of Brain Macromolecule and Diffusion Tensor Image Analysis Along the Perivascular Space Index.

The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index. Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity. MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01). Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain's waste clearance may offer a potential therapeutic approach for patients with SCZ-SD.

Shared and Specific Changes of Cortico-Striatal Functional Connectivity in Stable Mild Cognitive Impairment and Progressive Mild Cognitive Impairment.

Mild cognitive impairment (MCI), the prodromal stage of Alzheimer's disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially.

Motivated cognitive control during cued anticipation and receipt of unfamiliar musical themes: An fMRI study

Principal themes, particularly choruses in pop songs, hold a central place in human music. Singing along with a familiar chorus tends to elicit pleasure and a sense of belonging, especially in group settings. These principal themes, which frequently serve as musical rewards, are commonly preceded by distinctive musical cues. Such cues guide listeners' attention and amplify their motivation to receive the impending themes. Despite the significance of cue-theme sequences in music, the neural mechanisms underlying the processing of these sequences in unfamiliar songs remain underexplored. To fill this research gap, we employed fMRI to examine neural activity during the cued anticipation of unfamiliar musical themes and the subsequent receipt of their opening phrase. Twenty-three Taiwanese participants underwent fMRI scans while listening to excerpts of Korean slow pop songs unfamiliar to them, with lyrics they could not understand. Our findings revealed distinct temporal dynamics in lateral frontal activity, with posterior regions being more active during theme anticipation and anterior regions during theme receipt. During anticipation, participants reported substantial increases in arousal levels, aligning with the observed enhanced activity in the midbrain, ventral striatum, inferior frontal junction, and premotor regions. We posit that when motivational musical cues are detected, the ventral striatum and inferior frontal junction played a role in attention allocation, while premotor regions may be engaged in monitoring the theme's entry. Notably, both the anticipation and receipt of themes were associated with pronounced activity in the frontal eye field, dorsolateral prefrontal cortex, posterior parietal cortex, dorsal caudate, and salience network. Overall, our results highlight that within a naturalistic music-listening context, the dynamic interplay between the frontoparietal, dopaminergic midbrain-striatal, and salience networks could allow for precise adjustments of control demands based on the cue-theme structure in unfamiliar songs.

Peripheral and central biomarkers associated with inflammation in antipsychotic naïve first episode psychosis: Pilot studies

BackgroundElevated serum pro-inflammatory molecules have been reported in early psychosis. What is not known is whether peripheral inflammatory biomarkers are associated with CNS biomarkers. In the brain, release of pro-inflammatory molecules by microglial hyperactivity may lead to neuronal apoptosis seen in neurodegenerative disorders and account for loss of brain tissue observed in psychotic disorders. Neurochemical changes, including elevated glutamate levels, are also associated with neuroinflammation, present in early psychosis and change with antipsychotic treatment. MethodsAntipsychotic naïve patients with first episode psychosis (FEP) were studied as part of a collaborative project of neuroinflammation. In Study 1 we explored associations between plasma inflammatory molecules and neurometabolites in the dorsal caudate using magnetic resonance spectroscopy (1H-MRS) in N = 13 FEP participants. Study 2 examined the relationship between inflammatory molecules in the Plasma and CSF in N = 20 FEP participants. ResultsIn Study 1, the proinflammatory chemokine MDC/CCL22 and IL10 were significantly positively correlated with Glutamate and Glx (glutamate + glutamine) levels in the dorsal caudate. In Study 2, plasma inflammatory molecules (MIP1β/CCL4, MCP1/CCL2, Eotaxin-1/CCL11 and TNFα) were significantly correlated with CSF MIP1β/CCL4, IL10, MCP1/CCL2 and Fractalkine/CX3CL1 and symptoms ratings. DiscussionPlasma inflammatory biomarkers are elevated in early psychosis, associated with neurochemical markers as well as CSF inflammatory molecules found in neurodegenerative disorders. Future studies are needed that combine both peripheral and central biomarkers in both FEP and HC to better understand a potential neuroinflammatory subtype of psychosis likely to respond to targeted interventions.

Neural circuit selective for fast but not slow dopamine increases in drug reward

The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported ‘high’ in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual ‘high’ ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled ‘high’ ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward.

Dynamic alterations of striatal-related functional networks in juvenile absence epilepsy

PurposeTo explore the features of dynamic functional connectivity (dFC) variability of striatal-cortical/subcortical networks in juvenile absence epilepsy (JAE). MethodsWe collected resting-state functional magnetic imaging data from 18 JAE patients and 28 healthy controls. The striatum was divided into six pairs of regions: the inferior-ventral striatum (VSi), superior-ventral striatum (VSs), dorsal-caudal putamen, dorsal-rostral putamen, dorsal-caudate (DC) and ventral-rostral putamen. We assessed the dFC variability of each subdivision in the whole brain using the sliding-window method, and correlated altered circuit with clinical variables in JAE patients. ResultsWe found altered dFC variability of striatal-cortical/subcortical networks in patients with JAE. The VSs exhibited decreased dFC variability with subcortical regions, and dFC variability between VSs and thalamus was negatively correlated with epilepsy duration. For the striatal-cortical networks, the dFC variability was decreased in VSi-affective network but increased in DC-executive network. The altered dynamics of striatal-cortical networks involved crucial nodes of the default mode network (DMN). ConclusionJAE patients exhibit excessive stability in the striatal-subcortical networks. For striatal-cortical networks in JAE, the striatal-affective circuit was more stable, while the striatal-executive circuit was more variable. Furthermore, crucial nodes of DMN were changed in striatal-cortical networks in JAE.

Disrupted functional connectivity of the striatum in patients with diffuse axonal injury: a resting-state functional MRI study.

Diffuse axonal injury (DAI) disrupts the integrity of white matter microstructure and affects brain functional connectivity, resulting in persistent cognitive, behavioral and affective deficits. Mounting evidence suggests that altered cortical-subcortical connectivity is a major contributor to cognitive dysfunction. The functional integrity of the striatum is particularly vulnerable to DAI, but has received less attention. This study aimed to investigate the alteration patterns of striatal subdivision functional connectivity. Twenty-six patients with DAI and 27 healthy controls underwent resting-state fMRI scans on a 3.0 T scanner. We assessed striatal subdivision functional connectivity using a seed-based analysis in DAI. Furthermore, a partial correlation was used to measure its clinical association. Compared to controls, patients with DAI showed decreased functional connectivity between the right inferior ventral striatum and right inferior frontal gyrus, as well as the right inferior parietal lobule, between the left inferior ventral striatum and right inferior frontal gyrus, between the right superior ventral striatum and bilateral cerebellar posterior lobe, between the bilateral dorsal caudal putamen and right anterior cingulate gyrus, and between the right dorsal caudal putamen and right inferior parietal lobule. Moreover, decreased functional connectivity was observed between the left dorsal caudate and the right cerebellar posterior lobe, while increased functional connectivity was found between the left dorsal caudate and right inferior parietal lobule. Correlation analyses showed that regions with functional connectivity differences in the DAI group correlated with multiple clinical scoring scales, including cognition, motor function, agitated behavior, and anxiety disorders. These findings suggest that abnormalities in cortico-striatal and cerebellar-striatal functional connectivity are observed in patients with DAI, enriching our understanding of the neuropathological mechanisms of post-injury cognitive disorders and providing potential neuroimaging markers for the diagnosis and treatment of DAI.

Striatal dopamine synthesis and cognitive flexibility differ between hormonal contraceptive users and nonusers.

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as a comparison group. A behavioral index of cognitive flexibility was assessed prior to PET imaging. Hormonal contraceptive users exhibited greater DA synthesis capacity than NC participants, particularly in dorsal caudate, and greater cognitive flexibility. Furthermore, across individuals, the magnitude of striatal DA synthesis capacity was associated with cognitive flexibility. No group differences were observed in D2/3 receptor binding or DA release. Analyses by sex alone may obscure underlying differences in DA synthesis tied to women's hormone status. Hormonal contraception (in the form of pill, shot, implant, ring, or intrauterine device) is used by ~400 million women worldwide, yet few studies have examined whether chronic hormonal manipulations impact basic properties of the DA system. Findings from this study begin to address this critical gap in women's health.

State-specific alterations in the neural computations underlying inhibitory control in women remitted from bulimia nervosa.

The neurocomputational processes underlying bulimia nervosa and its primary symptoms, out-of-control overeating and purging, are poorly understood. Research suggests that the brains of healthy individuals form a dynamic internal model to predict whether control is needed in each moment. This study tested the hypothesis that this computational process of inhibitory control is abnormally affected by metabolic state (being fasted or fed) in bulimia nervosa. A Bayesian ideal observer model was fit to behavioral data acquired from 22 women remitted from bulimia nervosa and 20 group-matched controls who completed a stop-signal task during two counterbalanced functional MRI sessions, one after a 16 h fast and one after a meal. This model estimates participants' trial-by-trial updating of the probability of a stop signal based on their experienced trial history. Neural analyses focused on control-related Bayesian prediction errors, which quantify the direction and degree of "surprise" an individual experiences on any given trial. Regardless of group, metabolic state did not affect behavioral performance on the task. However, metabolic state modulated group differences in neural activation. In the fed state, women remitted from bulimia nervosa had attenuated prediction-error-dependent activation in the left dorsal caudate. This fed-state activation was lower among women with more frequent past binge eating and self-induced vomiting. When they are in a fed state, individuals with bulimia nervosa may not effectively process unexpected information needed to engage inhibitory control. This may explain the difficulties these individuals have stopping eating after it begins.

DARPP-32 cells and neuropil define striosomal system and isolated matrix cells in human striatum.

The dorsal striatum forms a central node of the basal ganglia interconnecting the neocortex and thalamus with circuits modulating mood and movement. Striatal projection neurons (SPNs) include relatively intermixed populations expressing D1-type or D2-type dopamine receptors (dSPNs and iSPNs) that give rise to the direct (D1) and indirect (D2) output systems of the basal ganglia. Overlaid on this organization is a compartmental organization, in which a labyrinthine system of striosomes made up of sequestered SPNs is embedded within the larger striatal matrix. Striosomal SPNs also include D1-SPNs and D2-SPNs, but they can be distinguished from matrix SPNs by many neurochemical markers. In the rodent striatum the key signaling molecule, DARPP-32, is a exception to these compartmental expression patterns, thought to befit its functions through opposite actions in both D1- and D2-expressing SPNs. We demonstrate here, however, that in the dorsal human striatum, DARPP-32 is concentrated in the neuropil and SPNs of striosomes, especially in the caudate nucleus and dorsomedial putamen, relative to the matrix neuropil in these regions. The generally DARPP-32-poor matrix contains scattered DARPP-32-positive cells. DARPP-32 cell bodies in both compartments proved negative for conventional intraneuronal markers. These findings raise the potential for specialized DARPP-32 expression in the human striosomal system and in a set of DARPP-32-positive neurons in the matrix. If DARPP-32 immunohistochemical positivity predicts differential functional DARPP-32 activity, then the distributions demonstrated here could render striosomes and dispersed matrix cells susceptible to differential signaling through cAMP and other signaling systems in health and disease. DARPP-32 is highly concentrated in cells and neuropil of striosomes in post-mortem human brain tissue, particularly in the dorsal caudate nucleus. Scattered DARPP-32-positive cells are found in the human striatal matrix. Calbindin and DARPP-32 do not colocalize within every spiny projection neuron in the dorsal human caudate nucleus.

Error-related brain activity associated with obsessive-compulsive symptoms in youth.

Subclinical obsessive-compulsive symptoms (OCS) are common in children, and increase risk for later onset of obsessive-compulsive disorder (OCD). In pediatric patients with OCD, neuroimaging research implicates altered neural mechanisms for error-processing, but whether abnormal brain response occurs with subclinical OCS remains poorly understood. Using functional magnetic resonance imaging (fMRI), 113 youth (8-18 years; 45 female) from a community sample were scanned during an error-eliciting Go/No-Go task. OCS were assessed dimensionally using the obsessive-compulsive subscale of the Child Behavior Checklist. The association between OCS scores and error-related brain activity was examined at the whole-brain level. Lower OCS scores associated with stronger response to errors in dorsal anterior cingulate cortex (dACC), caudate, putamen, thalamus, and occipital cortex. Additionally, lower OCS related to higher capacity for inhibitory control, as indexed by greater accuracy on No-Go trials during fMRI scanning. The relationship between lower OCS and better accuracy on No-Go trials was mediated by greater error-related dACC activity. The inverse relationship between OCS and error-related activity in the dACC and extended cortical-striatal-thalamic circuitry may index an adaptive process by which subclinical OCS are minimized in youth. Further, these results identify an observable pattern of brain activity that tracks with subclinical OCS severity. Understanding the link between neural networks for error processing and the normal to abnormal range of OCS may pave the way for brain-based strategies to identify children who are more likely to develop OCD and enable the targeting of preventive strategies to reduce risk.

Resting-state brain activity dysfunctions in schizophrenia and their associations with negative symptom domains

IntroductionNegative symptoms represent a fundamental aspect of schizophrenia: they have a substantial impact on patients’ real-life functioning and do not respond satisfactorily to currently available treatments. Therefore, a better understanding of the pathophysiological mechanisms underlying these symptoms could favor the development of new treatments.To date, the most validated pathophysiological hypothesis indicates an association between the Motivational domain (consisting of avolition, anhedonia and asociality) and alterations in the neuronal circuits involved in motivation. The Expressive Deficit domain (consisting of blunted affect and alogia) would be subtended by widespread alterations of cortical connectivity and associated with impaired neurocognition, social cognition, and the presence of neurological soft signs.ObjectivesThe aim of the present study is to examine the neurobiological correlates of the two domains of negative symptoms, starting from the brain areas that have been most commonly found in the literature to be associated with negative symptoms.MethodsResting-state (rs) fMRI data were acquired in 62 subjects with schizophrenia (SZ) and 46 healthy controls (HC). The two negative symptom domains were assessed using the Brief Negative Symptom Scale. In addition, the following assessment tools were used: the Positive and Negative Syndrome Scale for the assessment of positive symptoms and disorganization, the Calgary Depression Scale for Schizophrenia for depression and the St. Hans Rating Scale for extrapyramidal symptoms. The study of the possible relationships between rs-brain activity and the negative symptoms domains was conducted through partial correlations, checking for possible confounding factors (positive, depressive, extrapyramidal symptoms and disorganization).ResultsThe SZ, compared to the HC, showed higher rs-brain activity of the right inferior parietal lobule and of the right temporoparietal junction and lower rs-brain activity of the right dorsolateral prefrontal cortex, bilateral anterior dorsal cingulate cortex, bilateral ventral caudate and bilateral dorsal caudate. Furthermore, in the group of patients, the rs-brain activity of the left ventral caudate showed a moderate negative correlation with the Expressive deficit domain (r = -0.401; p = 0.003), but not with the Motivational domain.ConclusionsThe results of the present study, in line with the literature, demonstrated how the two domains of negative symptomatology are subtended by different pathophysiological mechanisms. Given the role played by the ventral caudate in neurocognitive processes, these results are in line with the hypothesis that Expressive deficit may have a common etiopathogenesis with cognitive deficits. A better understanding of the neurobiology of negative symptoms could foster the development of innovative treatment strategies targeting the two negative symptom domains.Disclosure of InterestNone Declared

Functional imaging and anatomical connections in squirrel monkeys reveal parietal-frontal circuits underlying eye movements.

The posterior parietal cortex (PPC) of squirrel monkeys contains subregions where long trains of intracortical microstimulation evoke complex, behaviorally meaningful movements. Recently, we showed that such stimulation of a part of the PPC in the caudal lateral sulcus (LS) elicits eye movements in these monkeys. Here, we studied the functional and anatomical connections of this oculomotor region we call parietal eye field (PEF) with frontal eye field (FEF) and other cortical regions in 2 squirrel monkeys. We demonstrated these connections with intrinsic optical imaging and injections of anatomical tracers. Optical imaging of frontal cortex during stimulation of the PEF evoked focal functional activation within FEF. Tracing studies confirmed the functional PEF-FEF connections. Moreover, tracer injections revealed PEF connections with other PPC regions on the dorsolateral and medial brain surface, cortex in the caudal LS, and visual and auditory cortical association areas. Subcortical projections of PEF were primarily with superior colliculus, and pontine nuclei as well as nuclei of the dorsal posterior thalamus and caudate. These findings suggest that PEF in squirrel monkey is homologous to lateral intraparietal (LIP) area of macaque, supporting the notion that these brain circuits are organized similarly to mediate ethologically relevant oculomotor behaviors.

Cerebrovascular integrity affects gradients of aging-related dopamine D1 differences in the striatum

Extant research suggest aging-related losses of different dopaminergic markers, including presynaptic dopamine transporters as well as post-synaptic DA receptors. Given the central role of DA in neurocognitive functions, maintenance of a healthy DA system may be a key to mitigate age-related cognitive decline. Mechanisms behind DA losses in aging are however largely uncharted. Past research documented an association between dopaminergic integrity and cerebrovascular health (via white matter lesion volumes). However, it remains unclear whether proximity to lesions affected the spatial patterns of age-related D1DR differences within the striatum, and whether such differences are related to mnemonic function. Here, a large cohort of middle-aged to older healthy participants (age = 40–80 years, n = 119, 50 % women) was assessed for D1-receptor (D1DR) availability with positron emission tomography using [11C]SCH23390, and for white matter lesions using FLAIR-MRI. We found evidence for variations in degree of age-related differences along the ventro-dorsal axis, with more pronounced differences in the dorsal caudate. Further analyses revealed an association between distance to lesions and extent of D1DR losses in the caudate. Furthermore, D1DR differences in dorsal caudate (proximal to lesions) was more strongly associated with memory performance. In conclusion, the present findings suggest that maintenance of cerebrovascular health may be a key factor in promoting successful dopaminergic and memory aging.