Limbic Striatum Research Articles

Vestibular system and human cognitive functions

The article is a review of scientific research on the influence of the vestibular system on human cognitive functions. The vestibular apparatus is well studied. Research in recent decades using functional tomography techniques has shown that it has extensive connections with the subcortical and cortical structures of the brain that provide cognitive activity. Hypotheses are put forward that the conduction and processing of bioelectric impulses by the brain, which are recorded by the vestibular apparatus, creates the necessary background for the course of all cognitive processes. The vestibular apparatus has connections with the limbic system, hippocampus, striatum and neocortex. Therefore, vestibular dysfunctions can reduce the ability to learn, cause impaired attention, memory, executive functions, cause disorientation, and affect stress levels. An urgent area of research is the study of the influence of vestibular sensory reactivity on children’s learning ability. This influence has long been underestimated, since it was generally assumed that motor and cognitive development occur independently of each other. The mechanisms linking vestibular dysfunction with cognitive impairment have not yet been sufficiently studied. Further studies are needed to assess the possible impact of vestibular dysfunctions on attention, memory, and speech. Such studies are already underway. Their results are most relevant for patients with neurodegenerative disorders and for children with special needs.

In vivo structural connectivity of the reward system along the hippocampal long axis.

Recent work has identified a critical role for the hippocampus in reward-sensitive behaviors, including motivated memory, reinforcement learning, and decision-making. Animal histology and human functional neuroimaging have shown that brain regions involved in reward processing and motivation are more interconnected with the ventral/anterior hippocampus. However, direct evidence examining gradients of structural connectivity between reward regions and the hippocampus in humans is lacking. The present study used diffusion MRI (dMRI) and probabilistic tractography to quantify the structural connectivity of the hippocampus with key reward processing regions in vivo. Using a large sample of subjects (N = 628) from the human connectome dMRI data release, we found that connectivity profiles with the hippocampus varied widely between different regions of the reward circuit. While the dopaminergic midbrain (ventral tegmental area) showed stronger connectivity with the anterior versus posterior hippocampus, the ventromedial prefrontal cortex showed stronger connectivity with the posterior hippocampus. The limbic (ventral) striatum demonstrated a more homogeneous connectivity profile along the hippocampal long axis. This is the first study to generate a probabilistic atlas of the hippocampal structural connectivity with reward-related networks, which is essential to investigating how these circuits contribute to normative adaptive behavior and maladaptive behaviors in psychiatric illness. These findings describe nuanced structural connectivity that sets the foundation to better understand how the hippocampus influences reward-guided behavior in humans.

Altered Metabolic Connectivity within the Limbic Cortico‐Striato‐Thalamo‐Cortical Circuit in Presymptomatic and Symptomatic Behavioral Variant Frontotemporal Dementia

AbstractBackgroundBehavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico‐cortical transmission, with limited direct investigation of cortical‐subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico‐striato‐thalamic‐cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.MethodThirty‐three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non‐carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed‐based metabolic connectivity based on [18F]‐fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford‐GSK‐Imanova Striatal Connectivity Atlas.ResultBvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.ConclusionThese findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’s disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.

Altered metabolic connectivity within the limbic cortico-striato-thalamo-cortical circuit in presymptomatic and symptomatic behavioral variant frontotemporal dementia

BackgroundBehavioral variant frontotemporal dementia (bvFTD) is predominantly considered a dysfunction in cortico-cortical transmission, with limited direct investigation of cortical-subcortical transmission. Thus, we aimed to characterize the metabolic connectivity between areas of the limbic cortico-striato-thalamic-cortical (CSTC) circuit in presymptomatic and symptomatic bvFTD patients.MethodsThirty-three bvFTD patients and 33 unrelated healthy controls were recruited for this study. Additionally, six asymptomatic carriers of the MAPT P301L mutation were compared with 12 non-carriers who were all from the same family of bvFTD. Each participant underwent neuropsychological assessment, genetic testing, and a hybrid PET/MRI scan. Seed-based metabolic connectivity based on [18F]-fluorodeoxyglucose PET between the main components within the limbic CSTC circuit was explored according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsBvFTD patients exhibited reduced metabolic connectivity between the relays in the limbic CSTC circuit, which included the frontal region (ventromedial prefrontal cortex, orbitofrontal cortex, rectus gyrus, and anterior cingulate cortex), the limbic striatum, and thalamus compared to controls. In the bvFTD patients, the involvement of the limbic CSTC circuit was associated with the severity of behavior disruption, as measured by the frontal behavior inventory, the disinhibition subscale, and the apathy subscale. Notably, asymptomatic MAPT carriers had weakened frontostriatal connectivity but enhanced striatothalamus and thalamofrontal connectivity within the limbic CSTC circuit compared with noncarriers.ConclusionThese findings suggested that aberrant metabolic connectivity within the limbic CSTC circuit is present in symptomatic and even asymptomatic stages of bvFTD. Thus, metabolic connectivity patterns could be used as a potential biomarker to detect the presymptomatic stage and track disease progression.

Striatal dopamine synthesis capacity and neuromelanin in the substantia nigra: A multimodal imaging study in schizophrenia and healthy controls

[18F]F-DOPA PET is an established in-vivo method for investigating striatal dopamine synthesis capacity (DSC) and has demonstrated abnormalities in striatal DSC in schizophrenia. Neuromelanin-sensitive MRI (NM-MRI) is a promising, more accessible, tool that indirectly assesses dopaminergic functioning in the substantia nigra (SN). However, how [18F]F-DOPA PET and NM-MRI, as measures of nigrostriatal dopaminergic functioning, interrelate is still unknown. We hypothesize that NM-MRI signal in the SN is positively correlated with striatal DSC in patients with a schizophrenia spectrum disorder (SSD) and healthy controls (HC). We acquired NM-MRI and dynamic [18F]F-DOPA PET scans in 12 patients with SSD and 16 HC. In both groups, we assessed the correlation between nigral NM-MRI signal and DSC in the whole, associative, limbic, and sensorimotor striatum using voxelwise analyses within the SN. In HC, we found subsets of voxels within the SN where NM-MRI signal correlated negatively with DSC in the whole and limbic striatum. There were no significant associations between NM-MRI and DSC in the associative or sensorimotor striatum in HC and no significant associations in patients. These results show that NM-MRI signal and striatal DSC are negatively related in HC, but not in patients. Our results indicate that [18F]F-DOPA PET and NM-MRI reflect different aspects of dopaminergic functioning. The negative correlation in HC might be explained by vesicular monoamine transporter-2 (VMAT-2) functioning. A lack of a correlation in patients might be due to the small sample size, effects of symptom severity or antipsychotic medication.

Disrupted functional connectivity of the brain reward system in substance use problems: A meta-analysis of functional neuroimaging studies.

Extensive literature suggests that the brain reward system is crucial in understanding the neurobiology of substance use disorders. However, evidence of reliable deficits in functional connectivity across studies on substance use problems remains limited. Therefore, a voxel-wise seed-based meta-analysis using brain regions of the reward system as seeds of interest was conducted on 96 studies representing 5757 subjects with substance use problems. The ventromedial prefrontal cortex exhibited hyperconnectivity with the ventral striatum and hypoconnectivity with the amygdala and hippocampus. The executive striatum showed hyperconnectivity with the motor thalamus and dorsolateral prefrontal cortex and hypoconnectivity with the anterior cingulate cortex and anterior insula. Finally, the limbic striatum was found to be hyperconnected to the orbitofrontal cortex and hypoconnected to the precuneus compared with healthy subjects. The current study provided meta-analytical evidence of deficient functional connectivity between brain regions of the reward system and cortico-striato-thalamocortical loops in addiction. These results are consistent with deficits in motivation and habit formation occurring in addiction, and they highlight alterations in brain regions involved in socio-emotional processing and attention salience.

Reduced basal ganglia tissue-iron concentration in school-age children with attention-deficit/hyperactivity disorder is localized to limbic circuitry.

Dopamine-related abnormalities in the basal ganglia have been implicated in attention-deficit/hyperactivity disorder (ADHD). Iron plays a critical role in supporting dopaminergic function, and reduced brain iron and serum ferritin levels have been linked to ADHD symptom severity in children. Furthermore, the basal ganglia is a central brain region implicated in ADHD psychopathology and involved in motor and reward functions as well as emotional responding. The present study repurposed diffusion tensor imaging (DTI) to examine effects of an ADHD diagnosis and sex on iron deposition within the basal ganglia in children ages 8-12years. We further explored associations between brain iron levels and ADHD symptom severity and affective symptoms. We observed reduced iron levels in children with ADHD in the bilateral limbic region of the striatum, as well as reduced levels of iron-deposition in males in the sensorimotor striatal subregion, regardless of diagnosis. Across the whole sample, iron-deposition increased with age in all regions. Brain-behavior analyses revealed that, across diagnostic groups, lower tissue-iron levels in bilateral limbic striatum correlated with greater ADHD symptom severity, whereas lower tissue-iron levels in the left limbic striatum only correlated with anxious, depressive and affective symptom severity. This study sheds light on the neurobiological underpinnings of ADHD, specifically highlighting the localization of tissue-iron deficiency in limbic regions, and providing support for repurposing DTI for brain iron analyses. Our findings highlight the need for further investigation of iron as a biomarker in the diagnosis and treatment of ADHD and sex differences.

Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum.

Dopamine and other neurotransmitters have the potential to induce neuroplasticity in the striatum via gene regulation. Dopamine receptor-mediated gene regulation relies on second messenger cascades that involve cyclic nucleotides to relay signaling from the synapse to the nucleus. Phosphodiesterases (PDEs) catalyze cyclic nucleotides and thus potently control cyclic nucleotide signaling. We investigated the role of the most abundant striatal PDE, PDE10A, in striatal gene regulation by assessing the effects of PDE10A inhibition (by a selective PDE10A inhibitor, TP-10) on gene regulation and by comparing the basal expression of PDE10A mRNA throughout the striatum with gene induction by dopamine agonists in the intact or dopamine-depleted striatum. Our findings show that PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum. The inhibition of PDE10A produced pronounced increases in gene expression that were directly related to levels of local PDE10A expression. Moreover, the gene expression induced by L-DOPA after dopamine depletion (by 6-OHDA), or by psychostimulants (cocaine, methylphenidate) in the intact striatum, was also positively correlated with the levels of local PDE10A expression. This relationship was found for gene markers of both D1 receptor- and D2 receptor-expressing striatal projection neurons. Collectively, these results indicate that PDE10A, a vital part of the dopamine receptor-associated second messenger machinery, is tightly linked to drug-induced gene regulation in the striatum. PDE10A may thus serve as a potential target for modifying drug-induced gene regulation and related neuroplasticity.

Downregulation of surface AMPA receptor expression in the striatum following prolonged social isolation, a role of mGlu5 receptors.

Major depressive disorder is a common and serious mood illness. The molecular mechanisms underlying the pathogenesis and symptomatology of depression are poorly understood at present. Multiple neurotransmitter systems are believed to be implicated in depression. Increasing evidence supports glutamatergic transmission as a critical element in depression and antidepressant activity. In this study, we investigated adaptive changes in expression of AMPA receptors in a key limbic reward structure, the striatum, in response to an anhedonic model of depression. Prolonged social isolation in adult rats caused anhedonic/depression- and anxiety-like behavior. In these depressed rats, surface levels of AMPA receptors, mainly GluA1 and GluA3 subunits, were reduced in the nucleus accumbens (NAc). Surface GluA1/A3 expression was also reduced in the caudate putamen (CPu) following chronic social isolation. No change was observed in expression of presynaptic synaptophysin, postsynaptic density-95, and dendritic microtubule-associated protein 2 in the striatum. Noticeably, chronic treatment with the metabotropic glutamate (mGlu) receptor 5 antagonist MTEP reversed the reduction of AMPA receptors in the NAc and CPu. MTEP also prevented depression- and anxiety-like behavior induced by social isolation. These data indicate that adulthood prolonged social isolation induces the adaptive downregulation of GluA1/A3-containing AMPA receptor expression in the limbic striatum. mGlu5 receptor activity is linked to this downregulation, and antagonism of mGlu5 receptors produces an antidepressant effect in this anhedonic model of depression.

A unidirectional but not uniform striatal landscape of dopamine signaling for motivational stimuli

Dopamine signals in the striatum are critical for motivated behavior. However, their regional specificity and precise information content are actively debated. Dopaminergic projections to the striatum are topographically organized. Thus, we quantified dopamine release in response to motivational stimuli and associated predictive cues in six principal striatal regions of unrestrained, behaving rats. Absolute signal size and its modulation by stimulus value and by subjective state of the animal were interregionally heterogeneous on a medial to lateral gradient. In contrast, dopamine-concentration direction of change was homogeneous across all regions: appetitive stimuli increased and aversive stimuli decreased dopamine concentration. Although cues predictive of such motivational stimuli acquired the same influence over dopamine homogeneously across all regions, dopamine-mediated prediction-error signals were restricted to the ventromedial, limbic striatum. Together, our findings demonstrate a nuanced striatal landscape of unidirectional but not uniform dopamine signals, topographically encoding distinct aspects of motivational stimuli and their prediction.

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain.

Background:Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity.Aims:To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor).Method:Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach.Results:Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks.Outcomes:THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Location, Location, Location: The Expression of D3 Dopamine Receptors in the Nervous System.

When the rat D3 dopamine receptor (D3R) was cloned and the distribution of its mRNA examined in 1990-1991, it attracted attention due to its peculiar distribution in the brain quite different from that of its closest relative, the D2 receptor. In the rat brain, the D3R mRNA is enriched in the limbic striatum as opposed to the D2 receptor, which is highly expressed in the motor striatal areas. Later studies in the primate and human brain confirmed relative enrichment of the D3R in the limbic striatum but also demonstrated higher abundance of theD3R in the primate as compared to the rodent brain. Additionally, in the rodent brain, the D3R in the dorsal striatum appears to be co-expressed with the D1 dopamine receptor-bearing striatal neurons giving rise to the direct output striatal pathway, although the picture is less clear with respect to the nucleus accumbens. In contrast, in the primate striatum, the D3R co-localizes with the D2 receptor throughout the basal ganglia as well as in extrastriatal brain areas. The relative abundance of the D3R in the limbic striatum, its output structures, secondary targets, and some of the other connected limbic territories may underpin its role in reward, drug dependence, and impulse control. Selective expression of D3R in the brain proliferative areas may point to its important role in the neural development as well as in neurodevelopmental abnormalities associated with schizophrenia and other developmental brain disorders.

White matter diffusivity and its correlations to state measures of psychopathology in male refugees with posttraumatic stress disorder

Post-traumatic stress disorder (PTSD) is a heterogenous condition and the underlying neurobiology is still poorly understood. In this study, we tested the hypothesis that PTSD is associated with microstructural changes in white matter (WM) fibre tracts that connect regions involved in emotional processing, memory, attention, and language. Furthermore, we examined how different response patterns to individualized trauma-provoking stimuli related to underlying WM microstructure. Sixty-nine trauma-affected male refugees with PTSD (N = 38) or without PTSD (N = 31) underwent clinical assessments and diffusion-weighted magnetic resonance imaging (DWI) of the whole brain at 3 Tesla. Diffusion tensor metrics were computed from DWI data and used to characterize regional white-matter microstructure. An automated tract segmentation method was used to extract diffusion tensor metrics from subject-based reconstructions of tract segments (ROI), including uncinate fasciculus (UF), cingulum bundle (CB), superior longitudinal fasciculus (SLF) in three subdivisions (SLF I - III), and fibre bundles connecting orbito-frontal cortex to striatum (OF-ST). Outside the scanner we obtained measures of immediate (state) arousal, avoidance and dissociation symptoms assessed in response to auditory exposure to a personal traumatic memory. Using mean FA of the middle part of each ROI, mixed ANOVA revealed a significant interaction between group, ROI and hemisphere. Post-hoc comparisons showed that, relative to refugees without PTSD, refugees with PTSD had lower FA in right CB, left SLF-I, bilateral OF-ST and bilateral SLF-II. Mean FA scaled negatively with avoidance in right CB while mean FA in bilateral UF scaled positively with individual scores reflecting dissociation symptoms. The results support a pathophysiological model of PTSD that implicates limbic structures, prefrontal cortex and striatum. The results also emphasize the need to consider PTSD’s multifaceted manifestations when searching for functional-structural relationships.

Heterogenous electrophysiological responses of functionally distinct striatal subregions to circadian and sleep-related homeostatic processes.

Basal ganglia (BG) are a set of subcortical nuclei that are involved in the control of a wide variety of motor, cognitive, and affective behaviors. Although many behavioral abnormalities associated with BG dysfunction overlap with the clinical picture precipitated by the lack of sleep, the impact of sleep alterations on neuronal activity in BG is unknown. Using wild-type C57BI mice, we investigated the circadian and sleep-related homeostatic modulation of neuronal activity in the three functional subdivisions of the striatum (i.e. sensorimotor, associative, and limbic striatum). We found no circadian modulation of activity in both ventral and dorsomedial striatum while the dorsolateral striatum displayed a significant circadian rhythm with increased firing rates during the subjective dark, active phase. By combining neuronal activity recordings with electroencephalogram (EEG) recordings, we found a strong modulation of neuronal activity by the nature of vigilance states with increased activity during wakefulness and rapid eye movement sleep relative to nonrapid eye movement sleep in all striatal subregions. Depriving animals of sleep for 6 h induced significant, but heterogenous alterations in the neuronal activity across striatal subregions. Notably, these alterations lasted for up to 48 h in the sensorimotor striatum and persisted even after the normalization of cortical EEG power densities. Our results show that vigilance and sleep states as well as their disturbances significantly affect neuronal activity within the striatum. We propose that these changes in neuronal activity underlie both the well-established links between sleep alterations and several disorders involving BG dysfunction as well as the maladaptive changes in behavior induced in healthy participants following sleep loss.

Cocaine cue-induced mesocorticolimbic activation in cocaine users: Effects of personality traits, lifetime drug use, and acute stimulant ingestion.

Stimulant drug-paired cues can acquire the ability to activate mesocorticolimbic pathways and lead to new bouts of drug use. Studies in laboratory animals suggest that these effects are augmented by progressively greater drug use histories, impulsive personality traits, and acute drug ingestion. As a preliminary test of these hypotheses in humans, we exposed cocaine users (n = 14) and healthy volunteers (n = 10) to cocaine-related videos during two functional magnetic resonance imaging (fMRI) sessions, once following acute administration of placebo and once following d-amphetamine (0.3 mg/kg, p.o.). Across sessions, cocaine users showed larger cocaine cue-induced responses than healthy controls in the associative striatum and midbrain. Among the cocaine users, larger drug cue-induced responses during the placebo session were correlated with higher Barratt Impulsiveness Scale (BIS-11) nonplanning scores (associative striatum) and greater lifetime use of stimulant drugs (limbic, associative, and sensorimotor striatum). The administration of d-amphetamine did not augment the cue-induced activations, but, in cocaine users, drug cue-induced striatal activations were more widespread following prolonged cocaine cue exposure. Together, these effects of past and present drug use might aggravate the risk for stimulant drug use problems.

The influence of conditioned stimuli on [11C]-(+)-PHNO PET binding in tobacco smokers after a one week abstinence

Stimuli previously paired with drugs of dependence can produce cravings that are associated with increased dopamine (DA) levels in limbic and striatal brain areas. Positron Emission Tomography (PET) imaging with [11C]-(+)-PHNO allows for a sensitive measurement of changes in DA levels. The purpose of the present study was to investigate changes in DA levels, measured with PET imaging with [11C]-(+)-PHNO, in regions of interest in smokers who had maintained abstinence for 7–10 days. Participants (N = 10) underwent two PET scans on separate days, during which they viewed either smoking-related or neutral images, in counterbalanced order. Craving was measured with the 12-item Tobacco Craving Questionnaire (TCQ) and the Questionnaire on Smoking Urges-Brief (QSU-B). Compared to neutral cues, smoking cues did not increase craving. There were no changes in [11C]-(+)-PHNO binding in the cue condition compared to the neutral condition for most regions of interest (ventral pallidum, globus pallidus, limbic striatum, associative striatum, sensorimotor striatum). However, binding potential in the substantia nigra was greater in the smoking-cue condition, indicating decreased synaptic dopamine. There is a potential change of DA level occurring in midbrain following the presentation of smoking-related cues. However, this preliminary finding would need to be validated with a larger sample.

Limbic and Executive Meso- and Nigrostriatal Tracts Predict Impulsivity Differences in Attention-Deficit/Hyperactivity Disorder

BackgroundImpulsivity is a defining characteristic of attention-deficit/hyperactivity disorder (ADHD), which has been associated with substance use disorders, higher accident rates, and lower educational and occupational outcomes. The meso- and nigrostriatal pathways of the dopamine system are hypothesized to be functionally heterogeneous, supporting diverse cognitive functions and impairments, including those associated with ADHD. We tested whether human midbrain pathways (where dopaminergic cell bodies originate) between the substantia nigra (SN) and ventral tegmental area (VTA) and the striatum differed between participants with ADHD and typically developing adolescent and young adult participants. We also assessed whether pathway connectivity predicted impulsivity regardless of diagnosis. MethodsDiffusion tensor imaging data were used to predict impulsivity (parent and self-report ratings, task-based behavioral measures) from participants with ADHD and typically developing adolescent and young adult participants (n = 155; 86 male, 69 female). Using probabilistic tractography, we mapped these pathways and divided the tracts into limbic, executive, and sensorimotor based on frontostriatal connectivity. ADHD and typically developing participants differed on all behavioral measures of impulsivity. We used correlation and machine learning analyses to test for a relationship between tract probabilities and impulsivity regardless of diagnosis. ResultsParticipants with ADHD had stronger structural connectivity between SN/VTA regions and the limbic striatum, weaker connectivity with the executive striatum, and no significant differences in sensorimotor tracts. Increased tract integrity between the limbic striatal and SN/VTA regions predicted greater impulsivity, while increased integrity between executive striatal and SN/VTA regions predicted reduced impulsivity. ConclusionsThese findings support the theory that functional diversity in the dopamine system is an important consideration for understanding dysfunction in ADHD.

Relationship between regional gray matter volumes and dopamine D2 receptor and transporter in living human brains.

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [11C]raclopride and [18F]FE‐PE2I, respectively, were acquired along with T1‐weighted magnetic resonance imaging data in our previous studies, and were re‐analyzed in this work. We quantified the binding potentials (BP ND) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP ND and regional GM volume were then examined by voxel‐based morphometry. In line with the functional and anatomical connectivity, [11C]raclopride BP ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [18F]FE‐PE2I BP ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.

Aberrant Salient and Corticolimbic Connectivity in Hypersexual Parkinson's Disease.

Introduction: Impulse control disorders (ICDs) represent a side effect of dopaminergic medication in Parkinson's disease (PD). Patients experience an excessive desire toward natural rewards paired with uncontrolled actions. Yet, the precise neural and behavioral mechanisms associated with ICDs and, importantly, each specific subdomain remain unclear. We aim to decipher resting-state and corticolimbic functional connectivity in PD patients with and without hypersexual ICD. Materials and Methods: Seventeen PD patients with hypersexuality (PD+HS) and 15 PD patients without hypersexuality (PD-HS) underwent two sessions (with and without medication) of resting-state functional magnetic resonance imaging and were compared with 17 healthy controls. Dual-regression independent component analyses extracted salience, sensorimotor, default-mode, and central executive networks. Seed-based functional connectivity with three striatal subdivisions (motor, associative, and limbic) was obtained and significant changes were correlated with key impulsivity and inhibitory measures. Results: Enhanced salience network (SN) activity represented by a significant rise in the right inferior frontal gyrus was found in PD+HS compared with PD-HS. Connectivity analyses revealed a functional disconnection between associative and limbic striatum with precuneus and superior parietal lobe in PD+HS, some connections explained by abnormal sexual behavior and inhibition in PD+HS. Conclusions: Hypersexual ICD is associated with enhanced SN signaling and corticolimbic disconnections, including striatal associative and limbic loops that contribute to altered control of sexually driven behavior and overall severity in PD and ICD. Impact statement We enlarge the neurobiological basis to one specific Parkinson's disease (PD) and impulse control disorder (ICD) (PD+ICD) subtype-that is, hypersexuality-and reveal its associated resting-state functional connectivity linked to altered behavior. We report enhanced salience network and right inferior frontal gyrus as part of the underlying resting-state functional networks in PD patients with hypersexuality (PD+HS). Corticolimbic changes were associated with sexual severity in PD+HS to hypoactive connectivity between associative-limbic striatum with precuneus and superior parietal lobe. The connectivity changes seen in PD+HS could explain baseline differences that engender aberrant control over sexual behavior in ICD.