Comparative Roles of the Caudate and Putamen in the Serial Order of Behavior: Effects of Striatal Glutamate Receptor Blockade on Variable versus Fixed Spatial Self-Ordered Sequencing in Marmosets.

Self-ordered sequencing is an important executive function involving planning and executing a series of steps to achieve goal-directed outcomes. The lateral frontal cortex is implicated in this behavior, but downstream striatal outputs remain relatively unexplored. We trained marmosets on a three-stimulus self-ordered spatial sequencing task using a touch-sensitive screen to explore the role of the caudate nucleus and putamen in random and fixed response arrays. By transiently blocking glutamatergic inputs to these regions, using intrastriatal CNQX microinfusions, we demonstrate that the caudate and putamen are both required for, but contribute differently to, flexible and fixed sequencing. CNQX into either the caudate or putamen impaired variable array accuracy, and infusions into both simultaneously elicited greater impairment. We demonstrated that continuous perseverative errors in variable array were caused by putamen infusions, likely due to interference with the putamen's established role in monitoring motor feedback. Caudate infusions, however, did not affect continuous errors, but did cause an upward trend in recurrent perseveration, possibly reflecting interference with the caudate's established role in spatial working memory and goal-directed planning. In contrast to variable array performance, while both caudate and putamen infusions impaired fixed array responding, the combined effects were not additive, suggesting possible competing roles. Infusions into either region individually, but not simultaneously, led to continuous perseveration. Recurrent perseveration in fixed arrays was caused by putamen, but not caudate, infusions. These results are consistent overall with a role of caudate in planning and flexible responding and the putamen in more rigid habitual or automatic responding.

Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.

Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy. Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS. Methods: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis. Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes. Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.

Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial.

The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values ≥ 4.21, p-values ≤ 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.

Corticostriatal activity related to performance during continuous de novo motor learning.

Corticostriatal regions play a pivotal role in visuomotor learning. However, less research has been done on how fMRI activity in their subregions is related to task performance, which is provided as visual feedback during motor learning. To address this, we conducted an fMRI experiment in which participants acquired a complex de novo motor skill using continuous or binary visual feedback related to performance. We found a highly selective response related to performance in the entire striatum in both conditions and a relatively higher response in the caudate nucleus for the binary feedback condition. However, the ventromedial prefrontal cortex (vmPFC) response was significant only for the continuous feedback condition. Furthermore, we also found functional distinction of the striatal subregions in random versus goal-directed motor control. These findings underscore the substantial effects of the visual feedback indicating performance on distinct corticostriatal responses, thereby elucidating its significance in reinforcement-based motor learning.

Topological alteration of the brain structural network in Parkinson's disease with apathy.

BACKGROUND: Apathy is a common neuropsychiatric manifestations in Parkinson's disease (PD), but neural network mechanisms still remain elusive. We aim to investigate the topological alteration of the brain structural network in PD with apathy. METHOD: In the present study, a total of 47 apathetic PD (aPD) patients, 37 non-apathetic PD (naPD) patients, and 40 healthy controls (HCs) were enrolled. Diffusion tensor imaging (DTI) in conjunction with graph-theoretic approaches were used to explore the alterations of topological properties of the WM structural network arising from apathy in PD. One-way analysis of covariance and post hoc analyses were performed to explore differences among the three groups. Correlations were ascertained to examine relationships between the Starkstein Apathy Scale (AS) scores and significantly different network metrics among the three groups. RESULTS: Both aPD and naPD patients remained small-world topology. However, compared with the naPD patients, aPD patients showed increased clustering coefficient (Cp) at the global level. At the regional level, aPD exhibited decreased nodal properties, mainly in the right dorsolateral prefrontal cortex (DLPFC), the right caudate nucleus (CAU), the right hippocampus, and the right superior parietal gyrus. Further, AS scores were negatively correlated with degree centrality of the right DLPFC (r = -0.254, p = 0.020) and the right CAU ( r = -0.357, p = 0.001) in the pooled patients with PD. CONCLUSIONS: The findings suggested that apathy in PD presented relatively optimized global topological properties of the brain structural network and disrupted topological organization of the regional network, particularly involving the fronto-striatal-limbic circuits. The altered topological properties of abnormal brain regions might be used to understand the physiopathologic mechanism of the neural network in aPD patients.

Visually evoked local field potential changes in the caudate nucleus are remarkably more frequent in awake, behaving cats than in anaesthetized animals.

Previous results show that halothane gas anaesthesia has a suppressive effect on the visually evoked single-cell activities in the feline caudate nucleus (CN). In this study, we asked whether the low-frequency neuronal signals, the local field potentials (LFP) are also suppressed in the CN of anaesthetized animals.To answer this question, we compared the LFPs recorded from the CN of two halothane-anaesthetized (1.0%), paralyzed, and two awake, behaving cats during static and dynamic visual stimulation. The behaving animals were trained to perform a visual fixation task.Our results denoted a lower proportion of significant power changes to visual stimulation in the CN of the anesthetized cats in each frequency range (from delta to beta) of the LFPs, except gamma. These differences in power changes were more obvious in static visual stimulation, but still, remarkable differences were found in dynamic stimulation, too. The largest differences were found in the alpha and beta frequency bands for static stimulation. Concerning dynamic stimulation, the differences were the biggest in the theta, alpha and beta bands.Similar to the single-cell activities, remarkable differences were found between the visually evoked LFP changes in the CN of the anaesthetized, paralyzed and awake, behaving cats. The halothane gas anaesthesia and the immobilization suppressed the significant LFP power alterations in the CN to both static and dynamic stimulation. These results suggest the priority of the application of behaving animals even in the analysis of the visually evoked low-frequency electric signals, the LFPs recorded from the CN.

Basis of executive functions in fine-grained architecture of cortical and subcortical human brain networks.

Theoretical models suggest that executive functions rely on both domain-general and domain-specific processes. Supporting this view, prior brain imaging studies have revealed that executive activations converge and diverge within broadly characterized brain networks. However, the lack of precise anatomical mappings has impeded our understanding of the interplay between domain-general and domain-specific processes. To address this challenge, we used the high-resolution multimodal magnetic resonance imaging approach of the Human Connectome Project to scan participants performing 3 canonical executive tasks: n-back, rule switching, and stop signal. The results reveal that, at the individual level, different executive activations converge within 9 domain-general territories distributed in frontal, parietal, and temporal cortices. Each task exhibits a unique topography characterized by finely detailed activation gradients within domain-general territory shifted toward adjacent resting-state networks; n-back activations shift toward the default mode, rule switching toward dorsal attention, and stop signal toward cingulo-opercular networks. Importantly, the strongest activations arise at multimodal neurobiological definitions of network borders. Matching results are seen in circumscribed regions of the caudate nucleus, thalamus, and cerebellum. The shifting peaks of local gradients at the intersection of task-specific networks provide a novel mechanistic insight into how partially-specialized networks interact with neighboring domain-general territories to generate distinct executive functions.

Brain changes following mindfulness: Reduced caudate volume is associated with decreased positive urgency.

Mindfulness training has been shown to improve psychological health and general well-being. However, it is unclear which brain and personality systems may be affected by this practice for improving adaptive behavior and quality of life. The present study explores the effects of a 5-week mindfulness-based intervention (MBI) at the neuroanatomical level and its relationship with dispositional mindfulness and impulsivity. Sixty-six risky drivers were quasi-randomly assigned to a mindfulness training group (MT) or a control group (N). Participants underwent magnetic resonance imaging and completed the Five Facet Mindfulness Questionnaire (FFMQ) and the UPPS-P impulsivity scale twice, at baseline and after receiving the MBI. We observed that MBI changes dispositional mindfulness in the non-reactivity and observing facets. Further, we observed that the magnitude of change in impulsivity was associated with the change in dispositional mindfulness. Whole-brain voxel-wise analysis revealed that the volume of the right caudate nucleus of the MT group (n = 27) showed a reduction compared to that of the control group (n = 33), which increased in terms of the pre-post measurement (MT=-1.76 mm3; N = 6.31 mm3). We also observed that reduced caudate nucleus volume correlated with decreased positive urgency in the MT group. Taken together, our results show that MBI improves the skills of observing and non-reactivity to inner experience, while producing changes in the structure of the caudate nucleus. These structural changes are associated with a reduction in impulsivity levels, decreasing the tendency to act rashly in situations that generate positive emotions and thus facilitating more adaptive behavior.

Sex steroid hormones, the estrous cycle, and rapid modulation of glutamatergic synapse properties in the striatal brain regions with a focus on 17ß-estradiol and the nucleus accumbens.

The striatal brain regions encompassing the nucleus accumbens core (NAcc), shell (NAcs) and caudate-putamen (CPu) regulate cognitive functions including motivated behaviors, habit, learning, and sensorimotor action, among others. Sex steroid hormone sensitivity and sex differences have been documented in all of these functions in both normative and pathological contexts, including anxiety, depression and addiction. The neurotransmitter glutamate has been implicated in regulating these behaviors as well as striatal physiology, and there are likewise documented sex differences in glutamate action upon the striatal output neurons, the medium spiny neurons (MSNs). Here we review the available data regarding the role of steroid sex hormones such as 17ß-estradiol (estradiol), progesterone, and testosterone in rapidly modulating MSN glutamatergic synapse properties, presented in the context of the estrous cycle as appropriate. Estradiol action upon glutamatergic synapse properties in female NAcc MSNs is most comprehensively discussed. In the female NAcc, MSNs exhibit development period-specific sex differences and estrous cycle variations in glutamatergic synapse properties as shown by multiple analyses, including that of miniature excitatory postsynaptic currents (mEPSCs). Estrous cycle-differences in NAcc MSN mEPSCs can be mimicked by acute exposure to estradiol or an ERα agonist. The available evidence, or lack thereof, is also discussed concerning estrogen action upon MSN glutamatergic synapse in the other striatal regions as well as the underexplored roles of progesterone and testosterone. We conclude that there is strong evidence regarding estradiol action upon glutamatergic synapse function in female NAcs MSNs and call for more research regarding other hormones and striatal regions.

Neural Representations of Post-Decision Accuracy and Reward Expectation in the Caudate Nucleus and Frontal Eye Field.

Performance monitoring that supports ongoing behavioral adjustments is often examined in the context of either choice confidence for perceptual decisions (i.e., "did I get it right?") or reward expectation for reward-based decisions (i.e., "what reward will I receive?"). However, our understanding of how the brain encodes these distinct evaluative signals remains limited because they are easily conflated, particularly in commonly used two-alternative tasks with symmetric rewards for correct choices. Previously we used a motion-discrimination task with asymmetric rewards to identify neural substrates of forming reward-biased perceptual decisions in the caudate nucleus (part of the striatum in the basal ganglia) and the frontal eye field (FEF, in prefrontal cortex). Here we leveraged this task design to partially decouple estimates of accuracy and reward expectation and examine their impacts on subsequent decisions and their representations in those two brain areas. We identified distinguishable representations of these two evaluative signals in individual caudate and FEF neurons, with regional differences in their distribution patterns and time courses. We observed that well-trained monkeys (both sexes) used both evaluative signals, infrequently but consistently, to adjust their subsequent decisions. We found further that these behavioral adjustments had reliable relationships with the neural representations of both evaluative signals in caudate, but not FEF. These results suggest that the cortico-striatal decision network may use diverse evaluative signals to monitor and adjust decision-making behaviors, adding to our understanding of the different roles that the FEF and caudate nucleus play in a diversity of decision-related computations.

Musculoskeletal pain in Parkinson's disease: Association with dopaminergic deficiency in the caudate nucleus.

BACKGROUND: Musculoskeletal (MSK) pain affects over 80% of People with Parkinson's (PD, PwP) and may, in part, be dopaminergic in origin, as dopaminergic medication often leads to its relief. METHODS: PwP who underwent striatal dopamine transporter visualization with a radiopharmaceutical DaTscan™ (123 I-Ioflupane Injection) using a single-photon emission computed tomography (SPECT) as a part of their clinical-diagnostic work up were enrolled in the "Non-motor International Longitudinal Study" (NILS; UK National Institute for Health Research Clinical Research Network Number 10084) and included in this cross-sectional analysis. The association between specific DaTscan binding ratios for each striatum, the caudate nucleus and putamen and clinical ratings for MSK pain (assessed using the King's Parkinson's Disease Pain Scale (KPPS)) were analysed. RESULTS: 53 PwP (30.2% female; age: 63.79 ± 11.31 years; disease duration (DD): 3.32 (0.31-14.41) years; Hoehn & Yahr stage (H&Y): 2 (1-4); Levodopa Equivalent Daily Dose (LEDD): 543.08 ± 308.94 mg) were assessed and included in this analysis. MSK pain was highly prevalent (71.7% of all participants, mean KPPS Item 1 score 5.34 ± 4.76) and did not correlate with the motor symptoms burden (SCOPA-Motor total score; p = 0.783) but showed a significant correlation with quality of life (PDQ-8, rs = 0.290, p = 0.035). z-scores for the caudate nucleus (Exp (B) = 0.367, 95% CI for Exp (B) 0.148-0.910, p = 0.031) and striatum (Exp (B) = 0.338, 95% CI for Exp (B) 0.123-0.931, p = 0.036), adjusted for DD, H&Y and LEDD, were significant determinants of MSK pain. CONCLUSIONS: Our findings suggest an association between MSK pain in PwP and the severity of dopaminergic deficiency in the caudate nucleus. SIGNIFICANCE: In People with Parkinson's, musculoskeletal pain does not arise simply as a direct sequel to motor symptoms-instead, it is linked to the severity of dopaminergic depletion in the caudate nucleus.

Quantitative susceptibility mapping from basal ganglia and related structures: correlation with disease severity in progressive supranuclear palsy.

OBJECTIVE: We examined whether mean magnetic susceptibility values from deep gray matter structures in patients with progressive supranuclear palsy (PSP) differed from those in patients with Parkinson's disease (PD) and healthy volunteers, and correlated with the PSP rating scale. METHODS: Head of caudate nucleus, putamen, globus pallidus, substantia nigra and red nucleus were the regions of interest. Mean susceptibility values from these regions in PSP patients were estimated using quantitative susceptibility mapping. Correlations with clinical severity of disease as measured by the PSP rating scale were examined. The mean susceptibility values were also compared with those from healthy volunteers and age- and disease duration-matched patients with PD. RESULTS: Data from 26 healthy volunteers, 26 patients with PD and 27 patients with PSP, were analysed. Patients with PSP had higher mean susceptibility values from all regions of interest when compared to both the other groups. The PSP rating scale scores correlated strongly with mean susceptibility values from the red nucleus and moderately with those from the putamen and substantia nigra. The scores did not correlate with mean susceptibility values from the caudate nucleus or globus pallidus. In patients with PD, the motor deficits correlated moderately with mean susceptibility values from substantia nigra. CONCLUSIONS: In patients with PSP, mean susceptibility values indicating the severity of mineralization of basal ganglia and related structures correlate with disease severity, the correlation of red nucleus being the strongest. Further studies are warranted to explore whether mean susceptibility values could serve as biomarkers for PSP.

Behavioral Variant Frontotemporal Dementia With the Dominantly Affected Caudate Nucleus in 18 F-FP-CIT PET/CT.

ABSTRACT: Frontotemporal dementia is a clinical syndrome that is characterized by a progressive deterioration in behavior, personality, and/or language, with relative preservation of memory, and its phenotype and molecular basis are heterogeneous. We present a case of a 62-year-old female patient who underwent 18 F-FDG PET/CT and 18 F-FP-CIT PET/CT for differential diagnosis of psychiatric disease and types of dementia. 18 F-FDG PET/CT image showed a compatible finding for frontotemporal dementia, and 18 F-FP-CIT PET/CT image showed dominantly decreased dopamine transporter activity in the bilateral caudate nucleus.

Relationship of irisin with disease severity and dopamine uptake in Parkinson's disease patients.

BACKGROUND: This study was designed to investigate the relationship of irisin with the severity of Parkinson's disease (PD) and dopamine (DOPA) uptake in patients with PD and to understand the role of irisin in PD. METHODS: The plasma levels of irisin and α-syn were measured by enzyme-linked immunosorbent assay (ELISA). Motor and nonmotor symptoms were assessed with the relevant scales. DOPA uptake was measured with DOPA positron emission tomography (PET)/magnetic resonance imaging (MRI). RESULTS: The plasma levels of α-syn and irisin in patients with PD gradually increased and decreased, respectively, with the progression of the disease. There was a negative correlation between plasma α-syn and irisin levels in patients with PD. The level of irisin in plasma was negatively correlated with Unified Parkinson's Disease Rating Scale (UPDRS)-III scores and positively correlated with Montreal Cognitive Assessment (MoCA) scores. The striatal/occipital lobe uptake ratios (SORs) of the ipsilateral and contralateral caudate nucleus and anterior and posterior putamen in the high-irisin group were significantly higher than those in the low-irisin group, and irisin levels in the caudate nucleus and anterior and posterior putamen contralateral to the affected limb were lower than those on the ipsilateral side. The level of irisin was positively correlated with the SORs of the ipsilateral and contralateral caudate nucleus and putamen in PD patients. CONCLUSIONS: Irisin plays a neuroprotective role by decreasing the level of α-syn. Irisin is negatively correlated with the severity of motor symptoms and cognitive impairment. More importantly, irisin can improve DOPA uptake in the striatum of patients with PD, especially on the side contralateral to the affected limb.

Abnormal caudate nucleus activity in patients with depressive disorder: Meta-analysis of task-based functional magnetic resonance imaging studies with behavioral domain.

During task-based functional magnetic resonance imaging (t-fMRI) patients with depressive disorder (DD) have shown abnormal caudate nucleus activation. There have been no meta-analyses that are conducted on the caudate nucleus using Activation Likelihood Estimation (ALE) in patients with DD, and the relationships between abnormal caudate activity and different behavior domains in patients with DD remain unclear. There were 24 previously published t-fMRI studies included in the study with the caudate nucleus as the region of interest. Meta-analyses were performed using the method of ALE. Included five ALE meta-analyses: (1) the hypoactivated caudate nucleus relative to healthy controls (HCs); (2) the hyper-activated caudate nucleus; (3) the abnormal activation in the caudate nucleus in the emotion domain; (4) the abnormal activation in cognition domain; (5) the abnormal activation in the affective cognition domain. Results revealed that the hypo-/hyper-activity in the caudate subregions is mainly located in the caudate body and head, while the relationships between abnormal caudate subregions and different behavior domains are complex. The hypoactivation of the caudate body and head plays a key role in the emotions which indicates there is a positive relationship between the decreased caudate activity and depressed emotional behaviors in patients with DD.

Abnormal interhemispheric functional cooperation in schizophrenia follows the neurotransmitter profiles.

BACKGROUND: Interhemispheric cooperation is one of the most prominent functional architectures of the human brain. In patients with schizophrenia, interhemispheric cooperation deficits have been reported using increasingly powerful neurobehavioural and neuroimaging measures. However, these methods rely in part on the assumption of anatomic symmetry between hemispheres. In the present study, we explored interhemispheric cooperation deficits in schizophrenia using a newly developed index, connectivity between functionally homotopic voxels (CFH), which is unbiased by hemispheric asymmetry. METHODS: Patients with schizophrenia and age- and sexmatched healthy controls underwent multimodal MRI, and whole-brain CFH maps were constructed for comparison between groups. We examined the correlations of differing CFH values between the schizophrenia and control groups using various neurotransmitter receptor and transporter densities. RESULTS: We included 86 patients with schizophrenia and 86 matched controls in our analysis. Patients with schizophrenia showed significantly lower CFH values in the frontal lobes, left postcentral gyrus and right inferior temporal gyrus, and significantly greater CFH values in the right caudate nucleus than healthy controls. Moreover, the differing CFH values in patients with schizophrenia were significantly correlated with positive symptom score and illness duration. Functional connectivity within frontal lobes was significantly reduced at the voxel cluster level compared with healthy controls. Finally, the abnormal CFH map of patients with schizophrenia was spatially associated with the densities of the dopamine D1 and D2 receptors, fluorodopa, dopamine transporter, serotonin transporter and acetylcholine transporter. CONCLUSION: Regional abnormalities in interhemispheric cooperation may contribute to the clinical symptoms of schizophrenia. These CFH abnormalities may be associated with dysfunction in neurotransmitter systems strongly implicated in schizophrenia.

Cortical and subcortical structural differences in psychostimulant-free ADHD youth with and without a family history of bipolar I disorder: a cross-sectional morphometric comparison.

Although attention-deficit/hyperactivity disorder (ADHD) and a family history of bipolar I disorder (BD) are associated with increased risk for developing BD, their neuroanatomical substrates remain poorly understood. This study compared cortical and subcortical gray matter morphology in psychostimulant-free ADHD youth with and without a first-degree relative with BD and typically developing healthy controls. ADHD youth (ages 10-18 years) with ('high-risk', HR) or without ('low-risk', LR) a first-degree relative with BD and healthy comparison youth (HC) were enrolled. High-resolution 3D T1-weighted images were acquired using a Philips 3.0 T MR scanner. The FreeSurfer image analysis suite was used to measure cortical thickness, surface area, and subcortical volumes. A general linear model evaluated group differences in MRI features with age and sex as covariates, and exploratory correlational analyses evaluated associations with symptom ratings. A total of n = 142 youth (mean age: 14.16 ± 2.54 years, 35.9% female) were included in the analysis (HC, n = 48; LR, n = 49; HR, n = 45). The HR group exhibited a more severe symptom profile, including higher mania and dysregulation scores, compared to the LR group. For subcortical volumes, the HR group exhibited smaller bilateral thalamic, hippocampal, and left caudate nucleus volumes compared to both LR and HC, and smaller right caudate nucleus compared with LR. No differences were found between LR and HC groups. For cortical surface area, the HR group exhibited lower parietal and temporal surface area compared with HC and LR, and lower orbitofrontal and superior frontal surface area compared to LR. The HR group exhibited lower left anterior cingulate surface area compared with HC. LR participants exhibited greater right pars opercularis surface area compared with the HC. Some cortical alterations correlated with symptom severity ratings. These findings suggest that ADHD in youth with a BD family history is associated with a more a severe symptom profile and a neuroanatomical phenotype that distinguishes it from ADHD without a BD family history.

Monoaminergic Degeneration and Ocular Motor Abnormalities in De Novo Parkinson's Disease.

BACKGROUND: Evaluating eye movements in Parkinson's disease (PD) provides valuable insights into the underlying pathophysiological changes. OBJECTIVE: The aim was to investigate the relationship between monoaminergic degeneration and ocular motor abnormalities in de novo PD. METHODS: Drug-naive PD patients who underwent N-(3-[18 F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane positron emission tomography scans and video-oculography at diagnosis were eligible. Measurements of saccadic accuracy, latency, and smooth pursuit gain and square wave jerk frequency were collected. Patients underwent Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and detailed cognitive tests. We investigated the associations between ocular motor measurements and specific tracer uptake ratios (SUR) in the caudate nucleus, anterior and posterior putamen, thalamus, and dorsal raphe nuclei, along with motor and cognitive symptoms. RESULTS: One-hundred twenty-four subjects were included in this study. Saccadic accuracy was positively associated with parkinsonian motor severity expressed as Hoehn and Yahr stages, MDS-UPDRS Part III scores, and subscores for bradykinesia and rigidity but not with tremor scores (PFDR < 0.05). Saccadic accuracy correlated with poor performances in the Rey-Complex-Figure copy, and latency with the Digit Symbol Coding and the Montreal Cognitive Assessment scores (PFDR < 0.05). Prolonged saccadic latency correlated with reduced thalamic SUR, whereas decreased saccadic accuracy correlated with reduced SUR in the anterior and posterior putamen (PFDR < 0.05). Reduced smooth pursuit gain showed associations with reduced SUR in the dorsal raphe, a serotonin-predominant region, but did not correlate with parkinsonism severity scores. CONCLUSION: Defective dopaminergic and nondopaminergic neural systems may discretely influence ocular motor function in de novo PD patients. © 2023 International Parkinson and Movement Disorder Society.

Novel heterozygous VPS13A pathogenic variants in chorea-neuroacanthocytosis: a case report.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a rare hereditary autosomal recessive neurodegenerative disorder caused by pathogenic variants of the Vacuolar Protein Sorting 13 homolog A (VPS13A) gene. The variant spectrum of VPS13A has not been completely elucidated. This study reports two novel heterozygous VPS13A pathogenic variants in ChAc that expand the variant spectrum of VPS13A. CASE PRESENTATION: We described a case of a 29-year-old man with typical clinical manifestations of ChAc, including chorea, orofacial lingual dyskinesia, vocal tics, elevated serum biochemical indicators, increased acanthocytes in peripheral blood, and caudate nucleus atrophy. Next-generation sequencing revealed two heterozygous variants of VPS13A: a nonsense variant (NM_033305.2: c.8215G > T, p. Glu2739Ter) and a deletion variant in the exons 25-31. CONCLUSION: The identified nonsense variant gives rise to premature translation termination, while the deletion variant is expected to cause a significant in-frame deletion of amino acid residues in the encoded protein. Both variants are considered to be pathogenic and result in loss-of-function proteins. These findings have implications for the genetic counseling of patients with VPS13A variants.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis).

BACKGROUND: Vacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea-acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease-specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation. OBJECTIVE: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis). METHODS: In this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case. RESULTS: Gross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62- and ubiquitin-positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one. CONCLUSIONS: We present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.