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While Parkinsons disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinsons Disease Rating Scale III but were insufficient in degree to diagnose Parkinsons disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinsons disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinsons disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.

Compensatory mechanisms in Parkinson's disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson's disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson's disease, the underlying pathophysiology is unclear. Here, we investigate motor compensation in Parkinson's disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson's disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson's disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit. In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity. In conclusion, the present study suggests that motor compensation involves M1–striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity. [ABSTRACT FROM AUTHOR]

The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se , but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration. [ABSTRACT FROM AUTHOR]

Quantitative susceptibility mapping (QSM) is an MRI technique that accurately measures iron concentration in brain tissues. This meta-analysis synthesized evidence from 30 studies that used QSM to quantify the iron levels in the putamen. The PRISMA statement was adhered to when conducting the systematic reviews and meta-analyses. We conducted a meta-analysis using a random-effects model, as well as subgroup analyses (disease type, geographic region, field strength, coil, disease type, age, and sex) and sensitivity analysis. A total of 1247 patients and 1035 controls were included in the study. Pooled results showed a standardized mean difference (SMD) of 0.41 (95% CI 0.19 to 0.64), with the strongest effect seen in Alzheimer's disease (AD) at 1.01 (95% CI 0.50 to 1.52). Relapsing-remitting multiple sclerosis (RRMS) also showed increased putaminal iron at 0.37 (95% CI 0.177 to 0.58). No significant differences were observed in Parkinson's disease (PD). No significant differences were found between subgroups based on geographic region, field strength, coil, disease type, age, and sex. The studies revealed significant heterogeneity, with field strength as the primary source, while other factors, such as disease type, location, age, sex, and coil type, may have contributed. The sensitivity analysis showed that these factors did not have a significant influence on the overall results. In summary, this meta-analysis supports abnormalities in putaminal iron content across different diseases with neurodegeneration, especially AD and RRMS, as measured by QSM. This highlights the potential of QSM as an imaging biomarker to better understand disease mechanisms involving disturbances in brain iron homeostasis. [ABSTRACT FROM AUTHOR]

The dorsal striatum is composed of the caudate nucleus and the putamen in human and non‐human primates. These two regions receive different cortical projections and are functionally distinct. The caudate is involved in the control of goal‐directed behaviors, while the putamen is implicated in habit learning and formation. Previous reports indicate that ethanol differentially influences neurotransmission in these two regions. Because neurotransmitters primarily signal through G protein‐coupled receptors (GPCRs) to modulate neuronal activity, the present study aimed to determine whether ethanol had a region‐dependent impact on the expression of proteins that are involved in the trafficking and function of GPCRs, including G protein subunits and their effectors, protein kinases, and elements of the cytoskeleton. Western blotting was performed to examine protein levels in the caudate and the putamen of male cynomolgus macaques that self‐administered ethanol for 1 year under free access conditions, along with control animals that self‐administered an isocaloric sweetened solution under identical operant conditions. Among the 18 proteins studied, we found that the levels of one protein (PKCβ) were increased, and 13 proteins (Gαi1/3, Gαi2, Gαo, Gβ1γ, PKCα, PKCε, CaMKII, GSK3β, β‐actin, cofilin, α‐tubulin, and tubulin polymerization promoting protein) were reduced in the caudate of alcohol‐drinking macaques. However, ethanol did not alter the expression of any proteins examined in the putamen. These observations underscore the unique vulnerability of the caudate nucleus to changes in protein expression induced by chronic ethanol exposure. Whether these alterations are associated with ethanol‐induced dysregulation of GPCR function and neurotransmission warrants future investigation. [ABSTRACT FROM AUTHOR]

The putamen has been proposed to play a critical role in the development of obsessive-compulsive disorder (OCD). The primary objective of this study was to examine the resting-state regional activity and functional connectivity patterns of the putamen in individuals diagnosed with OCD. To achieve this, we employed resting-state functional magnetic resonance imaging (rs-fMRI) to collect data from a sample of 45 OCD patients and 53 healthy control participants. We aimed to use the regional amplitude of low-frequency fluctuation (ALFF) analysis to generate the ROI masks of the putamen and then conduct the whole brain functional connectivity of the putamen in individuals with OCD. Compared to controls, the OCD group demonstrated decreased ALFF in bilateral putamen. The right putamen also displayed decreased FC with the left putamen extending to the inferior frontal gyrus (IFG), bilateral precuneus extending to calcarine, the right middle occipital cortex extending to the right middle temporal cortex, and the left middle occipital gyrus. The decreased connectivity between the right putamen and the left IFG was negatively correlated with Yale-Brown Obsessive Compulsive scale (Y-BOCS) Obsession Scores. This study aimed to reveal the putamen changes in resting-state activity and connectivity in OCD patients, highlighting the significance of aberrant ALFF/FC of the putamen is a key characteristic of OCD. • Explored network-level neural function of the putamen in OCD patients. • Patients showed decreased ALFF in bilateral putamen. • Abnormal FC with the left putamen/IFG, precuneus, visual and auditory networks. • Dysconnectivitybetween the right patumen and the left putamen/IFG negatively correlated with Y-BOCS Obsession Scores. [ABSTRACT FROM AUTHOR]

Rs3851179, a variant of PICALM gene, and age are the risk factors of Alzheimer's disease (AD). AD is divided into early-onset AD (EOAD, < 65 years) and late-onset AD (LOAD, ≥ 65 years) by age. The purpose was to investigate the impact of different genotypes of PICALM rs3851179 on brain atrophy and cognitive decline across the AD continuum in different age groups. Four hundred seven cognitive normal (CN) controls, 362 mild cognitive impairment (MCI) patients, and 94 AD patients were enrolled to assess the interaction between AD continuum, age status, and PICALM on gray matter volume (GMV), global cognition, memory function, and executive function using full factorial ANCOVA (3 × 2 × 2). The interaction between AD continuum and PICALM significantly affected the GMV of the left putamen (PUT.L). rs3851179 A-allele carriers did not show a significant decrease in PUT.L GMV from CN to MCI to AD, while GG-allele carriers did. The interaction between AD continuum and age status was significant on GMV of the left angular gyrus (ANG.L) and right superior occipital gyrus (SOG.R). LOAD had higher GMV of ANG.L and SOG.R than EOAD. The interactive effects among AD continuum, age status, and PICALM were not significant on GMV but were significant on global cognition and executive function. The A-allele was found to have a protective effect on global cognition and executive function in EOAD, but not significantly so in LOAD. PICALM rs3851179 A-allele might alleviate the atrophy of PUT.L across the AD continuum than GG-allele. Age status did not affect the interaction between AD continuum and PICALM on brain atrophy. The ANG.L and SOG.R atrophied more severely in EOAD than in LOAD. Rs3851179 A-allele was protective for global cognition and executive function in EOAD. [ABSTRACT FROM AUTHOR]

Qiaoting Huang,1 Changzheng Shi,2 Saurabh Sonkusare,3 Congrui Li,1 Valerie Voon,3 Jiyang Pan1 1Department of Psychiatry, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 2Medical Imaging Center, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 3Department of Psychiatry, University of Cambridge, Cambridge, UKCorrespondence: Jiyang Pan, Department of Psychiatry, The First Affiliated Hospital of Jinan University, 613 West Huangpu Avenue, Guangzhou, 510630, People’s Republic of China, Tel +86 20 38688651, Email jiypan@163.com Valerie Voon, Department of Psychiatry, University of Cambridge, Box 189, Level E4, Addenbrooke’s Hospital, Cambridge, CB2 0QQ, UK, Tel +44 1223 765088, Email vv247@cam.ac.ukPurpose: Converging evidence implicates the putamen in sleep-wake regulation. However, its role remains unclear. We hypothesized that metabolic abnormalities in the putamen are linked to insomnia disorder, which has not been previously addressed, and investigated putaminal N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) in patients with insomnia disorder compared to healthy controls.Participants and Methods: In the present study, the concentrations of NAA, Cho, and Cr in the putamen of 23 patients with insomnia disorder and 18 healthy controls were determined using proton magnetic resonance spectroscopy. Sociodemographic, psychometric, and polysomnography data were obtained from all participants.Results: We found that the mean NAA/Cr ratio of the right putamen was significantly greater in the insomnia group compared to the control group and also greater than the left putamen within the insomnia group. The NAA/Cr ratio of the right putamen distinguished insomnia disorder from normal sleep with 78.3% sensitivity and 61.1% specificity. Furthermore, this ratio positively correlated with both objective and subjective insomnia severity and sleep quality.Conclusion: Our findings provide critical evidence for the dysfunctional putaminal metabolism of NAA/Cr in insomnia disorder, suggesting that the abnormal NAA/Cr ratio of the right putamen is linked to wakefulness in patients with insomnia disorder and may serve as a potential biomarker of insomnia disorder.Keywords: insomnia disorder, wakefulness, putamen, proton magnetic resonance spectroscopy, NAA/Cr ratio, polysomnography

Background: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. Methods: In 410 male and female participants aged 17–35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPI bipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. Results: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. Conclusions: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) manifests as a wide variety of clinical phenotypes and its progression varies greatly. However, the factors associated with different disease progression remain largely unknown. Methods: In this retrospective cohort study, we enrolled 113 patients who underwent 18F-FP-CIT PET scan twice. Given the negative exponential progression pattern of dopamine loss in PD, we applied the natural logarithm to the specific binding ratio (SBR) of two consecutive 18F-FP-CIT PET scans and conducted linear mixed model to calculate individual slope to define the progression rate of nigrostriatal degeneration. We investigated the clinical and dopamine transporter (DAT) availability patterns associated with the progression rate of dopamine depletion in each striatal sub-region. Results: More symmetric parkinsonism, the presence of dyslipidemia, lower K-MMSE total score, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the caudate nucleus. More symmetric parkinsonism and lower anteroposterior gradient of the mean putaminal SBR were associated with faster depletion of dopamine in the anterior putamen. Older age at onset, more symmetric parkinsonism, the presence of dyslipidemia, and lower anteroposterior gradient of the mean putaminal SBR were associated with faster progression rate of dopamine depletion in the posterior putamen. Lower striatal mean SBR predicted the development of LID, while lower mean SBR in the caudate nuclei predicted the development of dementia. Discussion: Our results suggest that the evaluation of baseline clinical features and patterns of DAT availability can predict the progression of PD and its prognosis. [ABSTRACT FROM AUTHOR]

The claustrum is structurally connected with many cortical areas. A major hurdle standing in the way of understanding claustrum function is the difficulty in assessing the global functional connectivity (FC) of this structure. The primary issues lie in the inability to isolate claustrum signal from the adjacent insular cortex (Ins), caudate/putamen (CPu), and endopiriform nucleus (Endo). To address this issue, we used (7T) fMRI in the rat and describe a novel analytic method to study claustrum without signal contamination from the surrounding structures. Using this approach, we acquired claustrum signal distinct from Ins, CPu, and Endo, and used this claustrum signal to determine whole brain resting state functional connectivity (RSFC). Claustrum RSFC was distinct from the adjacent structures and displayed extensive connections with sensory cortices and the cingulate cortex, consistent with known structural connectivity of the claustrum. These results suggest fMRI and improved analysis can be combined to accurately assay claustrum function. [ABSTRACT FROM AUTHOR]

Background: Recent research has demonstrated that the dorsal striatum is directly associated with the integration of cognitive, sensory-motor, and motivational/emotional data. Disruptions in the corticostriatal circuit have been implicated in the pathophysiology of psychosis. The dorsal striatum was reported to show lateralized pathology in psychotic disorders. In this study, we aimed to analyze the laterality of the dorsal striatum with texture analysis of T2-weighted magnetic resonance imaging (MRI) images from schizoaffective disorder (SAD) patients. Methods: Twenty SAD patients, met the inclusion criteria and had available cranial MRI data were assigned as the patient group. Twenty healthy individuals were determined as the control group. Texture analysis values were obtained from striatum region of interests (ROI) generated from T2-weighted MRI images. Data are presented as mean and standard deviation. The suitability of the data for normal distribution was analyzed with the Kolmogorov-Smirnov test. Analysis of variance (ANOVA) test (Post Hoc TUKEY) was employed to compare the group data based on test findings. Results: There was no significant difference between the groups in terms of gender and age. There were differences in the values of texture analysis parameters of both caudate and putamen nuclei in comparison to controls. We identified differences in the left dorsal striatum nuclei in SAD. The differences in the putamen were more and more pronounced than in the caudate. Conclusions: Texture analyses suggest that the left dorsal striatum nuclei may be different in SAD patients. Further studies are needed to determine the pathophysiology of SAD and how it may affect disease treatment. [ABSTRACT FROM AUTHOR]

Classic research has shown a division in the neuroanatomical structures that support flexible (e.g., short‐cutting) and habitual (e.g., familiar route following) navigational behavior, with hippocampal–caudate systems associated with the former and putamen systems with the latter. There is, however, disagreement about whether the neural structures involved in navigation process particular forms of spatial information, such as associations between constellations of cues forming a cognitive map, versus single landmark‐action associations, or alternatively, perform particular reinforcement learning algorithms that allow the use of different spatial strategies, so‐called model‐based (flexible) or model‐free (habitual) forms of learning. We sought to test these theories by asking participants (N = 24) to navigate within a virtual environment through a previously learned, 9‐junction route with distinctive landmarks at each junction while undergoing functional magnetic resonance imaging (fMRI). In a series of probe trials, we distinguished knowledge of individual landmark‐action associations along the route versus knowledge of the correct sequence of landmark‐action associations, either by having absent landmarks, or "out‐of‐sequence" landmarks. Under a map‐based perspective, sequence knowledge would not require hippocampal systems, because there are no constellations of cues available for cognitive map formation. Within a learning‐based model, however, responding based on knowledge of sequence would require hippocampal systems because prior context has to be utilized. We found that hippocampal–caudate systems were more active in probes requiring sequence knowledge, supporting the learning‐based model. However, we also found greater putamen activation in probes where navigation based purely on sequence memory could be planned, supporting models of putamen function that emphasize its role in action sequencing. [ABSTRACT FROM AUTHOR]

Introduction: Suicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt. Methods: We examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male). Results: Only the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p<.001, clusterwise p<.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted. Discussion: The results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome. [ABSTRACT FROM AUTHOR]

Objective: Schizophrenia is often associated with volumetric reductions in cortices and expansions in basal ganglia, particularly the putamen. Recent genome-wide association studies have highlighted the significance of variants in the 3' regulatory region adjacent to the kinectin 1 gene (KTN1) in regulating gray matter volume (GMV) of the putamen. This study aimed to comprehensively investigate the involvement of this region in schizophrenia. Methods: We analyzed 1136 single-nucleotide polymorphisms (SNPs) covering the entire 3' regulatory region in 4 independent dbGaP samples (4604 schizophrenia patients vs. 4884 healthy subjects) and 3 independent Psychiatric Genomics Consortium samples (107 240 cases vs. 210 203 controls) to identify consistent associations. Additionally, we examined the regulatory effects of schiz ophre nia-a ssoci ated alleles on KTN1 mRNA expression in 16 brain areas among 348 subjects, as well as GMVs of 7 subcortical nuclei in 38 258 subjects, and surface areas (SA) and thickness (TH) of the entire cortex and 34 cortical areas in 36 936 subjects. Results: The major alleles (f > 0.5) of 25 variants increased (β > 0) the risk of schizophrenia across 2 to 5 independent samples (8.4 x 10-4 ≤ P ≤ .049). These schiz ophre nia-a ssoci ated alleles significantly elevated (β > 0) GMVs of basal ganglia, including the putamen (6.0 x 10-11 ≤ P ≤ 1.1 x 10-4 ), caudate (8.7 x 10-4 ≤ P ≤ 9.4 x 10-3 ), pallidum (P = 6.0 x 10-4), and nucleus accumbens (P = 2.7 x 10-5). Moreover, they potentially augmented (β > 0) the SA of posterior cingulate and insular cortices, as well as the TH of frontal (pars triangularis and medial orbitofrontal), parietal (superior, precuneus, and inferior), and temporal (transverse) cortices, but potentially reduced (β < 0) the SA of the whole, frontal (medial orbito-frontal), and temporal (pole, superior, middle, and entorhinal) cortices, as well as the TH of rostral middle frontal and superior frontal cortices (8.9 x 10-4 ≤ P ≤ .050). Conclusion: Our findings identify significant and functionally relevant risk alleles in the 3' regulatory region adjacent to KTN1, implicating their crucial roles in the development of schizophrenia. [ABSTRACT FROM AUTHOR]

Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering. Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16–77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45–87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18–43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering. In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (P FWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (P FWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (P FWE < 0.05). We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies. [ABSTRACT FROM AUTHOR]

Objective: Grey matter, a crucial component of the brain, has been found altered in generalized anxiety disorder (GAD) of several voxel‐based morphometry studies. The conclusive and consistent grey matter alterations in GAD have not been confirmed. Method: Eleven voxel‐based morphometry studies of GAD patients were included in the current systematic review and meta‐analysis. The linear model of anxiety severity scores was applied to explore the relationship of grey matter alterations and anxiety severity. The subgroup analysis of adult GAD and adolescent GAD was also performed. Results: Significantly modest grey matter alterations in the left superior temporal gyrus of patients with GAD were found. The anxiety severity score was significantly correlated with grey matter alterations in the right insula, lenticular nucleus, putamen and striatum. The subgroup analysis of adult GAD and adolescent GAD all failed to show significant grey matter alterations. However, in the adult GAD subgroup, anxiety severity score was significantly correlated with grey matter alterations in the right insula. Conclusion: GAD might have the modest grey matter alterations in the left superior temporal gyrus. Anxiety severity might be related to the grey matter alterations in the limbic regions, such as the right insula, lenticular nucleus, putamen and striatum. This kind of correlation might be related to the effects of adult GAD. Future studies with adequate sample sizes and sophisticated GAD categories will be needed. [ABSTRACT FROM AUTHOR]

Pain is a highly subjective and multidimensional experience, significantly influenced by various psychological factors. Placebo analgesia and nocebo hyperalgesia exemplify this influence, where inert treatments result in pain relief or exacerbation, respectively. While extensive research has elucidated the psychological and neural mechanisms behind these effects, most studies have focused on transient pain stimuli. To explore these mechanisms in the context of tonic pain, we conducted a study using a 15-minute tonic muscle pain induction procedure, where hypertonic saline was infused into the left masseter of healthy participants. We collected real-time Visual Analogue Scale (VAS) scores and functional magnetic resonance imaging (fMRI) data during the induction of placebo analgesia and nocebo hyperalgesia via conditioned learning. Our findings revealed that placebo analgesia was more pronounced and lasted longer than nocebo hyperalgesia. Real-time pain ratings correlated significantly with neural activity in several brain regions. Notably, the putamen was implicated in both effects, while the caudate and other regions were differentially involved in placebo and nocebo effects. These findings confirm that the tonic muscle pain paradigm can be used to investigate the mechanisms of placebo and nocebo effects and indicate that placebo analgesia and nocebo hyperalgesia may have more distinct than common neural bases.

Background and hypothesisThe neuronal mechanisms that underlie deficits in effort cost computation in schizophrenia (SZ) are poorly understood. Given the role of frontostriatal circuits in valence-oriented motivation, we hypothesized that these circuits are either dysfunctional in SZ or do not appropriately predict behavior in SZ when task conditions are difficult and good performance is rewarded.Study designA total of 52 people with recent onset SZ-spectrum disorders and 48 healthy controls (HCs) performed a 3T fMRI task with 2 valence conditions (rewarded vs neutral) and 2 difficulty conditions. Frontostriatal connectivity was extracted during the cue (anticipatory) phase. Individual behavior was fit using a drift-diffusion model, allowing the performance parameter, drift rate (DR), to vary between task conditions. Three models were examined: A group × condition model of DR, a group × condition model of connectivity, and a regression model of connectivity predicting DR depending on group and condition.Study resultsDRs showed the expected positive correlation with accuracy and a negative association with reaction time. The SZ group showed a deficit in DR but did not differ in overall connectivity or show a valence-specific deficit in connectivity. Significant group × valence × difficulty interactions, however, were observed on the relationship between right dorsolateral prefrontal (DLPFC)-striatal connectivity and DR (DLPFC-Caudate: F = 10.92, PFDR = .004; DLPFC-Putamen: F = 5.14, PFDR = .048) driven by more positive relationships between DR and connectivity during cues for the difficult-rewarded condition in HCs compared to SZ.ConclusionsThese findings suggest that frontostriatal connectivity is less predictive of performance in SZ when task difficulty is increased and a reward incentive is applied.

BackgroundEpidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.MethodsIn this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.Results[18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.ConclusionsThese findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

Abstract The putamen is a subcortical structure. However, neuroimaging studies have demonstrated the involvement of the left putamen in other language functions such as bilingual language processing. Some studies have also shown the role of the right putamen in higher-order language functions. The present reanalysis aims to investigate the role of the bilateral putamen during the L1-L2 sentence comprehension in bilinguals using functional magnetic resonance imaging (fMRI). Hence, 36 Turkish-Persian bilinguals (21 females and 15 males), who had acquired their second language at the age of seven after entering school, were selected in a purposive sampling method to perform an auditory grammaticality judgment task within an alternative language switching paradigm. After detecting the activity of the bilateral putamen at the whole-brain level, in FSL, percent signal change was extracted per participant as an intensity measure and analyzed statistically in SPSS. At the whole-brain level, the findings demonstrated that the bilateral putamen was involved in the comprehension of syntactic structures during the alternating presentation of L1 and L2 stimuli. In addition, regardless of the hemisphere involved, the significant grammaticality effect for L1 as well as the increased sensitivity for L1-violation stimuli compared to L2-violation stimuli may imply the standard language dominance effect also in the putamen. Keywords: Bilingualism, Sentence comprehension, Putamen, L1, fMRI Introduction Subcortical structures are considered a key component in language processing in bilinguals. Basal ganglia are a group of subcortical structures found deep within the White Matter of the brain and have extensive connections with the cerebral cortex, especially Broca's area and speech motor cortex. These nuclei include Putamen, Caudate, Pallidum, substantia nigra and subthalamic. Nowadays, the involvement of Putamen in production processes is evidenced, nevertheless, very little is known about the contribution of this region in understanding syntax in bilinguals. To our knowledge, no studies have examined the role of Putamen in syntactic processing in bilinguals. Here, we aimed to explore it within an alternative language switching paradigm. To address this gap, the current reanalysis focuses on the following research question. How is the performance of bilateral Putamen during L1-L2 syntactic processing? To answer this research question guiding this study, a bilingual task with alternating language switching paradigm were developed. In this task, brain imaging was performed using event-related fMRI while the participants listened to a total of 128 sentences in two Turkish and Persian languages. Materials and methods To allow for reliable ROI-based analysis, 36 right-handed and balanced Turkish-Persian bilingual students were recruited to participate in this study. All participants were native speakers of Turkish and learned Persian at school from the age of seven. Participants' language proficiency levels were assessed by the Bilingual Dominance Scale (BDS) and no significant difference was observed between Turkish and Persian (i.e., between L1 and L2) in language dominance. During a bilingual grammaticality judgement task, participants heard 128 test sentences (64 in L1 and 64 in L2, with 50% violation per language) and made their judgment by pressing a button. Stimuli were presented using the Psychtoolbox in MATLAB via headphones. Stimuli were randomized for each condition, but alternated in a fixed sequence for language. MRI data were collected in NBML, Tehran, Iran, using a Siemens Prisma 3T scanner with a 20-channel head coil. For each participant, a high-resolution T1-weighted anatomical scan was acquired (TR = 1800msec, TE = 3053 msec, flip angle: 7°, 192 axial slices, slice thickness = 1 mm, field of view (FOV) = 256 mm2, 256 × 256 acquisition matrix, voxel size: 1×1×1 mm). After the anatomical scan, participants underwent a 21.5-min fMRI scan that used a whole brain echo planar imaging (EPI) sequence (TE: 30 ms, TR: 3000 ms, flip angle: 90°, slice thickness: 3 mm, voxel size: 3×3×3 mm, matrix size: 64×64, FOV: 192 mm2, 430 volumes and 45 axial slices per volume). Processing of the fMRI data was carried out using FEAT in FSL. Preprocessing steps included motion correction, slice-timing correction, non-brain removal using BET, spatial smoothing (6 mm FWHM), normalization, temporal filtering (with sigma = 50.0 s), and exploratory ICA-based data analysis. Statistical analyses of fMRI data were conducted using general linear modeling (GLM), as implemented in FSL. Z statistic images were thresholded using clusters determined by Z > 2.6 and a (corrected) cluster significance threshold of P < 0.05. After detecting the Cerebellum activation in the whole-brain analysis, percent signal changes were extracted as an intensity measure in this brain region. All statistical analyses were conducted in IBM SPSS Statistics 26. Discussion of results and conclusions The present reanalysis investigate the contribution of Putamen in Turkish-Persian participants during processing syntax. Our research question concerns whether there are differences in syntactic processing between L1 and L2 in bilateral Putamen in non-native participants. At the whole-brain level, the findings indicated that the bilateral Putamen is involved in modulating the syntactic aspects of language, supporting the previous pathological studies on Putamen as well as its association with cortical areas in the realm of bilingualism. Another crucial point is regarding the significant effect of grammaticality in L1 and significant differences between L1-ungrammatical and L2-ungrammatical sentences, irrespective of the involved hemisphere. This is in line with the behavioral performance of present sample in which bilinguals had longer reaction time and more errors for L1 which was leading to more brain activations. This could be arguably because of the standard language dominance effect placed on L1, as mentioned by Declerck & Koch (2023), demonstrating that the present population may have relied more on their L1 than L2. Accordingly, using Chinese-English bilingual speakers, Wang and his colleagues (2009) found that sustained and transient language control induced differential activation patterns, and that sustained and transient activities in the human brain modulate the behavioral costs during switching-related language control. Thus, it is reasonable to say that in mixed-language blocks, balanced bilinguals performed better in L1 than in L2. In sum, based on current sample and task, we propose that bilinguals who had learnt L2 at the age of seven when entering school have employed the bilateral Putamen during processing syntax with standard language dominance effect (i.e., better performance in L1 than in L2).

Abstract Brain structural changes in Parkinson’s disease (PD) are progressive throughout the disease course. Changes in surface morphology with disease progression remain unclear. This study aimed to assess the volumetric and shape changes of the subcortical nuclei during disease progression and explore their association with clinical symptoms. Thirty-four patients and 32 healthy controls were enrolled. The global volume and shape of the subcortical nuclei were compared between patients and controls at baseline. The volume and shape changes of the subcortical nuclei were also explored between baseline and 2 years of follow-up. Association analysis was performed between the volume of subcortical structures and clinical symptoms. In patients with PD, there were significantly atrophied areas in the left pallidum and left putamen, while in healthy controls, the right putamen was dilated compared to baseline. The local morphology of the left pallidum was correlated with Mini Mental State Examination scores. The left putamen shape variation was negatively correlated with changes in Unified Parkinson’s Disease Rating Scale PART III scores. Local morphological atrophy of the putamen and pallidum is an important pathophysiological change in the development of PD, and is associated with motor symptoms and cognitive status in patients with PD.

Background: The neurobiological basis of delusional disorder is less explored through neuroimaging techniques than in other psychotic disorders. This study aims to provide information about the neural origins of delusional disorder (DD) by examining the neuroanatomical features of some basal nuclei with magnetic resonance imaging (MRI) texture analysis. Materials and Methods: Twenty DD patients and 20 healthy individuals were included in the study. Globus pallidus, putamen, and caudate nuclei were selected individually with a region of interest (ROI) on the axial MRI images. The entire texture analysis algorithm applied to all selected ROIs was done with an in-house software. Nuclei on both sides were taken as separate samples. Results: There were no significant differences between groups in terms of age and gender. The average "mean, median and maximum" values of all three nuclei were decreased in DD patients. The small putamen area and the differences detected in different tissue parameters for all three nuclei in delusional disorder patients indicate that they differ in delusional disorder from normal controls (p < 0.05). Conclusion: The differences detected in the texture parameters for all three nuclei indicate that there is something different in the DD from in the normal controls. Neuroimaging studies with larger samples and different techniques in the future may shed light on the etiology of delusional disorder. [ABSTRACT FROM AUTHOR]

Movement and muscle control are crucial for the survival of all free-living organisms. This study aimed to explore differential patterns of cortical and subcortical activation across different stages of muscle control using functional magnetic resonance imaging (fMRI). An event-related design was employed. In each trial, participants (n = 10) were instructed to gently press a button with their right index finger, hold it naturally for several seconds, and then relax the finger. Neural activation in these temporally separated stages was analyzed using a General Linear Model. Our findings revealed that a widely distributed cortical network, including the supplementary motor area and insula, was implicated not only in the pressing stage, but also in the relaxation stage, while only parts of the network were involved in the steady holding stage. Moreover, supporting the direct/indirect pathway model of the subcortical basal ganglia, their substructures played distinct roles in different stages of muscle control. The caudate nucleus exhibited greater involvement in muscle contraction, whereas the putamen demonstrated a stronger association with muscle relaxation; both structures were implicated in the pressing stage. Furthermore, the subthalamic nucleus was exclusively engaged during the muscle relaxation stage. We conclude that even the control of simple muscle movements involves intricate automatic higher sensory–motor integration at a neural level, particularly when coordinating relative muscle movements, including both muscle contraction and muscle relaxation; the cortical and subcortical regions assume distinct yet coordinated roles across different stages of muscle control. [ABSTRACT FROM AUTHOR]

The cognitive impairment will gradually appear over time in Parkinson's patients, which is closely related to the basal ganglia-cortex network. This network contains two parallel circuits mediated by putamen and caudate nucleus, respectively. Based on the biophysical mean-field model, we construct a dynamic computational model of the parallel circuit in the basal ganglia-cortex network associated with Parkinson's disease dementia. The simulated results show that the decrease of power ratio in the prefrontal cortex is mainly caused by dopamine depletion in the caudate nucleus and is less related to that in the putamen, which indicates Parkinson's disease dementia may be caused by a lesion of the caudate nucleus rather than putamen. Furthermore, the underlying dynamic mechanism behind the decrease of power ratio is investigated by bifurcation analysis, which demonstrates that the decrease of power ratio is due to the change of brain discharge pattern from the limit cycle mode to the point attractor mode. More importantly, the spatiotemporal course of dopamine depletion in Parkinson's disease patients is well simulated, which states that with the loss of dopaminergic neurons projecting to the striatum, motor dysfunction of Parkinson's disease is first observed, whereas cognitive impairment occurs after a period of onset of motor dysfunction. These results are helpful to understand the pathogenesis of cognitive impairment and provide insights into the treatment of Parkinson's disease dementia. [ABSTRACT FROM AUTHOR]

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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. [ABSTRACT FROM AUTHOR]

Background: Studies on the brain structures of shift workers are limited; thus, this cross-sectional study aimed to compare the brain structures and the brain structural correlates of subjective sleepiness and insomnia symptoms between shift workers and non-shift workers. Methods: Shift workers (n = 63) and non-shift workers (n = 58) completed questionnaires assessing subjective sleepiness and insomnia symptoms. Cortical thickness, cortical surface area, and subcortical volumes were measured by magnetic resonance imaging. The brain morphometric measures were compared between the groups, and interaction analyses using the brain morphometric measures as the dependent variable were performed to test the interactions between the study group and measures of sleep disturbance (i.e., subjective sleepiness and insomnia symptoms). Results: No differences in cortical thickness, cortical surface area, or subcortical volumes were detected between shift workers and non-shift workers. A single cluster in the left motor cortex showed a significant interaction between the study group and subjective sleepiness in the cortical surface area. The correlation between the left motor cortex surface area and the subjective sleepiness level was negative in shift workers and positive in non-shift workers. Significant interaction between the study group and insomnia symptoms was present for the left/right putamen volumes. The correlation between the left/right putamen volumes and insomnia symptom levels was positive in shift workers and negative in non-shift workers. Conclusion: Left motor cortex surface area and bilateral putamen volumes were unique structural correlates of subjective sleepiness and insomnia symptoms in shift workers, respectively. [ABSTRACT FROM AUTHOR]

The putamen is a subcortical structure. However, neuroimaging studies have demonstrated the involvement of the left putamen in other language functions such as bilingual language processing. Some studies have also shown the role of the right putamen in higher-order language functions. The present reanalysis aims to investigate the role of the bilateral putamen during the L1-L2 sentence comprehension in bilinguals using functional magnetic resonance imaging (fMRI). Hence, 36 Turkish-Persian bilinguals (21 females and 15 males), who had acquired their second language at the age of seven after entering school, were selected in a purposive sampling method to perform an auditory grammaticality judgment task within an alternative language switching paradigm. After detecting the activity of the bilateral putamen at the whole-brain level, in FSL, percent signal change was extracted per participant as an intensity measure and analyzed statistically in SPSS. At the whole-brain level, the findings demonstrated that the bilateral putamen was involved in the comprehension of syntactic structures during the alternating presentation of L1 and L2 stimuli. In addition, regardless of the hemisphere involved, the significant grammaticality effect for L1 as well as the increased sensitivity for L1-violation stimuli compared to L2-violation stimuli may imply the standard language dominance effect also in the putamen. [ABSTRACT FROM AUTHOR]

Pacientes com doença de Parkinson frequentemente experimentam sinais motores e sintomas não motores ocasionados pela doença. A estimulação cerebral profunda do Núcleo Subtalâmico (NST) ou de suas bordas ventral ou dorsal é uma das opções de tratamento indicada para tratar sintomas refratários dessa doença. No entanto, ainda não se sabe qual a borda que, ao ser estimulada, gera mais efeitos benéficos a esses pacientes, sendo esse o objetivo dessa revisão sistemática. Para responder essa questão foram realizadas buscas eletrônicas e manuais em cinco bancos de dados e na literatura cinzenta para identificar estudos que abordassem essa temática. Foram executados a seleção dos estudos, extração de dados e análise do risco de viés dos estudos incluídos. No total, sete artigos foram selecionados para comporem o estudo. A maioria dos estudos apresentou baixo risco de viés, sendo que a principal limitação metodológica deles se relacionou com os critérios de inclusão da amostra. A estimulação da borda dorsal ou ventral do NST resultou na melhora dos sinais motores da doença de Parkinson, com alguns dos estudos inclusos com tendência para a escolha da estimulação da borda dorsal para melhores efeitos motores, enquanto a melhora dos sintomas não motores e do controle inibitório foi devido à estimulação da borda ventral. Os achados sugerem que a melhora dos sinais motores da doença de Parkinson pode ser ocasionada ao estimular a borda dorsal ou ventral do Núcleo subtalâmico, enquanto os sintomas não motores, como a ansiedade, melhoram com a estimulação da borda ventral.

IntroductionSuicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt.MethodsWe examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male).ResultsOnly the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer's disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression. [ABSTRACT FROM AUTHOR]

The sense of body ownership (i.e. the feeling that our body or its parts belong to us) plays a key role in bodily self-consciousness and is believed to stem from multisensory integration. Experimental paradigms such as the rubber hand illusion have been developed to allow the controlled manipulation of body ownership in laboratory settings, providing effective tools for investigating malleability in the sense of body ownership and the boundaries that distinguish self from other. Neuroimaging studies of body ownership converge on the involvement of several cortical regions, including the premotor cortex and posterior parietal cortex. However, relatively less attention has been paid to subcortical structures that may also contribute to body ownership perception, such as the cerebellum and putamen. Here, on the basis of neuroimaging and neuropsychological observations, we provide an overview of relevant subcortical regions and consider their potential role in generating and maintaining a sense of ownership over the body. We also suggest novel avenues for future research targeting the role of subcortical regions in making sense of the body as our own. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. An association has been described between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson's Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to unaffected individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA) clinically manifests with either predominant nigrostriatal or cerebellopontine degeneration. This corresponds to two different phenotypes, one with predominant Parkinson's symptoms (MSA‐P [multiple system atrophy‐parkinsonian subtype]) and one with predominant cerebellar deficits (MSA‐C [multiple system atrophy‐cerebellar subtype]). Both nigrostriatal and cerebellar degeneration can lead to impaired dexterity, which is a frequent cause of disability in MSA. Objective: The aim was to disentangle the contribution of nigrostriatal and cerebellar degeneration to impaired dexterity in both subtypes of MSA. Methods: We thus investigated nigrostriatal and cerebellopontine integrity using diffusion microstructure imaging in 47 patients with MSA‐P and 17 patients with MSA‐C compared to 31 healthy controls (HC). Dexterity was assessed using the 9‐Hole Peg Board (9HPB) performance. Results: Nigrostriatal degeneration, represented by the loss of cells and neurites, leading to a larger free‐fluid compartment, was present in MSA‐P and MSA‐C when compared to HCs. Whereas no intergroup differences were observed between the MSAs in the substantia nigra, MSA‐P showed more pronounced putaminal degeneration than MSA‐C. In contrast, a cerebellopontine axonal degeneration was observed in MSA‐P and MSA‐C, with stronger effects in MSA‐C. Interestingly, the degeneration of cerebellopontine fibers is associated with impaired dexterity in both subtypes, whereas no association was observed with nigrostriatal degeneration. Conclusion: Cerebellar dysfunction contributes to impaired dexterity not only in MSA‐C but also in MSA‐P and may be a promising biomarker for disease staging. In contrast, no significant association was observed with nigrostriatal dysfunction. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Multiple cortical (planum temporale, supramarginal gyrus, fusiform gyrus) and subcortical (caudate, putamen, and thalamus) regions have shown different functional lateralization patterns for skilled vs. dyslexic readers. The extent to which skilled and dyslexic adult readers show differential structural lateralization remains to be seen. Method: Participants included 72 adults (N = 41 skilled; N = 31 dyslexic) who underwent a high-resolution MRI brain scan. The grey matter volume of the cortical and subcortical structures was extracted. Results: While there were clear behavioral differences between the groups, there were no differences in any of the isolated structures (i.e., either total size or asymmetry index) and limited evidence for any brain–behavior relationships. We did find a significant cortical–cortical relationship (p = 0.006) and a subcortical–subcortical relationship (p = 0.008), but not cross-over relationships. Overall, this work provides unique information on neural structures as they relate to reading in skilled and dyslexic readers. [ABSTRACT FROM AUTHOR]

Inactivation of the Snca gene in young mice by chronic injections of tamoxifen (TAM), a selective estrogen receptor modifier, has been shown to decrease the level of alpha-synuclein, a key peptide in the pathogenesis of Parkinson's disease. In young mice, different time courses of the effect were observed in different brain areas, meaning associated disturbances in the intracerebral relations, namely in brain function after TAM-induced synucleinopathy. Methods: We analyzed electroencephalogram (EEG) coherence ("functional connectivity") between the cortex (MC), putamen (Pt), and dopamine-producing brain regions (ventral tegmental area, VTA, and substantia nigra, SN) in two groups of two-month-old male mice. We compared EEG coherences in the conditional knockout Sncaflox/flox mice with those in their genetic background (C57Bl6J) one, two, and three months after chronic (for five days) intraperitoneal injections of TAM or the vehicle (corn oil). The EEG coherences in the TAM-treated group were compared with those in the alpha-synuclein knockout mice. Results: A significant suppression of EEG coherence in the TAM-treated mice versus the vehicle group was observed in all inter-structural relations, with the exception of MC-VTA at one and three months and VTA-SN at two months after the injections. Suppressive changes in EEG coherence were observed in the alpha-synuclein knockout mice as well; the changes were similar to those in TAM-treated mice three months after treatment. Conclusion: our data demonstrate a combined time-dependent suppressive effect induced by TAM on intracerebral EEG coherence. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) techniques, such as quantitative susceptibility mapping (QSM) and susceptibility-weighted imaging (SWI), can detect iron deposition in the brain. Iron accumulation in the putamen (PUT) can contribute to the pathogenesis of Parkinson's disease (PD) and atypical Parkinsonian disorders. This systematic review aimed to synthesize evidence on iron deposition in the PUT assessed by MRI susceptibility techniques in PD and Parkinsonism syndromes. The PubMed and Scopus databases were searched for relevant studies. Thirty-four studies from January 2007 to October 2023 that used QSM, SWI, or other MRI susceptibility methods to measure putaminal iron in PD, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and healthy controls (HCs) were included. Most studies have found increased putaminal iron levels in PD patients versus HCs based on higher quantitative susceptibility. Putaminal iron accumulation correlates with worse motor scores and cognitive decline in patients with PD. Evidence regarding differences in susceptibility between PD and atypical Parkinsonism is emerging, with several studies showing greater putaminal iron deposition in PSP and MSA than in PD patients. Alterations in putaminal iron levels help to distinguish these disorders from PD. Increased putaminal iron levels appear to be associated with increased disease severity and progression. Thus, magnetic susceptibility MRI techniques can detect abnormal iron accumulation in the PUT of patients with Parkinsonism. Moreover, quantifying putaminal susceptibility may serve as an MRI biomarker to monitor motor and cognitive changes in PD and aid in the differential diagnosis of Parkinsonian disorders.

Objectives: To investigate the association between neuropsychiatric symptoms (NPS) and nutritional status, and explore their shared regulatory brain regions on the Alzheimer’s disease (AD) continuum. Design: A longitudinal, observational cohort study. Setting: Data were collected from the Chinese Imaging, Biomarkers, and Lifestyle study between June 1, 2021 and December 31, 2022. Participants: Overall, 432 patients on the AD continuum, including amnestic mild cognitive impairment and AD dementia, were assessed at baseline, and only 165 patients completed the (10.37 ± 6.08) months’ follow-up. Measurements: The Mini-Nutritional Assessment (MNA) and Neuropsychiatric Inventory (NPI) were used to evaluate nutritional status and NPS, respectively. The corrected cerebral blood flow (cCBF) measured by pseudo-continuous arterial spin labeling of the dietary nutrition-related brain regions was analyzed. The association between the NPS at baseline and subsequent change in nutritional status and the association between the changes in the severity of NPS and nutritional status were examined using generalized linear mixed models. Results: Increased cCBF in the left putamen was associated with malnutrition, general NPS, affective symptoms, and hyperactivity (P < 0.05). The presence of general NPS (β = −1.317, P = 0.003), affective symptoms (β = −1.887, P < 0.001), and appetite/eating disorders (β = −1.714, P < 0.001) at baseline were associated with a decline in the MNA scores during follow-up. The higher scores of general NPI (β = −0.048), affective symptoms (β = −0.181), and appetite/eating disorders (β = −0.416; all P < 0.001) were longitudinally associated with lower MNA scores after adjusting for confounding factors. Conclusions: We found that baseline NPS were predictors of a decline in nutritional status on the AD continuum. The worse the severity of affective symptoms and appetite/eating disorders, the poorer the nutritional status. Furthermore, abnormal perfusion of the putamen may regulate the association between malnutrition and NPS, which suggests their potentially common neural regulatory basis.

Brain iron dyshomeostasis disrupts various critical cellular functions, and age-related iron accumulation may contribute to deficient neurotransmission and cell death. While recent studies have linked excessive brain iron to cognitive function in the context of neurodegenerative disease, little is known regarding the role of brain iron accumulation in cognitive aging in healthy adults. Further, previous studies have focused primarily on deep gray matter regions, where the level of iron deposition is highest. However, recent evidence suggests that cortical iron may also contribute to cognitive deficit and neurodegenerative disease. Here, we used quantitative susceptibility mapping (QSM) to measure brain iron in 67 healthy participants 18-78 years of age. Speed-dependent (fluid) cognition was assessed from a battery of 12 psychometric and computer-based tests. From voxelwise QSM analyses, we found that QSM susceptibility values were negatively associated with fluid cognition in the right inferior temporal gyrus, bilateral putamen, posterior cingulate gyrus, motor, and premotor cortices. Mediation analysis indicated that susceptibility in the right inferior temporal gyrus was a significant mediator of the relation between age and fluid cognition, and similar effects were evident for the left inferior temporal gyrus at a lower statistical threshold. Additionally, age and right inferior temporal gyrus susceptibility interacted to predict fluid cognition, such that brain iron was negatively associated with a cognitive decline for adults over 45 years of age. These findings suggest that iron may have a mediating role in cognitive decline and may be an early biomarker of neurodegenerative disease.

Obsessions and compulsions are central components of obsessive-compulsive disorder (OCD) and obsessive-compulsive related disorders such as body dysmorphic disorder (BDD). Compulsive behaviours may result from an imbalance of habitual and goal-directed decision-making strategies. The relationship between these symptoms and the neural circuitry underlying habitual and goal-directed decision-making, and the arbitration between these strategies, remains unknown. This study examined resting state effective connectivity between nodes of these systems in two cohorts with obsessions and compulsions, each compared with their own corresponding healthy controls: OCD (nOCD = 43; nhealthy = 24) and BDD (nBDD = 21; nhealthy = 16). In individuals with OCD, the left ventrolateral prefrontal cortex, a node of the arbitration system, exhibited more inhibitory causal influence over the left posterolateral putamen, a node of the habitual system, compared with controls. Inhibitory causal influence in this connection showed a trend for a similar pattern in individuals with BDD compared with controls. Those with stronger negative connectivity had lower obsession and compulsion severity in both those with OCD and those with BDD. These relationships were not evident within the habitual or goal-directed circuits, nor were they associated with depressive or anxious symptomatology. These results suggest that abnormalities in the arbitration system may represent a shared neural phenotype across these two related disorders that is specific to obsessive-compulsive symptoms. In addition to nosological implications, these results identify potential targets for novel, circuit-specific treatments.

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega-analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case- and control-only sites led to the inadvertent learning of site-effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary-based feature selection leveraging leave-one-site-out cross-validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test-set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi-site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD.

BackgroundObsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The contribution of environmental risk factors to OCD development suggests that epigenetic mechanisms may contribute to its pathophysiology. DNA methylation changes and gene expression were evaluated in post-mortem brain tissues of the cortical (anterior cingulate gyrus and orbitofrontal cortex) and ventral striatum (nucleus accumbens, caudate nucleus and putamen) areas from eight OCD patients and eight matched controls.ResultsThere were no differentially methylated CpG (cytosine-phosphate-guanine) sites (DMSs) in any brain area, nevertheless gene modules generated from CpG sites and protein-protein-interaction (PPI) showed enriched gene modules for all brain areas between OCD cases and controls. All brain areas but nucleus accumbens presented a predominantly hypomethylation pattern for the differentially methylated regions (DMRs). Although there were common transcriptional factors that targeted these DMRs, their targeted differentially expressed genes were different among all brain areas. The protein-protein interaction network based on methylation and gene expression data reported that all brain areas were enriched for G-protein signaling pathway, immune response, apoptosis and synapse biological processes but each brain area also presented enrichment of specific signaling pathways. Finally, OCD patients and controls did not present significant DNA methylation age differences.ConclusionsDNA methylation changes in brain areas involved with OCD, especially those involved with genes related to synaptic plasticity and the immune system could mediate the action of genetic and environmental factors associated with OCD.

Abstract Background Freezing of gait (FOG) is one of the most debilitating symptoms in patients with idiopathic Parkinson’s disease (IPD). Visual cues can relieve FOG symptoms. However, there is no consensus on patient characteristics that can benefit from visual cues. Therefore, we examined the differences in IPD patient characteristics according to the effectiveness of visual cueing. Methods Through gait experiments, we investigated the number of FOG occurrences, average FOG period per episode, proportion of FOG duration in the total gait cycles, and FOG-free period gait spatiotemporal parameters in ten participants diagnosed with FOG due to IPD. Subsequently, the differences between their clinical characteristics and striatal dopamine active transporter availability from six subregions of the striatum were compared by dividing them into two groups based on the three reduction rates: occurrence numbers, mean durations per episode, and proportion of FOG duration in the total gait cycles improved by visual cueing using laser shoes. The relationships among these three reduction rates and other FOG-related parameters were also investigated using Spearman correlation analyses. Results According to the three FOG-related reduction rates, the group assignments were the same, which was also related to the baseline self-reported FOG severity score (New Freezing of Gait Questionnaire): the more severe the FOG, the poorer the response to the visual cueing. By visual cueing, the better response group demonstrated the characteristics of lower new FOG questionnaire total scores, higher dopamine active transporter availability of the anterior and posterior putamen, and shorter mean duration of FOG per episode in the absence of cueing. These results were replicated using Spearman correlation analyses. Conclusions For FOG symptoms following IPD, gait assistance by visual cueing may be more effective when the total NFOGQ score is lower and the DAT of putamen is higher. Through this study, we demonstrated clinical and striatal dopaminergic conditions to select patients who may be more likely to benefit from visual cueing with laser shoes, and these findings lead to the need for early diagnosis of FOG in patients with IPD. Trial registration ClinicalTrials.gov identifier: NCT05080413. Registered on September 14, 2021.

Background: In typical patients with multiple system atrophy with predominant parkinsonism (MSA-P) levodopa is ineffective. However, there are some of these patients who respond well to levodopa treatment. Levodopa efficacy in MSA-P patients is thought to be related to the degree of putaminal damage, but the pathological causation between the putaminal involvement and levodopa efficacy has not been established in detail. Objective: This study aimed to evaluate the neuropathological features of the nigrostriatal dopaminergic system in a “levodopa-responsive” MSA-P patient in comparison with “levodopa-unresponsive” conventional MSA-P patients. Materials and methods: Clinicopathological findings were assessed in a 53-year-old Japanese man with MSA who presented with asymmetric parkinsonism, levodopa response, and later wearing-off phenomenon. During autopsy, the nigrostriatal pathology of presynaptic and postsynaptic dopaminergic receptor density and α-synuclein status were investigated. The other two patients with MSA-P were examined using the same pathological protocol. Results: Four years after the onset, the patient died of sudden cardiopulmonary arrest. On autopsy, numerous α-synuclein-positive glial cytoplasmic inclusions in the basal ganglia, pons, and cerebellum were identified. The number of neurons in the putamen and immunoreactivity for dopamine receptors were well-preserved. In contrast, significant neuronal loss and decreased dopamine receptor immunoreactivity in the putamen were observed in the “levodopa-unresponsive” MSA-P control patients. These putaminal pathology results were consistent with the findings of premortem magnetic resonance imaging (MRI). All three patients similarly exhibited severe neuronal loss in the substantia nigra and decreased immunoreactivity for dopamine transporter. Conclusion: Levodopa responsiveness in patients with MSA-P may be corroborated by the normal putamen on MRI and the preserved postsynaptic nigrostriatal dopaminergic system on pathological examination. The results presented in this study may provide a rationale for continuation of levodopa treatment in patients diagnosed with MSA-P. [ABSTRACT FROM AUTHOR]

Introduction: Social anxiety disorder (SAD) is characterized by abnormal processing of performance-related social stimuli. Previous studies have shown altered emotional experiences and activations of different sub-regions of the striatum during processing of social stimuli in patients with SAD. However, whether and to what extent social comparisons affect behavioural and neural responses to feedback stimuli in patients with SAD is unknown. Materials and Methods: To address this issue, emotional ratings and functional magnetic resonance imaging (fMRI) responses were assessed while patients suffering from SAD and healthy controls (HC) were required to perform a choice task and received performance feedback (correct, incorrect, non-informative) that varied in relation to the performance of fictitious other participants (a few, half, or most of others had the same outcome). Results: Across all performance feedback conditions, fMRI analyses revealed reduced activations in bilateral putamen when feedback was assumed to be received by only a few compared to half of the other participants in patients with SAD. Nevertheless, analysis of rating data showed a similar modulation of valence and arousal ratings in patients with SAD and HC depending on social comparison-related feedback. Conclusions: This suggests altered neural processing of performance feedback depending on social comparisons in patients with SAD. [ABSTRACT FROM AUTHOR]