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Introduction: 123 I-FP-CIT ( 123 I-Ioflupane) SPECT shows strong accumulation in the striatum, but morphological standardization is challenging due to low accumulation outside the striatum, particularly in subjects with marked striatal decline. In this study, morphological standardization without MRI was achieved using the adaptive template registration (ATR) method to create a subject-specific optimized template with weighted images of normal-type and egg-shape-type templates. The accuracy of a quantitative method for calculating the ratio with nonspecific accumulation in the occipital lobe was evaluated by placing voxels-of-interest (VOI) on standardized images, particularly targeting the striatum., Methods: The average images of eight subjects, demonstrating normal-type and egg-shape-type tracer accumulation in 123 I-Ioflupane SPECT, were utilized as normal and disease templates, respectively. The study included 300 subjects that underwent both 123 I-Ioflupane SPECT and MRI for the diagnosis of suspected Parkinson's disease or for exclusion diagnosis. Morphological standardization of SPECT images using structural MRI (MRI-based method) was considered the standard of truth (SOT). Three morphological standardizations without MRI were conducted. The first involved conventional morphological standardization using a normal template (fixed template method), the second employed the ATR method, with a weighted template, and the third used the split-ATR method, processing the left and right striatum separately to address asymmetrical accumulation. VOIs were set on the striatum, caudate, putamen as regions of specific accumulation, and on the occipital lobe as a reference region for nonspecific accumulation., Results: Results showed significant and robust linearity in the striatal accumulation ratios for all templates when compared with the occipital lobe accumulation ratio when using the MRI-based method. Comparing intra-class correlations for different linearities, the ATR method and split-ATR method demonstrated higher linearity in the striatum, caudate, and putamen. The split-ATR method showed similar improvements, although more linearity than some of the ATR methods; the effectiveness of the Split-ATR method may vary by image quality, and further validation of its effectiveness in diverse asymmetric accumulation cases seemed warranted., Conclusion: The use of optimized templates, such as the ATR and split-ATR methods, improved reproducibility in fully automated processing and demonstrated superior linearity compared to that of MRI-based method, in the ratio to the occipital lobe. The ATR method, which enables morphological standardization when using SPECT images only, proved highly reproducible for clinical quantitative analysis of striatal accumulation, facilitating its clinical use., (© 2024. The Author(s).)

Ethnic differences exist among patients with Parkinson disease (PD). PD is more common in the White than the African American population. This study aimed to explore whether differences exist in [ 123 I]ioflupane binding, which reflects dopamine transporter binding, between African American and White individuals. Methods: Medical charts were reviewed for patients who underwent [ 123 I]ioflupane SPECT imaging as part of routine practice in a single academic medical center. All images were visually graded as showing normal or abnormal presynaptic dopaminergic function (normal or abnormal scan status). Quantitative [ 123 I]ioflupane uptake as measured by the specific binding ratios in the right and left striata and their subregions (caudate nucleus and anterior and posterior putamen) and by bilateral putamen-to-caudate ratios were compared between African American and White patients using multiple linear regression adjusted for age, sex, and abnormal scan status. Additional models included an ethnicity-by-abnormal-scan-status interaction term to determine whether abnormal scan status was modulated by ethnicity effect. Results: The percentage of patients with abnormal scan status was comparable between African American and White patients. Compared with White patients ( n = 173), African American patients ( n = 82) had statistically significantly higher uptake as measured by specific binding ratios in the right and left striata and some of their subregions (right and left caudate nuclei and right posterior putamen). Ethnicity-by-abnormal-scan-status interactions were not statistically supported for any models. Conclusion: We observed differences in [ 123 I]ioflupane binding between African American and White patients independent of presynaptic dopaminergic dysfunction status. Future studies are needed to examine whether and how ethnicity affects dopamine transporter binding activities and its clinical relevance., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Developmental language disorder (DLD) is a common neurodevelopmental disorder with adverse impacts that continue into adulthood. However, its neural bases remain unclear. Here we address this gap by systematically identifying and quantitatively synthesizing neuroanatomical studies of DLD using co-localization likelihood estimation, a recently developed neuroanatomical meta-analytic technique. Analyses of structural brain data (22 peer-reviewed papers, 577 participants) revealed highly consistent anomalies only in the basal ganglia (100% of participant groups in which this structure was examined, weighted by group sample sizes; 99.8% permutation-based likelihood the anomaly clustering was not due to chance). These anomalies were localized specifically to the anterior neostriatum (again 100% weighted proportion and 99.8% likelihood). As expected given the task dependence of activation, functional neuroimaging data (11 peer-reviewed papers, 414 participants) yielded less consistency, though anomalies again occurred primarily in the basal ganglia (79.0% and 95.1%). Multiple sensitivity analyses indicated that the patterns were robust. The meta-analyses elucidate the neuroanatomical signature of DLD, and implicate the basal ganglia in particular. The findings support the procedural circuit deficit hypothesis of DLD, have basic research and translational implications for the disorder, and advance our understanding of the neuroanatomy of language., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The externalizing spectrum is characterized by disinhibition, impulsivity, antisocial-aggressive behavior as well as substance (mis)use. Studies in forensic samples and mentally impaired children suggested that higher rates of externalization are linked to lower cortisol stress responses and altered affect-related neural activation. In this fMRI-study, we investigated whether externalizing behavior in healthy participants is likewise associated with altered cortisol responses and neural activity to stress. Following a quasi-experimental approach, we tested healthy participants (N = 61, 31 males) from the higher versus lower range of the non-clinical variation in externalization (31 participants with high externalization) as assessed by the subscales disinhibition and meanness of the Triarchic-Psychopathy-Measure. All participants were exposed to ScanSTRESS, a standardized psychosocial stress paradigm for scanner environments. In both groups, ScanSTRESS induced a significant rise in cortisol levels with the high externalization group showing significantly lower cortisol responses to stress than the low externalization group. This was mainly driven by males. Further, individual increases in cortisol predicted neural response differences between externalization groups, indicating more activation in the dorsal striatum in low externalization. This was primarily driven by females. In contrast, post-hoc analysis showed that hypothalamic-pituitary-adrenal axis hyporeactivity in males was associated with prefrontal and hippocampal activation. Our data substantiate that individuals from the general population high on externalization, show reduced cortisol stress responses. Furthermore, dorsal striatum activity as part of the mesolimbic system, known to be sensitive to environmental adversity, seems to play a role in externalization-specific cortisol stress responses. Beyond that, a modulating influence of gender was disclosed., (© 2021 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Background: Between unaffected mental health and diagnosable psychiatric disorders, there is a vast continuum of functioning. The hypothesized link between striatal dopamine signaling and psychosis has guided a prolific body of research. However, it has been understudied in the context of multiple interacting factors, subclinical phenotypes, and pre-postsynaptic dynamics., Method: This work investigated psychotic-like experiences and D2/3 dopamine postsynaptic receptor availability in the dorsal striatum, quantified by in vivo [11C]-raclopride positron emission tomography, in a sample of 24 healthy male individuals. Additional mediation and moderation effects with childhood trauma and key dopamine-regulating genes were examined., Results: An inverse relationship between nondisplaceable binding potential and subclinical symptoms was identified. D2/3 receptor availability in the left putamen fully mediated the association between traumatic childhood experiences and odd beliefs, that is, inclinations to see meaning in randomness and unfounded interpretations. Moreover, the effect of early adversity was moderated by a DRD2 functional variant (rs1076560). The results link environmental and neurobiological influences in the striatum to the origination of psychosis spectrum symptomology, consistent with the social defeat and diathesis-stress models., Conclusions: Adversity exposure may affect the dopamine system as in association with biases in probabilistic reasoning, attributional style, and salience processing. The inverse relationship between D2/3 availability and symptomology may be explained by endogenous dopamine occupying the receptor, postsynaptic compensatory mechanisms, and/or altered receptor sensitivity. This may also reflect a cognitively stabilizing mechanism in non-help-seeking individuals. Future research should comprehensively characterize molecular parameters of dopamine neurotransmission along the psychosis spectrum and according to subtype profiling., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D 2 receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D 2 receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [ 11 C]raclopride and [ 18 F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BP ND ) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP ND and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [ 11 C]raclopride BP ND in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP ND of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP ND in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [ 18 F]FE-PE2I BP ND and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D 2 receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To determine changes in clinical features and striatal dopamine reuptake transporter (DAT) density after shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH)., Methods: Participants with probable iNPH were assessed at baseline by means of clinical rating scales, brain MRI, and SPECT with [ 123 I]-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT). Levodopa responsiveness was also evaluated. Patients who did or did not undergo lumboperitoneal shunt were clinically followed up and repeated SPECT after 2 years., Results: We enrolled 115 patients with iNPH. Of 102 patients without significant levodopa response and no signs of atypical parkinsonism, 92 underwent FP-CIT SPECT (58 also at follow-up) and 59 underwent surgery. We identified a disequilibrium subtype (phenotype 1) and a locomotor subtype (phenotype 2) of higher-level gait disorder. Gait impairment correlated with caudate DAT density in both phenotypes, whereas parkinsonian signs correlated with putamen and caudate DAT binding in patients with phenotype 2, who showed more severe symptoms and lower striatal DAT density. Gait and caudate DAT binding improved in both phenotypes after surgery ( p < 0.01). Parkinsonism and putamen DAT density improved in shunted patients with phenotype 2 ( p < 0.001). Conversely, gait, parkinsonian signs, and striatal DAT binding worsened in patients who declined surgery ( p < 0.01)., Conclusions: This prospective interventional study highlights the pathophysiologic relevance of striatal dopaminergic dysfunction in the motor phenotypic expression of iNPH. Absence of levodopa responsiveness, shunt-responsive parkinsonism, and postsurgery improvement of striatal DAT density are findings that corroborate the notion of a reversible striatal dysfunction in a subset of patients with iNPH., (© 2021 American Academy of Neurology.)

Successful response selection relies on constantly updating stimulus-response associations. The Theory of Event Coding (TEC) proposes that perception and action are conjointly coded in event files, for which fronto-striatal networks seem to play an important role. However, the exact neurobiochemical mechanism behind event file coding has remained unknown. We investigated the functional relevance of the striatal and anterior cingulate (ACC) GABAergic system using magnetic resonance spectroscopy (MRS). Specifically, the striatal and ACC concentrations of GABA+ referenced against N-acetylaspartate (NAA) were assessed in 35 young healthy males, who subsequently performed a standard event file task. As predicted by the TEC, the participants' responses were modulated by pre-established stimulus response bindings in event files. GABA+/NAA concentrations in the striatum and ACC were not correlated with the overall event binding effect. However, higher GABA+/NAA concentrations in the ACC were correlated with stronger event file binding processes in the early phase of the task. This association disappeared by the end of the task. Taken together, our findings show that striatal GABA+ levels does not seem to modulate event file binding, while ACC GABA+ seem to improve event file binding, but only as long as the participants have not yet gathered sufficient task experience. To the best of our knowledge, this is the first study providing direct evidence for the role of striatal and ACC GABA+ in stimulus-response bindings and thus insights into the brain structure-specific neurobiological aspects of the TEC., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Previous histopathologic and animal studies have shown axonal impairment and loss of connectivity of the nigrostriatal pathway in Parkinson disease (PD). However, there are conflicting reports from in vivo human studies. 11 C-dihydrotetrabenazine ( 11 C-DTBZ) is a vesicular monoamine type 2 transporter PET ligand that allows assessment of nigrostriatal presynaptic dopaminergic terminal integrity. Correlational tractography based on diffusion MRI can incorporate ligand-specific information provided by 11 C-DTBZ PET into the fiber-tracking process. The purpose of this study was to assess the in vivo association between the integrity of the nigrostriatal tract (defined by correlational tractography) and the degree of striatal dopaminergic denervation based on 11 C-DTBZ PET. Methods: The study involved 30 subjects with mild to moderate PD (23 men and 7 women; mean age, 66 ± 6.2 y; disease duration, 6.4 ± 4.0 y; Hoehn and Yahr stage, 2.1 ± 0.6; Movement Disorder Society [MDS]-revised Unified Parkinson Disease Rating Scale [UPDRS] [I-III] total score, 43.4 ± 17.8) and 30 control subjects (18 men and 12 women; mean age, 62 ± 10.3 y). 11 C-DTBZ PET was performed using standard synthesis and acquisition protocols. Correlational tractography was performed to assess quantitative anisotropy (QA; a measure of tract integrity) of white matter fibers correlating with information derived from striatal 11 C-DTBZ data using the DSI Studio toolbox. Scans were realigned according to least and most clinically affected cerebral hemispheres. Results: Nigrostriatal tracts were identified in both hemispheres of PD patients. Higher mean QA values along the identified tracts were significantly associated with higher striatal 11 C-DTBZ distribution volume ratios (least affected: r = 0.57, P = 0.001; most affected: r = 0.44, P = 0.02). Lower mean QA values of the identified tract in the LA hemisphere associated with increased severity of bradykinesia sub-score derived from MDS-UPDRS part III ( r = -0.42; P = 0.02). Cross-validation revealed the generalizability of these results. Conclusion: These findings suggest that impaired integrity of dopaminergic nigrostriatal nerve terminals is associated with nigrostriatal axonal dysfunction in mild to moderate PD. Assessment of nigrostriatal tract integrity may be suitable as a biomarker of early- or even prodromal-stage PD., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor., Methods: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI)., Results: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions., Conclusion: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Freezing of gait (FOG) is a common symptom in Parkinson's Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid β deposition. However, there is a paucity of research on the concurrent impact of white matter damage., Objectives: To assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other., Methods: We used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid β were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid β on future FOG., Results: SN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid β levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid β levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels., Conclusions: Amyloid β might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Childhood maltreatment (CM) is regarded as an important risk factor for major depressive disorder (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear. To explore the neural basis of the effects of CM on MDD and the potential role of microRNA-9 (miR-9) in these processes, we recruited 40 unmedicated MDD patients and 34 healthy controls (HCs) to complete resting-state fMRI scans and peripheral blood miR-9 tests. The neural substrates of CM, miR-9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) networks were investigated in MDD patients. Two-step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR-9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs. MDD patients showed higher miR-9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR-9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal-striatum pathway and limbic system. The connection of amygdala to prefrontal-limbic circuits could mediate the effects of CM severity on the miR-9 levels, as well as the impacts of miR-9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR-9 levels, CM severity, and AFC strength in prefrontal-limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%). MiR-9 may play a crucial role in the process of CM experience-produced brain changes targeting prefrontal-limbic regions and that subsequently leads to depression. The present neuroimaging-epigenetic results provide new insight into our understanding of MDD pathophysiology., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest. All authors have made substantial intellectual contributions to this manuscript in one or more of the following areas: design or conceptualization of the study, analysis or interpretation of the data, drafting or revision of the manuscript. Ms. He recruited the subjects and conducted the statistical analysis, Ms. Bai was responsible for the detection of miR-9. All authors have given final approval of this manuscript., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms include the initial appearance of dystonia, followed by parkinsonian traits after 10-15 years. The basal ganglia, particularly the striatum, is an area of focus in XDP neuropathology research, as the striatum shows marked atrophy that correlates with disease progression. Thus, XDP shares features of Parkinson's disease symptomatology, in addition to the genetic predisposition and presence of striatal atrophy resembling Huntington's disease. However, further research is required to reveal the detailed pathology and indicators of disease in the XDP brain. First, there are limited neuropathological studies that have investigated neuronal changes and neuroinflammation in the XDP brain. However, multiple neuroimaging studies on XDP patients provide clues to other affected brain regions. Furthermore, molecular pathological studies have elucidated that the main genetic cause of XDP is in the TAF-1 gene, but how this mutation relates to XDP neuropathology still remains to be fully investigated. Hence, we aim to provide an extensive overview of the current literature describing neuropathological changes within the XDP brain, and discuss future research avenues, which will provide a better understanding of XDP neuropathogenesis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

When people are forced to be isolated from each other, do they crave social interactions? To address this question, we used functional magnetic resonance imaging to measure neural responses evoked by food and social cues after participants (n = 40) experienced 10 h of mandated fasting or total social isolation. After isolation, people felt lonely and craved social interaction. Midbrain regions showed selective activation to food cues after fasting and to social cues after isolation; these responses were correlated with self-reported craving. By contrast, striatal and cortical regions differentiated between craving food and craving social interaction. Across deprivation sessions, we found that deprivation narrows and focuses the brain's motivational responses to the deprived target. Our results support the intuitive idea that acute isolation causes social craving, similar to the way fasting causes hunger.

Introduction: To investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly., Methods: We recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18 F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups., Results: Individuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls., Conclusions: Our results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: To investigate the spatial patterns and the probable sequences of gray matter atrophy in spinocerebellar ataxia type 3 (SCA3)., Methods: A total of 47 patients with SCA3 and 49 age- and sex-matched healthy controls participated in the study. High-resolution T1-weighted MRI were examined in all participants. We used the causal network of structural covariance (CasCN) to identify the sequence of gray matter atrophy patterns. This was achieved by applying Granger causality analysis to a gray matter atrophy staging scheme performed by voxel-based morphometry from the network level., Results: Participants in the premanifest stage of the disease showed the presence of focal gray matter atrophy in the vermis. As the disease duration increased, there was progressive gray matter atrophy in the cerebellar, neostriatum, frontal lobe, and parietal lobe. The patients with SCA3 also showed proximal and distal cortical atrophy sequences exerting from the vermis to the regions mainly located in the cerebellum-neostriatum-cortical network., Conclusion: Our results, although preliminary in nature, indicate that the gray matter atrophy in SCA3 lies and extends to involve more regions according to distinct anatomical patterns, mainly in the cerebellum-neostriatum-cortical network. These findings advance our understanding on the natural history of structural damage in SCA3, while confirming known clinical features. This could provide unique insight into the ordered sequential process of regional brain atrophy that targets a particular network., (© 2020 American Academy of Neurology.)

Internal and external segments of globus pallidus (GP) exert different functions in basal ganglia circuitry, despite their main connectional systems share the same topographical organization, delineating limbic, associative, and sensorimotor territories. The identification of internal GP sensorimotor territory has therapeutic implications in functional neurosurgery settings. This study is aimed at assessing the spatial coherence of striatopallidal, subthalamopallidal, and pallidothalamic pathways by using tractography-derived connectivity-based parcellation (CBP) on high quality diffusion MRI data of 100 unrelated healthy subjects from the Human Connectome Project. A two-stage hypothesis-driven CBP approach has been carried out on the internal and external GP. Dice coefficient between functionally homologous pairs of pallidal maps has been computed. In addition, reproducibility of parcellation according to different pathways of interest has been investigated, as well as spatial relations between connectivity maps and existing optimal stimulation points for dystonic patients. The spatial organization of connectivity clusters revealed anterior limbic, intermediate associative and posterior sensorimotor maps within both internal and external GP. Dice coefficients showed high degree of coherence between functionally similar maps derived from the different bundles of interest. Sensorimotor maps derived from the subthalamopallidal pathway resulted to be the nearest to known optimal pallidal stimulation sites for dystonic patients. Our findings suggest that functionally homologous afferent and efferent connections may share similar spatial territory within the GP and that subcortical pallidal connectional systems may have distinct implications in the treatment of movement disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To test the hypothesis that REM sleep behavior disorder (RBD) in early Parkinson's disease (PD) predicts rapid progression of dopaminergic denervation., Methods: 123I-FP-CIT single photon emission computed tomography (SPECT) scans were performed sequentially at baseline, 1 year, 2 years, and 4 years in 416 de novo patients with PD. RBD screening questionnaire scores >5 at baseline placed the participant in the likely-RBD group. Temporal changes in the specific binding ratio (SBR; caudate, putamen. sum of both, striatum) were compared between the likely-RBD and the non-likely-RBD groups for more or less affected striatum with a repeated measure ANOVA., Results: Likely-RBD was reported in 37.7% of the drug-naïve PD patients at baseline. The likely-RBD and non-likely-RBD groups did not have significant differences in the baseline clinical features including gender, age, disease duration, UPDRS motor score, and striatal SBR. Striatal SBR decreased significantly over four years in both groups (P < .001). In the analysis of a more affected striatum, striatal SBR decreased significantly faster in the likely-RBD group than in the non-likely-RBD group (P < .05 for all), whereas it was not statistically significant for the less affected striatum. The mean striatal SBR value (mean value of both striata), especially the caudate SBR, indicated greater acceleration of denervation in the likely-RBD group than in the non-likely-RBD group over time (P < .05)., Conclusion: Likely-RBD in PD predicts accelerating dopaminergic denervation, thereby implicating it as a marker for a poor prognosis or distinctive subtype in PD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's Disease (PD) is a common neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons and whose cause remains unclear. Brain-Derived Neurotrophic factor (BDNF) is a protein involved in dopaminergic cells survival. Previous studies have shown decreased serum BDNF levels in PD patients., Aim and Objectives: The aim of the study was to evaluate serum BDNF levels in a group of recently diagnosed non-medicated PD patients and its relationship with the nigrostriatal system degeneration using I-123-FP-CIT., Methods: 30 recently diagnosed, unmedicated PD patients were included in this study. Serum BDNF levels were measured twice using a sandwich enzyme linked immunoabsorbent assay and compared with levels of 27 unrelated Caucasian healthy adults. A I-123-FP-CIT SPECT was performed in all PD Patients in order to assess the association between serum BDNF levels and I-123-FP CIT uptake in several brain areas using a volumetric semi-automatic method., Results: PD patients showed lower serum BDNF levels (Median = 49.61, IQ range: 43.55 to 61.82) than the controls (Median = 68.82, IQ range: 51.87 to 88.14) (U = 211.00, z = -3.10, p = 0.002). BDNF levels in PD patients correlated with both caudate (Spearman r = 0.58, p = 0.001 for ispilateral and r 0.55, p = 0.002 for contralateral) and putamen (Spearman r = 0.68, p < 0.001 for ipsilateral and r = 0.80, p < 0.001 for contralateral) I-123-FP-CIT uptake ratios., Conclusions: Serum BDNF levels were lower in recently diagnosed, untreated PD patients compared to controls. These lower levels were significantly correlated with the I-123-FP-CIT uptake ratios., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Recent findings suggest that individuals with Huntington's disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear., Objectives: To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments., Methods: Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment., Results: Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test-retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls., Conclusions: Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To elucidate the timeframe and spatial patterns of cortical reorganization after different stroke-induced basal ganglia lesions, we measured cortical thickness at 5 time points over a 6-month period. We hypothesized that cortical reorganization would occur very early and that, along with motor recovery, it would vary based on the stroke lesion site., Methods: Thirty-three patients with unilateral basal ganglia stroke and 23 healthy control participants underwent MRI scanning and behavioral testing. To further decrease heterogeneity, we split patients into 2 groups according to whether or not the lesions mainly affect the striatal motor network as defined by resting-state functional connectivity. A priori measures included cortical thickness and motor outcome, as assessed with the Fugl-Meyer scale., Results: Within 14 days poststroke, cortical thickness already increased in widespread brain areas ( p = 0.001), mostly in the frontal and temporal cortices rather than in the motor cortex. Critically, the 2 groups differed in the severity of motor symptoms ( p = 0.03) as well as in the cerebral reorganization they exhibited over a period of 6 months (Dice overlap index = 0.16). Specifically, the frontal and temporal regions demonstrating cortical thickening showed minimal overlap between these 2 groups, indicating different patterns of reorganization., Conclusions: Our findings underline the importance of assessing patients early and of considering individual differences, as patterns of cortical reorganization differ substantially depending on the precise location of damage and occur very soon after stroke. A better understanding of the macrostructural brain changes following stroke and their relationship with recovery may inform individualized treatment strategies., (© 2020 American Academy of Neurology.)

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Research in primates and rodents ascribes the striatum a critical role in integrating elementary movements into unitary action sequences through reinforcement-based learning. Yet it remains to be shown whether the human striatum represents action sequence-specific information. Young right-handed volunteers underwent functional magnetic resonance imaging while they performed four discrete finger sequences with their right hand, consisting of five button presses. Specific finger sequences could be discriminated based on the distributed activity patterns in left and right striatum, but not by average differences in single-voxel activity. Multiple bilateral clusters in putamen and caudate nucleus belonging to motor, associative, parietal and limbic territories contributed to classification sensitivity. The results show that individual finger movement sequences are widely represented in human striatum, supporting functional integration rather than segregation. The findings are compatible with the idea that the basal ganglia simultaneously integrate motor, associative and limbic aspects in the control of complex overlearned behaviour.

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain., (© 2019 Society for the Study of Addiction.)

Identification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant biomarkers by combining biological specificity provided by 1 H-MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)-the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD-were used. Animals were scanned at 11.7 T using a protocol combining 1 H-MRS and gluCEST imaging. We measured a significant decrease in levels of N-acetyl-aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that 1 H-MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarkers., (© 2020 John Wiley & Sons, Ltd.)

Objective: Positron emission tomography (PET) is a non-invasive technique measuring quantification of physiological and biochemical processes in the living organism. However, there are many considerations including anesthesia and fasting to acquire small animal imaging. We aimed to evaluate the effects of anesthesia and fasting of rats in dopamine transporter (DAT) imaging acquisition., Methods: Male Sprague Dawley (SD) rats aged 7 weeks and weighing 180-260 g were used in this study. Rats were randomly divided by 4 groups. Group A was kept under anesthesia for 40 min and fasted over 12 h. Group B was only fasted over 12 h. Group C was only kept under anesthesia for 40 min. Group D was neither kept under anesthesia nor fasted over 12 h. PET scans were started at 40 min after 18 F-FP-CIT injection and obtained for 20 min. Volumes-of-interest for striatum and extrastriatal area were used for 18 F-FP-CIT PET analysis. Cerebellum was considered as a reference region. Specific binding ratio (SBR) was calculated as follows: [(uptake of target-uptake of cerebellum)]/(uptake of cerebellum)., Results: SBR without fasting and anesthesia (group D) was significantly lower than those of other groups (vs group A, p = 0.0004; vs group B, p = 0.0377; vs group C, p = 0.0134). However, SBRs of extrastriatal area (p = 0.5120) were not affected by fasting and anesthesia., Conclusions: In conclusion, the SBR of striatum was increased after anesthesia by isoflurane and fasting. When designing an experiment using DAT imaging, the effects of isoflurane and fasting should be considered.

Background: Multiple system atrophy (MSA) may develop levodopa-induced dyskinesia, which is dystonic and predominant in the orofacial region. We aimed to characterize the patterns of presynaptic dopaminergic degeneration in patients with MSA and dyskinesia using 123 I-N-x-fluoropropyl-2b-carbo-methoxy-3b-(4-iodophenyl) nortropan single-photon emission computed tomography ( 123 I-FP-CIT SPECT)., Methods: A single center cross-sectional retrospective study was conducted using consecutive chart review of patients with probable MSA who underwent 123 I-FP-CIT SPECT. The degeneration patterns were compared between the groups with and without dyskinesia via visual assessment of 123 I-FP-CIT SPECT images., Results: Twenty-five patients with probable MSA who had undergone dopamine transporter imaging were identified (age [mean ± standard error], 62.5 ± 1.7 years; disease duration, 48.8 ± 7.0 months). Four of them presented dyskinesia and 21 of patients did not. Twenty-five patients with MSA were visually classified into five grades: one Grade 1 (normal), two Grade 2 (eagle wing), three Grade 3 (mixed), nine Grade 4 (egg shape), and ten Grade 5 (burst striatum). All patients with MSA and dyskinesia were classified into Grade 5. Visual grading significantly correlated with disease duration and levodopa responsiveness., Conclusions: Severe presynaptic dopaminergic dysfunction in 123 I-FP-CIT SPECT images, higher doses of dopaminergic medication, and longer disease durations were associated with occurrence of levodopa-induced dyskinesia, even in MSA., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

The brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns that formally mediate the relationship between stimulus intensity and pain. We applied the model to a large-scale analysis of functional magnetic resonance imaging data (N = 284), focusing on brain mediators of the relationship between noxious stimulus intensity and trial-to-trial variation in pain reports. We identify mediators in both traditional nociceptive pathways and in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole-brain mediators are specific for pain versus aversive sounds and are organized into five functional networks. Brain mediators predicted pain ratings better than previous brain measures, including the neurologic pain signature (Wager et al. 2013). Our results provide a broader view of the networks underlying pain experience, as well as novel brain targets for interventions., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adequate control of impulsive urges to act is demanded in everyday life but is impaired in neuropsychiatric conditions such as stimulant use disorder. Despite intensive research it remains unclear whether failures in impulse control are caused by impaired suppression of behavior or by the over invigoration of behavior by stimuli associated with salient incentives such as drugs, food, and money. We investigated failures in impulse control using functional magnetic resonance imaging (fMRI) to map the neural correlates of premature (impulsive) responses during the anticipation phase of the Monetary Incentive Delay (MID) task in healthy controls (HC), stimulant-dependent individuals (SDIs), and their unaffected first-degree siblings (SIB). We combined task-based fMRI analyses with dynamic causal modeling to show that failures of impulse control were associated with interactions between cingulo-opercular and dorsal striatal networks regardless of group status and incentive type. We further report that group-specific incentive salience plays a critical role in modulating impulsivity in SDIs since drug-related incentives specifically increased premature responding and shifted task modulation away from the dorsal striatal network to the cingulo-opercular network. Our findings thus indicate that impulsive actions are elicited by salient personally-relevant incentive stimuli and those such slips of action recruit a distinct fronto-striatal network., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Choosing actions that result in advantageous outcomes is a fundamental function of nervous systems. All computational decision-making models contain a mechanism that controls the variability of (or confidence in) action selection, but its neural implementation is unclear-especially in humans. We investigated this mechanism using two influential decision-making frameworks: active inference (AI) and reinforcement learning (RL). In AI, the precision (inverse variance) of beliefs about policies controls action selection variability-similar to decision 'noise' parameters in RL-and is thought to be encoded by striatal dopamine signaling. We tested this hypothesis by administering a 'go/no-go' task to 75 healthy participants, and measuring striatal dopamine 2/3 receptor (D2/3R) availability in a subset (n = 25) using [11C]-(+)-PHNO positron emission tomography. In behavioral model comparison, RL performed best across the whole group but AI performed best in participants performing above chance levels. Limbic striatal D2/3R availability had linear relationships with AI policy precision (P = 0.029) as well as with RL irreducible decision 'noise' (P = 0.020), and this relationship with D2/3R availability was confirmed with a 'decision stochasticity' factor that aggregated across both models (P = 0.0006). These findings are consistent with occupancy of inhibitory striatal D2/3Rs decreasing the variability of action selection in humans., (© The Author(s) 2020. Published by Oxford University Press.)

Pavlovian biases influence instrumental learning by coupling reward seeking with action invigoration and punishment avoidance with action suppression. Using a probabilistic go/no-go task designed to orthogonalize action (go/no-go) and valence (reward/punishment), recent studies have shown that the interaction between the two is dependent on the striatum and its key neuromodulator dopamine. Using this task, we sought to identify how structural and neuromodulatory age-related differences in the striatum may influence Pavlovian biases and instrumental learning in 25 young and 31 older adults. Computational modeling revealed a significant age-related reduction in reward and punishment sensitivity and marked (albeit not significant) reduction in learning rate and lapse rate (irreducible noise). Voxel-based morphometry analysis using 7 Tesla MRI images showed that individual differences in learning rate in older adults were related to the volume of the caudate nucleus. In contrast, dopamine synthesis capacity in the dorsal striatum, assessed using [18F]-DOPA positron emission tomography in 22 of these older adults, was not associated with learning performance and did not moderate the relationship between caudate volume and learning rate. This multiparametric approach suggests that age-related differences in striatal volume may influence learning proficiency in old age., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Corticostriatal circuits (CSC) have been implicated in the presentation of some restricted and repetitive behaviours (RRBs) in children with autism-spectrum disorder (ASD), and preliminary evidence suggests that disruptions in these pathways may be associated with differences in genetic and environmental influences on brain development. The objective of this investigation was to examine the impact of genetic and environmental factors on CSC regions in twins with and without ASD and to evaluate their relationship with the severity of RRBs., Methods: We obtained T1-weighted MRIs from same-sex monozygotic and dizygotic twin pairs, aged 6–15 years. Good-quality data were available from 48 ASD pairs (n = 96 twins; 30 pairs concordant for ASD, 15 monozygotic and 15 dizygotic; 18 pairs discordant for ASD, 4 monozygotic and 14 dizygotic) and 34 typically developing control pairs (n = 68 twins; 20 monozygotic and 14 dizygotic pairs). We generated structural measures of the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), caudate, putamen, pallidum and thalamus using FreeSurfer. Twin pair comparisons included intraclass correlation analyses and ACE modelling (a2 = additive genetics; c2 = common or shared environment; e2 = unique or nonshared environment). We also assessed correlations with RRB severity., Results: Structural variation in CSC regions was predominantly genetically mediated in typically developing twins (a2 = 0.56 to 0.87), except for ACC white matter volume (a2 = 0.42, 95% confidence interval [CI] 0.08 to 0.77). We also observed similar magnitudes of genetic influence in twins with ASD (a2 = 0.65 to 0.97), but the cortical thickness of the ACC (c2 = 0.44, 95% CI 0.22 to 0.66) and OFC (c2 = 0.60, 95% CI 0.25 to 0.95) was primarily associated with environmental factors in only twins with ASD. Twin pair differences in OFC grey matter volume were also correlated with RRB severity and were predominantly environmentally mediated., Limitations: We obtained MRIs on 2 scanners, and analytical approaches could not identify specific genetic and environmental factors., Conclusion: Genetic factors primarily contribute to structural variation in subcortical CSC regions, regardless of ASD, but environmental factors may exert a greater influence on the development of grey matter thickness in the OFC and ACC in children with ASD. The increased vulnerability of OFC grey matter to environmental influences may also mediate some heterogeneity in RRB severity in children with ASD., Competing Interests: None declared., (© 2020 Joule Inc. or its licensors)

Chronic use of methamphetamine impairs frontostriatal structure and function, which may result in increased incentive-motivational responses to drug cues and decreased regulation of drug-seeking behavior. However, less is known regarding how the drug affects these circuits after acute administration. The current study examined the effects of a single dose of methamphetamine on resting state frontostriatal functional connectivity in healthy volunteers. Participants (n = 22, 12 female) completed two sessions in which they received methamphetamine (20 mg) and placebo before a resting state scan during functional magnetic resonance imaging. Participants also provided self-report measures of euphoria and stimulation at regular intervals. We conducted seed-based voxelwise functional connectivity analyses using three bilateral striatal seed regions: nucleus accumbens (NAcc), caudate, and putamen and compared connectivity following methamphetamine versus placebo administration. Additionally, we conducted correlational analyses to assess if drug-induced changes in functional connectivity were related to changes in subjective response. Methamphetamine increased NAcc functional connectivity with medial frontal regions (ie, orbitofrontal cortex, medial frontal gyrus, and superior frontal gyrus) and decreased NAcc functional connectivity with subgenual anterior cingulate cortex (ACC). Methamphetamine also increased functional connectivity between putamen and left inferior frontal gyrus (IFG), and individuals who displayed greater drug-induced increase in connectivity reported less euphoria and stimulation. These findings provide important information regarding the effects of methamphetamine on brain function in nonaddicted individuals. Further studies will reveal whether such effects contribute to the abuse potential of the drug and whether they are related to the frontostriatal impairments observed after chronic methamphetamine use., (© 2019 Society for the Study of Addiction.)

Background: Bipolar disorder I (BD-I) is defined by episodes of mania, depression and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood., Methods: We first assessed the severity of NS in 25 euthymic BD-I patients compared with 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral (VS) and dorsal striatal (DS) activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS., Results: In BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant VS and DS activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole-brain analyses revealed reduced extra-striatal activation in BD-I patients compared with HC and an association between reduced activation of the inferior frontal gyrus and apathy., Conclusion: This study found that in BD-I patients apathy is present to an extent comparable to SZ, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [ 18 F]-fluorodopa positron emission tomography studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxelwise analyses to identify group differences in striatal [ 18 F]-fluorodopa uptake (K i ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of K i and K i change found significant effects of Parkinson disease. However, at baseline and over time, striatal [ 18 F]-fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. ANN NEUROL 2020;87:652-657., (© 2020 American Neurological Association.)

Executive function (EF) is a set of cognitive capabilities considered essential for successful daily living, and is negatively affected by ageing and neurodegenerative conditions. Underpinning EF performance are functional nodes in the executive control network (ECN), while the structural connectivity underlying this network is not well understood. In this paper, we evaluated the structural white matter tracts that interconnect the ECN and investigated their relationship to the EF performance. Using high-angular resolution diffusion MRI data, we performed tractography analysis of structural connectivity in a cognitively normal cohort (n = 140), specifically targeting the connectivity between ECN nodes. Our data revealed the presence of a strongly-connected "structural core" of the ECN comprising three components: interhemispheric frontal connections, a fronto-parietal subnetwork and fronto-striatal connections between right dorsolateral prefrontal cortex and right caudate. These pathways were strongly correlated with EF performance (p = .003). Post-hoc analysis of subregions within the significant ECN connections showed that these effects were driven by a highly specific subset of interconnected cortical regions. The structural core subnetwork of the functional ECN may be an important feature crucial to a better future understanding of human cognition and behaviour., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Aims: Diabetes mellitus is a risk factor for Parkinson's disease. These diseases share similar pathogenic pathways, such as mitochondrial dysfunction, inflammation, and altered metabolism. Despite these similarities, the pathogenic relationship between these two diseases is unclear. [ 18 F]FP-(+)-DTBZ is a promising radiotracer targeting VMAT2, which has been used to measure β-cell mass and to diagnose Parkinson's disease. The aim of this study was to examine the effect of type 1 diabetes on VMAT2 expression in the striatum using [ 18 F]FP-(+)-DTBZ., Materials and Methods: A longitudinal study of type 1 diabetic rats was established by intraperitoneally injecting male Wistar rats with streptozotocin. Rats injected with saline were used as the control group. Glucose level, body weight, and [ 18 F]FP-(+)-DTBZ uptake in the striatum and pancreas were evaluated at 0.5, 1, 4, 6 and 12 months after STZ or saline injection., Results: At one-half month post-STZ injection, the glucose levels in these rats increased and then returned to a normal level at 6 months. Along with increased glucose levels, body weight was also decreased significantly and returned slowly to a normal level. β-Cell mass and striatal [ 18 F]FP-(+)-DTBZ uptake were impaired significantly at 2 weeks post-STZ injection in type 1 diabetic rats and returned to a normal level at 6 and 4 months post-STZ injection., Conclusions: Due to increased glucose levels and decreased β-cell mass, decreased [ 18 F]FP-(+)-DTBZ uptake in the striatum was observed in type 1 diabetic rats. Decreased BCM and increased glucose levels were correlated with VMAT2 expression in the striatum which indicated DM is a risk factor for PD., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2020. Published by Elsevier Inc.)

Background: Non-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored., Methods: We evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models., Results: Multiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: β AVG  = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (β AVG =0.055, SE = 0.022; p = 0.01) and visuospatial (β AVG =0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (β AVG = -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding., Conclusions: Multiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD., Competing Interests: Declaration of competing interest Dr. Tröster has received royalties from Oxford University Press, grant funding from Barrow Neurological Foundation and served on scientific advisory boards of Medtronic and Takeda. None reported for other authors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Reward deficits and associated striatal circuitry have been implicated in the onset and progression of major depressive disorder (MDD). This work was conducted to clarify how the striatal circuitry is involved in the established risk, acute episodes, and remission of MDD., Methods: Striatal subregion resting-state functional connectivity (RSFC) was calculated for 29 currently depressed and 28 remitted patients diagnosed with MDD per the Structured Clinical Interview for DSM-IV, 19 first-degree relatives of these patients, and 57 healthy controls (HCs) based on resting-state fMRI data collected between May 2007 and September 2014., Results: Compared with HCs, the other 3 groups showed increased RSFC between left dorsal caudate (DC) and right insula but reduced RSFC between right putamen and left cerebellum. The currently depressed group showed increased FC between right DC and superior frontal gyrus but reduced RSFC between putamen and right anterior cingulate as well as other striatal nuclei compared with the other 3 groups. Although no results were found in ventral striatum (VS) seeds during analysis of covariance, the comparison between currently depressed and remitted patients showed increased RSFC between right superior VS and left inferior frontal gyrus in currently depressed patients at a more linear threshold. Also, both superior and inferior VS showed increased RSFC with superior and inferior frontal gyri but reduced RSFC with cerebellum in relatives compared with HCs. Higher DC-superior frontal gyrus RSFC (r = 0.438, P = .022) was correlated with more severe depression, but lower within-putamen FC was correlated with more severe depression (r = -0.446, P = .02) and retardation (r = -0.465, P = .011)., Conclusions: The findings suggest that reduced VS-frontal, within-putamen, and putamen-cingulate RSFC in currently depressed patients is dependent on current depressive episode and has implications for symptomatic monitoring, while increased caudate-insular and reduced VS-cerebellar RSFC in remitted patients and first-degree relatives might be related to the disease itself and have potential for predicting risk for and recurrence of MDD., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Mental imagery related to the recent death of a loved one is associated with intense sadness and distress. Social relations, such as with one's significant other, can regulate negative emotions and provide comfort, but the neural correlates of social comfort are largely unknown. In this functional magnetic resonance imaging study, we examined brain responses to sad mental imagery and how these are modulated by holding hands with one's romantic partner. We found that mental imagery of a recently deceased loved one was associated with increased reactivity in the dorsal striatum, medial prefrontal cortex, anterior and posterior cingulate cortex, thalamus and cerebellum. Holding hands with one's partner as compared to being alone or holding hands with a stranger provided subjective comfort and reduced neural reactivity in the dorsal striatum without affecting the vividness of the imagery. Our findings indicate an important role for the dorsal striatum in sad mental imagery and social comfort and suggest that tactile social support by one's romantic partner regulates subjective distress through other processes than mere distraction from the mental imagery., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

From a traditional variable-centered perspective, the personality traits specifically linked to depressive symptoms are neuroticism, extraversion, and conscientiousness (NEC). Few studies have considered the interactive effects of personality traits within individuals from the taxonomic perspective. We explored novel NEC personality subtypes in general and subthreshold depressive subjects by using graph-based classification algorithms and multiple external validators. Personality and depressive symptoms were assessed in 1055 healthy subjects (150 with subthreshold depression) using the NEO-PI-R and BDI at baseline. NEC personality data were used to identify subtypes in healthy and subthreshold depressive samples, and external validators, including current and longitudinal depressive symptoms and seven subcortical gray matter volumes, were examined. Four novel NEC personality types in the general sample showed superior current and longitudinal behavioral validation of depressive symptoms as well as some discrimination in biological indicators (putamen, nucleus accumbens, and amygdala). Four profiles defined in subthreshold depression selectively exhibited meaningful differences in longitudinal depressive symptoms. In both samples, some types adhere to the principles previously described NEC three-way interaction. The resulting typology, especially the four types in the general population, linked depressive symptoms provided a superior description of within-person organization of neuroticism, extraversion, and conscientiousness., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Attention deficit hyperactivity disorder (ADHD) has been associated with neural hyposensitivity to reward-predicting cues. Methylphenidate is widely used in the management of the disorder's symptoms, but its effects on reward sensitivity in ADHD are unknown. The current study used fMRI to measure striatal responses to reward-predicting cues in adults with ADHD on and off methylphenidate and a control group, during a classical conditioning task. Responses to cued reward were also explored. Larger differences in the ventral striatum activation to reward cues versus non-reward cues were observed when the ADHD participants were on methylphenidate compared to placebo. In response to cued-reward outcome, an exploratory analysis showed methylphenidate reduced the BOLD time-series correlation between the dorsal striatum and dorsal medial prefrontal cortex. Methylphenidate's therapeutic effects may be mediated by altering reward processing in individuals with ADHD., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abnormal interactions between the striatum and salience network (SN) are considered as etiological and treatment-sensitive marker in schizophrenia. However, whether alterations in the intrinsic dynamics as reflected by resting-state functional connectivity (RSFC) between the striatum and salience network may predict treatment response to the widely used antipsychotic treatment strategies (risperidone, monotherapy) has not been examined systematically. To this end, treatment-naive first-episode schizophrenia patients (n = 41) underwent task-free resting-state fMRI assessment before (baseline) and after 8 weeks of risperidone monotherapy (n = 38). Intrinsic connectivity between striatal sub-regions and core salience processing nodes were examined and compared to carefully matched healthy controls (HC) to determine disorder-specific and treatment-predictive neural markers. Findings demonstrate hypo-connectivity of both ventral and dorsal striatal-SN pathways in patients at baseline. Importantly, specifically the dorsal striatal pathway at baseline could predict negative symptoms improvement in patients; while ventral striatal pathways could predict positive symptoms improvement. Together, results indicate that distinct striatal-SN pathways represent specific treatment-success markers for the effects of risperidone, suggesting that alterations in dorsal versus ventral striatal network markers may represent brain-based markers for specific symptomatologic improvements following risperidone mono-therapy., Competing Interests: Declaration of competing interest All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2019. Published by Elsevier B.V.)

Cognitive control is supported by a dynamic interplay of transient (i.e., trial-related) brain activation across fronto-parietal networks and sustained (i.e., block-related) activation across fronto-striatal networks. Older adults show disturbances in this dynamic functional recruitment. There is evidence suggesting that cognitive-control training may enable older adults to redistribute their brain activation across cortical and subcortical networks, which in turn can limit behavioral impairments. However, previous studies have only focused on spatial rather than on temporal aspects of changes in brain activation. In the present study, we examined training-related functional plasticity in old age by applying a hybrid fMRI design that sensitively tracks the spatio-temporal interactions underlying brain-activation changes. Fifty healthy seniors were assigned to a task-shifting training or an active-control group and their pretest/posttest activation-change maps were compared against 25 untrained younger adults. After training, older adults showed the same performance as untrained young adults. Compared to the control group, task-shifting training promoted proactive (i.e., early, cue-related) changes in transient mechanisms supporting the maintenance and top-down biasing of task-set representations in a specific prefrontal circuitry; reactive (i.e., late, probe-related) changes in transient mechanisms supporting response-selection processes in dissociable fronto-parietal networks; overall reductions of sustained activation in striatal circuits. Results highlight the importance of spatio-temporal interactions in training-induced neural changes in age., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD., Objective: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD., Methods: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared between patients with and those without NSD as assessed by [123I]FP-CIT SPECT., Results: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123I]FP-CIT SPECT scan (p < 0.05). Statistical analyses revealed no significant differences comparing reaction times to visual stimuli or dispersion of reaction times between groups. Exploratory analysis in a subgroup of patients with available [18F]FDG PET revealed that longer reaction times were associated with decreased glucose metabolism in the prefrontal cortex (statistical parametric mapping, adjusted for age and sex; p < 0.005, cluster extent > 50 voxels)., Conclusion: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD.

Background and Purpose: Considerable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction., Methods: Seventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study-group-specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures., Results: Increased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self-initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato-cerebellar connectivity., Conclusions: Our findings indicate that, despite the dysfunction of SMA-striatal and SMA-cerebellar networks, cerebello-striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS., (© European Academy of Neurology 2019.)

The functional connectome reflects a network architecture enabling adaptive behavior that becomes vulnerable in advanced age. The cellular mechanisms that contribute to altered functional connectivity in old age, however, are not known. Here we used a multiscale imaging approach to link age-related changes in the functional connectome to altered expression of the activity-dependent immediate-early gene Arc as a function of training to multitask on a working memory (WM)/biconditional association task (BAT). Resting-state fMRI data were collected from young and aged rats longitudinally at three different timepoints during cognitive training. After imaging, rats performed the WM/BAT and were immediately sacrificed to examine expression levels of Arc during task performance. Aged behaviorally impaired, but not young, rats had a subnetwork of increased connectivity between the anterior cingulate cortex (ACC) and dorsal striatum (DS) that was correlated with the use of a suboptimal response-based strategy during cognitive testing. Moreover, while young rats had stable rich-club organization across three scanning sessions, the rich-club organization of old rats increased with cognitive training. In a control group of young and aged rats that were longitudinally scanned at similar time intervals, but without cognitive training, ACC-DS connectivity and rich-club organization did not change between scans in either age group. These findings suggest that aberrant large-scale functional connectivity in aged animals is associated with altered cellular activity patterns within individual brain regions., (Copyright © 2019 Colon-Perez et al.)

Background: Using dual time F-18 FP-CIT, we evaluated cortical perfusion, striatal binding and neuropsychological performance simultaneously in Parkinson disease (PD) with and without mild cognitive impairment (MCI), to investigate neural correlates between caudate and frontal cortex., Methods: According to the neuropsychological scores, subjects were classified into 26 healthy controls (HC), 38 PD-MCI (executive) (PE), 24 PD-MCI (non-executive) (PN) and 21 PD (motor) (PM). Scans were acquired at 10 minutes and 2 hours. Group differences of early perfusion and delayed binding were compared using SPM and volume of interest method. The relationships between neuropsychological variables and the striatal binding were investigated with correlation and regression analysis., Results: Compared with PM, PE showed decreased prefrontal perfusion and binding of both caudates (right: P=0.0010, left: P=0.014), but not of both putamens. Compared with PN, PE showed decreased binding of both caudates (right: P=0.001, left: P=0.005), but not in both putamens. Binding of both caudates correlated with the Stroop z-score, but not of both putamens. Executive score was a contributing factor to binding of the caudate, and not the putamen., Conclusions: PE showed decreased prefrontal perfusion and caudate binding, supporting neural correlates between the caudate and the prefrontal cortex. Dopaminergic binding of the caudate, but not of the putamen, was related to executive scores. Caudate hypofunction was specific to executive domain. This is the first study that elucidated the clinical use of dual time F-18 FP-CIT for integrative evaluation of cognitive and motor function in PD.

A 59-year-old man had developed within a few months walking disorders and rigidity of the left upper limb. I-FP-CIT SPECT/CT was performed in response to the suspicion of atypical parkinsonian syndrome. It showed an anomaly in presynaptic dopaminergic transmission on the right striatum and a voluminous expansive process on CT. MRI revealed an atypical meningioma. The patient had surgery for tumor removal. Later I-FP-CIT SPECT/CT showed normalization of presynaptic dopaminergic transmission on the right striatum.

Multiple-system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS) have signs and symptoms overlapping those of Parkinson disease (PD), complicating their clinical diagnosis. Although presynaptic dopaminergic brain imaging with PET and SPECT is clinically widely used for patients with suspected PD, the benefit of functional imaging in atypical parkinsonism syndromes remains unclear. We compared striatal presynaptic dopaminergic function in MSA parkinsonism variant (MSA-P), MSA cerebellar variant (MSA-C), PSP, CBS, and PD using combined quantitative data from all published studies. Methods: The PubMed database was searched from inception to August 2018 for the terms "dopamine" OR "dopaminergic" AND "PET" OR "SPECT" OR "SPET" and keywords related to PD, MSA, PSP, and CBS. In total, 1,711 publications were identified. PET or SPECT studies comparing patients with atypical parkinsonism to another diagnostic group (PD, MSA, PSP, or CBS) were included. Tracers for dopamine transporter (DAT), aromatic amino acid decarboxylase (AADC), or vesicular monoamine type 2 were investigated. Tracer binding data were extracted from the original articles. Heterogeneity of the data was examined using I 2 statistics, and a random-effects model was used to summarize data. Hedges g was used as an estimator of effect size in group comparisons. Results are reported according to PRISMA guidelines. Results: Thirty-five studies (29 DAT, 6 AADC, no vesicular monoamine type 2 studies) with 356 MSA-P patients, 204 PSP patients, 79 CBS patients, and 62 MSA-C patients were included in the metaanalysis. Caudate nucleus and putamen DAT function was clearly lower in PSP than in PD (caudate: 34.1% difference, g = -1.08, 95% confidence interval [CI] = -1.52 to -0.64; putamen: 18.2%, g = -0.86, 95% CI = -1.50 to -0.21) and MSA-P (striatum: 31.4%, g = -0.70, 95% CI = -1.21 to -0.19) and was clearly lower in MSA-P than in MSA-C (striatum: 46.0%, g = 1.46, 95% CI = 0.23 to 2.68). Although not significant because of limited data, aromatic l-AADC results paralleled the DAT findings. Conclusion: Striatal presynaptic DAT function is clearly lower in PSP patients than in PD and MSA-P patients and is clearly lower in MSA-P patients than in MSA-C patients., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)