Neurocomputational model of compulsivity: deviating from an uncertain goal-directed system.

Despite a theory that an imbalance in goal-directed versus habitual systems serve as building blocks of compulsions, research has yet to delineate how this occurs during arbitration between the two systems in obsessive-compulsive disorder. Inspired by a brain model in which the inferior frontal cortex selectively gates the putamen to guide goal-directed or habitual actions, this study aimed to examine whether disruptions in the arbitration process via the fronto-striatal circuit would underlie imbalanced decision-making and compulsions in patients. Thirty patients with obsessive-compulsive disorder [mean (standard deviation) age = 26.93 (6.23) years, 12 females (40%)] and 30 healthy controls [mean (standard deviation) age = 24.97 (4.72) years, 17 females (57%)] underwent functional MRI scans while performing the two-step Markov decision task, which was designed to dissociate goal-directed behaviour from habitual behaviour. We employed a neurocomputational model to account for an uncertainty-based arbitration process, in which a prefrontal arbitrator (i.e. inferior frontal gyrus) allocates behavioural control to a more reliable strategy by selectively gating the putamen. We analysed group differences in the neural estimates of uncertainty of each strategy. We also compared the psychophysiological interaction effects of system preference (goal-directed versus habitual) on fronto-striatal coupling between groups. We examined the correlation between compulsivity score and the neural activity and connectivity involved in the arbitration process. The computational model captured the subjects' preferences between the strategies. Compared with healthy controls, patients had a stronger preference for the habitual system (t = -2.88, P = 0.006), which was attributed to a more uncertain goal-directed system (t = 2.72, P = 0.009). Before the allocation of controls, patients exhibited hypoactivity in the inferior frontal gyrus compared with healthy controls when this region tracked the inverse of uncertainty (i.e. reliability) of goal-directed behaviour (P = 0.001, family-wise error rate corrected). When reorienting behaviours to reach specific goals, patients exhibited weaker right ipsilateral ventrolateral prefronto-putamen coupling than healthy controls (P = 0.001, family-wise error rate corrected). This hypoconnectivity was correlated with more severe compulsivity (r = -0.57, P = 0.002). Our findings suggest that the attenuated top-down control of the putamen by the prefrontal arbitrator underlies compulsivity in obsessive-compulsive disorder. Enhancing fronto-striatal connectivity may be a potential neurotherapeutic approach for compulsivity and adaptive decision-making.

Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Optimizing Screening for Intrastriatal Interventions in Huntington's Disease Using Predictive Models.

BACKGROUND: Intrastriatal delivery of potential therapeutics in Huntington's disease (HD) requires sufficient caudate and putamen volumes. Currently, volumetric magnetic resonance imaging is rarely done in clinical practice, and these data are not available in large research cohorts such as Enroll-HD. OBJECTIVE: The objective of this study was to investigate whether predictive models can accurately classify HD patients who exceed caudate and putamen volume thresholds required for intrastriatal therapeutic interventions. METHODS: We obtained and merged data for 1374 individuals across three HD cohorts: IMAGE-HD, PREDICT-HD, and TRACK-HD/TRACK-ON. We imputed missing data for clinical variables with >72% non-missing values and used the model-building algorithm BORUTA to identify the 10 most important variables. A random forest algorithm was applied to build a predictive model for putamen volume >2500 mm3 and caudate volume >2000 mm3 bilaterally. Using the same 10 predictors, we constructed a logistic regression model with predictors significant at P < 0.05. RESULTS: The random forest model with 1000 trees and minimal terminal node size of 5 resulted in 83% area under the curve (AUC). The logistic regression model retaining age, CAG repeat size, and symbol digit modalities test-correct had 85.1% AUC. A probability cutoff of 0.8 resulted in 5.4% false positive and 66.7% false negative rates. CONCLUSIONS: Using easily obtainable clinical data and machine learning-identified initial predictor variables, random forest, and logistic regression models can successfully identify people with sufficient striatal volumes for inclusion cutoffs. Adopting these models in prescreening could accelerate clinical trial enrollment in HD and other neurodegenerative disorders when volume cutoffs are necessary enrollment criteria. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

White Matter Microstructural Underpinnings of Mild Behavioral Impairment in Parkinson's Disease.

BACKGROUND: Patients with Parkinson's disease (PD) experience changes in behavior, personality, and cognition that can manifest even in the initial stages of the disease. Previous studies have suggested that mild behavioral impairment (MBI) should be considered an early marker of cognitive decline. However, the precise neurostructural underpinnings of MBI in early- to mid-stage PD remain poorly understood. OBJECTIVE: The aim was to explore the changes in white matter microstructure linked to MBI and mild cognitive impairment (MCI) in early- to mid-stage PD using diffusion magnetic resonance imaging (dMRI). METHODS: A total of 91 PD patients and 36 healthy participants were recruited and underwent anatomical MRI and dMRI, a comprehensive neuropsychological battery, and the completion of the Mild Behavioral Impairment-Checklist. Metrics of white matter integrity included tissue fractional anisotropy (FAt) and radial diffusivity (RDt), free water (FW), and fixel-based apparent fiber density (AFD). RESULTS: The connection between the left amygdala and the putamen was disrupted when comparing PD patients with MBI (PD-MBI) to PD-non-MBI, as evidenced by increased RDt (η2 = 0.09, P = 0.004) and both decreased AFD (η2 = 0.05, P = 0.048) and FAt (η2 = 0.12, P = 0.014). Compared to controls, PD patients with both MBI and MCI demonstrated increased FW for the connection between the left orbitofrontal gyrus (OrG) and the hippocampus (η2 = 0.22, P = 0.008), augmented RDt between the right OrG and the amygdala (η2 = 0.14, P = 0.008), and increased RDt (η2 = 0.25, P = 0.028) with decreased AFD (η2 = 0.10, P = 0.046) between the right OrG and the caudate nucleus. CONCLUSION: MBI is associated with abnormal microstructure of connections involving the orbitofrontal cortex, putamen, and amygdala. To our knowledge, this is the first assessment of the white matter microstructure in PD-MBI using dMRI. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Lower Dorsal Putamen D2/3 Receptor Availability and Amphetamine-Induced Dopamine Release are Related to Poorer Cognitive Function in Recently Abstinent People Who Smoke and Healthy Controls.

INTRODUCTION: In the dopamine system, the mesolimbic pathway, including the dorsal striatum, underlies the reinforcing properties of tobacco smoking, and the mesocortical pathway, including the dorsolateral prefrontal cortex (dlPFC), is critical for cognitive functioning. Dysregulated dopamine signaling has been linked to drug-seeking behaviors and cognitive deficits. The dorsal striatum and dlPFC are structurally and functionally connected and are key regions for cognitive functioning. We recently showed that people who smoke have lower dlPFC dopamine (D2/3R) receptor availability than people who do not, which is related to poorer cognitive function. AIMS AND METHODS: The goal of this study was to examine the same brain-behavior relationship in the dorsal striatum. Twenty-nine (18 males) recently abstinent people who smoke and 29 sex-matched healthy controls participated in 2 same-day [11C]-(+)-PHNO positron emission tomography scans before and after amphetamine administration to provoke dopamine release. D2/3R availability (binding potential; BPND) and amphetamine-induced dopamine release (%ΔBPND) were calculated. Cognition (verbal learning and memory) was assessed with the CogState computerized battery. RESULTS: There were no group differences in baseline BPND. People who smoke have a smaller magnitude %ΔBPND in dorsal putamen than healthy controls (p = .022). People who smoke perform worse on immediate (p = .035) and delayed (p = .011) recall than healthy controls. In all people, lower dorsal putamen BPND was associated with worse immediate (p = .006) and delayed recall (p = .049), and lower %ΔBPND was related to worse delayed recall (p = .022). CONCLUSIONS: Lower dorsal putamen D2/3R availability and function are associated with disruptions in cognitive function that may underlie difficulty with resisting smoking. IMPLICATIONS: This study directly relates dopamine imaging outcomes in the dorsal striatum to cognitive function in recently abstinent people who smoke cigarettes and healthy controls. The current work included a well-characterized subject sample in terms of demographics, smoking characteristics, and a validated neurocognitive test of verbal learning and memory. The findings of this study extend previous literature relating dopamine imaging outcomes to cognition in recently abstinent people who smoke and people who do not smoke, expanding our understanding of brain-behavior relationships.

Mechanisms of imbalanced frontostriatal functional connectivity in obsessive-compulsive disorder.

The diagnosis of obsessive-compulsive disorder (OCD) has been linked with changes in frontostriatal resting-state connectivity. However, replication of prior findings is lacking, and the mechanistic understanding of these effects is incomplete. To confirm and advance knowledge on changes in frontostriatal functional connectivity in OCD, participants with OCD and matched healthy controls underwent resting-state functional, structural and diffusion neuroimaging. Functional connectivity changes in frontostriatal systems were here replicated in individuals with OCD (n = 52) compared with controls (n = 45). OCD participants showed greater functional connectivity (t = 4.3, PFWE = 0.01) between the nucleus accumbens (NAcc) and the orbitofrontal cortex (OFC) but lower functional connectivity between the dorsal putamen and lateral prefrontal cortex (t = 3.8, PFWE = 0.04) relative to controls. Computational modelling suggests that NAcc-OFC connectivity changes reflect an increased influence of NAcc over OFC activity and reduced OFC influence over NAcc activity (posterior probability, Pp > 0.66). Conversely, dorsal putamen showed reduced modulation over lateral prefrontal cortex activity (Pp > 0.90). These functional deregulations emerged on top of a generally intact anatomical substrate. We provide out-of-sample replication of opposite changes in ventro-anterior and dorso-posterior frontostriatal connectivity in OCD and advance the understanding of the neural underpinnings of these functional perturbations. These findings inform the development of targeted therapies normalizing frontostriatal dynamics in OCD.

A link between synaptic plasticity and reorganization of brain activity in Parkinson's disease.

The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D2 receptors (using 11C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D2 binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.

Is the Caudate, Putamen, and Globus Pallidus the Delusional Disorder's Trio? A Texture Analysis Study.

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.

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Low-frequency rTMS targeting individual self-initiated finger-tapping task activation modulates the amplitude of local neural activity in the putamen.

Repetitive transcranial magnetic stimulation (rTMS) has been used in the clinical treatment of Parkinson's disease (PD). Most of rTMS studies on PD used high-frequency stimulation; however, excessive nonvoluntary movement may represent abnormally cortical excitability, which is likely to be suppressed by low-frequency rTMS. Decreased neural activity in the basal ganglia on functional magnetic resonance imaging (fMRI) is a characteristic of PD. In the present study, we found that low-frequency (1 Hz) rTMS targeting individual finger-tapping activation elevated the amplitude of local neural activity (percentage amplitude fluctuation, PerAF) in the putamen as well as the functional connectivity (FC) of the stimulation target and basal ganglia in healthy participants. These results provide evidence for our hypothesis that low-frequency rTMS over the individual task activation site can modulate deep brain functions, and that FC might serve as a bridge transmitting the impact of rTMS to the deep brain regions. It suggested that a precisely localized individual task activation site can act as a target for low-frequency rTMS when it is used as a therapeutic tool for PD.

Aerobic Exercise Alters Brain Function and Structure in Parkinson's Disease: A Randomized Controlled Trial.

OBJECTIVE: Randomized clinical trials have shown that aerobic exercise attenuates motor symptom progression in Parkinson's disease, but the underlying neural mechanisms are unclear. Here, we investigated how aerobic exercise influences disease-related functional and structural changes in the corticostriatal sensorimotor network, which is involved in the emergence of motor deficits in Parkinson's disease. Additionally, we explored effects of aerobic exercise on tissue integrity of the substantia nigra, and on behavioral and cerebral indices of cognitive control. METHODS: The Park-in-Shape trial is a single-center, double-blind randomized controlled trial in 130 Parkinson's disease patients who were randomly assigned (1:1 ratio) to aerobic exercise (stationary home trainer) or stretching (active control) interventions (duration = 6 months). An unselected subset from this trial (exercise, n = 25; stretching, n = 31) underwent resting-state functional and structural magnetic resonance imaging (MRI), and an oculomotor cognitive control task (pro- and antisaccades), at baseline and at 6-month follow-up. RESULTS: Aerobic exercise, but not stretching, led to increased functional connectivity of the anterior putamen with the sensorimotor cortex relative to the posterior putamen. Behaviorally, aerobic exercise also improved cognitive control. Furthermore, aerobic exercise increased functional connectivity in the right frontoparietal network, proportionally to fitness improvements, and it reduced global brain atrophy. INTERPRETATION: MRI, clinical, and behavioral results converge toward the conclusion that aerobic exercise stabilizes disease progression in the corticostriatal sensorimotor network and enhances cognitive performance. ANN NEUROL 2022;91:203-216.

Subcortical Volumes as Early Predictors of Fatigue in Multiple Sclerosis.

OBJECTIVE: Fatigue is a frequent and severe symptom in multiple sclerosis (MS), but its pathophysiological origin remains incompletely understood. We aimed to examine the predictive value of subcortical gray matter volumes for fatigue severity at disease onset and after 4 years by applying structural equation modeling (SEM). METHODS: This multicenter cohort study included 601 treatment-naive patients with MS after the first demyelinating event. All patients underwent a standardized 3T magnetic resonance imaging (MRI) protocol. A subgroup of 230 patients with available clinical follow-up data after 4 years was also analyzed. Associations of subcortical volumes (included into SEM) with MS-related fatigue were studied regarding their predictive value. In addition, subcortical regions that have a central role in the brain network (hubs) were determined through structural covariance network (SCN) analysis. RESULTS: Predictive causal modeling identified volumes of the caudate (s [standardized path coefficient] = 0.763, p = 0.003 [left]; s = 0.755, p = 0.006 [right]), putamen (s = 0.614, p = 0.002 [left]; s = 0.606, p = 0.003 [right]) and pallidum (s = 0.606, p = 0.012 [left]; s = 0.606, p = 0.012 [right]) as prognostic factors for fatigue severity in the cross-sectional cohort. Moreover, the volume of the pons was additionally predictive for fatigue severity in the longitudinal cohort (s = 0.605, p = 0.013). In the SCN analysis, network hubs in patients with fatigue worsening were detected in the putamen (p = 0.008 [left]; p = 0.007 [right]) and pons (p = 0.0001). INTERPRETATION: We unveiled predictive associations of specific subcortical gray matter volumes with fatigue in an early and initially untreated MS cohort. The colocalization of these subcortical structures with network hubs suggests an early role of these brain regions in terms of fatigue evolution. ANN NEUROL 2022;91:192-202.

Magnetic Resonance T1w/T2w Ratio in the Putamen and Cerebellum as a Marker of Cognitive Impairment in MSA: a Longitudinal Study.

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T0) and 1-year follow-up (T1). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T1, we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (ß = - 9.45, p = .02) and T1w/T2w value in the left putamen (ß = 230.64, p = .01) were significant predictors of global cognitive status at T0, explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (ß = 2188.70, p = .02) significantly predicted cognitive worsening at T1, explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA.

Patterns of striatal dopamine depletion and motor deficits in de novo Parkinson's disease.

The background of this study is to investigate whether striatal dopamine depletion patterns (selective involvement in the sensorimotor striatum or asymmetry) are associated with motor deficits in Parkinson's disease (PD). We enrolled 404 drug-naïve patients with early stage PD who underwent dopamine transporter (DAT) imaging. After quantifying DAT availability in each striatal sub-region, principal component (PC) analysis was conducted to yield PCs representing the spatial patterns of striatal dopamine depletion. Subsequently, multivariate linear regression analysis was conducted to investigate the relationship between striatal dopamine depletion patterns and motor deficits assessed using the Unified PD Rating Scale Part III (UPDRS-III). Mediation analyses were used to evaluate whether dopamine deficiency in the posterior putamen mediated the association between striatal dopamine depletion patterns and parkinsonian motor deficits. Three PCs indicated patterns of striatal dopamine depletion: PC1 (overall striatal dopamine deficiency), PC2 (selective dopamine loss in the sensorimotor striatum), and PC3 (symmetric dopamine loss in the striatum). Multivariate linear regression analysis revealed that PC1 (ß = - 1.605, p < 0.001) and PC2 (ß = 3.201, p < 0.001) were associated with motor deficits (i.e., higher UPDRS-III scores in subjects with severe dopamine depletion throughout the whole striatum or more selective dopamine loss in the sensorimotor striatum), whereas PC3 was not (ß = - 0.016, p = 0.992). Mediation analyses demonstrated that the effects of PC1 and PC2 on UPDRS-III scores were indirectly mediated by DAT availability in the posterior putamen, with a non-significant direct effect. Dopamine deficiency in the posterior putamen was most relevant to the severity of motor deficits in patients with PD, while the spatial patterns of striatal dopamine depletion were not a key determinant.

Deep learning segmentation results in precise delineation of the putamen in multiple system atrophy.

OBJECTIVES: The precise segmentation of atrophic structures remains challenging in neurodegenerative diseases. We determined the performance of a Deep Neural Patchwork (DNP) in comparison to established segmentation algorithms regarding the ability to delineate the putamen in multiple system atrophy (MSA), Parkinson's disease (PD), and healthy controls. METHODS: We retrospectively included patients with MSA and PD as well as healthy controls. A DNP was trained on manual segmentations of the putamen as ground truth. For this, the cohort was randomly split into a training (N = 131) and test set (N = 120). The DNP's performance was compared with putaminal segmentations as derived by Automatic Anatomic Labelling, Freesurfer and Fastsurfer. For validation, we assessed the diagnostic accuracy of the resulting segmentations in the delineation of MSA vs. PD and healthy controls. RESULTS: A total of 251 subjects (61 patients with MSA, 158 patients with PD, and 32 healthy controls; mean age of 61.5 ± 8.8 years) were included. Compared to the dice-coefficient of the DNP (0.96), we noted significantly weaker performance for AAL3 (0.72; p < .001), Freesurfer (0.82; p < .001), and Fastsurfer (0.84, p < .001). This was corroborated by the superior diagnostic performance of MSA vs. PD and HC of the DNP (AUC 0.93) versus the AUC of 0.88 for AAL3 (p = 0.02), 0.86 for Freesurfer (p = 0.048), and 0.85 for Fastsurfer (p = 0.04). CONCLUSION: By utilization of a DNP, accurate segmentations of the putamen can be obtained even if substantial atrophy is present. This allows for more precise extraction of imaging parameters or shape features from the putamen in relevant patient cohorts. CLINICAL RELEVANCE STATEMENT: Deep learning-based segmentation of the putamen was superior to currently available algorithms and is beneficial for the diagnosis of multiple system atrophy. KEY POINTS: • A Deep Neural Patchwork precisely delineates the putamen and performs equal to human labeling in multiple system atrophy, even when pronounced putaminal volume loss is present. • The Deep Neural Patchwork-based segmentation was more capable to differentiate between multiple system atrophy and Parkinson's disease than the AAL3 atlas, Freesurfer, or Fastsurfer.

Altered Putamen Activation for Social Comparison-Related Feedback in Social Anxiety Disorder: A Pilot Study.

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.

Onset pattern of nigrostriatal denervation in early Parkinson's disease.

The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson's disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson's disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson's disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson's disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson's disease and eventually monitor the impact of putative therapies.

Morphological development of the human fetal striatum during the second trimester.

The morphological development of the fetal striatum during the second trimester has remained poorly described. We manually segmented the striatum using 7.0-T MR images of the fetal specimens ranging from 14 to 22 gestational weeks. The global development of the striatum was evaluated by volume measurement. The absolute volume (Vabs) of the caudate nucleus (CN) increased linearly with gestational age, while the relative volume (Vrel) showed a quadratic growth. Both Vabs and Vrel of putamen increased linearly. Through shape analysis, the changes of local structure in developing striatum were specifically demonstrated. Except for the CN tail, the lateral and medial parts of the CN grew faster than the middle regions, with a clear rostral-caudal growth gradient as well as a distinct "outside-in" growth gradient. For putamen, the dorsal and ventral regions grew obviously faster than the other regions, with a dorsal-ventral bidirectional developmental pattern. The right CN was larger than the left, whereas there was no significant hemispheric asymmetry in the putamen. By establishing the developmental trajectories, spatial heterochrony, and hemispheric dimorphism of human fetal striatum, these data bring new insight into the fetal striatum development and provide detailed anatomical references for future striatal studies.

Analysis of synthetic magnetic resonance images by multi-channel segmentation increases accuracy of volumetry in the putamen and decreases mis-segmentation in the dural sinuses.

BACKGROUND: Voxel-based morphometry (VBM) using magnetic resonance imaging (MR) has been used to estimate cortical atrophy associated with various diseases. However, there are mis-segmentations of segmented gray matter image in VBM. PURPOSE: To study a twofold evaluation of single- and multi-channel segmentation using synthetic MR images: (1) mis-segmentation of segmented gray matter images in transverse and cavernous sinuses; and (2) accuracy and repeatability of segmented gray matter images. MATERIAL AND METHODS: A total of 13 healthy individuals were scanned with 3D quantification using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (3D-QALAS) sequence on a 1.5-T scanner. Three of the 13 healthy participants were scanned five consecutive times for evaluation of repeatability. We used SyMRI software to create images with three contrasts: T1-weighted (T1W), T2-weighted (T2W), and proton density-weighted (PDW) images. Manual regions of interest (ROI) on T1W imaging were individually set as the gold standard in the transverse sinus, cavernous sinus, and putamen. Single-channel (T1W) and multi-channel (T1W + T2W, T1W + PDW, and T1W + T2W + PDW imaging) segmentations were performed with statistical parametric mapping 12 software. RESULTS: We found that mis-segmentations in both the transverse and cavernous sinuses were large in single-channel segmentation compared with multi-channel segmentations. Furthermore, the accuracy of segmented gray matter images in the putamen was high in both multi-channel T1W + PDW and T1W + T2W + PDW segmentations compared with other segmentations. Finally, the highest repeatability of left putamen volumetry was found with multi-channel segmentation T1WI + PDWI. CONCLUSION: Multi-channel segmentation with T1WI + PDWI provides good results for VBM compared with single-channel and other multi-channel segmentations.

Cortical iron mediates age-related decline in fluid cognition.

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.