Social Cognition in Parkinson's Disease after Focused Ultrasound Subthalamotomy: A Controlled Study.

Social cognition (SC) encompasses a set of cognitive functions that enable individuals to understand and respond appropriately to social interactions. Although focused ultrasound subthalamotomy (FUS-STN) effectively treats Parkinson's disease (PD) clinical motor features, its impact and safety on cognitive-behavioral interactions/interpersonal awareness are unknown. This study investigated the effects of unilateral FUS-STN on facial emotion recognition (FER) and affective and cognitive theory of mind (ToM) in PD patients from a randomized sham-controlled trial (NCT03454425). Subjects performed SC evaluation before and 4 months after the procedure while still under blind assessment conditions. The SC assessment included the Karolinska Directed Emotional Faces task for FER, the Reading the Mind in the Eyes (RME) test for affective ToM, and The Theory of Mind Picture Stories Task (ToM PST) (order, questions, and total score) for cognitive ToM. The active treatment group showed anecdotal-to-moderate evidence of no worsening in SC after FUS-STN. Anecdotal evidence for an improvement was recognized in the SC score changes, from baseline to post-treatment, for the active treatment group compared with sham for the RME, ToM PST order, ToM PST total, FER total, and recognition of fear, disgust, and anger. This study provides the first evidence that unilateral FUS-STN does not impair social cognitive abilities, indicating that it can be considered a safe treatment approach for this domain in PD patients. Furthermore, the results suggest FUS-STN may even lead to some improvement in social cognitive outcomes, which should be considered as a preliminary finding requiring further investigation with larger samples sizes. © 2024 International Parkinson and Movement Disorder Society.

The causal role of the subthalamic nucleus in the inhibitory network.

The neural network mediating successful response inhibition mainly includes right hemisphere activation of the pre-supplementary motor area, inferior frontal gyrus (IFG), subthalamic nucleus (STN), and caudate nucleus. However, the causal role of these regions in the inhibitory network is undefined. Five patients with Parkinson's disease were assessed prior to and after therapeutic thermal ablation of the right STN in two separate functional magnetic resonance imaging (fMRI) sessions while performing a stop-signal task. Initiation times were faster but motor inhibition with the left hand (contralateral to the lesion) was significantly impaired as evident in prolonged stop-signal reaction times. Reduced inhibition after right subthalamotomy was associated (during successful inhibition) with the recruitment of basal ganglia regions outside the established inhibitory network. They included the putamen and caudate together with the anterior cingulate cortex and IFG of the left hemisphere. Subsequent network connectivity analysis (with the seed over the nonlesioned left STN) revealed a new inhibitory network after right subthalamotomies. Our results highlight the causal role of the right STN in the neural network for motor inhibition and the possible basal ganglia mechanisms for compensation upon losing a key node of the inhibition network.

Context, transparency and culture in motor resonance phenomena: Causal evidence of the motor cortex.

A connection between language and movement information in metaphorical and literal expressions activates the motor system. Despite numerous studies exploring distinctions between idioms and metaphors, a notable research gap remains in the specific effect of idioms with different transparency levels concerning motor resonance. Our primary focus was analysing the functional role of the primary motor cortex (M1) in processing hand motor verbs both in literal expressions and in two idiomatic contexts, i.e., opaque and transparent idioms. Additionally, we explored a potential language and cultural effect by comparing Turkish and Spanish speakers. An overt priming task with self-paced reading was used to judge the relatedness of a primer and a target sentence. We implemented a repetitive transcranial magnetic stimulation (TMS) protocol using continuous theta-burst stimulation (cTBS) compared to sham stimulation over the M1 in both Turkish and Spanish native speakers prior to the experimental task. Our findings reveal that the performance of Turkish and Spanish participants in processing hand motor actions was facilitated after the application of cTBS over the left M1. Moreover, brain stimulation specifically facilitated the processing of only transparent-but not opaque-idioms in both Spanish and Turkish participants. Our study reports distinct motor resonance results between different types of idioms with a parallel cross-cultural effect.

Causal computations of supplementary motor area on spatial impulsivity.

Spatial proximity to important stimuli often induces impulsive behaviour. How we overcome impulsive tendencies is what determines behaviour to be adaptive. Here, we used virtual reality to investigate whether the spatial proximity of stimuli is causally related to the supplementary motor area (SMA) functions. In two experiments, we set out to investigate these processes using a virtual environment that recreates close and distant spaces to test the causal contributions of the SMA in spatial impulsivity. In an online first experiment (N = 93) we validated and measured the influence of distant stimuli using a go/no-go task with close (21 cm) or distant stimuli (360 cm). In experiment 2 (N = 28), we applied transcranial static magnetic stimulation (tSMS) over the SMA (double-blind, crossover, sham-controlled design) to test its computations in controlling impulsive tendencies towards close vs distant stimuli. Reaction times and error rates (omission and commission) were analysed. In addition, the EZ Model parameters (a, v, Ter and MDT) were computed. Close stimuli elicited faster responses compared to distant stimuli but also exhibited higher error rates, specifically in commission errors (experiment 1). Real stimulation over SMA slowed response latencies (experiment 2), an effect mediated by an increase in decision thresholds (a). Current findings suggest that impulsivity might be modulated by spatial proximity, resulting in accelerated actions that may lead to an increase of inaccurate responses to nearby objects. Our study also provides a first starting point on the role of the SMA in regulating spatial impulsivity.

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Importance: Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. Objective: To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. Design, Setting, and Participants: This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Intervention: Staged bilateral FUS-STN. Main Outcomes and Measures: Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Results: Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Conclusions: Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

Anatomical correlates of apathy and impulsivity co-occurrence in early Parkinson's disease.

BACKGROUND: Although apathy and impulse control disorders (ICDs) are considered to represent opposite extremes of a continuum of motivated behavior (i.e., hypo- and hyperdopaminergic behaviors), they may also co-occur in Parkinson's disease (PD). OBJECTIVES: We aimed to explore the co-occurrence of ICDs and apathy and its neural correlates analyzing gray matter (GM) changes in early untreated PD patients. Moreover, we aimed to investigate the possible longitudinal relationship between ICDs and apathy and their putative impact on cognition during the first five years of PD. METHODS: We used the Parkinson's Progression Markers Initiative (PPMI) database to identify the co-occurrence of apathy and ICDs in 423 early drug-naïve PD patients at baseline and at 5-year follow-up. Baseline MRI volumes and gray matter changes were analyzed between groups using voxel-based morphometry. Multi-level models assessed the longitudinal relationship (across five years) between apathy and ICDs and cognitive functioning. RESULTS: At baseline, co-occurrence of apathy and ICDs was observed in 23 patients (5.4%). This finding was related to anatomical GM reduction along the cortical regions involved in the limbic circuit and cognitive control systems. Longitudinal analyses indicated that apathy and ICDs were related to each other as well as to the combined use of levodopa and dopamine agonists. Worse apathetic and ICDs states were associated with poorer executive functions. CONCLUSIONS: Apathy and ICDs are joint non-exclusive neuropsychiatric disorders also in the early stages of PD and their co-occurrence was associated with GM decrease in several cortical regions of the limbic circuit and cognitive control systems.

Cognitive Reserve in Parkinson's Disease without Dementia: ß-Amyloid and Metabolic Assessment.

BACKGROUND: Cognitive reserve (CR) is the mismatch between preserved cognition and neuropathological damage. Amyloidopathy in Parkinson's disease (PD) could be associated with faster progression to dementia, but the putative protective effect of CR is unknown. OBJECTIVES: To evaluate the effect of CR on ß-amyloid burden and brain metabolism in non-demented PD subjects. METHODS: Participants with PD (n = 53) underwent a clinical evaluation, [18 F]-fluorodeoxyglucose and [18 F]-flutemetamol positron emission tomography magnetic resonances, and were classified according to CR. The metabolic pattern of 16 controls was compared to PD subjects. RESULTS: The PD subjects showed hypometabolism mainly in the bilateral posterior cortex. Superior-CR subjects (n = 22) exhibited better cognitive performance, increased amyloid burden, and higher metabolism in several right hemisphere areas compared to low-medium-CR subjects (n = 31). CONCLUSIONS: Higher CR in non-demented PD is associated with better cognitive performance, which might reduce vulnerability to the effect of ß-amyloid. Whether superior CR leads to protection against metabolic deterioration, and predominantly right hemisphere involvement, deserves further exploration.

Unilateral focused ultrasound subthalamotomy in early Parkinson's disease: a pilot study.

BACKGROUND: Unilateral focused ultrasound subthalamotomy (FUS-STN) improves motor features of Parkinson's disease (PD) in moderately advanced patients. The less invasive nature of FUS makes its early application in PD feasible. We aim to assess the safety and efficacy of unilateral FUS-STN in patients with PD of less than 5 years from diagnosis (early PD). METHODS: Prospective, open-label study. Eligible patients with early PD had highly asymmetrical cardinal features. The primary outcome was safety, defined as treatment-related adverse events at 6 months. Secondary outcomes included efficacy, assessed as motor improvement in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), motor fluctuations, non-motor symptoms, daily living activities, quality of life, medication and patients' impression of change. RESULTS: Twelve patients with PD (median age 52.0 (IQR 49.8-55.3) years, median time from diagnosis 3.0 (2.1-3.9) years) underwent unilateral FUS-STN. Within 2 weeks after treatment, five patients developed dyskinesia on the treated side, all resolved after levodopa dose adjustment. One patient developed mild contralateral motor weakness which fully resolved in 4 weeks. One patient developed dystonic foot and another hand and foot dystonia. The latter impaired gait and became functionally disabling initially. Both cases were well controlled with botulinum toxin injections. The off-medication motor MDS-UPDRS score for the treated side improved at 12 months by 68.7% (from 14.5 to 4.0, p=0.002), and the total motor MDS-UPDRS improved by 49.0% (from 26.5 to 13.0, p=0.002). Eleven patients (92%) reported global improvement 12 months after treatment. CONCLUSION: Unilateral FUS-STN may be safe and effective to treat motor manifestations in patients with early PD. A larger confirmatory trial is warranted. TRIAL REGISTRATION NUMBER: NCT04692116.

Theory of mind in mild cognitive impairment and Parkinson's disease: The role of memory impairment.

BACKGROUND: Social cognition is impaired in Parkinson's disease (PD). Whether social cognitive impairment (iSC) is a by-product of the underlying cognitive deficits in PD or a process independent of cognitive status is unknown. To this end, the present study was designed to investigate the weight of specific cognitive deficits in social cognition, considering different mild cognitive impairment subtypes of PD (PD-MCI). METHODS: Fifty-eight PD patients underwent a neuropsychological battery assessing executive functions, memory, language, and visuospatial domains, together with social cognitive tests focused on theory of mind (ToM). Patients were divided into subgroups according to their clinical cognitive status: amnestic PD-MCI (PD-aMCI, n = 18), non-amnestic PD-MCI (PD-naMCI, n = 16), and cognitively unimpaired (PD-CU, n = 24). Composite scores for cognitive and social domains were computed to perform mediation analyses. RESULTS: Memory and language impairments mediated the effect of executive functioning in social cognitive deficits in PD patients. Dividing by MCI subgroups, iSC occurred more frequently in PD-aMCI (77.8%) than in PD-naMCI (18.8%) and PD-CU (8.3%). Moreover, PD-aMCI performed worse than PD-CU in all social cognitive measures, whereas PD-naMCI performed worse than PD-CU in only one subtype of the affective and cognitive ToM tests. CONCLUSIONS: Our findings suggest that ToM impairment in PD can be explained by memory dysfunction that mediates executive control. ToM downsides in the amnesic forms of PD-MCI may suggest that subtle changes in social cognition could partly explain future transitions into dementia. Hence, the evaluation of social cognition in PD is critical to characterize a possible behavioral marker of cognitive decline.

Early Detection of Depression in Parkinson's Disease: Psychometrics and Diagnostics of the Spanish Version of the Beck Depression Inventory.

OBJECTIVE: Depression is one of the most disabling non-motor symptoms in Parkinson's disease (PD) and requires proper diagnosis as it negatively impacts patients' and their relatives quality of life. The present study aimed to examine the psychometric and diagnostic properties of the Beck Depression Inventory-I (BDI-I) in a Spanish PD cohort. METHOD: Consecutive PD outpatients completed the Spanish version of the BDI-I and other questionnaires assessing anxiety and apathy. Patients' caregivers completed the depression/dysphoria domain of the Neuropsychiatric Inventory (NPI-D). The internal consistency, convergent and divergent validity and the factorial structure of BDI-I were evaluated, and an optimal cut-off was defined by means of the Youden index. RESULTS: The BDI-I proved to have a good internal consistency and was underpinned by a mono-component structure. Regarding construct validity, the BDI-I was substantially related to anxiety and apathy measures in PD. Furthermore, the BDI-I overall showed good accuracy with adequate sensitivity and specificity. The optimal cut-off point was defined at 10. CONCLUSIONS: We provided evidence of the psychometric and diagnostic properties of the Spanish version of the BDI-I as a screening tool for depression in Spanish speaking PD patients, suggesting its usefulness in clinical research and practice.

The Impact of Emotions on Habitual Inhibition.

Emotional information prioritizes human behavior. How much emotions influence ongoing behavior critically depends on the extent of executive control functions in a given context. One form of executive control is based on stimulus-stop associations (i.e., habitual inhibition) that rapidly and effortlessly elicits control over the interruption of ongoing behavior. So far, no behavioral accounts have explored the emotional impact on habitual inhibition. We aimed to examine the emotional modulation on habitual inhibition and associated psycho-physiological changes. A go/no-go association task asked participants to learn stimulus-stop and stimulus-response associations during 10-day training to form habitual inhibition (without emotional interference). Probabilistic feedback guided learning with varying probabilities of congruent feedback, generating stronger versus weaker pairings. A reversal test measured habitual inhibition strength counteracted by emotional cues (high-arousal positive and negative stimuli compared with neutral ones). Our training protocol induced stable behavioral and psycho-physiological responses compatible with habitual behavior. At reversal, habitual inhibition was evident as marked by significant speed costs of reversed no-go trials for strongly associated stimuli. Positive and negative emotional cues produced larger impact on habitual inhibition. We report first evidence on a cognitive control mechanism that is vulnerable to emotional stimuli and suggest alternative explanations on how emotions may boost or counteract certain behavioral abnormalities mediated by habitual inhibition.

Longitudinal assessment of social cognition in de novo Parkinson's disease patients and its relationship with dopaminergic innervation.

BACKGROUND: Social Cognition (SC) has been scarcely studied in Parkinson's disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people's intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one's own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. OBJECTIVES: To prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. METHODS: We compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. RESULTS: SC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. CONCLUSION: SC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Brain hypometabolism in non-demented microtubule-associated protein tau H1 carriers with Parkinson's disease.

BACKGROUND AND PURPOSE: The microtubule-associated protein tau (MAPT) H1 homozygosity (H1/H1 haplotype) is a genetic risk factor for neurodegenerative diseases, such as Parkinson's disease (PD). MAPT H1 homozygosity has been associated with conversion to PD; however, results are conflicting since some studies did not find a strong influence. Cortical hypometabolism is associated with cognitive impairment in PD. In this study, we aimed to evaluate the metabolic pattern in nondemented PD patients MAPT H1/H1 carriers in comparison with MAPT H1/H2 haplotype. In addition, we evaluated domain-specific cognitive differences according to MAPT haplotype. METHODS: We compared a group of 26 H1/H1 and 20 H1/H2 carriers with late-onset PD. Participants underwent a comprehensive neuropsychological cognitive evaluation and a [18F]-Fluorodeoxyglucose PET-MR scan. RESULTS: MAPT H1/H1 carriers showed worse performance in the digit span forward test of attention compared to MAPT H1/H2 carriers. In the [18F]-Fluorodeoxyglucose PET comparisons, MAPT H1/H1 displayed hypometabolism in the frontal cortex, parahippocampal, and cingulate gyrus, as well as in the caudate and globus pallidus. CONCLUSION: PD patients MAPT H1/H1 carriers without dementia exhibit relative hypometabolism in several cortical areas as well as in the basal ganglia, and worse performance in attention than MAPT H1/H2 carriers. Longitudinal studies should assess if lower scores in attention and dysfunction in these areas are predictors of dementia in MAPT H1/H1 homozygotes.

Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Prospective Long-term Follow-up of Focused Ultrasound Unilateral Subthalamotomy for Parkinson Disease.

BACKGROUND AND OBJECTIVES: Unilateral magnetic resonance-guided focused ultrasound subthalamotomy (FUS-STN) has been shown to improve the cardinal motor features of Parkinson disease (PD). Whether this effect is sustained is not known. This study aims to report the long-term outcome of patients with PD treated with unilateral FUS-STN. METHODS: We conducted a prospective open-label study of patients with asymmetrical PD who underwent unilateral FUS-STN. All patients were evaluated up to 36 months after treatment. The primary outcome was the difference from baseline to 36 months after FUS-STN in the score of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor part (III) for the treated hemibody in the off-medication state. The safety outcome included all adverse events occurring during follow-up. Secondary outcomes were the change in the MDS-UPDRS III score on-medication; subscores of rigidity, bradykinesia, tremor, and axial features; total MDS-UPDRS III; and the MDS-UPDRS part IV. Functional disability and quality of life were assessed using the MDS-UPDRS II and the PDQ39, respectively. Patient impression of change and satisfaction with the treatment were self-assessed. The Wilcoxon signed-rank test with subsequent Bonferroni's correction was used for data analysis. RESULTS: Thirty-two patients with PD were evaluated at 36 months after treatment. The mean (±SD) age at baseline was 56.0 ± 10.1 years, with a mean disease duration of 6.8 ± 2.8 years. The MDS-UPDRS III score for the treated hemibody off-medication was improved by 52.3% from baseline to 3 years (score reduction from 19.0 ± 3.2 to 8.9 ± 3.3, 95% CI 8.7 to 11.6, p < 0.001), and all specific motor features were improved from baseline. No disabling or delayed adverse events were reported. The total MDS-UPDRS III off-medication score was 22.9% lower at 3 years than before treatment (36.8 ± 7.4 vs 27.4 ± 6.2, 95% CI 6.0 to 11.5, p < 0.001). The MDS-UPDRS II, IV, and PDQ39 scores and levodopa dose were equivalent to those at baseline. DISCUSSION: The benefit of unilateral FUS-STN on PD motor features is sustained in the long term. FUS-STN contributes to better clinical control over several years of evolution. NCT02912871/03454425. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the utility of focused ultrasound unilateral subthalamotomy in the treatment of people with Parkinson disease.

The Supplementary Motor Area and Automatic Cognitive Control: Lack of Evidence from Two Neuromodulation Techniques.

The SMA is fundamental in planning voluntary movements and execution of some cognitive control operations. Specifically, the SMA has been known to play a dominant role in controlling goal-directed actions as well as those that are highly predicted (i.e., automatic). Yet, the essential contribution of SMA in goal-directed or automatic control of behavior is scarce. Our objective was to test the possible direct role of SMA in automatic and voluntary response inhibition. We separately applied two noninvasive brain stimulation (NIBS) inhibitory techniques over SMA: either continuous theta-burst stimulation using repetitive transcranial magnetic stimulation or transcranial static magnetic field stimulation. Each NIBS technique was performed in a randomized, crossover, sham-controlled design. Before applying NIBS, participants practiced a go/no-go learning task where associations between stimulus and stopping behaviors were created (initiation and inhibition). After applying each NIBS, participants performed a go/no-go task with reversed associations (automatic control) and the stop signal task (voluntary control). Learning associations between stimuli and response initiation/inhibition was achieved by participants and therefore automatized during training. However, no significant differences between real and sham NIBS were found in either automatic (go/no-go learning task) or voluntary inhibition (stop signal task), with Bayesian statistics providing moderate evidence of absence. In conclusion, our results are compatible with a nondirect involvement of SMA in automatic control of behavior. Further studies are needed to prove a noncausal link between prior neuroimaging findings relative to SMA controlling functions and the observed behavior.

A circuit-based approach to modulate hypersexuality in Parkinson's disease.

AIM: Impulse-control disorder is a common neuropsychiatric complication in Parkinson's disease (PD) under dopamine replacement therapy. Prior studies tested the balance between enhanced desire towards reward and cognitive control deficits, hypothesized to be biased towards the former in impulse control disorders. We provide evidence for this hypothesis by measuring behavioral and neural patterns behind the influence of sexual desire over response inhibition and tools towards functional restoration using repetitive transcranial stimulation in patients with hypersexuality as predominant impulsive disorder. METHODS: The effect of sexual cues on inhibition was measured with a novel erotic stop-signal task under on and off dopaminergic medication. Task-related functional and anatomical connectivity models were estimated in 16 hypersexual and 17 nonhypersexual patients with PD as well as in 17 healthy controls. Additionally, excitatory neuromodulation using intermittent theta-burst stimulation (sham-controlled) was applied over the pre-supplementary motor area in 20 additional hypersexual patients with PD aiming to improve response inhibition. RESULTS: Compared with their nonhypersexual peers, patients with hypersexuality recruited caudate, pre-supplementary motor area, ventral tegmental area, and anterior cingulate cortex while on medication. Reduced connectivity was found between pre-supplementary motor area and caudate nucleus in hypersexual compared with nonhypersexual patients (while medicated), a result paralleled by compensatory enhanced anatomical connectivity. Furthermore, stimulation over the pre-supplementary motor area improved response inhibition in hypersexual patients with PD when exposed to sexual cues. CONCLUSION: This study, therefore, has identified a specific fronto-striatal and mesolimbic circuitry underlying uncontrolled sexual responses in medicated patients with PD where cortical neuromodulation halts its expression.

The impact of executive dysfunctions on Theory of Mind abilities in Parkinson's disease.

Theory of Mind (ToM) is the ability to infer and reason about others' mental states, a process impaired by Parkinson's disease (PD). ToM performance in PD seems to be strongly related to executive functioning but the exact nature of this relationship is still unclear. We aim to investigate the direct impact of several executive dysfunctions on ToM deficits (Affective and Cognitive ToM) in PD patients. Sixty-eight PD patients underwent neuropsychological tests evaluating executive control such as inhibition, cognitive flexibility, processing speed or working memory and Cognitive and Affective ToM. We divided participants into two groups based on their performance on executive tests: PD patients with poor executive functioning (PD-EF-) and those with preserved executive functioning (PD-EF+). To explore the direct impact of executive subdomains on ToM abilities, two mediation models were executed in the whole sample. We found that PD patients with poor executive functioning reported poorer scores on Affective and Cognitive ToM tasks than PD patients with preserved executive functions, controlling for age and education. Moreover, parallel mediation models, conducted in the whole sample, indicated that performance on phonological fluency mediated the relationships between educational level and both Affective and Cognitive ToM, controlling the effect of other executive tests. These findings further support the idea that executive functions are crucial in ToM processes. Particularly, phonological fluency, whose execution requires both verbal abilities and cognitive flexibility, mediated ToM performance controlling the effect of other executive functions. The identification of neuropsychological processes underpinning ToM abilities might represent a plausible target for cognitive training to strengthen ToM abilities in PD.

An fMRI meta-analysis of the role of the striatum in everyday-life vs laboratory-developed habits.

The dorsolateral striatum plays a critical role in the acquisition and expression of stimulus-response habits that are learned in experimental laboratories. Here, we use meta-analytic procedures to contrast the neural circuits activated by laboratory-acquired habits with those activated by stimulus-response behaviours acquired in everyday-life. We confirmed that newly learned habits rely more on the anterior putamen with activation extending into caudate and nucleus accumbens. Motor and associative components of everyday-life habits were identified. We found that motor-dominant stimulus-response associations developed outside the laboratory primarily engaged posterior dorsal putamen, supplementary motor area (SMA) and cerebellum. Importantly, associative components were also represented in the posterior putamen. Thus, common neural representations for both naturalistic and laboratory-based habits were found in the left posterior and right anterior putamen. These findings suggest a partial common striatal substrate for habitual actions that are performed predominantly by stimulus-response associations represented in the posterior striatum. The overlapping neural substrates for laboratory and everyday-life habits supports the use of both methods for the analysis of habitual behaviour.

Striatal Blood-Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study.

BACKGROUND: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. OBJECTIVE: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. METHODS: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.