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Impulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (preSMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of preSMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the preSMA. We expected low-frequency rTMS to modulate task-related engagement of the preSMA and hereby, tune the tendency to make risky choices. 24 healthy volunteers (12 females, 19-52 years) received real or sham rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait-impulsivity, the lower was the task-related increase in preSMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in preSMA activation. These results provide converging evidence for a causal link between the level of task-related preSMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.Significance statementImpulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. The pre-supplementary motor area (preSMA) has been implicated in inhibitory control. Here, we provide evidence that this region contributes to the implementation of general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). When healthy volunteers performed a sequential gambling task, their choice behavior (i.e., state impulsivity) correlated positively with their impulsivity score (i.e, trait impulsivity). Additionally, participants with lower trait impulsivity showed a stronger increase in task-related activity of the preSMA with increasing risk. Both of these relationships were uncoupled after perturbing the preSMA with repetitive transcranial stimulation (rTMS).

Background: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. Objectives: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. Methods: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. Results: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. Conclusion: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 International Parkinson and Movement Disorder Society

BackgroundParkinson’s disease (PD) leads to a loss of neuromelanin positive, noradrenergic neurons in the locus coeruleus (LC) which has been implicated in non-motor dysfunction. “Neuromelanin sensitive” magnetic resonance imaging (MRI) has emerged as a promising tool for mapping the structural integrity of LC in vivo.ObjectivesTo identify spatial patterns of structural LC disintegration in PD and regions in the LC where structural disintegration is associated with specific non-motor dysfunctions.Methods42 patients with PD and 24 age-matched healthy volunteers underwent ultra-high field MRI of the LC using a “neuromelanin sensitive” magnetization transfer weighted (MTw) sequence. The contrast-to-noise ratio of the MTw signal (CNRMTw) served as an estimate of structural integrity, slice- and voxel-wise analyses of CNRMTw were performed to map the spatial pattern of structural disintegration, complemented by Principal Component Analysis (PCA). We also tested for correlations between CNRMTw and the severity of non-motor symptoms.ResultsMean CNRMTw of LC was reduced in patients relative to controls. The attenuation of CNRMTw was not uniformly expressed in LC, but confined to the middle and caudal LC. CNRMTw attenuation in caudal LC scaled with the orthostatic drop in systolic blood pressure and apathy ratings. PCA identified a bilaterally expressed component that was more weakly expressed in patients. This component was characterized by a gradual change in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of non-motor symptoms.ConclusionPD related structural disintegration of LC mainly affects its caudal part and may determine the individual expression of specific non-motor symptoms such as orthostatic dysregulation or apathy.

Background: Motor-related brain activity in Parkinson's disease has been investigated in a multitude of functional neuroimaging studies, which often yielded apparently conflicting results. Our previous meta-analysis did not resolve inconsistencies regarding cortical activation differences in Parkinson's disease, which might be related to the limited number of studies that could be included. Therefore, we conducted a revised meta-analysis including a larger number of studies. The objectives of this study were to elucidate brain areas that consistently show abnormal motor-related activation in Parkinson's disease and to reveal their functional connectivity profiles using meta-analytic approaches.Methods: We applied a quantitative meta-analysis of functional neuroimaging studies testing limb movements in Parkinson's disease comprising data from 39 studies, of which 15 studies (285 of 571 individual patients) were published after the previous meta-analysis. We also conducted meta-analytic connectivity modeling to elucidate the connectivity profiles of areas showing abnormal activation.Results: We found consistent motor-related underactivation of bilateral posterior putamen and cerebellum in Parkinson's disease. Primary motor cortex and the supplementary motor area also showed deficient activation, whereas cortical regions localized directly anterior to these areas expressed overactivation. Connectivity modeling revealed that areas showing decreased activation shared a common pathway through the posterior putamen, whereas areas showing increased activation were connected to the anterior putamen.Conclusions: Despite conflicting results in individual neuroimaging studies, this revised meta-analytic approach identified consistent patterns of abnormal motor-related activation in Parkinson's disease. The distinct patterns of decreased and increased activity might be determined by their connectivity with different subregions of the putamen. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.Keywords: Parkinson's disease; functional neuroimaging; meta-analysis; motor.

Levodopa-induced dyskinesia gradually emerges during long-term dopamine therapy, causing major disability in patients with Parkinson disease. Using pharmacodynamic functional MRI, we have previously shown that the intake of levodopa triggers an excessive activation of the pre-supplementary motor area in Parkinson disease patients with peak-of-dose dyskinesia. In this pre-registered, interventional study, we tested whether the abnormal responsiveness of the pre-supplementary motor area to levodopa may constitute a ‘stimulation target’ for treating dyskinesia. A gender-balanced group of 17 Parkinson disease patients with peak-of-dose dyskinesia received 30 min of robot-assisted repetitive transcranial magnetic stimulation, after they had paused their anti-Parkinson medication. Real-repetitive transcranial magnetic stimulation at 100% or sham-repetitive transcranial magnetic stimulation at 30% of individual resting corticomotor threshold of left first dorsal interosseous muscle was applied on separate days in counterbalanced order. Following repetitive transcranial magnetic stimulation, patients took 200 mg of oral levodopa and underwent functional MRI to map brain activity, while they performed the same go/no-go task as in our previous study. Blinded video assessment revealed that real-repetitive transcranial magnetic stimulation delayed the onset of dyskinesia and reduced its severity relative to sham-repetitive transcranial magnetic stimulation. Individual improvement in dyskinesia severity scaled linearly with the modulatory effect of real-repetitive transcranial magnetic stimulation on task-related activation in the pre-supplementary motor area. Stimulation-induced delay in dyskinesia onset correlated positively with the induced electrical field strength in the pre-supplementary motor area. Our results provide converging evidence that the levodopa-triggered increase in pre-supplementary motor area activity plays a causal role in the pathophysiology of peak-of-dose dyskinesia and constitutes a promising cortical target for brain stimulation therapy., Levodopa-induced dyskinesia constitutes a major side-effect to dopamine treatment of Parkinson’s disease. Lohse et al. show that low-frequency transcranial magnetic stimulation of the pre-supplementary motor area alleviates levodopa-induced dyskinesia. A causal contribution of pre-supplementary motor area in the pathophysiology of levodopa-induced dyskinesia is indicated and pre-supplementary motor area is identified as a candidate target for future stimulation-based therapy., Graphical Abstract Graphical Abstract

The locus coeruleus is the site of the earliest pathological changes in many neurodegenerative diseases. Betts et al. describe how in vivo locus coeruleus imaging can be used as a biomarker for noradrenergic dysfunction in neurodegenerative diseases, and outline a strategy for achieving reliable and biologically validated imaging approaches., Pathological alterations to the locus coeruleus, the major source of noradrenaline in the brain, are histologically evident in early stages of neurodegenerative diseases. Novel MRI approaches now provide an opportunity to quantify structural features of the locus coeruleus in vivo during disease progression. In combination with neuropathological biomarkers, in vivo locus coeruleus imaging could help to understand the contribution of locus coeruleus neurodegeneration to clinical and pathological manifestations in Alzheimer’s disease, atypical neurodegenerative dementias and Parkinson’s disease. Moreover, as the functional sensitivity of the noradrenergic system is likely to change with disease progression, in vivo measures of locus coeruleus integrity could provide new pathophysiological insights into cognitive and behavioural symptoms. Locus coeruleus imaging also holds the promise to stratify patients into clinical trials according to noradrenergic dysfunction. In this article, we present a consensus on how non-invasive in vivo assessment of locus coeruleus integrity can be used for clinical research in neurodegenerative diseases. We outline the next steps for in vivo, post-mortem and clinical studies that can lay the groundwork to evaluate the potential of locus coeruleus imaging as a biomarker for neurodegenerative diseases.

Background STN-DBS effectively treats motor symptoms of advanced PD. Nonmotor cognitive symptoms, such as impaired impulse control or decision making, may either improve or worsen with DBS. A potential mediating factor of DBS-induced modulation of cognition is the electrode position within the STN with regard to functional subareas of parallel motor, cognitive, and affective basal ganglia loops. However, to date, the volume of tissue activated and weighted stimulation of STN motor versus nonmotor territories are yet to be linked to differential DBS effects on cognition. Objectives We aim to investigate whether STN-DBS influences risk-reward trade-off decisions and analyze its dependency on electrode placement. Methods Seventeen PD patients ON and OFF STN-DBS and 17 age-matched healthy controls conducted a sequential decision-making task with escalating risk and reward. We computed the effect of STN-DBS on risk-reward trade-off decisions, localized patients' bilateral electrodes, and analyzed the predictive value of volume of tissue activated in STN motor and nonmotor territories on behavioral change. Results We found that STN-DBS not only improves PD motor symptoms, but also normalizes overly risk-averse decision behavior in PD. Intersubject variance in electrode location could explain this behavioral change. Specifically, if STN-DBS activated preferentially STN motor territory, patients' risk-reward trade-off decisions more resembled those of healthy controls. Conclusions Our findings support the notion of convergence of different functional circuits within the STN and imply a positive effect of well-placed STN-DBS on nonmotor cognitive functioning in PD. © 2018 International Parkinson and Movement Disorder Society.

Within one experiment and one T-maze, we examined the consequences of (i) bilateral lesions of the anteromedial prefrontal cortex (PFC), (ii) bilateral transections of the fimbria-fornix (FF), or (iii) combined lesions of both PFC and FF (COMB) on rats’ ability to perform reversal or set-shifting. Postoperatively, the animals were trained to perform a spatial discrimination go-right task. This was followed by (1) a spatial reversal go-left task (reversal learning), or (2) a visual pattern discrimination task (set-shift). Neither single (PFC or FF) lesion nor combined (COMB) lesions affected the animals’ ability to acquire the original spatial discrimination task. Regarding the reversal learning, the performance of the PFC and the FF groups was not significantly different from that of the sham operated control animals (Sham). In contrast, animals with combined lesion of both structures were impaired on both error rate and acquisition speed relative to all other groups. Regarding the set-shifting, all lesioned groups were impaired relative to the Sham group both regarding the error rate and the acquisition speed. There was, however, no difference in the degree of impairment between the lesioned groups. We conclude that both the PFC and the hippocampus contributed to the mediation of the reversal learning and set-shifting. During functional recovery of reversal learning, these two structures exhibited a mutual dependency, whilst the functional recovery of set-shifting was mediated by a substrate outside these two structures.

Background Depressed individuals often exhibit impaired inhibition to negative input and identification of positive stimuli, but it is unclear whether this is a state or trait feature. We here exploited a naturalistic model, namely individuals with seasonal affective disorder (SAD), to study this feature longitudinally. Aim The goal of this study was to examine seasonal changes in inhibitory control and identification of emotional faces in individuals with SAD. Method Twenty-nine individuals diagnosed with winter-SAD and 30 demographically matched controls with no seasonality symptoms completed an emotional Go/NoGo task, requiring inhibition of prepotent responses to emotional facial expressions and an emotional face identification task twice, in winter and summer. Results In winter, individuals with SAD showed impaired ability to inhibit responses to angry (p = .0006) and sad faces (p = .011), and decreased identification of happy faces (p = .032) compared with controls. In summer, individuals with SAD and controls performed similarly on these tasks (ps > .24). Conclusion We provide novel evidence that inhibition of angry and sad faces and identification of happy faces are impaired in SAD in the symptomatic phase, but not in the remitted phase. The affective biases in cognitive processing constitute state-dependent features of SAD. Our data show that reinstatement of a normal affective cognition should be possible and would constitute a major goal in psychiatric treatment to improve the quality of life for these patients. (PsycINFO Database Record

When gathering valued goods, risk and reward are often coupled and escalate over time, for instance, during foraging, trading, or gambling. This escalating frame requires agents to continuously balance expectations of reward against those of risk. To address how the human brain dynamically computes these tradeoffs, we performed whole-brain fMRI while healthy young individuals engaged in a sequential gambling task. Participants were repeatedly confronted with the option to continue with throwing a die to accumulate monetary reward under escalating risk, or the alternative option to stop to bank the current balance. Within each gambling round, the accumulation of gains gradually increased reaction times for “continue” choices, indicating growing uncertainty in the decision to continue. Neural activity evoked by “continue” choices was associated with growing activity and connectivity of a cortico-subcortical “braking” network that positively scaled with the accumulated gains, including pre-supplementary motor area (pre-SMA), inferior frontal gyrus, caudate, and subthalamic nucleus (STN). The influence of the STN on continue-evoked activity in the pre-SMA was predicted by interindividual differences in risk-aversion attitudes expressed during the gambling task. Furthermore, activity in dorsal anterior cingulate cortex (ACC) reflected individual choice tendencies by showing increased activation when subjects made nondefault “continue” choices despite an increasing tendency to stop, but ACC activity did not change in proportion with subjective choice uncertainty. Together, the results implicate a key role of dorsal ACC, pre-SMA, inferior frontal gyrus, and STN in computing the trade-off between escalating reward and risk in sequential decision-making.SIGNIFICANCE STATEMENTUsing a paradigm where subjects experienced increasing potential rewards coupled with increasing risk, this study addressed two unresolved questions in the field of decision-making: First, we investigated an “inhibitory” network of regions that has so far been investigated with externally cued action inhibition. In this study, we show that the dynamics in this network under increasingly risky decisions are predictive of subjects' risk attitudes. Second, we contribute to a currently ongoing debate about the anterior cingulate cortex's role in sequential foraging decisions by showing that its activity is related to making nondefault choices rather than to choice uncertainty.

Adaptive actions build on internal probabilistic models of possible outcomes that are tuned according to the errors of their predictions when experiencing an actual outcome. Prediction errors (PEs) inform choice behavior across a diversity of outcome domains and dimensions, yet neuroimaging studies have so far only investigated such signals in singular experimental contexts. It is thus unclear whether the neuroanatomical distribution of PE encoding reported previously pertains to computational features that are invariant with respect to outcome valence, sensory domain, or some combination of the two. We acquired functional MRI data while volunteers performed four probabilistic reversal learning tasks which differed in terms of outcome valence (reward-seeking versus punishment-avoidance) and domain (abstract symbols versus facial expressions) of outcomes. We found that ventral striatum and frontopolar cortex coded increasingly positive PEs, whereas dorsal anterior cingulate cortex (dACC) traced increasingly negative PEs, irrespectively of the outcome dimension. Individual reversal behavior was unaffected by context manipulations and was predicted by activity in dACC and right inferior frontal gyrus (IFG). The stronger the response to negative PEs in these areas, the lower was the tendency to reverse choice behavior in response to negative events, suggesting that these regions enforce a rule-based strategy across outcome dimensions. Outcome valence influenced PE-related activity in left amygdala, IFG, and dorsomedial prefrontal cortex, where activity selectively scaled with increasingly positive PEs in the reward-seeking but not punishment-avoidance context, irrespective of sensory domain. Left amygdala displayed an additional influence of sensory domain. In the context of avoiding punishment, amygdala activity increased with increasingly negative PEs, but only for facial stimuli, indicating an integration of outcome valence and sensory domain during probabilistic choices.

We assessed the perceptions of physicians, dentists, and nurses working within the same hospital on variables relevant to stress and well-being. The guiding model incorporated job characteristics, job strain, job attitudes, so- cial support, personal characteristics, and health outcomes. The results showed differences among the three occupational groups in how they perceive their work environment, the amount of social support they receive, their level of satisfaction, and their degree of psychological well-being. Physicians reported greater satisfaction, professional orientation, and psychological well-being than did the nurses or dentists. Nurses reported the least satisfaction, and dentists reported the most social support from their peers and significant others. Dentists reported more qualitative workload demands and greater ability to predict job events, whereas nurses reported the most control over others, influence on decisions, self-determination on the job, and under- standing of events occurring ...