Biology subjects

Meder, D.

Publications and source records attributed to Meder, D..

5 recordsLinked to original sources

bioRxiv2026

Striatal Dopaminergic Dysfunction Constrains Motor Invigoration in Parkinson's Disease

Bradykinesia is a cardinal motor feature of Parkinson's disease and is characterised by a reduced ability to generate movements with normal speed and force. Although nigrostriatal dopamine loss is regarded as the primary cause, direct human evidence linking dopaminergic degeneration to striatal dysfunction and impaired motor output and vigour remains limited. To investigate this relationship, we developed a grip-force paradigm that quantified movement vigour as the ability to rapidly generate force. Fifty-three individuals with Parkinson's disease, 30 with levodopa-induced dyskinesia and 23 without, and 25 age-matched healthy controls performed the task during 3T functional MRI. Thirty-five patients additionally underwent dopamine transporter PET imaging to assess associations among nigrostriatal dopaminergic integrity, striatal activity and motor performance. Patients with Parkinson's disease showed marked reductions in initial movement vigour accompanied by reduced bilateral putaminal activation during force generation. Lower putaminal dopamine transporter binding was associated with both poorer movement vigour and weaker grip-related putaminal activation during functional MRI, establishing a direct link between nigrostriatal degeneration, impaired striatal recruitment and motor slowing. Functional MRI further revealed reduced reward-related responses in the nucleus accumbens. Across participants, stronger reward-related ventral striatal activity was associated with greater movement vigour, suggesting that motivational processes contribute independently to motor performance. Patients with levodopa-induced dyskinesia exhibited more severe putaminal dopaminergic denervation than patients without dyskinesia but showed no additional impairment of movement vigour or striatal task responses. These findings provide direct in vivo evidence that dorsal nigrostriatal dopaminergic degeneration constrains movement vigour in Parkinson's disease through reduced striatal recruitment during action generation. Impaired reward-related signalling in ventral striatum emerges as an additional, partly independent mechanism influencing motor performance, highlighting distinct motor and motivational contributions to bradykinesia.

neuroscience↗

bioRxiv2025

Blunted response of caudal locus coeruleus to arousing stimuli in Parkinson's Disease

Parkinsons disease (PD) causes progressive degeneration of noradrenergic neurons in the locus coeruleus (LC), contributing to non-motor symptoms. Using neuromelanin-sensitive ultra-high field (7T) MRI, we previously identified a reduction in neuromelanin signal in the caudal LC, indicating a rostro-caudal gradient of noradrenergic cell loss. Caudal LC degeneration was associated with greater severity of non-motor symptoms such as orthostatic hypotension and apathy. In the current study, we expanded the PD cohort to further validate the structure-symptom relationships within the LC and investigate how degeneration along the rostro-caudal LC axis affects arousal-related functional responsivity. To this end, 71 people with PD in the ON-medication state and 40 age- and sex-matched healthy controls underwent clinical assessments and 7T magnetization transfer-weighted (MTw) MRI to quantify structural changes along the rostro-caudal LC axis. A subgroup of 30 people with PD and 27 controls underwent 7T fMRI to assess LC responsivity to arousing auditory and visual stimuli in two fMRI sessions on separate days. Healthy controls were scanned twice without medication, while people with PD were studied on and off dopaminergic medication in counterbalanced order. In the PD group, MTw MRI confirmed a significant reduction of the regional neuromelanin signal in caudal LC relative to the control group (P = 0.0099). This structural disintegration correlated with orthostatic hypotension (P = 0.0087) and cognitive impairment (P = 0.036), corroborating its clinical relevance. Functional MRI revealed reduced activation of the caudal LC to arousing visual and auditory stimuli in people with PD relative to controls (P = 0.012). This difference reached statistical significance only in the ON-medication state, with a similar but non-significant trend in the OFF-medication state (P = 0.10). In an exploratory analysis of a smaller sub-sample, structural and functional caudal LC signals were significantly correlated in both people with PD and healthy controls (P = 0.0069). Together, the findings provide evidence for a rostro-caudal gradient of LC pathology in PD at both structural and functional levels. While structural MRI provides fine-grained insights into spatial gradients of disease-related pathology, functional MRI captures impaired functional responsivity of caudal LC. The presence of arousal-induced hypoactivation of caudal LC in the ON-medication state indicates that LC dysfunction extends beyond dopamine deficits in PD, highlighting complex interactions between dopaminergic and noradrenergic systems.

neuroscience↗

bioRxiv2023

Brain network reconfiguration during prediction error processing

Learning from experience is driven by reward prediction errors--signals that reflect updates to our expectations of reward. Despite numerous studies on neural correlates of reward prediction errors, the question of how large-scale brain networks reconfigure in response to reward prediction error signalling remains open. Here we ask how functional networks change in response to reward prediction errors depending on the context. In our study participants performed the probabilistic reversal learning task in functional magnetic resonance imaging (fMRI) scanner in two experimental contexts: a reward-seeking setting and a punishment-avoiding. We found that the participants learning speed depended on the sign of the prediction error but not on the experimental context. Whole-brain network analysis revealed a multi-scale community structure with a separate striatal reward network emerging at a finer topological scale and a ventromedial prefrontal network emerging at a coarser scale. We also found that the integration between large-scale networks increased when switching from positive to negative prediction error events. This pattern of large-scale network reconfiguration aligns with the broad range of research showing increased network integration with increased cognitive demands. Our findings offer a first sketch of how processing reward prediction error affects the functional connectivity of brain-wide networks.

neuroscience↗

bioRxiv2022

Linking impulsivity to activity levels in pre-supplementary motor area during sequential gambling

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).

neuroscience↗

bioRxiv2017

Simultaneous representation of a spectrum of dynamically changing value estimates during decision making

Decisions are based on value expectations derived from experience. We show that dorsal anterior cingulate cortex and three other brain regions hold multiple representations of choice value based on different time-scales of experience organized in terms of systematic gradients across the cortex. Some parts of each area represent value estimates based on recent reward experience while others represent value estimates based on experience over the longer term. The value estimates within these four brain areas interact with one another according to their temporal scaling. Some aspects of the representations change dynamically as the environment changes. The spectrum of value estimates may act as a flexible selection mechanism for combining experience-derived value information with other aspects of value to allow flexible and adaptive decisions in changing environments.

neuroscience↗