Predictors of stress resilience in Parkinson's disease and associations with symptom progression.

People with Parkinson's disease (PD) are sensitive to effects of long-term stress, but might differ in stress resilience, i.e. the ability to maintain mental health despite adversity. It is unclear whether stress resilience in PD is predominantly determined by dopamine deficiency, psychosocial factors, or both. In PD animal models, chronic stressors accelerate disease progression, but evidence in humans is lacking. Our objectives were to (1) distinguish stressor-reactive from resilient PD patients, (2) identify resilience factors, and (3) compare symptom progression between stressor-reactive and resilient patients. We conducted a longitudinal survey in Personalized Parkinson Project participants (N = 350 PD). We used the COVID-19 pandemic as a model of a stressor, aligned in time for the entire cohort. COVID-19-related stressors, perceived stress, and PD symptoms were assessed at 11 timepoints (April-October 2020). Both pre-COVID and in-COVID clinical assessments were available. We quantified stressor-reactivity as the residual between actual and predicted perceived stress relative to COVID-19-related stressors, and modeled trajectories of stressor-reactivity across timepoints. We explored pre-COVID predictors of 6-month average stressor-reactivity, and tested whether stressor-reactivity was prospectively associated with one-year clinical progression rates. Latent class trajectory models distinguished patients with high (N = 123) or low (N = 227) stressor-reactivity. Pre-existing anxiety, rumination and non-motor symptom severity predicted high stressor-reactivity (risk factors), whereas quality of life, social support, positive appraisal style and cognitive abilities predicted low stressor-reactivity (resilience factors). PD-specific factors, e.g. disease duration, motor severity, and levodopa use, did not predict stressor-reactivity. The COVID-19 pandemic did not accelerate disease progression, but worsened depressive symptoms in stressor-reactive PD patients.

Alleviating Stress in Parkinson's Disease: Symptomatic Treatment, Disease Modification, or Both?

Psychological stress, a state of mental strain caused by mentally or physically threatening situations, plays a significant role in Parkinson's disease (PD). Motor symptoms worsen during acute stress and common non-motor symptoms in PD, such as anxiety and depression, are linked to chronic stress. Although evidence in humans is lacking, animal models of PD suggest that chronic stress can accelerate dopaminergic cell death. This suggests that stress-reducing interventions have not only symptomatic, but perhaps also disease-modifying effects. Our objective was to identify the most promising strategies for stress-reduction in PD and to analyze their potential value for disease-modification. An unstructured literature search was performed, primarily focusing on papers published between 2020-2023. Several large clinical trials have tested the efficacy of aerobic exercise and mindfulness-based interventions on PD symptoms. The evidence is promising, but not definitive yet: some exercise trials found a reduction in stress-related symptoms, whereas others did not or did not report it. In the majority of trials, biological measures of stress and of disease progression are missing. Furthermore, follow-up periods were generally too short to measure disease-modifying effects. Hence, mechanisms underlying the intervention effects remain largely unclear. These effects may consist of attenuating progressive neurodegeneration (measured with MRI-markers of substantia nigra integrity or cortical thickness), or a strengthening of compensatory cerebral mechanisms (measured with functional neuroimaging), or both. Lifestyle interventions are effective for alleviating stress-related symptoms in PD. They hold potential for exerting disease-modifying effects, but new evidence in humans is necessary to fulfill that promise.

Clinical severity in Parkinson's disease is determined by decline in cortical compensation.

Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Integrative Brain States Facilitate the Expression of Parkinson's Tremor.

BACKGROUND: Parkinson's disease (PD) rest tremor emerges from pathological activity in the basal ganglia and cerebello-thalamo-cortical circuits. A well-known clinical feature is the waxing and waning of PD tremor amplitude, but the mechanisms that drive this variability are unclear. Previous work has shown that arousal amplifies PD tremor by increasing between-network connectivity. Furthermore, brain states in PD are biased toward integration rather than segregation, a pattern that is also associated with increased arousal. OBJECTIVE: The aim was to test the hypothesis that fluctuations in integrative brain states and/or arousal drive spontaneous fluctuations in PD rest tremor. METHODS: We compared the temporal relationship between cerebral integration, the ascending arousal system, and tremor, both during cognitive load and in the resting state. In 40 tremor-dominant PD patients, we performed functional magnetic resonance imaging using concurrent tremor recordings and proxy measures of the ascending arousal system (pupil diameter, heart rate). We calculated whole-brain dynamic functional connectivity and used graph theory to determine a scan-by-scan measure of cerebral integration, which we related to the onset of tremor episodes. RESULTS: Fluctuations in cerebral integration were time locked to spontaneous changes in tremor amplitude: cerebral integration increased 13 seconds before tremor onset and predicted the amplitude of subsequent increases in tremor amplitude. During but not before tremor episodes, pupil diameter and heart rate increased and correlated with tremor amplitude. CONCLUSIONS: Integrative brain states are an important cerebral environment in which tremor-related activity emerges, which is then amplified by the ascending arousal system. New treatments focused on attenuating enhanced cerebral integration in PD may reduce tremor. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impulse control disorder in Parkinson's disease is associated with abnormal frontal value signalling.

Dopaminergic medication is well established to boost reward- versus punishment-based learning in Parkinson's disease. However, there is tremendous variability in dopaminergic medication effects across different individuals, with some patients exhibiting much greater cognitive sensitivity to medication than others. We aimed to unravel the mechanisms underlying this individual variability in a large heterogeneous sample of early-stage patients with Parkinson's disease as a function of comorbid neuropsychiatric symptomatology, in particular impulse control disorders and depression. One hundred and ninety-nine patients with Parkinson's disease (138 ON medication and 61 OFF medication) and 59 healthy controls were scanned with functional MRI while they performed an established probabilistic instrumental learning task. Reinforcement learning model-based analyses revealed medication group differences in learning from gains versus losses, but only in patients with impulse control disorders. Furthermore, expected-value related brain signalling in the ventromedial prefrontal cortex was increased in patients with impulse control disorders ON medication compared with those OFF medication, while striatal reward prediction error signalling remained unaltered. These data substantiate the hypothesis that dopamine's effects on reinforcement learning in Parkinson's disease vary with individual differences in comorbid impulse control disorder and suggest they reflect deficient computation of value in medial frontal cortex, rather than deficient reward prediction error signalling in striatum. See Michael Browning (https://doi.org/10.1093/brain/awad248) for a scientific commentary on this article.

A vision of 14 T MR for fundamental and clinical science.

OBJECTIVE: We outline our vision for a 14 Tesla MR system. This comprises a novel whole-body magnet design utilizing high temperature superconductor; a console and associated electronic equipment; an optimized radiofrequency coil setup for proton measurement in the brain, which also has a local shim capability; and a high-performance gradient set. RESEARCH FIELDS: The 14 Tesla system can be considered a 'mesocope': a device capable of measuring on biologically relevant scales. In neuroscience the increased spatial resolution will anatomically resolve all layers of the cortex, cerebellum, subcortical structures, and inner nuclei. Spectroscopic imaging will simultaneously measure excitatory and inhibitory activity, characterizing the excitation/inhibition balance of neural circuits. In medical research (including brain disorders) we will visualize fine-grained patterns of structural abnormalities and relate these changes to functional and molecular changes. The significantly increased spectral resolution will make it possible to detect (dynamic changes in) individual metabolites associated with pathological pathways including molecular interactions and dynamic disease processes. CONCLUSIONS: The 14 Tesla system will offer new perspectives in neuroscience and fundamental research. We anticipate that this initiative will usher in a new era of ultra-high-field MR.

MRI factors associated with cognitive functioning after acute onset brain injury: Systematic review and meta-analysis.

Impairments of memory, attention, and executive functioning are frequently reported after acute onset brain injury. MRI markers hold potential to contribute to identification of patients at risk for cognitive impairments and clarification of mechanisms. The aim of this systematic review was to summarize and value the evidence on MRI markers of memory, attention, and executive functioning after acute onset brain injury. We included ninety-eight studies, on six classes of MRI factors (location and severity of damage (n = 15), volume/atrophy (n = 36), signs of small vessel disease (n = 15), diffusion-weighted imaging measures (n = 36), resting-state functional MRI measures (n = 13), and arterial spin labeling measures (n = 1)). Three measures showed consistent results regarding their association with cognition. Smaller hippocampal volume was associated with worse memory in fourteen studies (pooled correlation 0.58 [95% CI: 0.46-0.68] for whole, 0.11 [95% CI: 0.04-0.19] for left, and 0.34 [95% CI: 0.17-0.49] for right hippocampus). Lower fractional anisotropy in cingulum and fornix was associated with worse memory in six and five studies (pooled correlation 0.20 [95% CI: 0.08-0.32] and 0.29 [95% CI: 0.20-0.37], respectively). Lower functional connectivity within the default-mode network was associated with worse cognition in four studies. In conclusion, hippocampal volume, fractional anisotropy in cingulum and fornix, and functional connectivity within the default-mode network showed consistent associations with cognitive performance in all types of acute onset brain injury. External validation and cut off values for predicting cognitive impairments are needed for clinical implementation.

Modulating arousal to overcome gait impairments in Parkinson's disease: how the noradrenergic system may act as a double-edged sword.

In stressful or anxiety-provoking situations, most people with Parkinson's disease (PD) experience a general worsening of motor symptoms, including their gait impairments. However, a proportion of patients actually report benefits from experiencing-or even purposely inducing-stressful or high-arousal situations. Using data from a large-scale international survey study among 4324 people with PD and gait impairments within the online Fox Insight (USA) and ParkinsonNEXT (NL) cohorts, we demonstrate that individuals with PD deploy an array of mental state alteration strategies to cope with their gait impairment. Crucially, these strategies differ along an axis of arousal-some act to heighten, whereas others diminish, overall sympathetic tone. Together, our observations suggest that arousal may act as a double-edged sword for gait control in PD. We propose a theoretical, neurobiological framework to explain why heightened arousal can have detrimental effects on the occurrence and severity of gait impairments in some individuals, while alleviating them in others. Specifically, we postulate that this seemingly contradictory phenomenon is explained by the inherent features of the ascending arousal system: namely, that arousal is related to task performance by an inverted u-shaped curve (the so-called Yerkes and Dodson relationship). We propose that the noradrenergic locus coeruleus plays an important role in modulating PD symptom severity and expression, by regulating arousal and by mediating network-level functional integration across the brain. The ability of the locus coeruleus to facilitate dynamic 'cross-talk' between distinct, otherwise largely segregated brain regions may facilitate the necessary cerebral compensation for gait impairments in PD. In the presence of suboptimal arousal, compensatory networks may be too segregated to allow for adequate compensation. Conversely, with supraoptimal arousal, increased cross-talk between competing inputs of these complementary networks may emerge and become dysfunctional. Because the locus coeruleus degenerates with disease progression, finetuning of this delicate balance becomes increasingly difficult, heightening the need for mental strategies to self-modulate arousal and facilitate shifting from a sub- or supraoptimal state of arousal to improve gait performance. Recognition of this underlying mechanism emphasises the importance of PD-specific rehabilitation strategies to alleviate gait disability.

Time trends in demographic characteristics of participants and outcome measures in Parkinson's disease research: A 19-year single-center experience.

Background: Females, people with young-onset PD and older individuals, and non-white populations are historically underrepresented in clinical Parkinson's disease (PD) research. Furthermore, research traditionally focused predominantly on motor symptoms of PD. Including a representative and diverse group of people with PD and also studying non-motor symptoms is warranted to better understand heterogeneity in PD and to generalize research findings. Objective: This project aimed to determine whether, within a consecutive series of PD studies performed within a single center in the Netherlands: (1) the proportion of included females, mean age and proportion of native Dutch people changed over time; and 2) reports of the ethnicity of participants and the proportion of studies with non-motor outcomes changed over time. Methods: Characteristics of participants and non-motor outcomes were analyzed using a unique dataset of summary statistics of studies with a large number of participants conducted at a single center during a 19-year period (2003-2021). Results: Results indicate no relationship between calendar time and proportion of females (mean 39 %), mean age (66 years), proportion of studies that reported ethnicity, and proportion of native Dutch people in studies (range 97-100 %). The proportion of participants in whom non-motor symptoms were assessed increased, but this difference was consistent with chance. Conclusion: Study participants in this center reflect the PD population in the Netherlands in terms of sex, but older individuals and non-native Dutch individuals are under-represented. We have still a lot to do in ensuring adequate representation and diversity in PD patients within our research.

Two-year clinical progression in focal and diffuse subtypes of Parkinson's disease.

Heterogeneity in Parkinson's disease (PD) presents a barrier to understanding disease mechanisms and developing new treatments. This challenge may be partially overcome by stratifying patients into clinically meaningful subtypes. A recent subtyping scheme classifies de novo PD patients into three subtypes: mild-motor predominant, intermediate, or diffuse-malignant, based on motor impairment, cognitive function, rapid eye movement sleep behavior disorder (RBD) symptoms, and autonomic symptoms. We aimed to validate this approach in a large longitudinal cohort of early-to-moderate PD (n = 499) by assessing the influence of subtyping on clinical characteristics at baseline and on two-year progression. Compared to mild-motor predominant patients (42%), diffuse-malignant patients (12%) showed involvement of more clinical domains, more diffuse hypokinetic-rigid motor symptoms (decreased lateralization and hand/foot focality), and faster two-year progression. These findings extend the classification of diffuse-malignant and mild-motor predominant subtypes to early-to-moderate PD and suggest that different pathophysiological mechanisms (focal versus diffuse cerebral propagation) may underlie distinct subtype classifications.

Effectiveness of an outpatient rehabilitation programme in patients with neuralgic amyotrophy and scapular dyskinesia: a randomised controlled trial.

BACKGROUND: Neuralgic amyotrophy (NA) is an acute inflammation of nerves within the brachial plexus territory leading to severe pain and multifocal paresis resulting in >60% of patients having residual complaints and functional limitations correlated with scapular dyskinesia. Our primary aim was to compare the effects of multidisciplinary rehabilitation (MR), focused on motor relearning to improve scapular dyskinesia and self-management strategies for reducing pain and fatigue, with usual care (UC) on shoulder, arm and hand functional capability in patients with NA. METHODS: In a non-blinded randomised controlled trial (RCT), patients with NA (aged≥18 years, scapular dyskinesia, >8 weeks after onset) were randomised to either an MR or an UC group. MR consisted of a diagnostic multidisciplinary consultation and eight sessions of physical and occupational therapy. Primary outcome was functional capability of the shoulder, arm and hand assessed with the Shoulder Rating Questionnaire-Dutch Language Version (SRQ-DLV). RESULTS: We included 47 patients with NA; due to drop-out, there were 22 participants in MR and 15 in UC for primary analysis. The mean group difference adjusted for sex, age and SRQ-DLV baseline score was 8.60 (95%CI: 0.26 to 16.94, p=0.044). The proportion attaining a minimal clinically relevant SRQ-DLV improvement (≥12) was larger for the MR group (59%) than the UC group (33%) with a number needed to treat of 4. CONCLUSION: This RCT shows that an MR programme focused on motor relearning to improve scapular dyskinesia, combined with self-management strategies for reducing pain and fatigue, shows more beneficial effects on shoulder, arm and hand functional capability than UC in patients with NA. TRIAL REGISTRATION NUMBER: NCT03441347.

Cerebral Adaptation Associated with Peripheral Nerve Recovery in Neuralgic Amyotrophy: A Randomized Controlled Trial.

BACKGROUND: Neuralgic amyotrophy (NA) is a common peripheral nerve disorder caused by auto-immune inflammation of nerves in the brachial plexus territory, characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Recent work has confirmed that NA patients with residual motor dysfunction have abnormal cerebral sensorimotor representations of their affected upper extremity. OBJECTIVE: To determine whether abnormal cerebral sensorimotor representations associated with NA can be altered by specialized, multidisciplinary outpatient rehabilitation focused on relearning motor control. METHODS: 27 NA patients with residual lateralized symptoms in the right upper extremity participated in a randomized controlled trial, comparing 17 weeks of multidisciplinary rehabilitation (n = 16) to usual care (n = 11). We used task-based functional MRI and a hand laterality judgment task, which involves motor imagery and is sensitive to altered cerebral sensorimotor representations of the upper extremity. RESULTS: Change in task performance and related brain activity did not differ significantly between the multidisciplinary rehabilitation and usual care groups, whereas the multidisciplinary rehabilitation group showed significantly greater clinical improvement on the Shoulder Rating Questionnaire. Both groups, however, showed a significant improvement in task performance from baseline to follow-up, and significantly increased activity in visuomotor occipito-parietal brain areas, both specific to their affected upper extremity. CONCLUSIONS: Abnormal cerebral sensorimotor representations of the upper extremity after peripheral nerve damage in NA can recover toward normality. As adaptations occurred in visuomotor brain areas, multidisciplinary rehabilitation after peripheral nerve damage may be further optimized by applying visuomotor strategies. This study is registered at ClinicalTrials.gov (NCT03441347).

MRI markers of brain network integrity relate to neurological outcome in postanoxic coma.

AIM: Current multimodal approaches leave approximately half of the comatose patients after cardiac arrest with an indeterminate prognosis. Here we investigated whether early MRI markers of brain network integrity can distinguish between comatose patients with a good versus poor neurological outcome six months later. METHODS: We performed a prospective cohort study in 48 patients after cardiac arrest submitted in a comatose state to the Intensive Care Unit of two Dutch hospitals. MRI was performed at three days after cardiac arrest, including resting state functional MRI and diffusion-tensor imaging (DTI). Resting state fMRI was used to quantify functional connectivity within ten resting-state networks, and DTI to assess mean diffusivity (MD) in these same networks. We contrasted two groups of patients, those with good (n = 29, cerebral performance category 1-2) versus poor (n = 19, cerebral performance category 3-5) outcome at six months. Mutual associations between functional connectivity, MD, and clinical outcome were studied. RESULTS: Patients with good outcome show higher within-network functional connectivity (fMRI) and higher MD (DTI) than patients with poor outcome across 8/10 networks, most prominent in the default mode network, salience network, and visual network. While the anatomical distribution of outcome-related changes was similar for functional connectivity and MD, the pattern of inter-individual differences was very different: functional connectivity showed larger inter-individual variability in good versus poor outcome, while the opposite was observed for MD. Exploratory analyses suggested that it is possible to define network-specific cut-off values that could help in outcome prediction: (1) high functional connectivity and high MD, associated with good outcome; (2) low functional connectivity and low MD, associated with poor outcome; (3) low functional connectivity and high MD, associated with uncertain outcome. DISCUSSION: Resting-state functional connectivity and mean diffusivity-three days after cardiac arrest are strongly associated with neurological recovery-six months later in a complementary fashion. The combination of fMRI and MD holds potential to improve prediction of outcome.

Clinical neurophysiology of Parkinson's disease and parkinsonism.

This review is part of the series on the clinical neurophysiology of movement disorders. It focuses on Parkinson's disease and parkinsonism. The topics covered include the pathophysiology of tremor, rigidity and bradykinesia, balance and gait disturbance and myoclonus in Parkinson's disease. The use of electroencephalography, electromyography, long latency reflexes, cutaneous silent period, studies of cortical excitability with single and paired transcranial magnetic stimulation, studies of plasticity, intraoperative microelectrode recordings and recording of local field potentials from deep brain stimulation, and electrocorticography are also reviewed. In addition to advancing knowledge of pathophysiology, neurophysiological studies can be useful in refining the diagnosis, localization of surgical targets, and help to develop novel therapies for Parkinson's disease.