@phdthesis{Pozzi2020,
  author    = {Pozzi, Nicol{\´o} Gabriele},
  title     = {Parkinson's disease revisited: multiple circuitopathies},
  doi       = {10.25972/OPUS-21671},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216715},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Parkinson's disease (PD) is among the most common neurodegenerative conditions, and it is characterized by the progressive loss of dopaminergic neurons and a great variability in clinical expression. Despite several effective medications, it still causes disability as all patients show treatment-resistant symptoms and complications. A possible reason for this therapeutic-burden and great clinical variability lies in a probable misconception about its pathophysiology, one that focuses on neurodegeneration, while largely neglecting its functional consequences and the related compensatory changes. In this thesis, I expand on the hypothesis that some PD symptoms have a dysfunctional origin and reflect derangements of neural network dynamics, the means by which brain coordination supports any motor behaviour. In particular, I have investigated resting tremor and freezing of gait, two common symptoms with an enigmatic mechanism and suboptimal management. In the case of tremor, I predicted a pathological change in response to dopamine loss, which included the activation of noradrenergic (NA) neurons of the locus coeruleus (LC) projecting to the cerebellum. This compensatory LC activation that supports dopaminergic neurons might indeed come at the expense of tremor development. To assess the role of LC-NA in tremor development, I recorded tremor occurrence in the reserpinized rat model of PD, one of very few showing tremor, after selective lesioning (with the neurotoxin DSP-4) of the LC-NA terminal axons. DSP-4 induced a severe reduction of LC-NA terminal axons in the cerebellar cortex and this was associated with a significant reduction in tremor development. Unlike its development, tremor frequency and the akinetic rigid signs did not differ between the groups, thus suggesting a dopaminergic dependency. These findings suggest that the LC-NA innervation of the cerebellum has a critical role for PD tremor, possibly by exerting a network effect, which gates the cerebello-thalamic-cortical circuit into pathological oscillations upon a dopaminergic loss in the basal ganglia. In contrast, for the study of freezing of gait, I worked with human PD subjects and deep brain stimulation, a therapeutic neuromodulation device that in some prototypes also allows the recording of neural activity in freely-moving subjects. Gait freezing is a disabling PD symptom that suddenly impairs effective stepping, thus causing falls and disability. Also in this study, I hypothesized that the underlying pathophysiology may be represented by dysfunctional neural network dynamics that abruptly impair locomotor control by affecting the communication in the supraspinal locomotor network. To test this hypothesis, I investigated the coupling between the cortex and the subthalamic nucleus, two main nodes of the supraspinal locomotor network, in freely-moving subjects PD patients and also performed molecular brain imaging of striatal dopamine receptor density and kinematic measurements. I found that in PD patients, walking is associated with cortical-subthalamic stable coupling in a low-frequency band (i.e. θ-α rhythms). In contrast, these structures decoupled when gait freezing occurred in the brain hemisphere with less dopaminergic innervation. These findings suggest that freezing of gait is a "circuitopathy", with dysfunctional cortical-subcortical communication. Altogether the results of my experiments support the hypothesis that the pathophysiology of PD goes beyond neurodegenerative (loss-of-function) processes and that derangement of neural network dynamics coincides with some disabling PD symptoms, thus suggesting that PD can be interpreted as the combination of multiple circuitopathies.},
  subject      = {Parkinson-Krankheit},
  language  = {en}
}
@article{PalmisanoBeccariaHaufeetal.2022,
  author    = {Palmisano, Chiara and Beccaria, Laura and Haufe, Stefan and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.},
  title     = {Gait initiation impairment in patients with Parkinson's disease and freezing of gait},
  series = {Bioengineering},
  volume    = {9},
  journal   = {Bioengineering},
  number    = {11},
  issn      = {2306-5354},
  doi       = {10.3390/bioengineering9110639},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297579},
  year      = {2022},
  abstract  = {Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson's disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD.},
  language  = {en}
}