Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

Rucco, Rosaria; Liparoti, Marianna; Jacini, Francesca; Baselice, Fabio; Antenora, Antonella; Michele, Giuseppe De; Criscuolo, Chiara; Vettoliere, A.; Mandolesi, Laura; Sorrentino, Giuseppe; Sorrentino, Pierpaolo

doi:10.1007/s10072-019-3725-y

Cited by 30 publications

(22 citation statements)

References 45 publications

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“…In fact, excessive synchronization reduces the variability of the behaviour of the system, hence narrowing the number of functional states that are readily accessible 27 , 40 . Hypersynchronization and hyperconnected topology have been associated with a variety of neurological diseases 41 , 42 , as well as in preclinical conditions that carry an increased risk of neurodegeneration 43 , hence investigations of the functional repertoires in these diseases and conditions could help characterizing these conditions.…”

Section: Discussionmentioning

confidence: 99%

Flexible brain dynamics underpins complex behaviours as observed in Parkinson’s disease

Sorrentino

Rucco

Baselice

et al. 2021

Sci Rep

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Rapid reconfigurations of brain activity support efficient neuronal communication and flexible behaviour. Suboptimal brain dynamics is associated to impaired adaptability, possibly leading to functional deficiencies. We hypothesize that impaired flexibility in brain activity can lead to motor and cognitive symptoms of Parkinson’s disease (PD). To test this hypothesis, we studied the ‘functional repertoire’—the number of distinct configurations of neural activity—using source-reconstructed magnetoencephalography in PD patients and controls. We found stereotyped brain dynamics and reduced flexibility in PD. The intensity of this reduction was proportional to symptoms severity, which can be explained by beta-band hyper-synchronization. Moreover, the basal ganglia were prominently involved in the abnormal patterns of brain activity. Our findings support the hypotheses that: symptoms in PD relate to impaired brain flexibility, this impairment preferentially involves the basal ganglia, and beta-band hypersynchronization is associated with reduced brain flexibility. These findings highlight the importance of extensive functional repertoires for correct behaviour.

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Section: Discussionmentioning

confidence: 99%

Flexible brain dynamics underpins complex behaviours as observed in Parkinson’s disease

Sorrentino

Rucco

Baselice

et al. 2021

Sci Rep

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“…It is also likely that clinical motor impairment in HSP is due to more global cerebral impairment than just the motor tracts. A study using magnetoencephalography to assess the connectivity of brain networks found changes that suggested global network rearrangement due to changes beyond motor impairment (54). One study looking at 118 patients with SPG4 HSP found 10% had psychiatric comorbidities and 3.5% had memory impairment, possible reflecting more global cerebral impairment (55).…”

Section: Discussionmentioning

confidence: 99%

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Siow

Smail

et al. 2019

Front. Neurol.

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Background: Hereditary Spastic Paraplegia (HSP) is a slowly progressive neurodegenerative disorder with no disease modifying treatment. Potential therapeutic approaches are emerging and large-scale clinical drug trials for patients with HSP are imminent. A sensitive biomarker to measure the drug efficacy in these trials is required. Motor evoked potentials (MEPs) are a potential biomarker for HSP as they assess the central motor pathways and can be standardized with set protocols and guidelines.Objectives: We performed a systematic review to investigate the utility of MEPs as a diagnostic and disease severity biomarker for HSP.Search Methods: Systematic searches of PubMed, Embase, Medline, and Scopus were performed.Selection Criteria: Studies reporting on central motor conduction time measured with MEPs in adult and pediatric patients with HSP were included. We excluded studies in non-HSP patient cohorts, not in English, not original research, and unpublished journal articles.Data Collection and analysis: Search results were de-duplicated and screened according to the inclusion and exclusion criteria. The included papers were reviewed independently by two reviewers and data was collected on patient cohorts, test methods, results, and study quality. Results were analyzed using descriptive methods.Results: Of the 882 search results, 32 studies were included in the review. The most common finding was absent or prolonged lower limb (LL) central motor conduction time (CMCT) in patients with HSP (78% of patients studied). Quality assessment revealed variability in study methodology and reporting of results. Variations included patient cohorts of various genotypes as well as variations in equipment and techniques used. Aside from CMCT, none of the MEP parameter measures correlated with disease severity and many did not show significant difference between HSP patients and controls.Conclusion: Systematic review of MEP studies in HSP patient cohorts demonstrated mixed findings. Lower limb CMCT was the most promising parameter in terms of differentiating HSP patients from controls, with one study demonstrating a weak correlation with clinical disease severity. It is possible that the lack of consistency in study methodologies and small patient cohorts have contributed to the variable findings. A longitudinal study of MEPs in a large cohort of HSP patients with the same genotype will help clarify the utility of MEPs as a biomarker for disease severity and use in clinical trials.

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“…In fact, excessive synchronization reduces the variability of the behaviour of the system, hence narrowing the number of states that are readily accessible (54,73,74). Hypersynchronization and hyperconnected topology have been associated with a variety of neurological diseases (75,76), as well as in preclinical conditions that carry an increased risk of neurodegeneration (77) hence investigations of the functional repertoires in these diseases and conditions could provide answers to this question.…”

Section: Discussionmentioning

confidence: 99%

Extensive functional repertoire underpins complex behaviours: insights from Parkinson’s disease

Sorrentino

Rucco

Baselice

et al. 2019

Preprint

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Rapid reconfigurations of brain activity support efficient neuronal communication and flexible behaviour. Suboptimal brain dynamics impair this adaptability, possibly leading to functional deficiencies. We hypothesize that impaired flexibility in brain activity can lead to motor and cognitive symptoms of Parkinson's disease (PD). To test this hypothesis, we studied the 'functional repertoire' the number of distinct configurations of neural activityusing source-reconstructed magnetoencephalography in PD patients and controls. We found stereotyped brain dynamics and reduced flexibility in PD. The intensity of this reduction was proportional to symptoms severity, and explained by beta-band hyper-synchronization. Moreover, the basal ganglia were prominently involved in the abnormal patterns of brain activity. Our findings support the hypotheses that: symptoms in PD reflect impaired brain flexibility, this impairment preferentially involves the basal ganglia, and beta-band hypersynchronization is associated with reduced brain flexibility. These findings highlight the importance of extensive functional repertoires for behaviour and motor.Parkinson's disease (PD) is a severe and disabling neurodegenerative disorder. It is characterized by reduced amplitude of movements, and slowing of cognitive processes, imposing major individual and social burden (24). The main histopathological finding in PD is a severe nigrostriatal dopamine depletion (25,26). PD has traditionally been regarded predominantly as a motor disease. However, recent clinical and neuroimaging findings have questioned these views (27). For example, the first symptoms to appear are often not motor, and the clinical phenotype clearly goes well beyond the motor impairment, with other domains, such as executive functioning, involved (28,29). Structural Magnetic Resonance Imaging (MRI) has also confirmed that PD is more widespread than previously thought (27). Although functional magnetic resonance (fMRI) studies have identified impairment in the corticostriatal network in PD patients, the observed changes in functional connectivity extend into many other brain systems (30). Similarly, magnetoencephalography (MEG) studies have also reported widespread functional connectivity alterations in PD (31-34) .The brain can be represented as a network, with, at the macro-scale, brain areas as 'nodes' and structural or functional relationships between the brain areas as 'edges ' (35, 36), following which the topology of the network can be characterised using graph theory. A rapidly growing body of research now uses graph theory to characterize large-scale patterns of brain activation in health (37) and disease (38). Graph theory has highlighted the multifaceted nature of large-scale interactions in PD, with studies reporting more-connected networks (39-42), less-connected networks (43-48), and a combination of both (49,50). However, most research in this area has assumed brain activity to be stationary, and did not explore the structure of dynamic fluctuations in activity...

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Mutations in the SPAST gene causing hereditary spastic paraplegia are related to global topological alterations in brain functional networks

Cited by 30 publications

References 45 publications

Flexible brain dynamics underpins complex behaviours as observed in Parkinson’s disease

Flexible brain dynamics underpins complex behaviours as observed in Parkinson’s disease

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

Extensive functional repertoire underpins complex behaviours: insights from Parkinson’s disease

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