Behind the mirror: clinical and neuroradiological significance of mirror movements in idiopathic REM sleep behavior disorder

Autori

Elisabetta Sarasso (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy)

Roberta Balestrino (Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy, Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Silvia Basaia (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy)

Andrea Gardoni (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy)

Saverio Sangermano (Vita-Salute San Raffaele University, Milan, Italy)

Sara Marelli (Sleep Disorders Center, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Alessandra Castlenuovo (Sleep Disorders Center, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Andrea Grassi (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy)

Elisa Canu (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Luigi Ferini-Strambi (Sleep Disorders Center, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy)

Massimo Filippi (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Federica Agosta (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy)

Background and aims

Idiopathic REM Sleep Behavior Disorder (iRBD) is a recognized prodromal stage of synucleinopathies such as Parkinson’s disease (PD). Mirror movements (MM), involuntary contralateral mirroring of voluntary motor actions, are paraphysiological phenomena present in childhood and minimally in elder healthy subjects. Their re-emergence is documented in a wide range of diseases such as stroke, multiple sclerosis and movement disorders. They have been observed in PD, where they may reflect a compensatory cortical activation. In this context, MM appear as an epiphenomenon, whose expression is amplified by impaired interhemispheric inhibition. To our knowledge their presence and significance in iRBD have not been explored.

Methods

We enrolled 49 polysomnography-confirmed iRBD patients, divided into MM-positive (n=33) and MM-negative (n=16) groups. MM were phenotyped as monolateral (n=10) or bilateral (n=23). All underwent neurological, cognitive (MMSE, FAB, Rey and Benson figures, Rey Word List, Corsi, Token Test), motor (UPDRS I–III, 9HPT, 5TSTS, 10MWT), and MRI evaluations. FLAIR, 3DT1, 3DT2 sequences were used to assess hyperintense lesions (juxtacortical lesions, deep grey matter (DGM) lesions, periventricular lesions, infratentorial lesion) via volumetric and lesion count analyses. This study was funded from the Italian Ministero della Salute (grant number RF-2018-12366746).

Results

MM-positive patients showed lower upper limb dexterity (9HPT: 24.16±3.38 s vs 22.43±3.05 s, p=0.029) and reduced visuospatial-executive function (Corsi: 4.97±0.64 vs 5.63±1.03, p=0.004; Rey copy: 32.58±2.41 vs 34.13±1.71, p=0.01). Monolateral MM had younger age and more pronounced cognitive impairment in visuospatial, memory, and language tasks. Bilateral MM presented significantly increased DGM lesion volume (32.00±39.28 mm³ vs 11.00±19.00 in monolateral MM, p=0.049) and lesion number (1.45±1.64 vs 0.22±0.44, p=0.029), as well as greater periventricular hyperintense lesions burden (p=0.071 trend). Correlation analyses revealed that periventricular lesion volume and number were significantly associated with worse visuospatial performance (e.g. Rey copy: p=0.002, r=–0.668), mood symptoms (BDI-II: p=0.013, r=0.572), and gait impairment (N° of steps at 10MWT: p=0.014, r=0.555).

Conclusion

MM are common in iRBD but display distinct clinical and radiological profiles. Monolateral MM may reflect more closely early neurodegenerative processes and initial cognitive changes, while bilateral MM may reflect a more aspecific pattern, potentially driven by vascular burden. MM assessment may help identifying subgroups with different trajectories and risk profiles in the prodromal phase of synucleinopathies: longitudinal analysis is warranted to explore this hypothesis.

REFERENCES

Cox BC, Cincotta M, Espay AJ. Mirror movements in movement disorders: a review. Tremor Other Hyperkinet Mov (N Y). 2012;2:tre-02-59-398-1. doi: 10.7916/D8VQ31DZ. Epub 2012 Apr 16. PMID: 23440079; PMCID: PMC3569961.

Poisson A, Ballanger B, Metereau E, Redouté J, Ibarolla D, Comte JC, Bernard HG, Vidailhet M, Broussolle E, Thobois S. A functional magnetic resonance imaging study of pathophysiological changes responsible for mirror movements in Parkinson’s disease. PLoS One. 2013 Jun 25;8(6):e66910. doi: 10.1371/journal.pone.0066910. PMID: 23825583; PMCID: PMC3692538.

 

Altered functional connectivity in sensorimotor, emotional, and cognitive networks and changes of cerebellar volumes in Functional Movement Disorders

Autori

Elisabetta Sarasso (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy) – Andrea Gardoni (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Marialuisa Gandolfi (University of Verona, Verona, Italy) – Silvia Basaia (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy)

Elisa Canu (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Elisa Sibilla (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Chiara Tripodi (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy) – Angela Sandri (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy)

Ilaria Antonella Di Vico (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Mirta Fiorio (University of Verona, Verona, Italy) – Giulia Pedrotti (University of Verona, Verona, Italy) – Anna Policelli (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy)

Paolo Barone (University of Salerno, Salerno, Italy) – Maria Teresa Pellecchia (University of Salerno, Salerno, Italy) – Roberto Erro (University of Salerno, Salerno, Italy) – Sofia Cuoco (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy)

Immacolata Carotenuto (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy) – Claudia Vinciguerra (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy) – Annibale Botto (Department of Neuroradiology, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy) – Marianna Amboni (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy)

Michela Russo (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy; Dipartimento di Ingegneria Elettrica e delle Tecnologie dell’Informazione, Università degli Studi di Napoli FEDERICO II, Naples, Italy) – Giancarlo Mansueto (University of Verona, Verona, Italy) – Francesca Benedetta Pizzini (University of Verona, Verona, Italy) – Marco Barillari (University of Verona, Verona, Italy)

Matteo Francesco Lauriola (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Maria Chiara Tozzi (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Francesca Rusciano (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Christian Geroin (University of Verona, Verona, Italy)

Melania Fasoli (University of Verona, Verona, Italy) – Angela Marotta (University of Verona, Verona, Italy) – Emanuela Pizzolla (University of Verona, Verona, Italy) – Francesca Salaorni (University of Verona, Verona, Italy)

Irene Lozzi (University of Verona, Verona, Italy) – Federica Bombieri (University of Verona, Verona, Italy) – Giovanna Maddalena Squintani (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Sara Mariotto (Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy) – Stefano Tamburin (University of Verona, Verona, Italy) – Fabio Paio (University of Verona, Verona, Italy) – Giuseppe De Biasi (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy) – Giuseppe Piscosquito (Neurological Clinic, AOU San Giovanni di Dio e Ruggi d’Aragona, Salerno, Italy)

Michele Tinazzi (University of Verona, Verona, Italy) – Massimo Filippi (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy, Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy, Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy, Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy, Neurophysiology service, IRCCS San Raffaele Scientific Institute, Milan, Italy) – Federica Agosta (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy, Neurotech Hub, Vita-Salute San Raffaele University, Milan, Italy, Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Background and aims

FMD remains a poorly understood phenomenon, characterized by inconsistent limb weakness, tremors, dystonia, and gait disturbances [1]. Preliminary evidence suggested that these symptoms might result from faulty neural processing, where disruptions in circuits integrating interoception, exteroception, and motor control lead to altered sensorimotor awareness [2]. The identification of neuroimaging biomarkers could enable earlier diagnosis and more effective management of FMD symptoms. This study aims to investigate alterations in brain functional connectivity (FC) and deep gray matter volume in patients with Functional Movement Disorders (FMD) compared to healthy controls. Specifically, it examines changes in resting-state FC networks and GM volume of areas involved in motor, exteroceptive and interoceptive domains.

Methods

Fifty-seven patients with FMD and 60 age- and sex-matched healthy controls underwent brain MRI. Brain MRI analyses included functional connectivity (FC) of the main resting-state networks using independent component analysis (MELODIC), cerebellar volumes using SUIT, and deep gray matter (GM) volumes using FMRIB’s Integrated Registration and Segmentation Tool and FreeSurfer. The study is funded by the European Union – Next Generation EU – NRRP M6C2 – Investment 2.1 Enhancement and strengthening of biomedical research in the NHS (PNRR-MAD-2022-12376826).

Results

FMD patients relative to healthy subjects exhibited an increased FC of bilateral putamen and caudate, right insula and inferior frontal gyrus within the basal ganglia network, an increased FC of bilateral precuneus within the ventral default-mode network, an increased FC of left cerebellum crus I within the primary visual network, and an increased FC of middle cingulate cortex in the precuneus network. Moreover, FMD patients showed increased volume of vermis crus II, VIIIa/b, and left lobules VIIIa/b.

Conclusion

The observed alterations of cerebellar volumes and of FC in the basal ganglia, default-mode, precuneus and primary visual networks may represent a mismatch between sensorimotor, emotional, and cognitive systems, leading to impaired self-awareness and motor intention, heightened attention to bodily signals, and compromised voluntary movement control mechanisms. These results support the neural basis of FMD, confirming that distinct mechanisms underlie the symptoms of this complex disorder.

REFERENCES

Tinazzi M, Morgante F, Marcuzzo E, Erro R, Barone P, Ceravolo R, Mazzucchi S, Pilotto A, Padovani A, Romito LM, Eleopra R, Zappia M, Nicoletti A, Dallocchio C, Arbasino C, Bono F, Pascarella A, Demartini B, Gambini O, Modugno N, Olivola E, Di Stefano V, Albanese A, Ferrazzano G, Tessitore A, Zibetti M, Calandra-Buonaura G, Petracca M, Esposito M, Pisani A, Manganotti P, Stocchi F, Coletti Moja M, Antonini A, Defazio G, Geroin C. Clinical Correlates of Functional Motor Disorders: An Italian Multicenter Study. Mov Disord Clin Pract. 2020 Sep 22;7(8):920-929. doi: 10.1002/mdc3.13077. PMID: 33163563; PMCID: PMC7604660.

Hallett M, Aybek S, Dworetzky BA, McWhirter L, Staab JP, Stone J. Functional neurological disorder: new subtypes and shared mechanisms. Lancet Neurol. 2022 Jun;21(6):537-550. doi: 10.1016/S1474-4422(21)00422-1. Epub 2022 Apr 14. Erratum in: Lancet Neurol. 2022 Jun;21(6):e6. doi: 10.1016/S1474-4422(22)00179-X. PMID: 35430029; PMCID: PMC9107510.

Il linguaggio del cammino: interpretare gli stati emotivi attraverso le caratteristiche del passo

The language of gait: interpreting emotional states through gait features

Autori

Elisabetta Sarasso (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy; Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy)

Martina Putzolu (Department of Experimental Medicine, Section of Human Physiology, University of Genoa, Genoa, Italy)

Elisa Canu (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Andrea Gardoni (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Elisa Ravizzotti (Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy)

Lucia Zenere (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Susanna Mezzarobba (Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy)

Silvia Basaia (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy)

Federica Agosta (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy) – Laura Avanzino (IRCCS Ospedale Policlinico San Martino, Genoa, Italy; Department of Experimental Medicine, Section of Human Physiology, University of Genoa, Genoa, Italy)

Massimo Filippi (Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy) – Elisa Pelosin (Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal Child Health, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy)

Introduction

Evidence suggests that action observation training can enhance spatio-temporal gait parameters in Parkinson’s disease (PD). Given the complex interplay between emotion and gait, gait videos with emotional contents might be useful in studying the interaction between gait and emotion in PD. The overall aim of the study was to investigate whether the observation of emotional gait conditions can modulate spatio-temporal gait parameters and gait-related functional brain correlates in healthy subjects and PD patients by evoking those emotions. To reach this overall objective, we first aimed at developing and testing gait videos evoking specific emotions in a large population of healthy subjects and then in a preliminary sample of PD.

Methods

We developed a questionnaire containing videos of an actress walking with different gait patterns according to specific emotions (happiness, sadness, fear, anxiety, anger, disgust, surprise and neutral). The actress was instructed to walk while embodying these emotions, and her facial expressions were intentionally blurred to promote emotion recognition through body movements. Participants were asked to select the emotion they believe the actress is experiencing from a list of emotions and to rate the valence and the intensity of the emotion perceived. To identify the most effective video for each emotion the percentage of correct answers and the mean value of valence and intensity were calculated. This step allows for the selection of videos based on data from a healthy population. The selected videos have been subsequently tested in a small sample of PD that were also asked to mimic the observed emotional gait. Gait parameters changes were assessed using wearable motion sensors.

Results

110 healthy subjects answered the questionnaire. Sadness, anger, neutral and happiness emotions were the most frequently recognized, with between 90 and 100% of subjects providing the correct answer. Participants attributed negative valence to sadness and anger, while positive valence to happiness. Fear and anxiety tend to be confused by healthy subjects, thus we decided to consider them as a unique feeling and to select a single video representing fear/anxiety. Regarding intensity, all emotions, except for the neutral video, were rated around 7 or 8 on a scale ranging from 0 to 10. The selected emotional gait videos (neutral, happiness, sadness and fear/anxiety) were administered to 10 PD patients that demonstrated 100% emotion recognition. During emotional gait imitation, PD subjects importantly modified spatio-temporal gait parameters, with positive emotions increasing step, arm and trunk movement amplitude and negative emotions altering gait speed, clearance and trunk kinematics.

Discussion and Conclusion

Effective videos for sadness, anger, fear/anxiety, neutral and happiness were identified. Probably surprise and disgust cannot be unequivocally detected from body movements as they are emotions transmitted though facial expression. Therefore, we excluded these emotions from our experiment. The selected emotional gait videos were easily recognized by a sample of 10 PD patients. Preliminary findings from wearable sensors suggested the possibility to modulate spatio-temporal gait parameters of PD patients through imitation of emotional gait patterns. To conclude, we developed effective emotional gait videos in healthy subjects and PD, which will help studying the interaction between gait and emotion in PD.

REFERENCES

1. Sarasso E, Filippi M, Agosta F. Clinical and MRI features of gait and balance disorders in neurodegenerative diseases. J Neurol. 2023 Mar;270(3):1798-1807. doi: 10.1007/s00415-022-11544-7. Epub 2022 Dec 28.
2. Sarasso E, Agosta F, Piramide N, Gardoni A, Canu E, Leocadi M, Castelnovo V, Basaia S, Tettamanti A, Volontè MA, Filippi M. Action Observation and Motor Imagery Improve Dual Task in Parkinson’s Disease: A Clinical/fMRI Study. Mov Disord. 2021 Nov;36(11):2569-2582. doi: 10.1002/mds.28717. Epub 2021 Jul 19.
3. Avanzino L, Lagravinese G, Abbruzzese G, Pelosin E. Relationships between gait and emotion in Parkinson’s disease: A narrative review. Gait Posture. 2018 Sep;65:57-64. doi: 10.1016/j.gaitpost.2018.06.171. Epub 2018 Jun 28.
4. Gross MM, Crane EA, Fredrickson BL. Effort-Shape and kinematic assessment of bodily expression of emotion during gait. Hum Mov Sci. 2012 Feb;31(1):202-21. doi: 10.1016/j.humov.2011.05.001. Epub 2011 Aug 10.