The olfactory circuit is a complex and partially unknown brain network that is involved in vital functions such as survival, sociality, and development. Indeed, its dysfunction has been linked to several neurodegenerative, inflammatory and mood disorders. Being a neural network, tractography is the only way to determine the connections between olfactory brain regions non-invasively in humans in vivo. This technique reconstructs axonal bundles starting from diffusion weighted (DW) Magnetic Resonance images but, unfortunately, it leads to several false positives. In this thesis, the curation of the olfactory circuit tracts was performed applying a priori biological constraints to realistically reconstruct the axonal bundles and to assess the impact of the process on functional and metabolic characterization of the circuit. DW images were obtained from 10 healthy subjects of the Human Connectome Project (HCP) database. The data was pre-processed, and whole-brain axonal bundles were extracted via anatomically constrained tractography, which combines anatomical information regarding different brain tissues to terminate and accept, or reject, probabilistic fibre streamlines. Then, an atlas of the grey matter regions, i.e. regions of interest (ROIs), known to be related to olfaction was used to extract only those tracts involved in the olfactory circuit. A two-step curation process was delineated. First, gross anatomical priori was applied at population level, then single tracts of each subject were visualised to discard those streamlines that were not anatomically trustful via a not-ROI procedure. For each subject, a structural connectivity matrix, or structural connectome (SC), before and one after curation were created representing all the olfactory tracts. Then, these tracts were moved to a common three-dimensional standard space, i.e., the Montreal Neurological Institute (MNI) space, and averaged across subjects taking the common part between most of the subjects, allowing to obtain a biologically realistic white-matter atlas of the olfactory circuit. To further evaluate the impact of the curation process, The Virtual Brain (TVB) platform was used to simulate the activity of the olfactory circuit by providing as input the two SC. As result of the two-step curation process, the number of the olfactory tracts decreased from 506 (raw tractography) to 98 (curated tractography). Furthermore, even the relative tracts’ weight into the circuit changed because some tracts suffered of a prominent presence of false positive (i.e., some streamlines were removed) while others were only partially or not at all influenced by the second-step curation process. Interestingly, even TVB simulation highlighted the curation process impact by demonstrating that the global coupling is doubled after curation while local feedback inhibitory and excitatory synaptic couplings are higher too. These findings show that, even if TVB simulator is not capable to fully catch the biological underpinning of brain activity, a higher anatomical reliability of the input heavily influences its outputs. Even the introduction of biologically grounded priors suggests that curated results better represent physiological mechanisms underlying brain activity, further quantitative evaluation of the curation effects in the SC should be made by using a multimodal approach, e.g., applying graph theory to understand whatever network organisation changes. The challenge with this curation approach is its reproducibility due to inter-subject and intra-subject variability of the process, i.e., different operators curate the same tract in different ways, and the same operator along multiple attempts would curate the tract differently. *The abstract is ended for limitations, in the thesis is full*
Il circuito olfattivo è una rete cerebrale complessa e parzialmente sconosciuta, coinvolta in funzioni vitali come la sopravvivenza, la socialità e lo sviluppo. Infatti, il suo malfunzionamento è stato collegato a diversi disturbi neurodegenerativi, infiammatori e dell'umore. Essendo una rete neurale, la trattografia è l’unico metodo per determinare le connessioni cerebrali tra regioni interessate nell’olfatto in maniera non invasiva negli esseri umani in vivo. Questa tecnica ricostruisce i fasci assonali a partire da immagini di risonanza magnetica pesate in diffusione (DW), ma purtroppo presenta diversi falsi positivi. In questa tesi, la pulizia dei tratti del circuito olfattivo è stata effettuata applicando vincoli biologici a priori per ricostruire realisticamente i fasci assonali e valutare l'impatto del processo sulla caratterizzazione funzionale e metabolica del circuito. Le immagini DW sono state ottenute da 10 soggetti sani del database Human Connectome Project (HCP). I dati sono stati pre-processati e i fasci assonali dell'intero cervello sono stati estratti tramite Anatomically Constrained Tractography, la quale combina informazioni anatomiche su diversi tessuti cerebrali per terminare e accettare, o rifiutare le streamline probabilistiche. Successivamente, è stato utilizzato un atlante di regioni di materia grigia, cioè regioni di interesse (ROIs), note per essere correlate all'olfatto, per estrarre solo i tratti coinvolti nel circuito olfattivo. È stato delineato un processo di cura in due fasi. Inizialmente, a livello di popolazione, sono stati applicati vincoli anatomici grossolani a priori, poi i singoli tratti di ciascun soggetto sono stati visualizzati per eliminare quelle streamline che non erano anatomicamente affidabili tramite una procedura utilizzante not-ROI. Per ciascun soggetto, sono state create due diverse matrici di connettività strutturale, o structural connectome (SC), cioè prima e dopo tale processo, le quali rappresentavano tutti i tratti olfattivi. Questi tratti sono poi stati spostati in uno spazio standard tridimensionale comune, cioè lo spazio del Montreal Neurological Institute (MNI), e mediati tra i soggetti considerando solo la parte comune alla maggior parte dei soggetti, permettendo di ottenere un atlante della sostanza bianca del circuito olfattivo biologicamente realistico. Per valutare ulteriormente l'impatto del processo di cura, è stata utilizzata la piattaforma The Virtual Brain (TVB) per simulare l'attività del circuito olfattivo fornendo in input le due SC. Come risultato del processo di cura in due fasi, il numero di tratti olfattivi è diminuito da 506 (trattografia grezza) a 98 (trattografia curata). Inoltre, anche il peso relativo dei tratti nel circuito è cambiato perché alcuni tratti erano significativamente influenzati dalla presenza di falsi positivi (cioè, molte streamline sono state rimosse), mentre altri sono stati solo parzialmente o per nulla influenzati dal processo di cura della seconda fase. È interessante notare che anche la simulazione TVB ha evidenziato l'impatto del processo di cura dimostrando che l'accoppiamento globale è raddoppiato dopo la cura, mentre gli accoppiamenti sinaptici inibitori ed eccitatori locali sono aumentati. Questi risultati mostrano che, anche se il simulatore TVB non è in grado di cogliere completamente i fondamenti biologici dell'attività cerebrale, una maggiore affidabilità anatomica dell'input influenza pesantemente i suoi output. *l'abstract è terminato per limitazioni del sito, nella tesi c'è completo*
Ricostruzione dei tratti assonali del circuito olfattivo mediante trattografia: valutazione dell'impatto dell'utilizzo di vincoli biologici a priori.
FUSARI, ANDREA
2023/2024
Abstract
The olfactory circuit is a complex and partially unknown brain network that is involved in vital functions such as survival, sociality, and development. Indeed, its dysfunction has been linked to several neurodegenerative, inflammatory and mood disorders. Being a neural network, tractography is the only way to determine the connections between olfactory brain regions non-invasively in humans in vivo. This technique reconstructs axonal bundles starting from diffusion weighted (DW) Magnetic Resonance images but, unfortunately, it leads to several false positives. In this thesis, the curation of the olfactory circuit tracts was performed applying a priori biological constraints to realistically reconstruct the axonal bundles and to assess the impact of the process on functional and metabolic characterization of the circuit. DW images were obtained from 10 healthy subjects of the Human Connectome Project (HCP) database. The data was pre-processed, and whole-brain axonal bundles were extracted via anatomically constrained tractography, which combines anatomical information regarding different brain tissues to terminate and accept, or reject, probabilistic fibre streamlines. Then, an atlas of the grey matter regions, i.e. regions of interest (ROIs), known to be related to olfaction was used to extract only those tracts involved in the olfactory circuit. A two-step curation process was delineated. First, gross anatomical priori was applied at population level, then single tracts of each subject were visualised to discard those streamlines that were not anatomically trustful via a not-ROI procedure. For each subject, a structural connectivity matrix, or structural connectome (SC), before and one after curation were created representing all the olfactory tracts. Then, these tracts were moved to a common three-dimensional standard space, i.e., the Montreal Neurological Institute (MNI) space, and averaged across subjects taking the common part between most of the subjects, allowing to obtain a biologically realistic white-matter atlas of the olfactory circuit. To further evaluate the impact of the curation process, The Virtual Brain (TVB) platform was used to simulate the activity of the olfactory circuit by providing as input the two SC. As result of the two-step curation process, the number of the olfactory tracts decreased from 506 (raw tractography) to 98 (curated tractography). Furthermore, even the relative tracts’ weight into the circuit changed because some tracts suffered of a prominent presence of false positive (i.e., some streamlines were removed) while others were only partially or not at all influenced by the second-step curation process. Interestingly, even TVB simulation highlighted the curation process impact by demonstrating that the global coupling is doubled after curation while local feedback inhibitory and excitatory synaptic couplings are higher too. These findings show that, even if TVB simulator is not capable to fully catch the biological underpinning of brain activity, a higher anatomical reliability of the input heavily influences its outputs. Even the introduction of biologically grounded priors suggests that curated results better represent physiological mechanisms underlying brain activity, further quantitative evaluation of the curation effects in the SC should be made by using a multimodal approach, e.g., applying graph theory to understand whatever network organisation changes. The challenge with this curation approach is its reproducibility due to inter-subject and intra-subject variability of the process, i.e., different operators curate the same tract in different ways, and the same operator along multiple attempts would curate the tract differently. *The abstract is ended for limitations, in the thesis is full*| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14239/28373