Tesi etd-10192025-160427
Link copiato negli appunti
Tipo di tesi
Corso Ordinario Ciclo Unico 6 Anni
Autore
MILANO, BEATRICE ANNUNZIATA
URN
etd-10192025-160427
Titolo
NETWORK AND RECEPTOR ARCHITECTURE CONSTRAIN BRAIN ALTERATIONS IN ADDICTION
Struttura
Classe Scienze Sperimentali
Corso di studi
SCIENZE MEDICHE - SCIENZE MEDICHE
Commissione
Tutor Prof. EMDIN, MICHELE
Membro Dott.ssa TOGNINI, PAOLA
Presidente Prof. PASSINO, CLAUDIO
Relatore Prof. Kirschner, MATthias
Membro Dott.ssa durante, angela
Membro Prof. RECCHIA, FABIO ANASTASIO
Membro Dott.ssa TOGNINI, PAOLA
Presidente Prof. PASSINO, CLAUDIO
Relatore Prof. Kirschner, MATthias
Membro Dott.ssa durante, angela
Membro Prof. RECCHIA, FABIO ANASTASIO
Parole chiave
- Connectome architecture
- Epicenter mapping
- Hub vulnerability
- Network neuroscience
- Neurobiology of addiction
- Substance use disorders (SUD)
Data inizio appello
15/12/2025;
Disponibilità
parziale
Riassunto analitico
Network and receptor architecture constrain brain alterations in addiction: Substance use disorders (SUD) show widespread structural brain alterations, yet the organizational principles shaping their topography remain unclear. We asked whether SUD-related morphometric changes reflect normative connectome architecture and neurotransmitter receptor distributions.
Methods: We analyzed MRI data from 2,847 individuals with SUD and 1,951 controls (ENIGMA Addiction Working Group). Cortical thickness and subcortical volumes were harmonized (ComBat) and modeled with age/sex/ICV covariates. Using normative connectivity from the Human Connectome Project (n=207), we tested (i) hub vulnerability (degree centrality vs. regional alterations) and (ii) epicenter mapping (similarity between each region’s normative connectivity profile and SUD alteration maps), with spatial permutation (spin) tests. We assessed substance-specific patterns, age/sex interactions, individual-level generalization, cross-disorder similarity (ENIGMA: SCZ, BD, MDD, OCD, ADHD, ASD), and receptor alignment using 20 PET-based maps (PCA and enrichment).
Results: SUD showed widespread cortical thinning (65/68 regions FDR<0.05) and subcortical volume loss (11/14; strongest in hippocampus/amygdala). Cortical alterations tracked hubs (r_functional = –0.51, p_spin=0.002; r_structural = –0.49, p_spin<0.0001); subcortical effects were limited. Substance-specific hub vulnerability was strongest for alcohol and cocaine, moderate for nicotine/amphetamine, smaller for cannabis, and weakest for opioids. Epicenters involved fronto-parietal, temporal, and striatal-thalamic territories; structural epicenters were more sensorimotor-weighted. Age×SUD interactions indicated steeper cortical decline in SUD; sex interactions were limited. Patterns generalized at the individual level. Cross-disorder, SUD epicenters aligned most with schizophrenia and bipolar disorder (both modalities), weaker/inconsistent for MDD, OCD, ADHD, ASD. Receptor analyses showed a principal receptor gradient peaking in paralimbic/temporal cortices; epicenters were enriched for cholinergic (VAChT) and histaminergic (H3) systems, with nominal contributions from opioid/glutamatergic/dopaminergic pathways.
Conclusions: Addiction-related brain alterations are constrained by normative network topology and receptor architecture, highlighting hub vulnerability and receptor-enriched epicenters as key systems-level mechanisms. These patterns partly converge with SCZ/BD, suggesting transdiagnostic network liability and circuit-/receptor-informed targets for intervention.
Methods: We analyzed MRI data from 2,847 individuals with SUD and 1,951 controls (ENIGMA Addiction Working Group). Cortical thickness and subcortical volumes were harmonized (ComBat) and modeled with age/sex/ICV covariates. Using normative connectivity from the Human Connectome Project (n=207), we tested (i) hub vulnerability (degree centrality vs. regional alterations) and (ii) epicenter mapping (similarity between each region’s normative connectivity profile and SUD alteration maps), with spatial permutation (spin) tests. We assessed substance-specific patterns, age/sex interactions, individual-level generalization, cross-disorder similarity (ENIGMA: SCZ, BD, MDD, OCD, ADHD, ASD), and receptor alignment using 20 PET-based maps (PCA and enrichment).
Results: SUD showed widespread cortical thinning (65/68 regions FDR<0.05) and subcortical volume loss (11/14; strongest in hippocampus/amygdala). Cortical alterations tracked hubs (r_functional = –0.51, p_spin=0.002; r_structural = –0.49, p_spin<0.0001); subcortical effects were limited. Substance-specific hub vulnerability was strongest for alcohol and cocaine, moderate for nicotine/amphetamine, smaller for cannabis, and weakest for opioids. Epicenters involved fronto-parietal, temporal, and striatal-thalamic territories; structural epicenters were more sensorimotor-weighted. Age×SUD interactions indicated steeper cortical decline in SUD; sex interactions were limited. Patterns generalized at the individual level. Cross-disorder, SUD epicenters aligned most with schizophrenia and bipolar disorder (both modalities), weaker/inconsistent for MDD, OCD, ADHD, ASD. Receptor analyses showed a principal receptor gradient peaking in paralimbic/temporal cortices; epicenters were enriched for cholinergic (VAChT) and histaminergic (H3) systems, with nominal contributions from opioid/glutamatergic/dopaminergic pathways.
Conclusions: Addiction-related brain alterations are constrained by normative network topology and receptor architecture, highlighting hub vulnerability and receptor-enriched epicenters as key systems-level mechanisms. These patterns partly converge with SCZ/BD, suggesting transdiagnostic network liability and circuit-/receptor-informed targets for intervention.
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