Fractal dynamics of the healthy human brain: A subcortical-to-cortical gradient of temporal complexity Lorenzo Pini, Sadaf Moaveninejad, Maurizio Corbetta, Camillo Porcaro Iscience, 2026 Loss of brain signal complexity can indicate signs of diseases, yet standard scans often miss these patterns. Establishing a high-resolution benchmark of healthy temporal complexity is essential for developing early cerebral biomarkers. To construct a fractal normative reference map of brain complexity, we analyzed high-resolution 7T fMRI scans from 173 healthy adults. We used fractal dimension analysis to map the brain spatiotemporal organization and test its relationship with human intelligence. We discovered a robust physiological gradient, from the globus pallidus (GP) (hub of maximal "healthy chaos") to fronto-parietal cognitive networks (which prioritize stability). This architecture predicts fluid intelligence. This study establishes the globus pallidus as the engine of neural flexibility while cortical network underlying cognitive abilities exhibit more regular dynamics, linked with fluid intelligence. These results offer insights to detect the dynamic rigidity that often precedes structural damage in neurological diseases, a hypothesis that requires validation in future clinical studies.
Brain connectivity as a new target for Alzheimer’s disease therapy? Lorenzo Pini, Gilles Allali, Bruno P Imbimbo, Massimiliano Germani, Maurizio Corbetta Brain, 2026 The recent introduction of immunotherapeutic agents targeting amyloid-β (Aβ) has advanced the pharmacological treatment of Alzheimer’s disease (AD). Although several anti-Aβ antibodies have dramatically reduced cerebral amyloid plaques, this has not translated into major cognitive or clinical benefits, thus questioning the clinical relevance of these biomarker changes. Indeed, there is an ongoing debate over whether amyloid reduction alone constitutes sufficient evidence of disease modification to justify regulatory approval. Against this backdrop, we propose a third pathway that transcends the binary framework of molecular versus clinical end points by positioning brain connectivity as a system-level intermediate phenotype. This approach is supported by a growing body of evidence. Alterations in brain networks are early, sensitive, and modifiable markers of AD pathology. Connectivity metrics capture the dynamic interplay between genetic and environmental factors, offering a unified model of disease. Advances in precision medicine, such as individualized connectivity ‘fingerprints’ and the emergence of digital twins, further position brain connectivity as a powerful platform for therapeutic innovation. We argue that adopting brain network analysis as a key outcome measure enables a shift beyond isolated biomarker achievements toward a more integrated, biologically grounded, and clinically meaningful framework for disease modification in AD, bridging the gap between molecular advances and real-world impact.
Targeting brain connectivity in Alzheimer's disease with repurposed drugs Lorenzo Pini, Bruno P. Imbimbo, Alessandra Griffa, Gilles Allali, Nunzio Pomara Ageing Research Reviews, 2026 Neuroimaging studies have highlighted both hyperconnectivity and hypoconnectivity across the Alzheimer's disease (AD) continuum, alongside task-induced activity changes. These alterations may reflect compensatory mechanisms or network breakdowns. While connectivity-based measures are not yet established as clinical biomarkers, they hold promises for evaluating therapeutic efficacy and informing the design of targeted interventions. Based on these insights, this review explores the potential of off-label FDA-approved drug repositioning as a cost-effective strategy to identify therapeutic approaches for AD. We examine the neurophysiological effects of certain repurposed drugs that modulate synaptic activity, reduce inflammation, enhance metabolic pathways and gut-brain axis interactions, in preclinical and clinical models. Emerging evidence suggests that these drugs (e.g., anticonvulsants, anti-diabetics, anti-inflammatory, and gastrointestinal agents) can influence brain connectivity and activity, mitigating cognitive deficits. By integrating connectivity-focused biomarkers into clinical trials, researchers can advance the development of disease-modifying treatments. This review underscores the importance of a connectivity-driven framework for repurposing existing drugs to address need for new treatments for AD.
Longitudinal Degeneration of Microstructural and Structural Connectivity Patterns Following Stroke Lorenzo Pini, Mohammad Hadi Aarabi, Alessandro Salvalaggio, Angela M. Colletta, Nicholas V. Metcalf, Joseph C. Griffis, Alexandre R. Carter, Gordon L. Shulman, Maurizio Corbetta Stroke, 2026 BACKGROUND: Stroke causes neurological impairment through local plasticity mechanisms, such as synaptic sprouting, and large-scale network reorganization. Although poststroke Wallerian degeneration is well established, whether white matter (WM) tracts’ remodel over time to support behavioral recovery remains controversial. We investigated whether longitudinal changes in WM microstructure and structural connectivity are coupled to poststroke behavior, and how structural connectivity reorganization relates to local disconnection microstructure. METHODS: In this prospective cohort study (Washington University, St. Louis; 2016–2018), patients with first-time stroke underwent diffusion-weighted magnetic resonance imaging and behavioral assessments at 2 weeks and 3 months poststroke; healthy controls were assessed twice. Latent factorial analysis was applied to behavioral and microstructural data from diffusion tensor imaging and neurite orientation dispersion and density imaging. Primary measures were whole-brain structural connectivity gradient divergences computed from tractography, microstructural diffusion parameters extracted from both WM and cortical regions disconnected by the lesion, and behavioral factors. Linear mixed models (adjusted for sociodemographic values) assessed longitudinal changes, linear regression assessed brain-behavior associations, and machine learning algorithms assessed differences between healthy controls and stroke. RESULTS: Seventy-nine patients (age, 60±12 years; 43% female; diffusion-weighted magnetic resonance imaging: 48 at 2 weeks and 26 at 3 months) and 33 age-matched healthy controls were included. At 2 weeks, patients with stroke exhibited diffuse whole-brain alterations in WM organization. These widespread changes were closely linked to microstructural abnormalities in WM pathways disconnected by the lesion. Notably, WM degeneration progressed between 2 weeks and 3 months poststroke. Whole-brain structural connectivity alterations were associated with cognitive deficits acutely but not at 3 months, whereas microstructural parameters in disconnected tracts were primarily related to motor impairment. CONCLUSIONS: In patients with predominantly mild-severity stroke, we observed widespread and progressive alterations in WM microstructure that persists beyond the lesion and continues to evolve over time. Although acute structural disconnection relates to behavioral deficits, chronic WM degeneration appears largely uncoupled from functional recovery.
The neural underpinnings of cognitive and postural profile of a young adult with congenital cerebellar athrophy: a longitudinal case report Maria Devita, Adele Ravelli, Chiara Ceolin, Marina De Rui, Lorenzo Pini, Matteo Bendini, Michela Sarlo, Giuseppe Sergi, Umberto Castiello, Daniela Mapelli, Chiara Begliomini Frontiers in Neuroscience, 2026 For decades the cerebellum has been conceived as an organ chiefly involved in motor control, gait and posture. However, more recent and increasing evidence shows that the cerebellum is also involved in cognition and affection, and that damage to this structure may significantly compromise the overall neuropsychological functioning. Here we report we report the evolution along time of a possible congenital cerebellar atrophy and its effects on gross motor and cognitive functioning in a 41-years old man. Advanced neuroimaging analyses are also provided in order to understand the anatomo-functional correlates of cerebellar damage, with a novel focus on its different lobules. It is hypothesized that congenital cerebellar atrophy, initially compromising motor control, gradually brings to cognitive frailties. Findings related to neuroimaging, neuropsychological and postural data reveal a progressive decline in cognitive and gross motor capacities, particularly affecting executive and attentional functions. Neuroimaging results suggest specific gray matter volume reductions within cerebellar regions known to influence cognitive processes. This case report provides a nuanced look into the neuropsychological impact of cerebellar atrophy over time, shedding light on the elusive cognitive role of the cerebellum and its potential link to cerebellar cognitive affective syndrome.
Spontaneously emerging patterns in human motor cortex code for somatotopic specific movements Lu Zhang, Lorenzo Pini, Gordon L. Shulman, Maurizio Corbetta Iscience, 2025 Spontaneous brain activity, which recapitulates stimulus-evoked patterns, may serve as internal priors for tasks. However, its functional-anatomical organization remains unclear. This study investigated whether spontaneous brain activity in the motor cortex is organized somatotopically. Using fMRI, we compared multi-voxel activity patterns during rest within effector-specific motor sub-regions (hand, foot, and mouth) with those evoked by specific movements (finger tapping, toe squeezing, and tongue movements). The results showed that spontaneous activity in each sub-region exhibited greater similarity to task patterns of its corresponding movement than to non-preferred ones. Furthermore, a positive correlation between similarity and the magnitude of the evoked response within each region emerged for the region's preferred movement, while significant negative correlations were found for non-preferred movements. These findings reveal that spontaneous activity in the human motor cortex is somatotopically organized, representing effector-specific functional priors, thus highlighting a structured rest-task relationship.
Resting-state functional connectivity guides motor hotspot localization Antonio Luigi Bisogno, Ilaria Mazzonetto, Valentina D’Onofrio, Ester Fusaro, Renzo Manara, Simone Sarasso, Silvia Casarotto, Mario Rosanova, Marcello Massimini, Camillo Porcaro, Lorenzo Pini, Maurizio Corbetta Clinical Neurophysiology, 2025
Integrated Gradients Demystified: An MRI Case Study on Aβ-T Protein Localization Giorgio Dolci, Cristian Morasso, Federica Cruciani, Lorenza Brusini, Lorenzo Pini, Vince D. Calhoun, Ilaria Boscolo Galazzo, Gloria Menegaz 2024 IEEE International Conference on Metrology for Extended Reality Artificial Intelligence and Neural Engineering Metroxraine 2024 Proceedings, 2024
White Matter Tract Density Index Prediction Model of Overall Survival in Glioblastoma Alessandro Salvalaggio, Lorenzo Pini, Matteo Gaiola, Aron Velco, Giulio Sansone, Mariagiulia Anglani, Lucius Fekonja, Franco Chioffi, Thomas Picht, Michel Thiebaut de Schotten, Vittorina Zagonel, Giuseppe Lombardi, Domenico D’Avella, Maurizio Corbetta JAMA Neurology, 2023
Brain network modulation in Alzheimer's and frontotemporal dementia with transcranial electrical stimulation Lorenzo Pini, Francesca Benedetta Pizzini, Ilaria Boscolo-Galazzo, Clarissa Ferrari, Samantha Galluzzi, Maria Cotelli, Elena Gobbi, Annamaria Cattaneo, Maria Sofia Cotelli, Cristina Geroldi, Orazio Zanetti, Maurizio Corbetta, Martijn van den Heuvel, Giovanni Battista Frisoni, Rosa Manenti, Michela Pievani Neurobiology of Aging, 2022
A low-dimensional structure of neurological impairment in stroke Antonio Luigi Bisogno, Chiara Favaretto, Andrea Zangrossi, Elena Monai, Silvia Facchini, Serena De Pellegrin, Lorenzo Pini, Marco Castellaro, Anna Maria Basile, Claudio Baracchini, Maurizio Corbetta Brain Communications, 2021
Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer’s disease Lorenzo Pini, Cristina Geroldi, Samantha Galluzzi, Roberta Baruzzi, Monica Bertocchi, Eugenia Chitò, Stefania Orini, Melissa Romano, Maria Cotelli, Sandra Rosini, Silvia Magnaldi, Mauro Morassi, Milena Cobelli, Cristian Bonvicini, Silvana Archetti, Orazio Zanetti, Giovanni B. Frisoni, Michela Pievani Brain Imaging and Behavior, 2020
Brain atrophy in Alzheimer's Disease and aging Lorenzo Pini, Michela Pievani, Martina Bocchetta, Daniele Altomare, Paolo Bosco, Enrica Cavedo, Samantha Galluzzi, Moira Marizzoni, Giovanni B. Frisoni Ageing Research Reviews, 2016
RECENT SCHOLAR PUBLICATIONS
Modeling Alzheimer’s disease through the integration of exposome, inflammasome, and connectome L Pini, BP Imbimbo, M Allegra Neural Regeneration Research 21 (6), 2359-2360 , 2026 2026
Considering biological limitations of lesion network mapping L Pini, A Salvalaggio, M Corbetta Nature Neuroscience, 1-3 , 2026 2026
ABSTRACT NUMBER: ESOC2026A1583 HYPOPERFUSION TOPOGRAPHY AS A PREDICTOR OF CLINICAL IMPROVEMENT AFTER MECHANICAL THROMBECTOMY IN ANTERIOR CIRCULATION STROKE G Adamo, AL Bisogno, L Pini, E Fabris, A De Rossi, JD Gabrieli, ... European Stroke Journal 11 (Supplement_1), i434-i434 , 2026 2026
Fractal Dynamics of the Healthy Human Brain: A Subcortical-to-Cortical Gradient of Temporal Complexity L Pini, S Moaveninejad, M Corbetta, C Porcaro iScience , 2026 2026
New survival prognostic index in glioblastoma multiforme based upon alterations of the connections of the brain white matter measured with nmr diffusion techniques M Corbetta, A Salvalaggio, L Pini US Patent App. 18/996,227 , 2026 2026
Brain connectivity as a new target for Alzheimer’s disease therapy? L Pini, G Allali, BP Imbimbo, M Germani, M Corbetta Brain 149 (2), 432-438 , 2026 2026 Citations: 4
Neural integrator and orchestrator communities shape spontaneous signaling in the human brain L Pini, R Dugo, P Pigato, M Corbetta bioRxiv, 2026.02. 04.703687 , 2026 2026
The neural underpinnings of cognitive and postural profile of a young adult with congenital cerebellar athrophy: a longitudinal case report M Devita, A Ravelli, C Ceolin, M De Rui, L Pini, M Bendini, M Sarlo, ... Frontiers in Neuroscience 20, 1724744 , 2026 2026
Neural networks and econometric models: Advancing brain connectivity for Alzheimer’s drug development L Pini, P Pigato, G Menegaz, IB Galazzo Neural Regeneration Research, 10.4103 , 2026 2026 Citations: 1
Spontaneously emerging patterns in human motor cortex code for somatotopic specific movements L Zhang, L Pini, GL Shulman, M Corbetta iScience 28 (12) , 2025 2025
Targeting brain connectivity in Alzheimer’s disease with repurposed drugs L Pini, BP Imbimbo, A Griffa, G Allali, N Pomara Ageing Research Reviews, 103001 , 2025 2025
Do anti-amyloid antibodies modulate brain function in Alzheimer's disease? L Pini, M Allegra, BP Imbimbo Neurodegenerative Diseases , 2025 2025
Resting-state functional connectivity guides motor hotspot localization AL Bisogno, I Mazzonetto, V D'Onofrio, E Fusaro, R Manara, S Sarasso, ... Clinical neurophysiology: official journal of the International Federation … , 2025 2025
Connectional diaschisis associated with acute psychosis after right thalamic stroke: A case report G Adamo, A Salvalaggio, L Pini, D Cecchin, S Facchini, AL Bisogno, ... Cortex , 2025 2025
Brain Connectivity Gradients Alterations in Discordant Cerebrospinal Fluid Profile for Alzheimer's Disease Biomarkers L Pini, C Tuzzato, A Griffa, L Brusini, F Cruciani, G Allali, M Corbetta, ... Human Brain Mapping 46 (16), e70406 , 2025 2025 Citations: 1
Insights from the brain connectome in patients with gliomas A Salvalaggio, G Sansone, L Pini, M Corbetta Current Opinion in Oncology 37 (6), 595-602 , 2025 2025 Citations: 2
Fractal Complexity of Brain Networks: Mapping Criticality by Detrended Fluctuation Analysis L Pini, S Moaveninejad, S Cauzzo, M Corbetta, C Porcaro 2025 IEEE International Conference on Metrology for eXtended Reality … , 2025 2025
P03. 07. B STRUCTURAL CONNECTIVITY-BASED SPREADING PATTERNS OF MULTIFOCAL AND MULTICENTRIC GLIOMAS G Sansone, L Pini, D Mirkarimi, V Baro, A Bosio, F Volpin, F Chioffi, ... Neuro-Oncology 27 (Supplement_3), iii51-iii52 , 2025 2025
Linking dynamic connectivity states to cognitive decline and anatomical changes in Alzheimer’s disease J Tessadori, IB Galazzo, SF Storti, L Pini, L Brusini, F Cruciani, D Sona, ... NeuroImage, 121448 , 2025 2025 Citations: 6
Behavioral clusters and lesion distributions in ischemic stroke, based on nihss similarity network LF Tshimanga, A Zanola, S Facchini, AL Bisogno, L Pini, M Atzori, ... Journal of Healthcare Informatics Research 9 (3), 401-436 , 2025 2025 Citations: 4
MOST CITED SCHOLAR PUBLICATIONS
Brain atrophy in Alzheimer’s disease and aging L Pini, M Pievani, M Bocchetta, D Altomare, P Bosco, E Cavedo, ... Ageing research reviews 30, 25-48 , 2016 2016 Citations: 1130
Aberrant brain network connectivity in presymptomatic and manifest Huntington's disease: a systematic review L Pini, C Jacquemot, A Cagnin, F Meneghello, C Semenza, D Mantini, ... Human Brain Mapping 41 (1), 256-269 , 2020 2020 Citations: 89
Glioblastoma and brain connectivity: the need for a paradigm shift A Salvalaggio, L Pini, A Bertoldo, M Corbetta The Lancet Neurology 23 (7), 740-748 , 2024 2024 Citations: 88
Abnormalities in functional connectivity in borderline personality disorder: Correlations with metacognition and emotion dysregulation G Quattrini, L Pini, M Pievani, LR Magni, M Lanfredi, C Ferrari, M Boccardi, ... Psychiatry Research: Neuroimaging 283, 118-124 , 2019 2019 Citations: 60
Non-invasive brain stimulation in dementia: a complex network story L Pini, R Manenti, M Cotelli, FB Pizzini, GB Frisoni, M Pievani Neurodegenerative Diseases 18 (5-6), 281-301 , 2019 2019 Citations: 55
Microstructural white matter alterations associated with migraine headaches: a systematic review of diffusion tensor imaging studies R Rahimi, M Dolatshahi, F Abbasi-Feijani, S Momtazmanesh, ... Brain Imaging and Behavior 16 (5), 2375-2401 , 2022 2022 Citations: 53
Breakdown of specific functional brain networks in clinical variants of Alzheimer’s disease L Pini, AM Wennberg, A Salvalaggio, A Vallesi, M Pievani, M Corbetta Ageing Research Reviews 72, 101482 , 2021 2021 Citations: 53
Coordinate-based meta-analysis of the default mode and salience network for target identification in non-invasive brain stimulation of Alzheimer’s disease and behavioral … M Pievani, L Pini, C Ferrari, FB Pizzini, I Boscolo Galazzo, C Cobelli, ... Journal of Alzheimer’s Disease 57 (3), 825-843 , 2017 2017 Citations: 53
Brain network modulation in Alzheimer's and frontotemporal dementia with transcranial electrical stimulation L Pini, FB Pizzini, I Boscolo-Galazzo, C Ferrari, S Galluzzi, M Cotelli, ... Neurobiology of Aging 111, 24-34 , 2022 2022 Citations: 52
White matter tract density index prediction model of overall survival in glioblastoma A Salvalaggio, L Pini, M Gaiola, A Velco, G Sansone, M Anglani, ... JAMA neurology 80 (11), 1222-1231 , 2023 2023 Citations: 43
A low-dimensional structure of neurological impairment in stroke AL Bisogno, C Favaretto, A Zangrossi, E Monai, S Facchini, ... Brain communications 3 (2), fcab119 , 2021 2021 Citations: 43
Structural imaging outcomes in subjective cognitive decline: community vs. clinical-based samples L Pini, AM Wennberg Experimental gerontology 145, 111216 , 2021 2021 Citations: 34
A novel stroke lesion network mapping approach: improved accuracy yet still low deficit prediction L Pini, A Salvalaggio, M De Filippo De Grazia, M Zorzi, ... Brain communications 3 (4), fcab259 , 2021 2021 Citations: 33
Cerebral PET glucose hypometabolism in subjects with mild cognitive impairment and higher EEG high-alpha/low-alpha frequency power ratio DV Moretti, M Pievani, L Pini, UP Guerra, B Paghera, GB Frisoni Neurobiology of aging 58, 213-224 , 2017 2017 Citations: 32
A low-dimensional cognitive-network space in Alzheimer’s disease and frontotemporal dementia L Pini, SC De Lange, FB Pizzini, I Boscolo Galazzo, R Manenti, M Cotelli, ... Alzheimer's research & therapy 14 (1), 199 , 2022 2022 Citations: 31
Age at onset reveals different functional connectivity abnormalities in prodromal Alzheimer’s disease L Pini, C Geroldi, S Galluzzi, R Baruzzi, M Bertocchi, E Chito, S Orini, ... Brain Imaging and Behavior 14 (6), 2594-2605 , 2020 2020 Citations: 31
The pollutome-connectome axis: a putative mechanism to explain pollution effects on neurodegeneration L Pini, A Salvalaggio, AM Wennberg, A Dimakou, M Matteoli, M Corbetta Ageing Research Reviews 86, 101867 , 2023 2023 Citations: 30
Neurite orientation dispersion and density imaging in multiple sclerosis: a systematic review H Seyedmirzaei, F Nabizadeh, MH Aarabi, L Pini Journal of Magnetic Resonance Imaging 58 (4), 1011-1029 , 2023 2023 Citations: 29
Spontaneous activity patterns in human motor cortex replay evoked activity patterns for hand movements T Livne, DH Kim, NV Metcalf, L Zhang, L Pini, GL Shulman, M Corbetta Scientific Reports 12 (1), 16867 , 2022 2022 Citations: 28
Fronto-parietal homotopy in resting-state functional connectivity predicts task-switching performance A Vallesi, A Visalli, Z Gracia-Tabuenca, V Tarantino, M Capizzi, S Alcauter, ... Brain Structure and Function 227 (2), 655-672 , 2022 2022 Citations: 28