Periodic Reporting for period 4 - DisConn (Neural drivers of functional disconnectivity in brain disorders)
Reporting period: 2023-08-01 to 2024-12-31
Autism and schizophrenia are complex developmental disorders that affect approximately 1 in 100 people. Despite their high societal impact of these disorders, current therapeutic options are mostly symptom-oriented, and often provide marginal or insufficient relief to those affected. DISCONN explored how brain networks become disrupted in disorders like autism and schizophrenia. To address this question, we used cross-species brain functional neuroimaging, electrophysiology, and targeted manipulations in rodents. Understanding the roots of these networks alterations is a required step towards an improved diagnosis and treatment of complex developmental disorders.
Our research revealed general principles underlying the organization of brain network activity in the mammalian brain. Specifically, we found a general inverse relationship between the activity of one brain region, and its functional connectivity, that is, its communication with other brain areas. This observation implies that when a region is silent, its connectivity is paradoxically strengthened. In contrast, when a region is highly active, its connectivity weakens. We also demonstrated that disruptions in the function and connectivity of specific brain regions can be traced to genetic, synaptic, or developmental alterations that are relevant to the biology of autism or schizophrenia.
A major outcome of our research is the ability to link patterns of atypical brain connectivity in people with autism or schizophrenia to their biological underpinnings. This result is of crucial importance, as it may enable the use of brain imaging to identify sub-groups of autistic or schizophrenic individuals who share the same underlying biological dysfunction. In turn, this could help unpack autistic or schizophrenic populations into biologically homogeneous cohorts, paving the way to targeted precision medicine approaches.
We are currently testing this paradigm for autism stratification in partnership with within large transdiagnostic neuroimaging initiatives.
Our research revealed general principles underlying the organization of brain network activity in the mammalian brain. Specifically, we found a general inverse relationship between the activity of one brain region, and its functional connectivity, that is, its communication with other brain areas. This observation implies that when a region is silent, its connectivity is paradoxically strengthened. In contrast, when a region is highly active, its connectivity weakens. We also demonstrated that disruptions in the function and connectivity of specific brain regions can be traced to genetic, synaptic, or developmental alterations that are relevant to the biology of autism or schizophrenia.
A major outcome of our research is the ability to link patterns of atypical brain connectivity in people with autism or schizophrenia to their biological underpinnings. This result is of crucial importance, as it may enable the use of brain imaging to identify sub-groups of autistic or schizophrenic individuals who share the same underlying biological dysfunction. In turn, this could help unpack autistic or schizophrenic populations into biologically homogeneous cohorts, paving the way to targeted precision medicine approaches.
We are currently testing this paradigm for autism stratification in partnership with within large transdiagnostic neuroimaging initiatives.
Our work investigated the organization of brain networks and their foundational properties at three levels. A first level of investigation dealt with the relationship between the anatomical connectivity of the brain (i.e. the organization of neuronal axons) and the resulting network activity. To do this, we used multiple approaches. One line of research examined how these networks change depending on brain states, such as wakefulness versus unconsciousness. In parallel, we conducted an unprecedented high-resolution analysis of the mouse axonal connectome (i.e. the intricate set of anatomical connections that support brain activity in rodents). These studies provided key insight into how network activity emerges in different behavioral states. This knowledge is of fundamental importance for understanding the origin of the network disruption identified in brain disorders such as autism and schizophrenia.
In a second level of investigation, we utilized cell-type specific neuromanipulations to examine how the activity of a brain region affects the organization of brain networks. This approach was instrumental in revealing how network disturbances (like those identified in autism, or schizophrenia) emerge. We found that imbalances in the activity of specific brain regions can trigger widespread disruption of network activity. We also identified early dysfunction in cortical regions as a key driver of network abnormalities in autism. We can now use this information to generate simple testable hypothesis on the origin of brain hypo- and hyperconnectivity seen across multiple brain disorders. This information can also be used to decode network maps and link patterns of network dysfunction to their biological mechanisms.
A third and final level of investigations revealed how changes in neuronal synapse organization influence large-scale brain network activity. Our research highlighted the crucial role of synaptic alterations in driving network dysfunction in the mammalian brain. Specifically, we identified a prevalent form of autism characterized by an excess of synapses and network hyperconnectivity. We also demonstrated that network alterations in schizophrenia can involve impaired synaptic remodeling during puberty. These findings are significant, as they establish synaptic alterations and brain network dysfunction as two interconnected aspects of the same underlying pathology.
Most outreach activities for this project have been conducted through social media platforms personally managed by the PI, including Twitter, LinkedIn, and, more recently, Bluesky. This approach was chosen to maximize impact and reach, as traditional websites often generate little engagement from external stakeholders and the general public. To explicitly highlight the role of ERC funding in my research, I have included a mention of the ERC grant (and its acronym) in my profile description. Additionally, I have participated in public science events such as the Italian Festival della Scienza, Wired Science Festival, and Researchers' Night. All publications resulting from this project have also been disseminated with explicit reference to ERC funding.
In a second level of investigation, we utilized cell-type specific neuromanipulations to examine how the activity of a brain region affects the organization of brain networks. This approach was instrumental in revealing how network disturbances (like those identified in autism, or schizophrenia) emerge. We found that imbalances in the activity of specific brain regions can trigger widespread disruption of network activity. We also identified early dysfunction in cortical regions as a key driver of network abnormalities in autism. We can now use this information to generate simple testable hypothesis on the origin of brain hypo- and hyperconnectivity seen across multiple brain disorders. This information can also be used to decode network maps and link patterns of network dysfunction to their biological mechanisms.
A third and final level of investigations revealed how changes in neuronal synapse organization influence large-scale brain network activity. Our research highlighted the crucial role of synaptic alterations in driving network dysfunction in the mammalian brain. Specifically, we identified a prevalent form of autism characterized by an excess of synapses and network hyperconnectivity. We also demonstrated that network alterations in schizophrenia can involve impaired synaptic remodeling during puberty. These findings are significant, as they establish synaptic alterations and brain network dysfunction as two interconnected aspects of the same underlying pathology.
Most outreach activities for this project have been conducted through social media platforms personally managed by the PI, including Twitter, LinkedIn, and, more recently, Bluesky. This approach was chosen to maximize impact and reach, as traditional websites often generate little engagement from external stakeholders and the general public. To explicitly highlight the role of ERC funding in my research, I have included a mention of the ERC grant (and its acronym) in my profile description. Additionally, I have participated in public science events such as the Italian Festival della Scienza, Wired Science Festival, and Researchers' Night. All publications resulting from this project have also been disseminated with explicit reference to ERC funding.
Our research uncovered fundamental principles of brain network organization in mammals. We identified a general inverse relationship between a region’s activity and its functional connectivity—when a region is silent, its connectivity paradoxically strengthens, whereas high activity weakens it. This challenges conventional models of brain communication and provides a novel framework for understanding network dynamics.
Crucially, we linked disruptions in brain function and connectivity to genetic, synaptic, and developmental alterations relevant to autism and schizophrenia. A key breakthrough is our ability to decode atypical connectivity patterns in brain imaging scans, tracing them to their biological origins. This has major clinical implications, as it could enable stratification of autistic and schizophrenic individuals into biologically homogeneous subgroups, a critical step toward precision medicine.
Crucially, we linked disruptions in brain function and connectivity to genetic, synaptic, and developmental alterations relevant to autism and schizophrenia. A key breakthrough is our ability to decode atypical connectivity patterns in brain imaging scans, tracing them to their biological origins. This has major clinical implications, as it could enable stratification of autistic and schizophrenic individuals into biologically homogeneous subgroups, a critical step toward precision medicine.