{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:37Z","timestamp":1787028577497,"version":"build-2736575974"},"reference-count":258,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T00:00:00Z","timestamp":1766361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Medicine and Pharmacy Carol Davila"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cognitive deterioration and the transition to neurodegenerative disease does not develop through simple, linear regression; it develops as rapid and global transitions from one state to another within the neural network. Developing understanding and control over these events is among the largest tasks facing contemporary neuroscience. This paper will discuss a conceptual reframing of cognitive decline as a transitional phase of the functional state of complex neural networks resulting from the intertwining of molecular degradation, vascular dysfunction and systemic disarray. The paper will integrate the latest findings that have demonstrated how the disruptive changes in glymphatic clearance mechanisms, aquaporin-4 polarity, venous output, and neuroimmune signaling increasingly correlate with the neurophysiologic homeostasis landscape, ultimately leading to the destabilization of the network attraction sites of memory, consciousness, and cognitive resilience. Furthermore, the destabilizing processes are exacerbated by epigenetic silencing; neurovascular decoupling; remodeling of the extracellular matrix; and metabolic collapse that result in accelerating the trajectory of neural circuits towards the pathological tipping point of various neurodegenerative diseases including Alzheimer\u2019s disease; Parkinson\u2019s disease; traumatic brain injury; and intracranial hypertension. New paradigms in systems neuroscience (connectomics; network neuroscience; and critical transition theory) provide an intellectual toolkit to describe and predict these state changes at the systems level. With artificial intelligence and machine learning combined with single cell multi-omics; radiogenomic profiling; and digital twin modeling, the predictive biomarkers and early warnings of impending collapse of the system are beginning to emerge. In terms of therapeutic intervention, the possibility of reprogramming the circuitry of the brain into stable attractor states using precision neurointervention (CRISPR-based neural circuit reprogramming; RNA guided modulation of transcription; lineage switching of glia to neurons; and adaptive neuromodulation) represents an opportunity to prevent further progression of neurodegenerative disease. The paper will address the ethical and regulatory implications of this revolutionary technology, e.g., algorithmic transparency; genomic and other structural safety; and equity of access to advanced neurointervention. We do not intend to present a list of the many vertices through which the mechanisms listed above instigate, exacerbate, or maintain the neurodegenerative disease state. Instead, we aim to present a unified model where the phenomena of molecular pathology; circuit behavior; and computational intelligence converge in describing cognitive decline as a translatable change of state, rather than an irreversible succumbing to degeneration. Thus, we provide a framework for precision neurointervention, regenerative brain medicine, and adaptive intervention, to modulate the trajectory of neurodegeneration.<\/jats:p>","DOI":"10.3390\/ijms27010122","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T11:30:18Z","timestamp":1766489418000},"page":"122","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Designing Neural Dynamics: From Digital Twin Modeling to Regeneration"],"prefix":"10.3390","volume":"27","author":[{"given":"Calin Petru","family":"Tataru","sequence":"first","affiliation":[{"name":"Department of Opthamology, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020021 Bucharest, Romania"},{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Central Military Emergency Hospital \u201cDr. Carol Davila\u201d, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian Vasile","family":"Dumitru","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 030167 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolaie","family":"Dobrin","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"\u201cNicolae Oblu\u201d Clinical Hospital, 700309 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugurel Petrinel","family":"R\u0103doi","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru Vlad","family":"Ciurea","sequence":"additional","affiliation":[{"name":"Puls Med Association, 051885 Bucharest, Romania"},{"name":"Department of Neurosurgery, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Medical Section, Romanian Academy, 010071 Bucharest, Romania"},{"name":"Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Octavian","family":"Munteanu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana Valentina","family":"Munteanu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mateos-Aparicio, P., and Rodr\u00edguez-Moreno, A. 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