Resting state functional connectivity changes after MR-guided focused ultrasound mediated blood-brain barrier opening in patients with Alzheimer's disease

• Published in: NeuroImage (Orlando, Fla.) Vol. 200; pp. 275 - 280
• Main Authors: Meng, Ying, MacIntosh, Bradley J., Shirzadi, Zahra, Kiss, Alex, Bethune, Allison, Heyn, Chinthaka, Mithani, Karim, Hamani, Clement, Black, Sandra E., Hynynen, Kullervo, Lipsman, Nir
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.10.2019; Elsevier Limited
• Subjects: Aged; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - physiopathology; Alzheimer's disease; Animal cognition; Blood-brain barrier; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - physiopathology; Blood-brain barrier opening; Brain research; Central nervous system; Clinical Trials, Phase I as Topic; Cognitive ability; Connectome; Drug delivery; Female; Frontal lobe; Functional connectivity; Functional magnetic resonance imaging; Functional morphology; Humans; Magnetic Resonance Imaging; Male; Medical imaging; Middle Aged; MR-Guided focused ultrasound; Nerve Net - diagnostic imaging; Nerve Net - physiopathology; Neural networks; Neurodegenerative diseases; Neuroimaging; Neuromodulation; Parietal Lobe - diagnostic imaging; Parietal Lobe - physiopathology; Prefrontal Cortex - diagnostic imaging; Prefrontal Cortex - physiopathology; Resting state functional MRI; Studies; Time Factors; Ultrasonic imaging; Ultrasonography, Doppler, Transcranial; Ultrasound; Functional connectivity; GLUT1; Resting state functional MRI; BBB; Blood-brain barrier; FUS; MR-Guided focused ultrasound; Blood-brain barrier opening; MRgFUS
• ISSN: 1053-8119; 1095-9572; 1095-9572
• DOI: 10.1016/j.neuroimage.2019.06.060

MR-guided focused ultrasound (MRgFUS) can temporarily permeabilize the blood-brain barrier (BBB), noninvasively, to allow therapeutics access to the central nervous system. However, its secondary and potential neuromodulation effects are not well understood. We aimed to characterize the functional impact of MRgFUS BBB opening in human subjects, based on the phase I trial in patients with Alzheimer's disease. We analyzed for changes in bilateral frontoparietal networks in resting state functional MRI from five subjects after BBB opening in the right frontal lobe. We found a transient functional connectivity decrease within only the ipsilateral frontoparietal network that was recovered by the next day. Additionally, baseline to month three comparisons did not reveal any significant differences from matched-controls from the Alzheimer's Disease Neuroimaging Initiative. Overall, MRgFUS may transiently affect neurologic function, but the functional organization is restored at one day and remains unchanged at three months. This first in human data has implications for the development of MRgFUS as a drug delivery platform to pathologic brain tissue and potential use for non-invasive neuromodulation. •Focused ultrasound causes transient mechanical disruption of blood-brain barrier.•First-in-human data; ultrasound to prefrontal cortex decreases functional connectivity.•Reductions are isolated to ipsilateral frontoparietal network, recovered next day.•Ensuing functional organization unaffected at month 3 and compared to matched controls.•Implications for technology's safety and potential for non-invasive neuromodulation.