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. 2015 May 6;10(5):e0125911.
doi: 10.1371/journal.pone.0125911. eCollection 2015.

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Matthew E Downs  1 , Amanda Buch  1 , Carlos Sierra  1 , Maria Eleni Karakatsani  1 , Tobias Teichert, Shangshang Chen  2 , Elisa E Konofagou  3 , Vincent P Ferrera  2
Affiliations

Long-Term Safety of Repeated Blood-Brain Barrier Opening via Focused Ultrasound with Microbubbles in Non-Human Primates Performing a Cognitive Task

Matthew E Downs et al. PLoS One. .

Erratum in

Abstract

Focused Ultrasound (FUS) coupled with intravenous administration of microbubbles (MB) is a non-invasive technique that has been shown to reliably open (increase the permeability of) the blood-brain barrier (BBB) in multiple in vivo models including non-human primates (NHP). This procedure has shown promise for clinical and basic science applications, yet the safety and potential neurological effects of long term application in NHP requires further investigation under parameters shown to be efficacious in that species (500 kHz, 200-400 kPa, 4-5 μm MB, 2 minute sonication). In this study, we repeatedly opened the BBB in the caudate and putamen regions of the basal ganglia of 4 NHP using FUS with systemically-administered MB over 4-20 months. We assessed the safety of the FUS with MB procedure using MRI to detect edema or hemorrhaging in the brain. Contrast enhanced T1-weighted MRI sequences showed a 98% success rate for openings in the targeted regions. T2-weighted and SWI sequences indicated a lack edema in the majority of the cases. We investigated potential neurological effects of the FUS with MB procedure through quantitative cognitive testing of' visual, cognitive, motivational, and motor function using a random dot motion task with reward magnitude bias presented on a touchpanel display. Reaction times during the task significantly increased on the day of the FUS with MB procedure. This increase returned to baseline within 4-5 days after the procedure. Visual motion discrimination thresholds were unaffected. Our results indicate FUS with MB can be a safe method for repeated opening of the BBB at the basal ganglia in NHP for up to 20 months without any long-term negative physiological or neurological effects with the parameters used.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Random dot motion and reward magnitude bias task.
Cues appear in the center of the left or right side of the screen randomly. Once the initial cue is touched three new stimuli appear: A correct target appears on either the inside (towards the middle of the screen) or the outside (towards the edge of the screen) on the same side the intial cue, and a distractor target will appear opposing the correct target as well as moving dots will appear where the initial cue was. Horizontal and vertical bars indicate high and low reward respectively. Reward magnitude is random so subjects cannot predict reward order.
Fig 2
Fig 2. Vital Monitoring.
Vitals collected at five points throughout the duration of the FUS with MB procedure. Results in the grey shaded region indicate time-points acquired during the FUS proceure.
Fig 3
Fig 3. Contrast Enhanced BBB opening.
The blue region shows a 10% increase in contrast over the background. A) Opening in the putamen of A. B) Opening in the caudate and putamen of N. C) Opening in the putamen of Ob. D) Opening in the caudate of O
Fig 4
Fig 4. T2-weighted MRI and SWI scans of NHP N and A.
T2-weighted sequences can be used to detect potential edema. The first column shows no atypical hyperintense voxels in the target region. The second column shows atypical hyperintense voxels in the target region. The third column verifies the atypical hyperintense voxels from the previous week were no longer present. The fourth column shows the SWI scans from the day when hyperintense voxels were detected on the T2 scan (acquired the same day as column 2).
Fig 5
Fig 5. Raw reaction time and touch error to initial cue (left column), and to the correct target (right column).
Blue diamonds indicate raw reaction time in seconds to either the initial cue or correct target. Red asterisks indicate raw touch error to either the initial cue or correct target. Reaction time is plotted on the left vertical axis while touch error is plotted on the right vertical axis. Dashed vertical lines indicate days when the FUS with MB procedure occurred.
Fig 6
Fig 6. Average reaction time to initial cue (left column), and to the correct target (right column).
Blue indicates group average while red is the 95% confidence interval for the mean. For all NHP there is a significant increase in reaction time on day 0 compared to the rest of the days (p < 0.05). The numbers above each average indicate the n value for that group. The horizontal bar indicates baseline reaction time.
Fig 7
Fig 7. Average touch error to initial cue (left column), and to the correct target (right column).
Blue indicates group average while red is the 95% confidence interval for the mean. There was a significant difference touch error to the cue on day 0 and the majority of the rest of the days (p < 0.05). There was a significant difference touch error to the correct on day 0 and some of the other days (p < 0.05). The numbers above each average indicate the n value for that group. The horizontal bar indicates baseline reaction time.
Fig 8
Fig 8. Difference in average reaction time between the ipsilateral and contralateral hands as a function of day relative to the day of the FUS procedure.
Responses to the cue are plotted in the left column. Responses to the target are plotted in the right column. Blue indicates group average (average ipsilateral hand reaction time—average contralateral hand reaction time) while red is the standard error of the mean. The numbers indicate the n value for that group. Asterisks above each average indicate a significant difference between the difference in reaction time on day 0 compared to the rest of the days (p < 0.05).
Fig 9
Fig 9. Difference in average touch error between ipsilateral and contralateral hands as a function of day relative to the day of the FUS procedure.
Responses to the cue are plotted in the left column. Responses to the target are plotted in the right column. Blue indicates group average (average ipsilateral hand touch error—average contralateral hand touch error) while red is the standard error of the mean. The numbers indicate the n value for that group. Asterisks above each average indicate a significant difference between the difference in reaction time on day 0 compared to the rest of the days (p < 0.05).
Fig 10
Fig 10. Difference in average reaction time between low and high reward as a function of day relative to the day of the FUS.
Responses to the cue are plotted in the left column. Responses to the target are plotted in the right column. Blue indicates group average (average low reward reaction time—average high reward reaction time) while red is the standard error of the mean. The numbers indicate the n value for that group. Asterisks above each average indicate a significant difference between the difference in reaction time on day 0 compared to the rest of the days (p < 0.05).
Fig 11
Fig 11. Difference in average touch error between low and high reward as a function of day relative to the day of the FUS.
Responses to the cue are plotted in the left column. Responses to the target are plotted in the right column. Blue indicates group average (average low reward touch error—average high reward touch error) while red is the standard error of the mean. The numbers indicate the n value for that group. Asterisks above each average indicate a significant difference between the difference in reaction time on day 0 compared to the rest of the days (p < 0.05).
Fig 12
Fig 12. Naka-Rushton model fits of accuracy against coherence for the RDM task completed by NHP N.
The red and blue circles indicate the average percent correct for each coherence level for the right and leftward moving dots respectively. The numbers in the top left corners correspond to days relative to the FUS with MB procedure. Other NHP coherence plots follow similar trends of no large variation in response to the FUS with MB procedure.
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