Table 4.
Summary of safe and effective parameters used in identified studies and reported relationships between parameter escalation and BBB disruption efficacy and safety outcomes.
| Parameter | Safe and Effective Parameters Commonly Used | Parameters Compared | Reported Effects on BBBD (Efficacy Outcomes) | Reported Safety Outcomes |
|---|---|---|---|---|
| Transducer Frequency | Preclinical: 0.20–1.50 MHz Clinical: 0.22, 0.50, and 1.05 MHz |
0.26, 0.69, 1.63, 2.04 MHz [119] |
Increasing frequency: greater PNP required to achieve BBBD [19,45,94,119]; smaller foci/area of BBBD [19,45,94] | Increasing frequency: increased density of microhaemorrhagic activity [119]; decreased haemorrhagic [19,45,94] and oedematous activity [45] |
| 1 and 10 MHz [45,94] | ||||
| 0.5 and 1.6 MHz [19] | ||||
| PNP | Preclinical: 0.2–0.5 MPa with <1 MHz transducers Clinical: 0.48–1.15 MPa and 2.5–60 W power |
0.30, 0.46, 0.61, 0.75, 0.98 MPa [73] |
Increasing PNP: increasing BBBD after surpassing threshold PNP [9,15,45,65,73]; eventual saturation point in BBBD [32]; prolonged BBB opening [65,66]; prolonged P-glycoprotein downregulation [15] | Increasing PNP: increased haemorrhagic [15,19,65,66,73,93] and microhaemorrhagic change [73,93]; neuropil loss; neuronal loss [73,93] and necrosis [93]; evidence of apoptosis [45]; cerebral oedema [9,45]; hypoactivity/ataxia/tremor [33] |
| 0.55, 0.81 MPa [15] | ||||
| 0.27, 0.39, 0.59, 0.78 MPa [93] | ||||
| 0.3, 0.5, 1.0, 1.5, 2.0, 2.5, 4.5 MPa [45,94] | ||||
| 1.1, 1.9, 2.45, and 3.5 MPa [65] | ||||
| 0.45, 0.62, 0.98, 1.32 MPa [101] | ||||
| 0.55, 0.78, 1.1, 1.9, 2.45, 3.47, 4.9 MPa [32] | ||||
| 0.2, 0.3, 0.6, 1.5 MPa [19] | ||||
| 0.30, 0.51, 0.89 MPa [33] | ||||
| 0.4, 0.5 0.8, 1.1, 1.4, 2.3, 3.1 MPa [28] | ||||
| 0.2, 0.4, 0.5, 0.8, 1.1, 1.8 MPa [25] | ||||
| 0.78, 0.90, 1.03, 1.15 MPa [9] | ||||
| PL | Preclinical: 10 ms Clinical: 2–3, 10, and 23.6 ms |
0.1, 0.2, 1.0, 2.0, 10, 20, 30 ms [76] |
Increasing PL: increasing BBBD with PL 0.1–10 ms; statistically non-significant increase in BBBD after PL > 10 ms [7,76]; decreased PNP threshold (PL = 0.1–10 ms) [120]; heterogeneous distribution of BBBD/greater perivascular accumulation of tracer [76] | Increasing PL: no microhaemorrhagic change with PL ≤ 10 ms [19,120]; significant haemorrhagic change with PL = 100 ms [19,23]; evidence of apoptosis with PL = 100 ms [23] |
| 1, 10, 100 ms [19] | ||||
| 10, 100 ms [7] | ||||
| 0.1, 1, 10 ms [120] | ||||
| 30, 100 ms [23] | ||||
| 10, 50 and 100 ms [102] | ||||
| PRF | Preclinical: 1–10 Hz Clinical: 1–10 Hz and 30–31 Hz |
0.1, 1, 1, 10, 25 Hz[76] | Increasing PRF: no BBBD with PRF = 0.1 Hz [76]; inconsistent improvements in BBBD with tonic pulsed sequences, some being statistically significant [19] and others not [76,120]; improvements in BBBD with rapid, phasic pulses [60,108] | Increasing PRF: no increase in adverse safety outcomes, via MRI [108] and histology [19,60,76,108,120] |
| 0.5, 1, 2, 5 Hz [120] | ||||
| 1, 2, 5 Hz [19] | ||||
| 1, 1667, 3333, 16,667, 166,667 Hz [108] | ||||
| 6250, 25,000, 100,000 Hz [60] | ||||
| SD | Preclinical: 30–120 sClinical: 30–120 s; 150–270 s in one study | 30, 660 s [76] |
Increasing SD: improved BBBD with pulsed [19,93,102] and continuously [40,121] applied US; plateauing effect thereafter [93,115]; one study reported no improvement in BBBD [76] | Increasing SD: minimal change in adverse safety outcomes with small increases, and significantly worsening safety outcomes with excessive increases [19,40,93,102,121]; no increase in histopathological outcomes in one study [76] |
| 240, 360, 480, 600 s [102] | ||||
| 30, 60, 120, 300 s [19] | ||||
| 30, 180, 300, 600, 1200 s [93] | ||||
| 60, 120, 180, 240 s[40] | ||||
| 6, 8 and 10 s [121] | ||||
| Dosing (Number and Frequency) of Sonications | Preclinical: 1–13 sonications/session (ISI = 5 min) Clinical: 1–8 sonications/session (ISI not stated) ISIs are listed within brackets |
1, 2 (10 min), 2 (120 min) sonications [71] |
Increasing sonication #: increase in BBBD [71,115]; improved doxorubicin uptake with shorter ISI [71] | Increasing sonication #: no [71] or mild [115] histopathological change (increased neuropil vacuolation) |
| 1, 2 (20 min), 2 (40 min) sonications [115] | ||||
| Dosing (Number and Frequency) of Sessions | Preclinical: 1–27 Clinical: 1–10 sessions Intersession intervals are listed within brackets |
2–10, 2–6 sessions (biweekly and monthly) [84] |
Increasing session #: higher PNP sonications required to achieve similar BBBD, but likely due to animal model growth [84] as not observed in developed adult clinical trials [9,11] | Increasing session #: no adverse safety outcomes [53,123]; transient MRI changes [9,21,22]; cortical atrophy, ventricular dilation, and lesion formation on MRI [100]; increased phosphorylated tau deposition [100]; increased neurogenesis [100] no change in motor and behavioural outcomes in rodents [84]; increased tissue damage and macrophage infiltration with doxorubicin co-delivery [70,91]; increasing number of apoptotic cells (significantly larger microbubble dose) [33]; mild increase in white matter vacuolation and mild neuronal injury (significantly larger microbubble dose) [43] |
| 1, 8 (3 days) sessions [43] | ||||
| 1, 4 (weekly) sessions [123] | ||||
| 1, 6 (weekly) sessions [100] | ||||
| 1, 3 (weekly) sessions [93] | ||||
| 1, 3 (weekly) sessions [70,91] | ||||
| 1, 2 (2 days), 3 (2 days) sessions [33] | ||||
| 3 (monthly), 6 (monthly) sessions [53] | ||||
| 4–27 (varying intersession intervals) sessions [21,22] | ||||
| 1–10 (monthly) sessions [9] |
US: ultrasound; BBBD: blood–brain barrier disruption; PL: pulse length; PRF: pulse repetition frequency; SD: sonication duration; ISI: intersonication interval.