Table 2.
Theoretical-, methodological-, and measurement-related factors implicated in failed phase III trial of invasive stimulation versus early clinical and animal studies
| Factors | Description | |
|---|---|---|
| Theoretical | Types of lesions: animals vs humans | Well-defined cortical lesions in animals, but diffuse, cortical/subcortical/cortical + subcortical lesions in humans |
| Mechanism of reorganization targeted by stimulation | Residual representations in peri-infarct M1 circumscribed in animals—consistent potential for reorganization with stimulation. Poorly-defined lesions of M1 and pathways in humans create inconsistent potential for peri-infarct M1 to reorganize. Other patient-specific neural mechanisms should instead be stimulated |
|
| Stimulation in patients: is it generalizable? | Best effects achieved only in patients with functioning corticospinal pathways. Refining patient selection in future studies. | |
| Methodological | Localization and its confirmation | fMRI activation localized implants in trials, but only phase I confirmed the site elicited contralateral response—signifying functioning pathways |
| Functionality of descending pathways | 83 % and 42 % of investigational group possessed functioning pathways in phase I and II, unlike 15 % in phase III | |
| Focality of stimulation | 2.7 × 2.6 cm2 area may be too focal for humans. Animal studies note greater benefit when stimulation is distributed at periphery of motor targets than in interior of M1. Less-focal, noninvasive cortical stimulation achieves greater ∆ (> 5 points on Fugl–Meyer) with comparable or shorter paired rehabilitation |
|
| % Volume of tissue activated | Volume of human precentral gyrus is 100 times than that in animals; however, stimulation contact area is only 4–7 times larger | |
| Task-specificity in rehabilitation | Animal studies note best effects for task paired with stimulation. Analogously, is stimulation in humans best for laboratory-based tasks or varied types of training used in clinical rehabilitative practice? | |
| Measurement | Study design | Blinded raters in phase III vs early trials, which were open-label. Phase III: large, multicenter set-up vs early trials employed smaller set-up across fewer centers |
| Differences in control | Control group in phase II apparently more impaired (Fugl–Meyer = 30.5 ±7.3; range = 20–44) than in phase III (Fugl–Meyer = 37.6, range = 29–50). So, more benefit for controls in phase III vs II (∆ Fugl–Meyer: 4 vs 1.9) | |
| Defining endpoint | Stricter criteria of efficacy in phase III vs phase II., so fewer % in investigational group achieved clinically meaningful ∆ in phase III |
fMRI functional magnetic resonance imaging; M1 primary motor cortex