Neuromodulatory non-invasive brain stimulation (NIBS) techniques are experimental
therapies for improving motor function after stroke. The aim of neuromodulation is
to enhance adaptive or suppress maladaptive processes of post-stroke reorganization.
However, results on the effectiveness of these methods, which include transcranial
magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), are
mixed. The results of recent large clinical trials and meta-analyses range from no
improvement in motor function (1, 2) to moderate improvement (1–6) at the group level.
Though evidence supporting efficacy is better for TMS (7) than for tDCS (6), individual
stroke patients' response to NIBS is nevertheless extremely variable (8–11). This
is reminiscent of the development of other stroke therapies, such as thrombolysis
and mechanical thrombectomy, where early studies were largely mixed before patient
selection was refined (12, 13). NIBS in stroke faces a similar challenge of refining
patient selection and individualizing protocols to determine its therapeutic potential.
The variable response to NIBS in stroke patients is a byproduct of multiple factors
that influence response to NIBS in healthy controls (14, 15), as well as factors that
influence the response specifically in stroke patients (8). The former include factors
such as age, gender, anatomical variability, intake of stimulant substances, and baseline
neurophysiological state but also technical factors such as stimulation intensity,
TMS coil orientation, and stimulation duration (16–18). Specifically in stroke patients,
symptom severity, size and location of lesions, stroke etiology, and time from symptom
onset to intervention influence the response to NIBS as well. Importantly, these different
variability-causing factors interact to affect the response to NIBS, such as the potential
amplification of inter-individual differences in brain anatomy (19, 20) by stroke
lesions (21, 22). Such interactions make understanding the causes of NIBS response
variability in stroke challenging.
Although the need for individualized stimulation protocols in stroke patients is widely
accepted, it is still unclear exactly how this will be achieved. At the very least,
the factors influencing variability in healthy subjects should be controlled as much
as possible through appropriate and careful study design (23) and checklist-based
reporting of factors during data collection (24). To address the specific factors
for stroke, patient selection for NIBS should be informed by pathophysiological processes.
This requires that we know which processes are relevant, that we are capable of measuring
them, and that we know the optimum timing and patient-related characteristics for
treatment administration.
Models of Reorganization as a Basis for Stimulation Protocols
Until recently, NIBS protocols have mostly been based on the interhemispheric competition
model (25, 26), which postulates that the unaffected hemisphere overly inhibits the
affected hemisphere. Despite NIBS strategies based on this model being largely ineffective
at the group level (27–30), it is still a popular approach used by several recent
(9) and ongoing clinical trials. In severely affected patients in particular, the
validity of this model has been questioned (31, 32) and an alternative, the vicariation
model, suggested (33). The vicariation model postulates that the function of the unaffected
hemisphere compensates for the impairment of the affected hemisphere, thereby presenting
an adaptive, rather than maladaptive, process (32, 34–37).
These contradictory models have been unified in the bimodal-balance recovery model,
taking us a step further to individualized therapy (25). This uses a metric, the “structural
reserve,” defined as the integrity of the white matter motor pathways, to determine
whether the inter-hemispheric competition or vicariation model is applicable in a
given patient. According to the model, in patients with high structural reserve, the
over-activation of the unaffected hemisphere is maladaptive, while in patients with
low structural reserve, this over-activation is compensatory. Supporting this model,
severely affected patients, with presumably low structural reserve, have poorer outcomes
when inhibitory NIBS protocols are applied to their unaffected hemispheres (28, 37),
emphasizing the need to modify “one-size-fit-all” NIBS protocols.
However, it is yet to be resolved which clinical and imaging characteristics are appropriate
proxies for structural reserve. Most evidence thus far comes from studies investigating
the ability of these characteristics to predict stroke outcome. White matter integrity,
quantified with the fractional anisotropy of white matter tracts on diffusion tensor
imaging, is commonly used (38–42). However, a good predictor of stroke outcome (prognostic
biomarker) is not necessarily useful for predicting the response to specific NIBS
paradigms (selection biomarker) (43). Prognostic biomarkers may provide a good starting
point; however, they need to be validated to demonstrate their specific role and relative
importance in influencing the response to NIBS after stroke. Two recent promising
studies show that behavioral measures such as the Action Research Arm Test and the
Fugl-Meyer score are predictors of the response to NIBS in correlation with white
matter integrity measured using imaging (44, 45). These studies show that both clinical
and imaging measures associated with structural reserve influence the effectiveness
of facilitation of the affected hemisphere or inhibition of the unaffected hemisphere,
providing direct support for the bimodal-balance recovery model, and setting the ground
for future studies validating these selection biomarkers.
On the methodological level, to develop a framework to guide individualized NIBS therapy,
large studies with many patients and variables must be conducted (46). The analysis
of such large-volume, complex data would be suited for machine learning approaches.
Considering preliminary evidence on the high correlation between clinical and imaging-based
biomarkers (44, 45), as well as the high correlation within the different clinical
features of stroke (47, 48), potential models guiding NIBS therapy need not to be
overly complex, and it is likely that highly correlated measures can be reduced to
factors of lower dimension that explain substantial variability.
Two potential imaging-based biomarkers of NIBS response in stroke—whole-brain connectivity
and the brain's propensity to respond to stimulation—have been largely ignored and
are addressed here (Figure 1).
Figure 1
Potential biomarkers to predict NIBS response. fMRI-based connectivity techniques
(top) provide information on the brain's large-scale functional organization. Moving
beyond the description of single networks, whole-brain (“connectome”) connectivity
models capture the heterogeneity and individual reorganization after stroke using
a single scan. The individual connectome “fingerprint” could therefore be used as
a predictor of NIBS response based on stroke pathophysiology in an individual patient.
Properties of ongoing neuronal oscillations measured using EEG (bottom) carry both
stable, heritable (“trait”), and transiently changing (“state”) information. EEG power
and temporal dynamics can be used as “trait” measures and provide prediction of NIBS
response at the individual level. EEG phase can be used to temporally align NIBS stimulation
with excitability states to improve NIBS efficacy at the individual level.
Whole-Brain Network Connectivity
Stroke is not a mere localized phenomenon. Widespread effects of stroke are found
within the affected network (49), but also beyond it (50–54), and connectivity has
been suggested as the underlying mechanism mediating these indirect effects (33, 55).
Whole-brain connectivity models based on resting-state functional magnetic resonance
imaging (rs-fMRI) show that modulation of long-range connections between different
regions outside lesions and their changes over time relate to stroke recovery on the
individual level (56–58). In addition, most strokes affect multiple behavioral domains
and thus changes in multiple functional networks better characterize a single patient.
These factors likely contribute to the observed response variability to NIBS, but
have not been sufficiently considered thus far, as both connectivity alterations in
stroke and NIBS protocols have mostly been investigated in the context of isolated
networks (8, 59–62). Given the effects of NIBS on distributed networks (63–65) and
the understanding of stroke as a distributed pathology (55, 66, 67), when applying
stimulation in these patients, assuming that a single functional network is being,
or indeed should be, targeted is problematic.
Whole-brain connectivity using rs-fMRI is well-suited for use in patients because
it captures, with a single task-free scan, information on functional connectivity
of multiple brain networks (55, 66). In our opinion, this approach can be used to
develop more realistic models of spontaneous reorganization after stroke, and could
prove beneficial for designing individualized stimulation protocols.
A methodological limitation of connectivity approaches is that they rely on a-priori
delineation of somewhat arbitrary boundaries between networks. Dimensionality reduction
of whole-brain connections overcomes this problem (68). Using this data-driven approach,
areas are clustered according to similarity of their connectivity patterns in a parametric,
continuous manner. Dimensionality reduction of whole-brain connections can provide
a fingerprint of the connectome at the individual patient level (69), thereby representing
a more realistic picture of stroke involving multiple functional domains. Using this
approach, we recently showed that the location of a stroke lesion in whole-brain connectivity
space is related to the degree of reorganization that occurs within the first week
of stroke onset, as measured by whole-brain functional connectivity (70). This preliminary
result supports the value of developing whole-brain connectivity models to characterize
the widespread effects of localized lesions in detail.
Given the promising results of predicting NIBS response using electroencephalogram
(EEG) connectivity (71) and the added value of functional connectivity changes to
prognostic models of stroke outcome (72), we suggest that connectivity patterns may
be useful biomarkers for response to NIBS. Going forward, the link between a connectome
fingerprint and spontaneous recovery in multiple functional domains has to be established,
followed by the predictive role of the connectome fingerprint prior to stimulation
on the clinical response to NIBS, with the eventual goal of using this information
to design NIBS protocols.
Ongoing Neuronal Oscillations
Factors influencing response to NIBS can be subclassified into momentary (“state”)
and phenotypic (“trait”) factors. Both can be assessed using properties of neuronal
oscillations that reflect the cortex's susceptibility to stimulation.
An individual's response to a stimulation protocol is hard to predict. The exact same
NIBS protocol may lead to excitatory, inhibitory, or no effects on motor evoked potentials
in different individuals, even in the absence of pathology (14, 15, 73, 74). One way
to reduce this variability is to align the stimulation with states in which the brain
is most susceptible (“excitability states”) (75). There is evidence for the relevance
of these states, including the observation that the variability of pre-stimulus alpha
oscillations correlate with the variability of responses to TMS (76), power of sensorimotor
mu (8–12 Hz oscillations above central-parietal electrodes) correlates with amplitude
of motor evoked potentials (77), and synchronicity of mu oscillations in bilateral
M1 is associated with stronger interhemispheric inhibition (75). These approaches
are currently being pursued for targeted “state-dependent” NIBS (78, 79).
Properties of neuronal oscillations define instantaneous cortical reactivity to NIBS
but are also subject-specific and highly heritable. This particularly relates to the
power in the alpha band (80), and the temporal dynamics of the oscillations in alpha
and beta bands (81). These results support the idea that beyond momentary states,
properties of neuronal oscillations during rest can also represent a phenotypic trait.
The response to NIBS itself is also highly heritable (82), and intra-subject reliability
of NIBS response is relatively high in healthy individuals (15). A recent EEG study
showed that the temporal dynamics in the alpha band obtained before stimulation correlates
on an individual level with the response to paired-pulse TMS in healthy individuals
(83). These studies provide evidence that cortical plasticity is in part genetically
determined, indicating a trait-like capacity of the brain to be modulated.
Studies show that neural networks might operate at the critical state, representing
a balance between excitation and inhibition which is optimal for information processing
(84–86). Critical states are also associated with the presence of long-range temporal
correlations (LRTC) in the amplitude dynamics of neuronal oscillations (87). Given
that LRTCs relate to cortical excitability (83), they are likely to be perturbed after
stroke, as they are in several other neurological and psychiatric disorders (88–90).
The patterns of perturbation may be linked to spontaneous recovery through reaching
a compensatory state that effectively balances out the state of the network.
Trait-like properties of neuronal oscillations can be quantified using clinically
accessible methods such as resting EEG. In our opinion, these may serve as potentially
meaningful biomarkers for response to NIBS by accounting for variability in the cortex's
susceptibility to stimulation in individual patients.
New NIBS Approaches
Recent developments in NIBS technology will likely contribute to individualized therapy.
Moving beyond single-area stimulation, targeting specific muscle groups that play
different roles in post-stroke motor recovery (for example, finger flexors vs. extensors)
will be possible using multi-locus TMS (91). This approach enables stimulation of
multiple regions with high temporal precision, as it does not involve repositioning
of the coil. The exact changes induced by NIBS on a sub-regional level (for example,
in specific parts of the motor homunculus) can be predicted using advanced induced
electrical field modeling (92, 93), further refining such targeting. Finally, deep
brain structures, inaccessible using TMS and tDCS yet relevant for dexterity deficits
and pathological synergies in stroke (94, 95), might be targeted using new non-invasive
stimulation approaches such as transcranial focused ultrasound (96) or temporal interference
(97). These technological advances along with the development and validation of meaningful
biomarkers associated with response to NIBS can help advance the translation of NIBS
while embracing the inevitable heterogeneity associated with stroke pathology.
Author Contributions
SO-C, AK, MN, and VN project planning and conceptualization. SO-C, AK, and MN literature
search and manuscript writing and revising. SO-C principle writing and revising. VN,
BS, and AV manuscript revising or drafting.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.