Non-invasive brain stimulation in the modulation of cerebral blood flow after stroke: A systematic review of Transcranial Doppler studies
Introduction
NIBS has been successfully explored as a biomarker and therapeutic adjunct for functional recovery after stroke. rTMS and tDCS are two such promising neuromodulatory techniques that have been widely investigated to prime the motor areas of the brain in combination with task-specific practice ( Bastani and Jaberzadeh, 2012, Hsu et al., 2012, Jodie et al., 2015, Le et al., 2014). Although these techniques have demonstrated modest efficacy, clinical translation is still limited as the underlying physiological mechanisms are not completely understood, nor is the inter-individual variability associated with these techniques resolved (López-Alonso et al., 2014, Maeda et al., 2000, Wiethoff et al., 2014). Many studies have explored the physiology of NIBS using neuroimaging such as fMRI and TMS, however the cerebral hemodynamics of neuromodulation is relatively less explored.
Neurovascular coupling is the close temporal and spatial relationship between neural activity and CBF, in response to metabolic demand of the brain tissue (Girouard and Iadecola, 2006, Hamel, 2006, Kontos, 1981, Muoio et al., 2014). The conceptual neurovascular unit comprises of the neurons, glia and vascular cells. Neuronal activity increases metabolic demand, triggering the hemodynamic response to increase CBF. Neurovascular coupling helps maintain the fine balance between neuronal activity and subsequent changes in CBF, which is critical for brain homeostasis. Cerebral hemodynamics is reported to be impaired after a stroke (Blicher et al., 2012), possibly due to disruption in the neurovascular unit function and/or impairment of auto regulatory mechanisms (Aries et al., 2010, Bakker et al., 1999, Girouard and Iadecola, 2006, Lin et al., 2011, Markus and Cullinane, 2001). Hence it is critical to understand the hemodynamic effects of NIBS in stroke before clinical implementation of this adjuvant neuromodulatory technique.
TCD ultrasonography is a non-invasive diagnostic tool that allows evaluation of CBFv within the large cerebral arteries which is reflective of changes in brain perfusion. TCD is based on the ‘Doppler Principle’, where ultrasonic waves from the Doppler probe travel through acoustic windows within the skull and are echoed by the moving red blood cells in large cerebral arteries, enabling measurement of CBFv (Aaslid, 1986). Factors such as insonating frequency (typically 2 MHz), the acoustic window for effective ultrasound penetration, lateral angle of doppler probe, and operator’s handling reliability play a key role in quantification of the CBF function (Naqvi et al., 2013, Newell and Aaslid, 1992). TCD is usually combined with finger plethysmography, capnometers, and ECG monitors for effectively understanding the instantaneous relationships between peripheral and cerebral circulation (Boehmer, 1987, Lenz et al., 1991). TCD allows for measurement of blood flow velocities in the Circle of Willis vessels and is now a recommended tool by the American Heart Association for monitoring arterial vasospasm, and can reach close to 100% specificity values for the middle cerebral artery (MCA) (Connolly et al., 2012, Robba et al., 2018, Wijman et al., 2001). Fig. 1 depicts the various CBFv parameters that are commonly measured with TCD.
TCD presents several advantages relative to more complicated and expensive techniques such as fMRI, near infrared spectroscopy (NIRS), positron emission topography (PET) and arterial spin labeling (ASL). The advantages of TCD include its high temporal resolution, ease of administration, relative insensitivity to movement artifacts, less expensive technology, better clinical accessibility and bedside availability. Numerous TCD studies have reliably and accurately measured changes in CBFv in sensorimotor and cognitive domains (Bakker et al., 2014, Li et al., 2014). These studies have demonstrated that TCD can accurately capture alterations in CBFv during verbal, motor and cognitive tasks. However, there is limited information regarding changes in CBFv following neuromodulation using NIBS especially in stroke. Neurovascular coupling becomes significantly altered after stroke; individuals with stroke present with impaired cerebrovascular reactivity measured by TCD (Lin et al., 2011, Maeda et al., 1993, Salinet et al., 2013a). In this article, our primary objective is to systematically review studies that have measured changes in CBFv after rTMS and tDCS using TCD. This information is significant as it may enable us to investigate the utility of CBFv, measured with a clinically relevant tool such as TCD, as a biomarker for understanding the variability in responsiveness to NIBS post stroke. Due to the scarcity of TCD and NIBS studies in the stroke population, we also include studies of the healthy brain to better inform this review.
Section snippets
Materials and methods
A systematic electronic literature search was carried out using PubMed, Medline, Ovid, Web of Science, Cinahl and Embase databases. The following norms were considered for the search: time line restricted to 1975, articles in English language, participant age above 18 years, and publication type as human clinical studies. Combinations of the following keywords were used to carry out multiple searches: stroke, transcranial direct current stimulation, transcranial magnetic stimulation, repetitive
Results
This report includes a critical analysis of 12 experimental studies with the inclusion of 1 randomized control trial (Table 2, Table 3). Out of these twelve studies, three were conducted on tDCS and nine on rTMS. Study samples varied from 8 to 50 participants. Eleven out of twelve studies included healthy participants in the age range of 21–50 years, three studies included individuals with stroke in the age range of 31–78 years, one study included healthy older adults in the age range of
Discussion
This review summarizes the effects of rTMS and tDCS on CBFv measured with TCD in healthy individuals and stroke survivors. Our interpretations are limited by the small number of studies that have examined the effects of NIBS protocols on cerebral hemodynamics using TCD. These studies indicate that rTMS increases or decreases CBFv according to the type of stimulation (facilitatory or inhibitory) in healthy individuals and stroke survivors. Studies using patterned rTMS did not either measure or
Conclusion
This review indicates that there is insufficient evidence regarding the effects of NIBS on cerebral hemodynamics using TCD. The studies we reviewed are of uneven quality, small scale and lacking standardization of measurement and intervention. We provide a few recommendations for future studies based on the results of this review. First, studies should include larger cohorts to validate the effects of NIBS on CBF. Given the variability of TMS and tDCS protocols, it has been indicated that at
Conflict of interest
None of the authors have potential conflicts of interest to be disclosed.
Funding source
No involvement of any funding source.
References (83)
- et al.
Stimulus intensity dependence of cerebral blood volume changes in left frontal lobe by low-frequency rTMS to right frontal lobe: a near-infrared spectroscopy study
Neurosci Res
(2009) - et al.
Does anodal transcranial direct current stimulation enhance excitability of the motor cortex and motor function in healthy individuals and subjects with stroke: a systematic review and meta-analysis
Clin Neurophysiol
(2012) - et al.
A near infra-red study of blood oxygenation changes resulting from high and low frequency repetitive transcranial magnetic stimulation
Brain Stimul
(2013) - et al.
Ipsilateral activation of the unaffected motor cortex in patients with hemiparetic stroke
Clin Neurophysiol
(2000) - et al.
Inter-and intra-individual variability in response to transcranial direct current stimulation (tDCS) at varying current intensities
Brain Stimul
(2015) - et al.
A comprehensive review of the effects of rTMS on motor cortical excitability and inhibition
Clin Neurophysiol
(2006) - et al.
Detection of cerebral blood flow changes during repetitive transcranial magnetic stimulation by recording hemoglobin in the brain cortex, just beneath the stimulation coil, with near-infrared spectroscopy
NeuroImage
(2006) - et al.
Transcranial Doppler ultrasound for the assessment of intracranial arterial flow velocity—Part 1. Examination technique and normal values
Surg Neurol
(1987) - et al.
Lateralized and frequency-dependent effects of prefrontal rTMS on regional cerebral blood flow
NeuroImage
(2006) - et al.
Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)
Clin Neurophysiol
(2014)