Elsevier

Clinical Neurophysiology

Volume 129, Issue 12, December 2018, Pages 2544-2551
Clinical Neurophysiology

Non-invasive brain stimulation in the modulation of cerebral blood flow after stroke: A systematic review of Transcranial Doppler studies

https://doi.org/10.1016/j.clinph.2018.09.019Get rights and content

Highlights

Abstract

Objective

Non-invasive brain stimulation (NIBS), such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), are promising neuromodulatory priming techniques to promote task-specific functional recovery after stroke. Despite promising results, clinical application of NIBS has been limited by high inter-individual variability. We propose that there is a possible influence of neuromodulation on cerebral blood flow (CBF), as neurons are spatially and temporally related to blood vessels. Transcranial Doppler (TCD), a clinically available non-invasive diagnostic tool, allows for evaluation of CBF velocity (CBFv). However, little is known about the role of neuromodulation on CBFv.

Methods

A systematic review of literature to understand the effects of NIBS on CBFv using TCD in stroke was conducted.

Results

Twelve studies fit our inclusion criteria and are included in this review. Our review suggested that CBFv and/or vasomotor reactivity maybe influenced by rTMS dosage (intensity and frequency) and the type of tDCS electrode montage.

Conclusion

There is limited evidence regarding the effects of NIBS on cerebral hemodynamics using TCD and the usefulness of TCD to capture changes in CBFv after NIBS is not evident from this review. We highlight the variability in the experimental protocols, differences in the applied neurostimulation protocols and discuss open questions that remain regarding CBF and neuromodulation.

Significance

TCD, a clinically accessible tool, may potentially be useful to understand the interaction between cortical neuromodulation and CBFv.

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)

  • M. Li et al.

    An analysis of cerebral blood flow from middle cerebral arteries during cognitive tasks via functional transcranial Doppler recordings

    Neurosci Res

    (2014)
  • V. López-Alonso et al.

    Inter-individual variability in response to non-invasive brain stimulation paradigms

    Brain Stimul

    (2014)
  • M. Moisa et al.

    Interleaved TMS/CASL: comparison of different rTMS protocols

    Neuroimage

    (2010)
  • Z. Nahas et al.

    Unilateral left prefrontal transcranial magnetic stimulation (TMS) produces intensity-dependent bilateral effects as measured by interleaved BOLD fMRI

    Biol Psychiatry

    (2001)
  • A. Orosz et al.

    Theta burst TMS increases cerebral blood flow in the primary motor cortex during motor performance as assessed by arterial spin labeling (ASL)

    Neuroimage

    (2012)
  • J.D. Rollnik et al.

    Decrease of middle cerebral artery blood flow velocity after low-frequency repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex

    Clin Neurophysiol

    (2002)
  • F. Sallustio et al.

    Changes in cerebrovascular reactivity following low-frequency repetitive transcranial magnetic stimulation

    J Neurol Sci

    (2010)
  • D. Sander et al.

    Effect of hemisphere-selective repetitive magnetic brain stimulation on middle cerebral artery blood flow velocity

    Electroencephalogr Clin Neurophysiol

    (1995)
  • D. Sander et al.

    Increase of posterior cerebral artery blood flow velocity during threshold repetitive magnetic stimulation of the human visual cortex: hints for neuronal activation without cortical phosphenes

    Electroencephalogr Clin Neurophysiol

    (1996)
  • H.R. Siebner et al.

    Imaging functional activation of the auditory cortex during focal repetitive transcranial magnetic stimulation of the primary motor cortex in normal subjects

    Neurosci Lett

    (1999)
  • H.R. Siebner et al.

    Continuous transcranial magnetic stimulation during positron emission tomography: a suitable tool for imaging regional excitability of the human cortex

    NeuroImage

    (2001)
  • A.M. Speer et al.

    Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: I. Effects of primary motor cortex rTMS

    Biol Psychiatry

    (2003)
  • A.M. Speer et al.

    Intensity-dependent regional cerebral blood flow during 1-Hz repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers studied with H215O positron emission tomography: II. Effects of prefrontal cortex rTMS

    Biol Psychiatry

    (2003)
  • B. Takano et al.

    Short-term modulation of regional excitability and blood flow in human motor cortex following rapid-rate transcranial magnetic stimulation

    NeuroImage

    (2004)
  • R. Urushihara et al.

    Effect of repetitive transcranial magnetic stimulation applied over the premotor cortex on somatosensory-evoked potentials and regional cerebral blood flow

    NeuroImage

    (2006)
  • F. Vernieri et al.

    1-Hz repetitive transcranial magnetic stimulation increases cerebral vasomotor reactivity: a possible autonomic nervous system modulation

    Brain Stimul

    (2014)
  • F. Vernieri et al.

    High frequency repetitive transcranial magnetic stimulation decreases cerebral vasomotor reactivity

    Clin Neurophysiol

    (2009)
  • S. Wiethoff et al.

    Variability in response to transcranial direct current stimulation of the motor cortex

    Brain Stimul

    (2014)
  • A.J. Woods et al.

    A technical guide to tDCS, and related non-invasive brain stimulation tools

    Clin Neurophysiol

    (2016)
  • X. Zheng et al.

    Effects of transcranial direct current stimulation (tDCS) on human regional cerebral blood flow

    NeuroImage

    (2011)
  • R. Aaslid

    The doppler principle applied to measurement of blood flow velocity in cerebral arteries

  • M.C. Aoi et al.

    Impaired cerebral autoregulation is associated with brain atrophy and worse functional status in chronic ischemic stroke

    PLoS One

    (2012)
  • M.J.H. Aries et al.

    Cerebral autoregulation in stroke. A review of transcranial doppler studies

    Stroke

    (2010)
  • D. Attwell et al.

    Glial and neuronal control of brain blood flow

    Nature

    (2010)
  • M.J. Bakker et al.

    Cerebrovascular function and cognition in childhood: a systematic review of transcranial doppler studies

    BMC Neurol.

    (2014)
  • S.L. Bakker et al.

    Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly

    Neurology

    (1999)
  • J. Baudewig et al.

    Regional modulation of BOLD MRI responses to human sensorimotor activation by transcranial direct current stimulation

    Magn Reson Med

    (2001)
  • J. Baudewig et al.

    Functional MRI of cortical activations induced by transcranial magnetic stimulation (TMS)

    Neuroreport

    (2001)
  • S. Bestmann et al.

    Functional MRI of the immediate impact of transcranial magnetic stimulation on cortical and subcortical motor circuits

    Eur J Neurosci

    (2004)
  • J.U. Blicher et al.

    Visualization of altered neurovascular coupling in chronic stroke patients using multimodal functional MRI

    J Cereb Blood Flow Metab

    (2012)
  • R.D. Boehmer

    Continuous, real-time, noninvasive monitor of blood pressure: Peňaz methodology applied to the finger

    J Clin Monit

    (1987)
  • Cited by (0)

    View full text