Noninvasive brain stimulation in traumatic brain injury

Abstract

Objective: To review novel techniques of noninvasive brain stimulation (NBS), which may have value in assessment and treatment of traumatic brain injury (TBI).

Methods: Review of the following techniques: transcranial magnetic stimulation, transcranial direct current stimulation, low-level laser therapy, and transcranial Doppler sonography. Furthermore, we provide a brief overview of TMS studies to date.

Main findings: We describe the rationale for the use of these techniques in TBI, discuss their possible mechanisms of action, and raise a number of considerations relevant to translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyperexcitability following TBI and/or counter the excessive GABAergic effects in the subacute stage. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI.

Conclusions: Different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical reorganization and enable functional restoration in TBI. Future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability.

Figures

Figure 1

After injury, compromised energy production elicits a cascade of excitatory neurotransmitters and overactivation of NMDA subclass of glutamate receptors. This provokes a massive increase in intracellular calcium concentration, which leads to the attenuation of mitochondrial potential and results in secondary release of calcium from the mitochondrial mass. A number of factors including stress, hemodynamics, intracranial pressure variations can contribute to the insult and disrupt natural recovery and remodeling. Axonal sprouting is most robust within days following TBI and these factors can cause sprouting fibers to lose direction and connect with the wrong terminals, leading to circuit dysfunction and functional abnormalities that likely contribute to long-term disabilities, such as pain, spasticity, seizures, and memory problems. Following the acute stage, the increased levels of GABA may cause excess inhibition hindering recovery. Targeted inputs and a complex environment may help maintain adequate levels of arousal for potentially rescuable circuits and hence, favor functional restoration. In the chronic stage, major loss of connectivity leading to lasting dysfunction will require compensatory approaches on the network level and neural plasticity may positively or negatively contribute to recovery. In the long term, cognitive problems, Parkinson’s disease, amyotrophic lateral sclerosis and Alzheimer’s disease may arise as a consequence of TBI. Different forms of noninvasive brain stimulation are proposed for these stages in order to reduce disability following TBI; see relevant sections of the text for details.

Figure 2

(A) Therapeutic application of rTMS in a patient with depression. (B) tDCS experimental set-up. Note the saline-soaked conductive electrodes on the surface of the scalp and the small, portable size of the stimulation device (hand-held by investigator).

Figure 3

(A) Illustration of light source emitting near-infrared light capable of penetrating biological tissues and therefore, capable of reaching the cerebral cortex (image courtesy of PhotoThera, Inc.). Caution: the above demonstrates the use of an investigational device – limited by Federal law to investigational use. (B) Multidirectional ultrasound device used for transcranial and/or transorbital Doppler sonography (with permission from the publisher and authors). This device is no different than those currently used in the clinic to assess cerebral blood flow. Hence, the devices for diagnostic transcranial ultrasound may someday be a commonly used therapeutic tool to prevent or minimize ischemic neuronal injury, such as that which may result secondary to TBI.

Figure 4

MEP of (A) a patient with DAI following recovery, revealing increased duration and number of turns indicative of temporal dispersion (B) a control subject (slightly modified from with permission from IOS press). Superimposed MEPs demonstrate significantly decreased variability in (C) a patient with severe DAI and clinical motor dysfunction, when compared with (D) a control subject (slightly modified from with permission from Mary Ann Liebert, Inc. publishers). Primary motor cortex activation by hand movements of (E) a patient with DAI following recovery, (F) a control subject (slightly modified from with permission from IOS press). The evident mesial frontal activation in the supplementary motor area of the patient likely represents recruitment of secondary motor areas resulting from reduced capacity of primary motor regions. DTI fiber tractography of hand motor tract in (G) a patient with DAI due to severe TBI, 18 months after trauma and (H) a control subject (modified from with permission from Mary Ann Liebert, Inc. publishers). Circles show the region of interests (ROI) for the FA measurements of (I) the same patient and (J) control subject (modified from with permission from Mary Ann Liebert, Inc. publishers). FA values were significantly lower in patients compared with controls and correlated with higher motor thresholds, presumably resulting from direct axonal damage due to DAI.