TRAUMATIC BRAIN INJURY (TBI) occurs across the lifespan, but it is most common among active and otherwise healthy teenagers and young adults.1,2 The consequences are staggering and include a broad spectrum of cognitive, behavioral, and sensorimotor disabilities, which dramatically reduce the quality of life, necessitate long-term care, and create a worldwide public health problem.3 Standard rehabilitation approaches that target functional recovery following focal brain damage have limited utility in severe TBI. The characteristic dual nature of injury, which combines diffuse and focal damage, makes anatomo-clinical correlations exceptionally challenging, and limits the success of conventional rehabilitation.4 Thus, there is an urgent need for improved therapeutic strategies to promote optimal functional recovery in TBI.
The neuropathophysiology of TBI is complex and involves many pathways that are incompletely characterized but may offer therapeutic targets. Unguided approaches to therapeutic innovation that do not consider known pathophysiology are unlikely to succeed. Therefore, it is worth reviewing key biochemical and molecular processes that are thought to play critical roles in the neuropathophysiology of TBI and might offer valuable targets for therapeutic intervention.
NEUROPATHOPHYSIOLOGY OF TBI: DIFFERENT POTENTIAL TARGETS AT DIFFERENT TIME-POINTS FOLLOWING INSULT
The detrimental effects of TBI evolve as a result of primary physical trauma and secondary biochemical/physiologic perturbations, both of which lead to neuronal loss and diffuse axonal injury (DAI).5
The impact of the primary physical trauma depends on the intensity and the temporal and spatial distributions of the insult. Insults of greater intensity and duration tend to result in neural necrosis while milder impacts preferentially induce apoptosis.6 Diffuse damage is most likely with inertial loading. However, even damage once deemed focal may actually be quite diffuse as demonstrated with stains specific for both neuronal axons and nerve terminals.7
Secondary biochemical perturbations involve several processes. First, excessive glutamate accumulation leads to NMDA (N-Methyl-D-aspartate)-mediated glutamatergic excitotoxicity and neurodegeneration.8–11 Cerebral ischemia leads to a lack of oxygen and glucose delivery to neurons, resulting in reduced adenosine triphosphate and elevated lactate levels indicative of metabolic stress. Energy substrate deprivation impairs the ability to maintain basal ionic gradients. This leads to enhanced voltage and NMDA-dependant depolarizing postsynaptic potentials, causing neuronal and glial depolarization. NMDA receptor activation results in intracellular calcium overload, stimulating inflammation, mitochondrial dysfunction, and apoptosis.5,12–15 Elevated intracellular calcium further exacerbates and propagates metabolic stress via cortical spreading depression.5 In addition, high calcium levels may trigger calcium-induced calpain proteolysis of cytoskeletal proteins and subsequent cellular collapse.5,6 Cellular destruction may also result from enhanced oxidative stress due to mitochondrial dysfunction and increased neuronal and inducible nitric oxide synthase (nNOS and iNOS), enhancing production of free radicals and lipid peroxidation.5,6,16–18 Therefore, suppression of the hyperexcitability cascade may minimize or prevent some of the disabling consequences of TBI and pose an exciting potential therapeutic target. However, excessive blockade may prevent acutely damaging mediators from later assisting in active recovery (ie, NMDA receptor blockers, matrix metalloproteinase blockers, c-Jun N-terminal kinase pathway inhibition), ultimately resulting in therapeutic failure.19 Methods aimed at modifying TBI-triggered excitotoxicity that are currently in trials, including hypothermia and pharmacologic glutamate receptor antagonism,5 remain unproven, are practically complex to implement, or affect the brain globally with potentially toxic side effects.
In addition to modulation of glutamate levels, there is also evidence for the involvement of GABA (γ-aminobutyric acid), the principal inhibitory neurotransmitter in the cerebral cortex, in response to TBI. In the acute stage, transplantation of GABAergic neurons can induce recovery of sensorimotor function in rats23 while GABAA agonists can increase survival and cognitive functioning.24 The GABA levels were found to be elevated in magnetic resonance spectroscopy performed at 24 to 48 hours post-TBI25 and in ventricular cerebrospinal fluid in patients with severe TBI.26 Although increasing inhibitory function via GABA receptors seems beneficial during the acute postinjury period,27 this increase may continue beyond the acute stage and hinder recovery. In rats, TBI induces long-lasting working memory deficits associated with increased GABA levels for as long as 1-month post-TBI and administration of GABA antagonists restores memory function, suggesting that lasting deficits following TBI are associated with “excess GABA-mediated inhibition.”28 Critically, these deficits do not remain amenable to GABAergic treatment by 4 months postinjury.29 GABAergic terminal loss correlates with recovery following TBI30 and accompanies injury-induced reorganization of the cortex.31 Therefore, in the subacute stage when GABAergic activity is excessive and promotes functional disability, increasing neuronal excitability may help counter the GABAergic tone to allow potentiation of previously unexpressed connections.31
Beyond the cascade of neurochemical responses, the nervous system reorganizes in response to injury.32 Rewiring of neural connections appears to make it possible for one part of the brain to assume the functions of a disabled region. Neuroplasticity following TBI likely includes the unmasking of previously latent synapses, synaptic alteration of receptor sensitivity, dendritic growth, collateral sprouting of new synaptic connections, and arborization from neighboring undamaged neural elements.33,34 Synaptic loss, disrupting pathways after DAI, may be reestablished by dendritic growth and arborization from neighboring undamaged axons.35,36 More severe DAI, however, may lead to more concentrated and profound damage to critical neural networks.33 In this stage, recovery mechanisms operating through synaptic reorganization may not be adequate, and more complex mechanisms on the network level are likely to intervene. However, the behavioral impact of such plasticity is not necessarily adaptive and may prove to be a dead-end strategy that ultimately limits functional recovery and promotes lasting disability.32
Therefore, promotion of functional recovery following TBI appears to require differential interventions at different time-points following injury (Figure 1). In the acute phase, suppression of glutamatergic activity might be desirable and may minimize neurologic damage and disability. In the subacute phase following TBI, modulation of GABAergic inhibition might be critical to minimize functional impact and promote well-being. In more chronic stages, modulation of brain plasticity to suppress functionally maladaptive changes and enhance those resulting in behavioral advantages is critical to counter disability and may be used for rehabilitation of disabling sequelae.
NONINVASIVE BRAIN STIMULATION TECHNIQUES IN THE CONTEXT OF TBI
In the following section, we introduce novel noninvasive stimulation methods worth considering in the context of TBI and provide a brief review of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), low-level laser therapy (LLLT), and transcranial Doppler (TCD) sonography techniques.
Transcranial magnetic stimulation
Transcranial magnetic stimulation is based on Faraday's principle of electromagnetic induction and features the application of rapidly changing magnetic fields to the scalp via a copper wire coil connected to a magnetic stimulator.37 These brief pulsed magnetic fields of 1 to 4 Tesla pass through the skull and create electric currents in discrete brain regions.38 Applied in single pulses (single-pulse TMS) appropriately delivered in time and space, the currents induced in the brain can be of sufficient magnitude to depolarize a population of neurons and evoke a certain phenomenon.39 Paired-pulse application of TMS can be used to evaluate intracortical inhibitory/excitatory circuits and cortico-cortical connectivity.40 These TMS measures have proved valuable in understanding the neurophysiologic basis of various neuropsychiatric diseases and can provide useful diagnostic information in conditions with intra- or intercortical excitability abnormalities.41
Repetitive trains of stimuli (repetitive TMS; rTMS) applied to targeted brain regions can suppress or facilitate cortical processes, depending upon stimulation parameters.37,39 In most instances, continuous low frequency (≤1 Hz) rTMS decreases the excitability of the underlying cortex while bursts of intermittent high frequency (≥5 Hz) rTMS enhance it. Also, a subtype of rTMS, known as theta burst stimulation (TBS), incorporates very short, high frequency (50 Hz) trains of stimuli delivered intermittently or continuously at 5 Hz.42,43 Theta burst stimulation can induce or decrease excitability when applied in an intermittent (iTBS) or continuous (cTBS) paradigm, respectively. The fact that the modulatory effects of rTMS can outlast the duration of its application has led to the exploration of the technique as a potential treatment modality with promising results in various neuropsychiatric disorders (Figure 2A). The rTMS aftereffects are influenced by the magnitude and duration of stimulation, the level of cortical excitability and the state of activity in the targeted brain region.44
Extensive neurophysiologic and neuroimaging studies in human and animal models are starting to illuminate the neurophysiology underlying rTMS effects. Overall, rTMS of a targeted brain region has been demonstrated to induce modulation distributed across corticosubcortical and corticocortical networks by means of transsynaptic spread, resulting in distant but specific changes in brain activity along functional networks.45–49 Modeling studies can provide essential information on the induced current and field distributions generated in biological tissue during TMS.38 Short-term effects of TMS on brain activity appear to result from changes in neural excitability caused by shifts in the ionic equilibrium surrounding cortical neurons, reafferent feedback from targeted structures, or the storage of charge induced by stimulation.50 The prolonged aftereffects are considered to result from modulation of long-term depression (LTD) and long-term potentiation (LTP) between synaptic connections, modifying neuronal plasticity (See Table 1). Increased expression of immediate early genes and neurotrophic effects have also been discussed as possible mechanisms. Following diffuse damage after TBI, the induction of LTP and LTD may be abnormal due to cellular injury and altered connectivity, which may ultimately account for lasting deficits. Importantly, this plastic potential might be guided using neuromodulatory strategies to improve clinical outcomes of TBI.
TMS-induced side effects primarily include transient headache, local pain, neck pain, toothache, paresthesias, transient hearing changes, transient changes in cognitive/neuropsychological functions, and syncope (possible as an epiphenomenon).51–53 The most serious adverse event related to TMS is induction of a seizure,51–56 but this is a rare complication if the stimulation is applied according to the safety guidelines (See “Safety considerations in TBI” Section).
While not yet widely popular in TBI research, TMS appears to be well suited to serve as a diagnostic and prognostic factor in the case of TBI. Online or offline combinations of TMS, electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) may assist in understanding the extent of injury and the mechanisms of plasticity underlying functional recovery in TBI. Its neuromodulatory potential in rehabilitation of patients with TBI also remains to be investigated. Importantly, the focality of TMS might be disadvantageous in the acute stage, as diffuse damage is frequently a key component of the insult. In the subacute stage, TMS may affect potentially salvageable lesioned circuits dependent on maintaining adequate levels of arousal and avoiding activation of competitor circuits. To optimize the therapeutic potential of neuromodulation in promoting functional recovery in the chronic stage, extensions of insights gained from other patient populations can be translated to TBI patients with carefully characterized deficits (See “Potential therapeutic applications” Section).
Transcranial direct current stimulation
Transcranial direct current stimulation is a noninvasive technique of neuromodulation, which uses low-amplitude direct current to alter neuronal firing. While the use of anodal or cathodal direct current polarization to induce changes in the firing rates of neurons was demonstrated in the 1960s, the technique has received renewed interest in recent years. Nitsche and colleagues57,58 investigated the modulatory effects of tDCS on motor cortical excitability and reported that anodal tDCS elicits prolonged increases in the cortical excitability and facilitates underlying regional activity, whereas cathodal stimulation shows the opposite effects. The duration of aftereffects outlasts the period of stimulation and largely depends on the duration of tDCS. Furthermore, several consecutive sessions of stimulation result in behavioral effects lasting several weeks, a particularly important feature with respect to cortical plasticity.59,60
The short-term effects of tDCS are likely elicited by a nonsynaptic mechanism and result from depolarization of neuronal resting membrane, presumably caused by alterations in transmembrane proteins and electrolysis-related changes in hydrogen ions.57,61–63 Long-term effects are believed to depend on changes in NMDA receptor activation as well as neuronal hyper- and depolarization and thus, may share similarities with LTP and LTD.64 Indeed, we have directly relevant pilot data demonstrating modulation of synaptic LTP by tDCS in a murine model.65 In addition, a functional neuroimaging study investigating the effects of tDCS, demonstrated persistent metabolic changes in oxygen metabolism consistent with electrode location and neural network modulation. Therefore, tDCS has the potential to modify spontaneous activity and synaptic strengthening, and to modulate neurotransmitter-dependent plasticity on the network level.66
The procedure consists of a 1 to 2 mA current applied through 35 cm2 pad electrodes placed on the scalp (Figure 2B). The low-level current flows from the positive electrode, anode, to the negative electrode, cathode, and increases the regional activity by the anode while decreasing the activity underneath the cathode. The process may be referred to as cathodal or anodal tDCS depending on the electrode placed over the region being modulated.67 Large electrode size limits the focality of stimulation but is preferential to avoid high current densities at the skin which may cause local irritation or even burning.63 It is also possible to apply the second electrode to an extracranial position (eg, shoulder) instead of the scalp. While providing greater specificity of stimulation effects on the brain, this application may lead to quite different effects at the primary site; modeling should be considered for such novel electrode arrangements to better predict and understand the current distribution.68 Future developments (eg, employing carrier frequencies) may help to bridge the scalp and skull and deliver the stimulating current to the brain more reliably. Even in its present form, the density of stimulation is low enough that subjects only perceive the stimulus during the rapid change in current at the onset and offset of the stimulation. Thus, from a practical point of view, it is easy to sham stimulate subjects by slowly ramping down the intensity after switch on, and ramping up before switch off. This method of sham stimulation has proven to be reliable with minimal discomfort.69
Transcranial direct current stimulation has been shown to enhance motor learning in healthy subjects70 and stroke patients,71,72 language in normal subjects73 and patients with aphasia,74 and verbal fluency75 and verbal working memory76 in healthy subjects and patients with early Alzheimer disease.77 Furthermore, modulation on the network level allows for modulation of behaviors such as decision-making or social interactions,78,79 and has been shown to have translational clinical applications in cases of impulsive behavior, addiction, and depression.80 Therefore, tDCS has the potential to improve learning by modification of spontaneous activity and synaptic strengthening, and to modulate neurotransmitter-dependent plasticity on the network level.81
Several studies of the safety of tDCS have concluded that it is a painless technique for electrically stimulating the brain with almost no risk of harm.63,82 The most frequent adverse effects include moderate fatigue (35%), mild headache (11.8%), nausea (2.9%) and temporary mild tingling sensation, itchiness, and/or redness in the area of stimulation. While the risks are rather minimal, tDCS may also result in temporary side effects such as dizziness, disorientation, or confusion.
Overall, tDCS features a highly portable, safe, noninvasive means to modulate cortical excitability with reasonable topographic resolution and reliable experimental blinding. It can focally suppress or enhance neuronal firing following TBI, depending on the size and location of the applied electrodes, and thus may offer a promising method to minimize the damage and promote functional recovery. Cathodal tDCS may be employed to suppress the acute glutamatergic hyperexcitability following TBI. In the subacute stage, when GABAergic activity is excessive and conditions neurologic, cognitive, and functional disability, anodal tDCS may increase excitability to counter these aberrant GABAergic effects. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills and cortical plasticity (See “Potential therapeutic applications” Section). In this stage, the relative ease of use and portability of tDCS may enable modulation of plasticity via concomitant behavioral interventions such as cognitive behavioral, occupational, and physical therapy.83–86
Low-level laser therapy
Low-level laser therapy, or photobiostimulation, is a novel method of noninvasive neural stimulation that, at specific wavelengths, can safely penetrate into the brain (Figure 3A). 87–90 Low-level laser therapy is thought to promote cellular survival in times of reduced energy substrate through interactions with cytochrome c oxidase to enhance oxidative phosphorylation. This interaction, believed to involve the photodissociation of nitric oxide from cytochrome c oxidase, ultimately improves mitochondrial function and increases adenosine triphosphate.91–96
Low-level laser therapy has been shown to accelerate wound healing, reduce neurological deficit following stroke, and improve outcome in spinal cord injury.88,89,91,95,97 A study assessing the effects of LLLT following transient middle cerebral artery occlusion (MCAo) in rats demonstrated that 10 minutes of LLLT could reduce levels of neurotoxic nitric oxide synthase, endothelial nitric oxide synthase, nNOS, and iNOS. Treatments also significantly increased neuroprotective TGF-β1.95 In addition, LLLT functions as a free radical scavenger, demonstrating a time-dependent decrease in the levels of reactive oxygen species while reducing expression of phospholipase A2.98,99 Beyond LLLTs anti-inflammatory role, it may also promote neurogenesis. Oron et al89 tested LLLT treatment 24 hours after permanent MCAo in rats and found significant functional improvements and increased newly formed neuronal cells in the injured hemisphere.
Recently, LLLT was used for the first time in a rodent TBI model. LLLT was administered to mice 4 hours after injury with subsequent monitoring for 28 days using the functional Neurological Severity Score (NSS) in addition to lesion histology. LLLT-treated rats showed significantly reduced NSS from 5 days to 28 days post TBI with reduced lesion volume.89 Although LLLT is new to TBI research, it is currently being used in human stroke trials as an acute neuroprotective therapy.88,100 Given these early successes in stroke research and the unique properties of LLLT, its therapeutic application in TBI is a viable prospect.
Transcranial Doppler sonography
Focal ultrasound, or TCD, is not new to the field of neurological diagnostics, but the novel way in which it can be used to interact with neurobiological systems may expand the applications of this tool (Figure 3B). In the setting of TBI, TCD is used in the acute assessment of cerebral ischemia.102 Cerebral perfusion pressure (CPP), defined as the difference between the mean arterial blood pressure and intracranial pressure (ICP), has emerged as the modifiable target of intensive care of TBI patients. However, CPP is complicated by the necessity of measuring ICP, an unfavorably invasive procedure.102 Recent work demonstrated that the pulsatility index (PI; the difference in systolic and diastolic flow velocities divided by mean flow velocity) strongly correlates with ICP and CPP and may therefore serve as a noninvasive surrogate for these measures.103,104 Transcranial Doppler sonography allows one to estimate intravascular flow noninvasively using the PI. A study in patients with mild to moderate TBI showed that PI measured at time of admission was associated with neurological outcomes 1 week later; higher PIs associated with greater neurological deterioration as assessed by the Glasgow Coma Scale.104,105 Thus, TCD is proving to be a powerful diagnostic and prognostic tool in TBI.
More recent advances in our understanding of TCD have lead to exciting possible therapeutic roles in TBI where clot formation may result from primary injury. One application is sonothrombolysis; a technique of focal TCD applied at diagnostic frequencies alone or in combination with standard thrombolytic therapy (tPA). A recent study assessed the thrombolytic capacity of TCD using conventional transcranial color-coded sonography applied to the MCA-M1 for 1 hour in stroke patients ineligible for tPA; TCD could achieve faster recanalization rates and improved short-term outcomes in acute stroke patients.106 In-vitro studies have shown that ultrasound (US) applied in combination with tPA can accelerate clot dissolution by 2.2- to 5.5-fold in direct proportion to the concentration of tPA.107,108 Subsequently, a multicenter collaboration tested the utility of the tPA-TCD combination in the CLOTBUST trial. They found that 83% of patients achieved recanalization with the tPA-TCD combination compared to 50% with tPA alone. Improved efficacy with tPA-TCD is believed to result from TCD-mediated mechanical disturbance at the plasma-thrombi interface, increasing exposure of thrombi sites upon which tPA can act.109 New developments in the area of therapeutic US are investigating the addition of microbubbles (air-filled microspheres), which increase focality of treatments and allow more conservative TCD settings. Transcranial Doppler sonography interacts with the microbubbles to promote mechanical disruption of clots independent of tPA and may cause size expansion, oscillations, or complete disruption of the microbubbles, transmitting mechanical energy at the clot-residual flow interface to improve thrombolysis.109,110 Thus, in TBI, where thrombosis may further complicate clinical outcome, sonothrombolysis may provide a viable therapeutic option.
Transcranial Doppler sonography may also have the potential to promote neuroprotection during acute TBI by increasing the local bioavailability of neuroprotective agents. Transcranial Doppler sonography has been shown to transiently (ie, hours) enhance blood brain barrier (BBB) permeability without adverse cellular effects. The mechanism is believed to be a process of stable cavitation, in which low acoustic energy causes administered microbubbles to oscillate and expand creating small eddy currents in the surrounding plasma. These currents provide shear stress on cells and large molecules to increase BBB transcellular and paracellular transport.110–112 Thus, TCD may increase the applicability of novel neuroprotective agents by allowing focal pharmacokinetic optimization.
Further studies have alluded to the potential of TCD as a direct means of neuroprotection. A recent study showed that low-intensity low-frequency US (LILFU) is capable of remote stimulation of mouse hippocampal slice and whole brain preparations. LILFU was shown to activate voltage-gated sodium and calcium channels triggering synaptic transmission. In addition, stimulation of cornu ammonis area 3 Schaffer collaterals was shown to exhibit the same kinetics and amplitudes of traditional monopolar electrical stimulation while prolonged periods of exposure (36–48 hours) did not produce aberrant membrane changes. Previous work by Rinaldi et al113 demonstrated that stimulation of hippocampal slices could suppress evoked potentials in cornu ammonis area 1 pyramidal neurons.114,115 In addition, high frequency US has been shown to elicit cortical spreading depression, a phenomenon of generalized cortical depolarization, loss of ionic gradients, and subsequent cessation of bioelectrical activity without damage.112 In the setting of TBI, these attributes of TCD may allow for suppression of neuronal activity in the acute energy-deficient phase and facilitation in the subacute phase of active recovery, strengthening our therapeutic capacity against TBI.
DIAGNOSTIC APPLICATIONS OF NONINVASIVE BRAIN STIMULATION IN TBI
Below, we review the current diagnostic evidence from TMS studies, which may offer potential neurophysiologic markers indicative of functional recovery in TBI. The monitoring of neurophysiologic impact of TMS using EEG and functional neuroimaging techniques may allow the systematic study of functional connectivity and brain-behavior relations along large-scale neural networks.116 An overview of published TMS studies on motor cortical excitability in TBI is provided in Table 2.
Evidence from a limited number of studies suggests that cortical excitability in TBI is different in early and late stages of injury. Chistyakov et al117,118 reported increased motor threshold (MT) levels and motor-evoked potential (MEP) variability, prolonged central motor conduction time and decreased MEP/M wave ratio in mild to moderate TBI patients as early as 2 weeks after the head trauma. However, they observed that these alterations returned to normal levels within 3 months.118
A number of investigations conducted in chronic TBI patients with preserved normal motor function did not report significant differences for MEP parameters.34,119–124 However, higher MT levels, decreased MEP area, MEP variability, and input-output curves were demonstrated when patients had clinically evident motor dysfunction.124,125 Moreover, alterations in the MEP parameters were more pronounced in those with severe DAI, highlighting the key influence of DAI severity on cortical excitability together with the clinical motor dysfunction (Figure 4).124
Silent period (SP), a parameter reflecting intracortical inhibitory mechanisms, has been investigated in a variety of patients with TBI. De Beaumont et al122 reported longer SP durations in a group of athletes who had experienced multiple concussions. Notably, the athletes with multiple concussions had sustained more severe concussions. The SP was significantly prolonged in such athletes but not in those with a single concussive episode. In a second study, they reported that prolongation of the SP persisted up to 40 years postconcussion and correlated with the level of bradykinesia in a group of former athletes.126
Chistyakov and colleagues127 reported a significantly longer SP in mild to moderate TBI patients when measured only at a TMS intensity of 130% of MT but not at lower intensities, in contrast to MEP findings. The authors concluded that the mechanisms related to the MEP and SP generation might be separately affected in TBI. Recently, Bernabeu et al124 reported no significant changes in SP in patients with severe TBI, while significant alterations in the MEP parameters were present. These studies support the evidence that excitatory and inhibitory responses probably demonstrate distinct aberrations following TBI and that the number of traumatic insults may be more critical than the severity of trauma for SP abnormalities. Further comprehensive evaluations seem requisite for clarification of intracortical inhibitory mechanisms following TBI.
Paired-pulse studies and connectivity measures
Three studies employed short-interval paired-pulse TMS to assess intracortical facilitation and inhibition and reported no significant differences in patients with mild TBI.119,120,122 Takeuchi and colleagues121 investigated whether ipsilateral silent period durations (iSP, a measure of interhemispheric connectivity that results from transcallosal modulation of activity in the unstimulated hemisphere) could detect a functional abnormality in the corpus callosum of TBI patients and reported significantly shorter iSP in patients with DAI.
TMS, EEG, and functional neuroimaging
Using TMS, EEG and PET, Crossley and colleagues128 investigated the restoration of functional integrity in an old adult who suffered from severe TBI. Transcranial magnetic stimulation assessment at 12 months revealed a remarkable increase in MEP amplitudes from those recorded at 4 weeks. 18-fluorodeoxyglucose PET suggested a general increase in the metabolic rate and showed a regression in the global reduction over the year. The EEG at 4 weeks showed symmetrical slow activity with a predominance of theta frequencies while background activity at 12 months was mostly restored, consistent with the recovery of neural integrity.
Jang and colleagues34 assessed motor recovery mechanisms in DAI using fMRI and TMS. Eight patients with persistent motor weakness for more than 4 weeks post-TBI were tested after achieving stable motor recovery (mean = 6 months). All patients but one had complete motor recovery. A hand grasp release fMRI paradigm revealed comparable activations in contralateral primary sensorimotor cortices of normal subjects and patients during affected hand movements. Motor-evoked potentials were not different from controls for MT or amplitude; however, duration, mean latency, and turns were significantly increased (Figure 4). The authors concluded that the MEP findings were likely to reflect comparable numbers of axonal fibers in the corticospinal tracts in the patient group who exhibited good recovery, and the heterogeneous characteristics of the tract were attributed to axons in the recovery process.
The combined use of TMS and fMRI may help elucidate the extent of neuropathology in severe TBI. Barba et al125 reported a patient who presented with left hemiparesis in the absence of any detectable lesions affecting the right motor areas. Transcranial magnetic stimulation assessments revealed a notably higher MT on the right while latency, amplitude, and interhemispheric interactions were normal. Motor mapping via TMS showed reduced cortical representation and a rostral shift on the right hemisphere. Conventional fMRI did not show activations in right motor areas during a motor task paradigm, whereas quantitative fMRI detected reduced activation comprising a lower number of voxels. The authors suggested that integrated investigations combining multimodal techniques should be of consideration to better clarify the relation between brain injury and clinical outcome in TBI.
TMS and diffusion tensor imaging
Diffusion tensor imaging (DTI) is a novel imaging technique for noninvasive in-vivo visualization of white matter tracts in the brain.129,130 The degree of anisotropy (fractional anisotropy, FA) changes as a function of the degree of fiber tract organization, that is, a reduction in FA values typically indicates histological abnormality.131 Yasokawa and colleagues132 hypothesized that the FA values could indicate the presence of MEPs and correlate with higher MT in patients with chronic DAI due to severe TBI. Indeed, they found significantly lower FA levels in the absence of MEP; lower FA levels also correlated with higher MT (Figure 4). These results provide a correlation between the neurophysiological motor dysfunction and the level of organization in the corticospinal tract following the DAI as detected by DTI.
POTENTIAL THERAPEUTIC APPLICATIONS OF NONINVASIVE BRAIN STIMULATION ACCORDING TO FUNCTIONAL CONSEQUENCES OF TBI
Here we propose future targets of intervention defined by post-TBI behavioral symptomatology rather than diagnostic categories. The selection of these functions and circuits is based on their very common and debilitating alterations following TBI and builds on insight and methodologies developed over the past decade. Given the enormous heterogeneity of the injury, implementation of individually tailored approaches using EEG- and fMRI-guided TMS to modulate activity may be considered to maximize the clinical outcome in TBI.
Hand motor function
Hand motor dysfunction following brain damage can be improved via direct enhancement of the perilesional activity in the affected primary motor cortex or the premotor cortex in the precentral gyrus using high-frequency rTMS or anodal tDCS.60,133 The alternative approach aims to decrease the excessive activation of unaffected motor cortex using low-frequency rTMS or cathodal tDCS to modify the imbalance in transcallosal motor activity, which results from the loss of inhibitory projections from the damaged area and decreased use of the affected hand. Behavioral gains from rTMS/tDCS protocols may be maximized when brain stimulation is coupled with carefully designed occupational/physical therapy.83–86 In a pilot study, tDCS has been reported to enhance the effects of upper extremity robotic motor training in TBI patients with no skull defects.134
Modulation of dysfunctional prefrontal cortico-subcortical networks via bilateral frontal tDCS, high-frequency rTMS to the left, or low-frequency rTMS to the right dorsolateral prefrontal cortex (DLPFC) results in clinically significant antidepressant effects.136 In the last decade, several multicenter studies have demonstrated safety and efficacy of rTMS in treatment of major depressive disorder137–139, and TMS has recently gained FDA approval for medically refractory depression. Accordingly, enhancing left DLPFC and/or inhibiting right DLPFC could be tested for post-TBI depression for reestablishment of balance in malfunctioning bihemispheric neural circuits. However, it should be noted that previously tested psychiatric populations had no comorbid brain injury, making the potential for demonstrating a positive benefit-to-risk ratio significantly better.
Transient inhibition of the contralesional parietal region using rTMS has been reported to improve visuospatial neglect.140,141 The same paradigm might be translated to patients with neglect due to TBI.
Left frontotemporal cathodal tDCS and 1 Hz rTMS to right BA 45 has been shown to improve naming in nonfluent aphasia patients.74,142,143 These strategies, in combination with speech therapies, may be of benefit in posttraumatic expressive aphasia.
Decision-making, working memory, and executive functions
Riskier decision-making has been reported following rTMS-induced virtual lesions of right DLPFC.144 Consequently, it seems plausible that increasing right DLPFC activity using high-frequency rTMS, or neuromodulation of the DLPFC bilaterally via tDCS, may diminish decision-making impairments following TBI.78,144 Also, enhancing right or left dorsolateral prefrontal cortices may prove effective for improving working memory and/or executive dysfunctions.76,145–148
It has been reported that high-frequency rTMS (5Hz) to primary motor cortex increases cortical excitability as well as the excitability of spinal motor neurons to Ia-afferent inhibitory input, resulting in improvements in clinical spasticity.45,46,149–151 Accordingly, post-TBI spasticity may benefit from this approach.
Modulating sensorimotor cortical activity via TMS or tDCS can suppress pain of central origin.152,153 This potential might be explored for relief of chronic pain subsequent to trauma.
Repeated sessions of rTMS have been proposed as a preventive treatment for limb disuse following brain injury.154 Stimulating the leg motor cortex using high-frequency rTMS may enhance gait rehabilitation in combination with gait therapy following TBI. Recently, tDCS has been reported to enhance fine motor control of the paretic ankle and improve hemiparetic gait patterns.155 In this context, one might envision coupling brain stimulation approaches with robot-assisted gait training.
It should, however, be underlined that the areas proposed here as intervention targets are based on a theoretical framework, as our understanding of brain stimulation mechanisms in TBI is yet very limited. While this framework renders noninvasive brain stimulation an attractive approach to enhance cognitive and motor functions in TBI survivors, the significant difficulties involved in demonstrating clear clinical efficacy of any form of clinical intervention in the TBI population need to be acknowledged. Hence, it is possible that following TBI, clinical heterogeneity and anatomical disconnections might necessitate modifications in the use of such neuromodulatory approaches or make these approaches fruitless. The use of correlative animal models may advance our understanding of how these modalities may act on the level of neuronal circuits and synapses following TBI and would be particularly valuable in clarifying the rationales and the potential spectrum of translational applications before large randomized controlled trials are commenced.
The guidelines establishing the safe settings for TMS applications were published in 199851 and revised recently.52 A decade and numerous rTMS studies later, rTMS has been shown to be safe with temporary minor side effects in normal subjects if these guidelines are followed.53,138 Although rTMS also appears to be a good candidate tool for neuromodulation following TBI, current safety guidelines have not yet been tested for this high-risk population and the risk profile of rTMS likely includes other potential side effects in patients with TBI.
The most concerning adverse event related to a possible therapeutic application of rTMS is induction of a seizure. Posttraumatic epilepsy is the most common delayed sequel of TBI with an overall incidence of about 5% in patients with closed head injuries and 50% in those who had a compound skull fracture.156 Importantly, the interval between the head injury and the first seizure varies greatly. Although TMS-induced seizures are self-limited and do not tend to recur, this risk could bring practical implications in a seizure-prone population, especially in patients with moderate to severe TBI.
Secondly, as skull damage and fractures are common in TBI, the conductance and magnitude of the electric current being induced in cortical regions may be different. A recent tDCS modeling study highlighted that skull injuries significantly change the distribution of the current induced, and current may become concentrated over the edges of large skull defects depending on the combination of electrode configuration and nature of the defect.155 Such changes may alter the efficacy of these applications and may lead to unfavorable neurophysiologic or pathological changes. Furthermore, the presence of a craniotomy with placement of skull plates might add another potential risk for application of these tools in TBI.158,159
Currently, there is only one case study, which performed detailed safety assessments and reported a lack of adverse events in a patient with severe TBI following application of a specific rTMS protocol over 5 consecutive days through 6 weeks.160 It is clear that the heterogeneity of TBI necessitates further extensive safety evaluation studies and definition of relative contraindications for brain stimulation in patients with TBI before a serious assessment of benefit can be undertaken. Such studies would contribute to development of safety guidelines for TBI, which may enable the safe and efficacious use of brain stimulation techniques in the rehabilitation of TBI survivors.
Different forms of noninvasive brain stimulation techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical reorganization and enable functional restoration in TBI. Available evidence is sparse, but the present understanding about the pathophysiology of posttraumatic brain damage and the mechanisms of action of various noninvasive brain stimulation methods justifies exploration of new interventions that may forestall the functional impact of TBI. Future lines of safety research and well-designed clinical trials in TBI are warranted to ascertain the capability of noninvasive brain stimulation to promote recovery and minimize disability.
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DAI; diffuse axonal injury; LLLT; low-level laser therapy; rTMS; TBI; TBS; TCD; tDCS; theta burst stimulation; TMS; transcranial direct current stimulation; transcranial Doppler sonography; transcranial magnetic stimulation; traumatic brain injury