Abstract
Traumatic brain injury (TBI) is the leading cause of death and disability in individuals below age 45, and five million Americans live with chronic disability as a result. Mild TBI (mTBI), defined as TBI in the absence of major imaging or histopathological defects, is responsible for a majority of cases. Despite the lack of overt morphological defects, victims of mTBI frequently suffer lasting cognitive deficits, memory difficulties, and behavioral disturbances. There is increasing evidence that cognitive and memory dysfunction is related to subtle physiological changes that occur in the hippocampus, and these impact both the phenotype of deficits observed and subsequent recovery. Therapeutic modulation of physiological activity by means of medications commonly used for other indications or brain stimulation may represent novel treatment approaches. This review summarizes the present body of knowledge regarding neurophysiologic changes that occur in the hippocampus after mTBI, as well as potential targets for therapeutic modulation of neurologic activity.
Introduction
Every year, one out of every 200 people worldwide will suffer a traumatic brain injury (TBI), including 1.7 million people in the United States alone, with an annual associated cost of approximately $76.5 billion (Faul et al., 2010). It is estimated that 5.3 million Americans live with long-term disability as a result of their injury (Centers for Disease Control and Prevention [CDC], 2013). Young men and the elderly are particularly vulnerable because of an increased incidence of trauma and falls, respectively (Susman et al., 2002). TBI is also prevalent in the military, with approximately 20% of all returning deployed American troops suffering some form of brain injury from a blast exposure (Terrio et al., 2009), the vast majority of these being mild injuries.
Mild TBI (mTBI), sometimes termed concussion, accounts for 75% of all head injuries (Faul et al., 2010). Symptoms include headache, sleep impairment, memory deficit, difficulty concentrating (Levin et al., 1987), and an increased incidence of affective disorders such as depression and anxiety (Park et al., 2008). These clinical problems are persistent and severe in 10% of cases, lasting for months to years, sometimes indefinitely (Greig et al., 2014). Due to the striking prevalence and disruptive clinical manifestations of mTBI, research has focused on elucidating the pathophysiological mechanisms underlying primary and secondary brain injury in order to develop therapies that may alter or prevent these processes. More recently, changes in neural circuitry underlying many of the clinical manifestations of mTBI, especially memory and affective disorders, has been studied in an attempt to understand mechanisms of disruption and how modulation of these networks may be used to therapeutic advantage. In order to determine how novel neuromodulation treatments might be able to improve TBI-associated deficits, it is important to establish how individual neurons and subpopulations of neurons contribute to network activity and how these networks respond to injury. This review will discuss neurophysiological changes in the hippocampus associated with mTBI, and ways in which therapeutic neuromodulation might be used to reverse these deficits.
Biochemical and Genetic Changes in the Hippocampus Following TBI
Neurological injury that occurs after a traumatic insult can result from two different mechanisms: primary and secondary injury. Primary injury refers to the mechanical forces of shearing and compression at the time of impact, while secondary injury involves the subsequent cascade of pathological events that occurs minutes to days after the insult (Greve and Zink, 2009). Such secondary processes include hypoxia/ischemia, edema, raised intracranial pressure, excitotoxity through glutamate release, calcium dysregulation, cytoskeletal proteolysis, free radical oxidative damage, altered synaptic physiology, cytokine release causing inflammation, and ultimately neuronal cell death (Choi et al., 1987; Raghupathi, 2004; Maas et al., 2008; Barkhoudarian et al., 2011; Greig et al., 2014; Merlo et al., 2014). These secondary injury mechanisms are especially important for therapeutic consideration as they can theoretically be altered or inhibited with the aim of preventing injury or protecting brain tissue that has the potential to recover.
There are several commonalities between the biochemical cascades involved in secondary mTBI injury mechanisms and those found in degenerative central nervous system (CNS) diseases such as Parkinson’s disease (PD; Eakin and Miller, 2012; van Bregt et al., 2012), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (Daneshvar et al., 2011). As a result, pathways that have been extensively characterized in these diseases can be extrapolated and applied to analogous pathways involved in TBI in order to better understand the mechanisms of injury and potential novel therapeutic approaches. This has important implications for diagnosis: a complex mathematical model of semantic predications was recently used to search almost 100,000 citations of neural injury networks and produced a list of 17 potential biomarkers that may indicate mTBI, with glutamate, glucose, and lactate being the most common (Cairelli et al., 2015). In combination with other compounds, such as the apolipoprotein E-4 allele which adversely influences recovery following brain injury (Lawrence et al., 2015), these biomarkers may aid in the early diagnosis of mTBI, allowing the prompt administration of neuroprotective drugs or neuromodulatory therapies.
Glutamate is particularly important, as this excitatory neurotransmitter is known to play a strong role in secondary injury mechanisms throughout the brain. Microdialysis studies, in both rodents (Folkersma et al., 2011) and humans (Chamoun et al., 2010), have shown that glutamate concentrations increase in the acute phase following injury, whereas magnetic resonance spectroscopy (MRS) studies have shown a persistent decrease in glutamate concentrations following injury. The reason for this discrepancy is that microdialysis measures extracellular glutamate, while MRS measures both intra and extracellular glutamate (Guerriero et al., 2015).
Specifically in the hippocampus, glutamate decreases following moderate to severe temporal cortex injury, as measured by in vivo proton MRS in a direct cortical injury model in rodents (Harris et al., 2012). Although the hippocampus was considered perilesional tissue in this experiment, the temporal neocortex, i.e., the lesional tissue, also showed a decrease in glutamate in the acute phase. Human MRS studies also in the acute phase following concussion, however, showed no changes in hippocampal glutamate concentrations, despite finding decreased glutamate levels in the motor cortex (Henry et al., 2010). A reason for this discrepancy may be that the human study was in patients with mTBI, whereas the rodent study looked at moderate to severe TBI.
Another important compound altered in the hippocampus after TBI is the neurotransmitter gamma-aminobutyric acid (GABA). The expression of various GABA receptor subunits is changed, causing reductions of inhibitory postsynaptic currents and increases in excitatory post-synaptic currents after TBI in rodents (Hunt et al., 2011; Almeida-Suhett et al., 2015; Drexel et al., 2015). As a result, deficits occur in long-term potentiation, which can translate into cognitive impairment. Similarly, up and down-regulation of other proteins can lead to impairments in hippocampal synaptic transmission, including those involved in the extracellular signal-regulated kinase (ERK) pathways (Atkins et al., 2009), and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex (Carlson et al., 2016).
The regulation of gene transcription affects not only the creation of proteins involved in neurotransmission after injury, but also the synthesis of neurons themselves. Because TBI is associated with hippocampal neuronal damage and death, it is important to develop therapeutic strategies to either protect immature neurons or enhance neurogenesis in the hippocampus after injury. Methods shown to drive neurogenesis post injury include forced overexpression of insulin-like growth factor 1 (IGF-1; Carlson et al., 2014), and the transplantation of synthetic human progenitor cells into the hippocampus after TBI (Blaya et al., 2015). Interestingly, TBI severity has been found to correlate with the degree of post-traumatic neurogenesis in rat hippocampus. Whereas mTBI had no effect on neurogenesis, moderate TBI promoted neural stem cell proliferation without increasing neurogenesis, and severe TBI increased neurogenesis (Wang et al., 2015a). A summary of the biochemical and genetic changes following TBI in rodent hippocampus can be found in Table 1.
Table 1
| Structure | Biochemical changes after TBI |
|---|---|
| CA1 | Decreased surface expression of α1, ß2/3, and γ2 subunits of the GABAA receptor caused reductions in the frequency and amplitude of spontaneous and miniature GABAA-receptor mediated inhibitory postsynaptic currents after TBI in rats. This led to deficits in long-term potentiation of synaptic transmission (Almeida-Suhett et al., 2015). |
| CA1, CA3 | Expression of GABAA and GABAB receptor subunit mRNAs α4 (GCL, CA3, CA1), α5 (CA1) and γ2 (GCL, CA3, CA1) was up-regulated after TBI in rats, with many of the changes being reversible (Drexel et al., 2015). |
| CA1, dentate | Mechanical stimulation using a stretchable microelectrode array disrupted bicuculline (GABAA antagonist) induced long-lasting network synchronization 24 h after TBI, despite the continued ability of injured neurons to fire (Kang et al., 2015). |
| CA4 | Action potential and excitatory post-synaptic current frequencies were increased in hilar GABA neurons after TBI in mice, with a further increase observed after photostimulation of dentate granule cell or CA3 pyramidal cell layers (Hunt et al., 2011). |
| Dentate | TBI severity affected hippocampal neurogenesis in rats: mild TBI did not affect neurogenesis; moderate TBI promoted neural stem cell proliferation without increasing neurogenesis; severe TBI increased neurogenesis (Wang et al., 2015a). |
| Survivin (apoptosis protein inhibitor) down-regulation inhibited adult hippocampal neurogenesis, promoted apoptotic cell death, and worsened memory capacity on water maze testing, after TBI in mice (Zhang et al., 2015). | |
| Entire hippocampal complex | Several microRNAs are significantly altered in hippocampal mitochondria and cytoplasm, including elevated levels of miR-155 and miR-223 (play a role in inflammation), after TBI in rats (Wang et al., 2015b). |
| Synthetic, human multineurotrophin neural progenitor cells (MNTS1-NPCs) conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis after TBI in rats (Blaya et al., 2015). | |
| Inhibition of population spikes was reduced in the Schaffer collateral pathway (CA3 to CA1) 2 days after TBI in rats, while increases in inhibition in the dentate gyrus (corresponding to increased GABA levels) was seen at both 2 and 15 days after injury (Reeves et al., 1997). | |
| Decreased field excitatory post-synaptic potentials were recorded in hippocampal subfield CA1 in response to electrical stimulation of the Schaffer collaterals, following TBI in vitro, indicating that expression of long-term potentiation and synaptic plasticity was inhibited following TBI (Sick et al., 1998). | |
| Gene transcriptome study identified upregulation of 193 transcripts and downregulation of 21 transcripts in the hippocampus, affecting mostly the transcription of non-neuronal genes, 24 h after mild TBI in mice (Samal et al., 2015). | |
| Hippocampus nuclear factor of activated T cells (NFAT) c3 levels (expressed in astrocytes) were decreased both in the cytoplasmic and nuclear fractions, while NFATc4 levels (expressed in neurons) were increased in the cytoplasmic fraction but decreased in the nuclear fraction, after TBI in rats (Yan et al., 2014). | |
| Insulin-like growth factor 1 (IGF-1) promotes neurogenesis after TBI in mice, in that overexpression of IGF-1 resulted in a marked increase in immature neuron density in the subgranular zone at 10 days after injury (Carlson et al., 2014). | |
| Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex was reduced in rat hippocampus following TBI, and resulted in a significant reduction in synaptic vesicle number (Carlson et al., 2016). | |
| TBI in rats results in chronic signaling deficits through the extracellular signal-regulated kinase (ERK)—cAMP response element-binding protein (CREB) pathway in the hippocampus (Atkins et al., 2009). | |
| Up-regulation of mRNA and protein for Nav1.6 (a voltage-gated sodium channels alpha subunit) occurred in rat hippocampal neurons after TBI (Mao et al., 2010). | |
| Nuclear factor erythoid related factor 2 (NRF2, transcription factor) mRNA increased significantly post-TBI at 48 and 72 h and 1 week in the hippocampus with a coincident increase in glial fibrillary acidic protein mRNA, overlapping with heme-oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone-oxidoreductase 1, glutathione reductase, and catalase mRNA (Miller et al., 2014). |
Biochemical changes in rodent hippocampus following TBI, with effects categorized by subsection of the hippocampal complex.
CA, cornu ammonis; GABA, gamma-aminobutyric acid; GCL, granule cell layer; RNA, ribonucleic acid.
Hippocampus Biochemical Pathways and Neuroprotective Agents in mTBI
Since mechanisms of secondary injury after mTBI are similar to other diseases, it is likely that drugs that are already in use for other indications may have efficacy for mTBI as well. One example of such a mechanism is the glucagon-like peptide-1 (GLP-1) signaling pathway. GLP-1 was initially described based on its role in the pancreatic regulation of insulin, but receptors are also found in the CNS and changes in this pathway have been implicated in a number of neurodegenerative diseases (Li et al., 2009, 2010, 2012; Martin et al., 2009; Salcedo et al., 2012). Through coupling to a cAMP second messenger pathway, activation of GLP-1 receptors elicits neurotrophic actions such as neuritic growth while protecting neurons against various insults (Perry et al., 2002). As a result, there have been a number of investigations into modulation of this pathway to treat neurological disease.
Exendin-4 is a synthetic GLP-1 receptor agonist currently approved as a drug for the treatment of hyperglycemia in type-2 diabetes that crosses the blood brain barrier (Kastin and Akerstrom, 2003). When administered after mTBI, this neuroprotective agent has been shown to prevent changes in rodent hippocampal gene expression following mTBI. Many of these genes protected by Exendin-4 are also associated with memory loss in AD (which has been associated with TBI), and administration ameliorated memory deficits after injury (Tweedie et al., 2013). Additional rodent studies using markers of cell death have shown that Exedin-4 improved hydrogen peroxide mediated oxidative stress and glutamate toxicity in neuronal cultures in vitro. In vivo, using markers of cognitive function, the drug ameliorated mTBI-induced deficits in novel object recognition and maze testing, both when administered prior to and after the insult (Eakin et al., 2013; Rachmany et al., 2013). Therefore, data is emerging to support a shift in indication for the use of Exedin-4 from an antihyperglycemic medication to a potential agent to minimize secondary injury after mTBI.
Another agent with potential efficacy for secondary injury after mTBI is N-Acetyl-cystein (NAC), which is currently used as a mucolytic agent and an antidote to acetaminophen overdose. NAC has been shown to have antioxidant and neurovascular-protective effects after mTBI (Ellis et al., 1991; Hicdonmez et al., 2006; Chen et al., 2008) and has been demonstrated to reverse behavioral deficits in mTBI rodents when administered 30–60 min after injury (Eakin et al., 2014). Specifically in the hippocampus, NAC was found to decrease levels of cytosolic-free Ca2+ and reactive oxygen species, reduce apoptosis, and lower caspase-3 and -9 neuronal activities, following TBI in rats (Naziroğlu et al., 2014). In humans, NAC has been shown in a randomized double-blind trial to improve auditory, vestibular, and cognitive functional sequelae after blast-induced mTBI in military personnel (Hoffer et al., 2013). Although the mechanism of action in the trauma setting has yet to be elucidated, the 40 year safety profile and ease of administration of the medication makes it an attractive option for widespread use.
Numerous other compounds have been found to exert effects in the hippocampus following injury. As summarized in Table 2, different substances affect different subsections of the hippocampal complex. Although all these investigations were performed in rodents, several of these biochemical compounds may prove to have beneficial effects in humans suffering from cognitive and memory impairments following TBI.
Table 2
| Structure | Compound | Effects |
|---|---|---|
| CA1 | WIN55, 212-2 | WIN55,212-2 (synthetic cannabinoid) restored CA1 interneuron GABAergic signaling after TBI in mice (Johnson et al., 2014). |
| CA2, CA3 | NT4/5 | Recombinant Neurotrophin-4/5 (Trk-B ligand) increased survival of CA2/3 pyramidal neurons after TBI in rats, but did not improve functional outcome (Royo et al., 2007). |
| CA1, CA3, Dentate gyrus | MK-801 | MK-801 (competitive NMDA receptor antagonist) ameliorated hippocampal neuronal loss after TBI in rats, and improved anxiety and hippocampus dependent memory (Sönmez et al., 2015). |
| Dentate gyrus | Rapamycin | Rapamycin (mTOR inhibitor) reduced dentate granule cell area, neurogenesis, and mossy fiber sprouting; increased recurrent excitation of dentate granule cells; and diminished seizure prevalence after TBI in rats (Butler et al., 2015). |
| Ara-C | Ara-C (arabinofuranosyl cytidine, antimitotic agent) reduced progenitor cell proliferation and neurogenesis in the dentate gyrus, and completely abolished innate cognitive recovery on water maze performance, after TBI in rats (Sun et al., 2015). | |
| Clioquinol | Clioquinol (zinc chelator) reduced progenitor cell proliferation and neurogenesis after TBI in rats (Choi et al., 2014). | |
| Entire hippocampal complex | DHF | DHF (7,8-dihydroxyflavone, brain derived neurotrophic factor imitator) increased the number of adult-born immature neurons in the hippocampus, and promoted their dendrite arborization in the injured brain following TBI in mice (Zhao et al., 2015). |
| NAC + selenium | N-acetylcysteine (NAC) and selenium (antioxidants) decreased levels of cytosolic-free Ca2+, apoptosis, cytosolic reactive oxygen species levels, and caspase-3 and -9 activities in hippocampal neurons, after TBI in rats (Naziroğlu et al., 2014). | |
| SB-3CT | SB-3CT (matrix metallopeptidase nine inhibitor) preserved hippocampal neurons and prevented declines in motor function and memory, following TBI in rats Jia et al., 2014). | |
| Oxaloacetate + pyruvate | Oxaloacetate and pyruvate (blood glutamate scavengers) increased hippocampus neuronal survival and neurologic severity scores, after TBI in rats (Zlotnik et al., 2012). | |
| Thymoquinone | Thymoquinone (phytochemical compound) increased hippocampus neuronal densities and malondialdehyde levels, after TBI in rats (Gülsen et al., 2015). | |
| Indomethacin | Indomethacin (anti-inflammatory) suppressed Nogo-A (membrane protein important in axonal remodeling) expression, leading to decreased levels of IL-1β, therefore lessening neuronal damage after TBI in rats (Chao et al., 2012). |
Biochemical compounds investigated in rodent hippocampus following TBI, with effects categorized by subsection of the hippocampal complex.
CA, cornu ammonis; GABA, gamma-aminobutyric acid; Trk, tyrosine kinase; NMDA, N-methyl-D-aspartate; mTOR, mammalian Target Of Rapamycin; IL-1β, Interleukin-1 beta.
Hippocampal Circuitry and Neurophysiologic Changes After mTBI
In addition to biochemical changes after injury, changes in electrical neural activity also play a role in the sequelae of TBI. The high prevalence of memory deficits after injury point to a relative vulnerability of the hippocampus and mesial temporal structures as compared to the rest of the brain (Hamm et al., 1993; Finset et al., 1999; Comper et al., 2005), and electrophysiologic studies have shown that changes occur in hippocampal circuit excitability after TBI (Witgen et al., 2005; Ortiz and Gutiérrez, 2015). In addition, moderate and severe TBI is associated with neuronal cell loss in several hippocampal regions (Lowenstein et al., 1992) as well as alterations in cellular homeostasis (D’Ambrosio et al., 1999) and dysregulated synaptic transmission (Toth et al., 1997; D’Ambrosio et al., 1998) in this region. On the other hand, mTBI has been associated with more subtle changes in firing patterns that are present even in the absence of morphological changes.
Studies comparing control rats to those who had undergone lateral fluid percussion induced mTBI found changes in working memory in the absence of differences in histology or neuronal loss (Eakin and Miller, 2012). Single unit recordings from cornu ammonis 1 (CA1) and CA3 subfields during a working memory task showed no differences in firing rates or spike characteristics between the two groups, but rats exposed to mTBI were found to have significantly fewer cells with spatiotemporal activity, and this correlated with task performance. Moreover, in a similar experiment looking at the burst characteristics of hippocampal cells during an object exploration task, memory deficits were found to be associated with decreased burst activity of certain subsets of neurons within the pyramidal cell layer (Munyon et al., 2014). Therefore, functional impairment may stem from an alteration in the activity of certain subpopulations of cells within the hippocampus.
These changes in neuronal firing patterns within the hippocampus can persist after TBI and correlate with changes in cognitive function (Witgen et al., 2005). In the analysis of local field potentials after injury, hippocampal broadband power decreased (Paterno et al., 2015), and specifically disruption of theta rhythm (4–7 Hz) has been implicated in the pathophysiology of memory loss (Winson, 1978; Fedor et al., 2010). It has been theorized that using electrical stimulation to artificially counteract and reverse these disrupted firing patterns within the hippocampus and other structures may regulate cellular and network processes and restore functional memory circuits (Diamond et al., 1988; Nakao et al., 2003; Shirvalkar et al., 2010; Tabansky et al., 2014; Hanell et al., 2015). Accordingly, theta burst stimulation (200 Hz in 50 ms trains, five trains per second; 60 mA biphasic pulses) delivered to the fornix of rats with mTBI improved deficits in learning and memory, whereas non-oscillatory low or high frequency stimulation did not (Sweet et al., 2014). In a related manner, theta band stimulation of the medial septal nucleus of mTBI rats resulted in a transient increase in hippocampal theta activity and improved spatial working memory (Lee et al., 2013), whereas 100 Hz gamma stimulation did not (Lee et al., 2015).
In humans, theta burst stimulation of the fornix has been studied in patients undergoing stereo-electroencephalography evaluation for drug-resistant epilepsy, and was shown to produce evoked potentials in the ipsilateral hippocampus. This resulted in significant and reversible improvements in immediate and delayed performance on a visual-spatial memory task (Miller et al., 2015). Temporally patterned stimulation paradigms may therefore present novel neuromodulatory strategies in the treatment of post-traumatic memory loss and cognitive deficits. Potential targets include the hippocampus, its associated white matter tracts, as well as the medial prefrontal cortex. The dysfunction of the latter is thought to play a role in the failure of emotion regulation after mTBI through top down amygdalar regulation (van der Horn et al., 2016), a mechanism that may result in persistent post-concussive symptoms.
Imaging in mTBI
Recent advances in imaging have allowed for in-depth structural analysis of brain regions both acutely after concussive injury and in the chronic phase. This is important because the ability to identify abnormalities that may previously have been missed is the first step in developing modalities to treat these phenomena, or in the least decide which patients require treatment. Although no single imaging modality has yet proven to be sufficient for all patients with TBI due to the heterogeneity of the condition (Amyot et al., 2015), each method offers its own advantages.
Conventional magnetic resonance imaging (MRI) and computed tomography (CT) are typically negative in mTBI patients with persistent symptoms of post-concussive syndrome. However, compared to controls, mTBI patients were found to have lower cortical thickness of the right temporal lobe and left insula, and increasing number of mTBIs was associated with lower cortical thickness in more brain areas, including bilateral insula, right middle temporal gyrus, and right entorhinal area (List et al., 2015). These findings are worrisome because if further deterioration of these structures occur as part of the aging process, subtle cognitive symptoms may progress to clinical dementia earlier than in age-matched controls. Diffusion tensor imaging is another technique that has recently emerged as a powerful adjunct to conventional MRI. It enables the measurement of fractional anisotropy, a value that indicates the degree of restriction experienced by water molecules diffusing along white matter fibers. Such a tool offers a noninvasive glimpse into the neurophysiology of these tracts and may allow detection of demyelination and axonal damage that would otherwise be missed on a conventional MRI. Indeed, fractional anisotropy was significantly reduced in the right superior longitudinal fasciculus of patients with mTBI and normal MRI as compared with controls, showing that diffusion tensor imaging is more sensitive than standard imaging in this population (Adam et al., 2015). Another study showed similar but subtler findings, as only those with mTBI who had abnormalities on conventional MRI had white matter changes on diffusion tensor imaging (Panenka et al., 2015).
Although increasing abnormality on post-injury CT and MRI correlate with lower neuropsychological performance (Bigler et al., 2015), diffusion tensor imaging has also shown promise in predicting neuropsychological outcomes following mTBI in patients with normal CT and MRI. Immediately following injury and 6 months post-trauma, patients with mTBI showed significant differences in fractional anisotropy and radial diffusivity as compared to controls, specifically in the corona radiata, anterior limb of internal capsule, cingulum, superior longitudinal fasciculus, optic radiation, and genu of corpus callosum, changes which demonstrated associations with neuropsychological outcomes across both time points (Veeramuthu et al., 2015). Another study has shown significantly reduced fractional anisotropy in the internal capsule of both TBI and depression patients (Maller et al., 2010), further underscoring the potential role for diffusion tensor imaging as a noninvasive biomarker useful in the prognostication of post-concussive symptoms.
MRS is another noninvasive technique that measures metabolic changes within brain tissue. In combination with vascular imaging techniques such as transcranial Doppler ultrasound, these modalities have begun to shed light on metabolic processes and the control and regulation of cerebral blood flow following mTBI (Len and Neary, 2011). In the hippocampus, N-acetyl aspartate to choline and N-acetyl aspartate to creatine ratios were decreased in patients with mTBI in comparison to control subjects (Hetherington et al., 2014). Similar changes were found following mTBI in the thalamus, with a reduction of N-acetyl aspartate to creatine and choline to creatine ratios, findings that are classically associated with ischemia (Sours et al., 2015). Of interest, these results correlated with self-reported sensory symptoms, leading the authors to speculate that novel interventions could target these changes in the hopes of treating patients with persistent post-concussive symptoms, as well as use the absence of such imaging features as an indicator to help predict safe return to work.
Magnetoencephalography is an imaging modality largely restricted to the study of epilepsy, but may prove useful as a sensitive detector of local field potentials in brain areas affected by mTBI. A recent innovative study looked at the tracking of eye movements as a marker for sustained attention over time and internal anticipatory control, measurements that are impaired in chronic mTBI while the patients were undergoing magnetoencephalography (Diwakar et al., 2015). Compared to controls, mTBI patients demonstrated impaired eye tracking that was concurrent with abnormal beta activity, which was suppressed in the right parietal cortex and enhanced in the left caudate and frontal-temporal areas. The clinical significance of these findings is yet to be seen, but this is a strong example of novel imaging methods being used in new and original ways to better understand the neurophysiology of injured neural circuits, methods that may alter the manner in which mTBI is diagnosed and treated in the future.
Future Directions
Direct modulation of neural activity via deep brain stimulation (DBS) currently does not play a direct role in the setting mTBI, but it does carry promise in the treatment of post-concussive affective disorders, trauma-induced tremor, and neurodegenerative disorders. DBS is an effective treatment for certain patients with severe major depression (Lozano et al., 2012) and obsessive-compulsive disorder (Kisely et al., 2014), but has yet to be investigated in the treatment of these disorders following brain injury. Likewise, PD often responds well to DBS of the subthalamic nucleus or globus pallidus internus (Okun, 2012), but data is lacking in the setting of trauma-induced Parkinson’s. However, tremor following severe brain injury has been shown in small studies to respond to both thalamic and pallidal DBS (Issar et al., 2013; Carvalho et al., 2014).
If neurostimulation augments improvements in cognitive deficits after brain injury, memory disorders may present other potential applications for DBS (Shin et al., 2014). Forniceal DBS in a mouse model of Rett syndrome restored in vivo hippocampal long-term potentiation and neurogenesis, and rescued contextual fear memory and spatial learning (Hao et al., 2015). In humans, the fornix and nucleus basalis of Meynert are being investigated as possible DBS targets for improvement of memory in the treatment of AD (Sankar et al., 2014; Suthana and Fried, 2014). Although these strategies seem promising, they will likely be tested for efficacy and safety in the setting of severe TBI, prior to being applied in patients with mTBI.
Less invasive neuromodulation options for the treatment of mTBI include transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (TDCS). TMS uses a surface coil to create a low frequency electric current that is delivered to the surface of the brain, while TDCS uses electrodes placed directly on the scalp. There is evidence in severe TBI that TMS may aid in motor recovery, aphasia, visuospatial neglect (Castel-Lacanal et al., 2014), and cognitive function (Polanowska and Seniów, 2010), but high frequencies are contraindicated due to the risk of seizures, especially in the setting of trauma as the injured brain is already predisposed to epileptiform activity. TDCS uses lower currents and therefore has a lower risk of seizures, but subsequently may also have less clinical effect, as current studies show mixed results in the treatment of post-concussive symptoms (Kang et al., 2012; Leśniak et al., 2014; Ulam et al., 2015). TMS is currently the most extensively studied brain stimulation modality in TBI, but most interventions have been non-targeted and focused on the chronic phase of recovery after the injury (Li et al., 2015). As can be expected, better clinical outcomes occur when these neuromodulatory approaches are coupled with cognitive therapy and neurorehabilitation (Chantsoulis et al., 2015; Page et al., 2015).
Finally, nanotechnology and brain-computer interfaces may present new opportunities. By using a computer to bridge the gap between the brain and peripheral nerves in the setting of an injured spinal cord, brain-computer interfaces are “a form of extended embodiment that become integrated into the individual’s conception of himself as an autonomous agent” (Glannon, 2014). Such systems are still in the experimental stage, but offer hope to those patients with severe motor deficits. Similarly, carbon nanotubes are being used to synthesize nanoelectrode arrays that permit real time monitoring and modulation of electrochemical events at the neural and synaptic level (Andrews, 2007), and may offer a glimpse into the future of the field of neuromodulation. As with DBS, however, these modalities will likely be reserved for patients with severe TBI until efficacy, safety, and economic feasibility can be established.
Conclusion
Despite the high incidence and prevalence of mTBI, only recently have the pathophysiologic mechanisms begun to emerge. Understanding the biochemical signaling pathways involved in the propagation of secondary injury mechanisms has led to the discovery of novel uses for medications currently used for other indications. Biochemical markers and advances in imaging are allowing for earlier diagnosis of concussions, and developments in the area of DBS for the treatment of memory and affective disorders are creating new avenues for the management of post-concussive syndrome. Ultimately, these advances in neuromodulation strive to improve outcomes in mTBI and substantially impact the lives of patients and families suffering from this condition.
Statements
Author contributions
FG, JP, JS and JPM wrote and edited the manuscript.
Conflict of interest
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.
References
1
Adam O. Mac Donald C. L. Rivet D. Ritter J. May T. Barefield M. et al . (2015). Clinical and imaging assessment of acute combat mild traumatic brain injury in Afghanistan. Neurology85, 219–227. 10.1212/WNL.0000000000001758
2
Almeida-Suhett C. P. Prager E. M. Pidoplichko V. Figueiredo T. H. Marini A. M. Li Z. et al . (2015). GABAergic interneuronal loss and reduced inhibitory synaptic transmission in the hippocampal CA1 region after mild traumatic brain injury. Exp. Neurol.273, 11–23. 10.1016/j.expneurol.2015.07.028
3
Amyot F. Arciniegas D. B. Brazaitis M. P. Curley K. C. Diaz-Arrastia R. Gandjbakhche A. et al . (2015). A review of the effectiveness of neuroimaging modalities for the detection of traumatic brain injury. J. Neurotrauma32, 1693–1721. 10.1089/neu.2013.3306
4
Andrews R. J. (2007). Neuroprotection at the nanolevel–Part II: nanodevices for neuromodulation—deep brain stimulation and spinal cord injury. Ann. N Y Acad. Sci.1122, 185–196. 10.1196/annals.1403.013
5
Atkins C. M. Falo M. C. Alonso O. F. Bramlett H. M. Dietrich W. D. (2009). Deficits in ERK and CREB activation in the hippocampus after traumatic brain injury. Neurosci. Lett.459, 52–56. 10.1016/j.neulet.2009.04.064
6
Barkhoudarian G. Hovda D. A. Giza C. C. (2011). The molecular pathophysiology of concussive brain injury. Clin. Sports Med.30, 33–48. 10.1016/j.csm.2010.09.001
7
Bigler E. D. Jantz P. B. Farrer T. J. Abildskov T. J. Dennis M. Gerhardt C. A. et al . (2015). Day of injury CT and late MRI findings: cognitive outcome in a paediatric sample with complicated mild traumatic brain injury. Brain Inj.29, 1062–1070. 10.3109/02699052.2015.1011234
8
Blaya M. O. Tsoulfas P. Bramlett H. M. Dietrich W. D. (2015). Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis and improves cognitive outcomes after traumatic brain injury. Exp. Neurol.264, 67–81. 10.1016/j.expneurol.2014.11.014
9
Butler C. R. Boychuk J. A. Smith B. N. (2015). Effects of rapamycin treatment on neurogenesis and synaptic reorganization in the dentate gyrus after controlled cortical impact injury in mice. Front. Syst. Neurosci.9:163. 10.3389/fnsys.2015.00163
10
Cairelli M. J. Fiszman M. Zhang H. Rindflesch T. C. (2015). Networks of neuroinjury semantic predications to identify biomarkers for mild traumatic brain injury. J. Biomed. Semantics6:25. 10.1186/s13326-015-0022-4
11
Carlson S. W. Madathil S. K. Sama D. M. Gao X. Chen J. Saatman K. E. (2014). Conditional overexpression of insulin-like growth factor-1 enhances hippocampal neurogenesis and restores immature neuron dendritic processes after traumatic brain injury. J. Neuropathol. Exp. Neurol.73, 734–746. 10.1097/NEN.0000000000000092
12
Carlson S. W. Yan H. Ma M. Li Y. Henchir J. Dixon C. E. (2016). Traumatic brain injury impairs soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex formation and alters synaptic vesicle distribution in the hippocampus. J. Neurotrauma33, 113–121. 10.1089/neu.2014.3839
13
Carvalho K. S. Sukul V. V. Bookland M. J. Koch S. A. Connolly P. J. (2014). Deep brain stimulation of the globus pallidus suppresses post-traumatic dystonic tremor. J. Clin. Neurosci.21, 153–155. 10.1016/j.jocn.2013.02.009
14
Castel-Lacanal E. Tarri M. Loubinoux I. Gasq D. de Boissezon X. Marque P. et al . (2014). Transcranial magnetic stimulation in brain injury. Ann. Fr. Anesth. Reanim.33, 83–87. 10.1016/j.annfar.2013.11.006
15
Centers for Disease Control and Prevention [CDC] . (2013). CDC grand rounds: reducing severe traumatic brain injury in the United States. MMWR Morb. Mortal. Wkly. Rep.62, 549–552.
16
Chamoun R. Suki D. Gopinath S. P. Goodman J. C. Robertson C. (2010). Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J. Neurosurg.113, 564–570. 10.3171/2009.12.JNS09689
17
Chantsoulis M. Mirski A. Rasmus A. Kropotov J. D. Pachalska M. (2015). Neuropsychological rehabilitation for traumatic brain injury patients. Ann. Agric. Environ. Med.22, 368–379. 10.5604/12321966.1152097
18
Chao P. K. Lu K. T. Jhu J. Y. Wo Y. Y. Huang T. C. Ro L. S. et al . (2012). Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1beta release through the inhibition of Nogo-A expression. J. Neuroinflammation9:121. 10.1186/1742-2094-9-121
19
Chen G. Shi J. Hu Z. Hang C. (2008). Inhibitory effect on cerebral inflammatory response following traumatic brain injury in rats: a potential neuroprotective mechanism of N-acetylcysteine. Mediators Inflamm.2008:716458. 10.1155/2008/716458
20
Choi B. Y. Kim J. H. Kim H. J. Lee B. E. Kim I. Y. Sohn M. et al . (2014). Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus. J. Trace. Elem. Med. Biol.28, 474–481. 10.1016/j.jtemb.2014.07.007
21
Choi D. W. Maulucci-Gedde M. Kriegstein A. R. (1987). Glutamate neurotoxicity in cortical cell culture. J. Neurosci.7, 357–368.
22
Comper P. Bisschop S. M. Carnide N. Tricco A. (2005). A systematic review of treatments for mild traumatic brain injury. Brain Inj.19, 863–880. 10.1080/02699050400025042
23
D’Ambrosio R. Maris D. O. Grady M. S. Winn H. R. Janigro D. (1998). Selective loss of hippocampal long-term potentiation, but not depression, following fluid percussion injury. Brain Res.786, 64–79. 10.1016/s0006-8993(97)01412-1
24
D’Ambrosio R. Maris D. O. Grady M. S. Winn H. R. Janigro D. (1999). Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia. J. Neurosci.19, 8152–8162.
25
Daneshvar D. H. Riley D. O. Nowinski C. J. Mckee A. C. Stern R. A. Cantu R. C. (2011). Long-term consequences: effects on normal development profile after concussion. Phys. Med. Rehabil. Clin. N Am.22, 683–700. 10.1016/j.pmr.2011.08.009
26
Diamond D. M. Dunwiddie T. V. Rose G. M. (1988). Characteristics of hippocampal primed burst potentiation in vitro and in the awake rat. J. Neurosci.8, 4079–4088.
27
Diwakar M. Harrington D. L. Maruta J. Ghajar J. El-Gabalawy F. Muzzatti L. et al . (2015). Filling in the gaps: anticipatory control of eye movements in chronic mild traumatic brain injury. Neuroimage Clin.8, 210–223. 10.1016/j.nicl.2015.04.011
28
Drexel M. Puhakka N. Kirchmair E. Hörtnagl H. Pitkänen A. Sperk G. (2015). Expression of GABA receptor subunits in the hippocampus and thalamus after experimental traumatic brain injury. Neuropharmacology88, 122–133. 10.1016/j.neuropharm.2014.08.023
29
Eakin K. Baratz-Goldstein R. Pick C. G. Zindel O. Balaban C. D. Hoffer M. E. et al . (2014). Efficacy of N-acetyl cysteine in traumatic brain injury. PLoS One9:e90617. 10.1371/journal.pone.0090617
30
Eakin K. Li Y. Chiang Y. H. Hoffer B. J. Rosenheim H. Greig N. H. et al . (2013). Exendin-4 ameliorates traumatic brain injury-induced cognitive impairment in rats. PLoS One8:e82016. 10.1371/journal.pone.0082016
31
Eakin K. Miller J. P. (2012). Mild traumatic brain injury is associated with impaired hippocampal spatiotemporal representation in the absence of histological changes. J. Neurotrauma29, 1180–1187. 10.1089/neu.2011.2192
32
Ellis E. F. Dodson L. Y. Police R. J. (1991). Restoration of cerebrovascular responsiveness to hyperventilation by the oxygen radical scavenger n-acetylcysteine following experimental traumatic brain injury. J. Neurosurg.75, 774–779. 10.3171/jns.1991.75.5.0774
33
Faul M. X. L. Wald M. Coronado V. (2010). Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths, 2002–2006.Atlanta, GA: Centers for Disease Control and Prevention.
34
Fedor M. Berman R. F. Muizelaar J. P. Lyeth B. G. (2010). Hippocampal theta dysfunction after lateral fluid percussion injury. J. Neurotrauma27, 1605–1615. 10.1089/neu.2010.1370
35
Finset A. Anke A. W. Hofft E. Roaldsen K. S. Pillgram-Larsen J. Stanghelle J. K. (1999). Cognitive performance in multiple trauma patients 3 years after injury. Psychosom. Med.61, 576–583. 10.1097/00006842-199907000-00024
36
Folkersma H. Foster Dingley J. C. van Berckel B. N. Rozemuller A. Boellaard R. Huisman M. C. et al . (2011). Increased cerebral (R)-[(11)C]PK11195 uptake and glutamate release in a rat model of traumatic brain injury: a longitudinal pilot study. J. Neuroinflammation8:67. 10.1186/1742-2094-8-67
37
Glannon W. (2014). Neuromodulation, agency and autonomy. Brain Topogr.27, 46–54. 10.1007/s10548-012-0269-3
38
Greig N. H. Tweedie D. Rachmany L. Li Y. Rubovitch V. Schreiber S. et al . (2014). Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury. Alzheimers Dement.10, S62–S75. 10.1016/j.jalz.2013.12.011
39
Greve M. W. Zink B. J. (2009). Pathophysiology of traumatic brain injury. Mt. Sinai J. Med.76, 97–104. 10.1002/msj.20104
40
Guerriero R. M. Giza C. C. Rotenberg A. (2015). Glutamate and GABA imbalance following traumatic brain injury. Curr. Neurol. Neurosci. Rep.15:27. 10.1007/s11910-015-0545-1
41
Gülsen I. Ak H. Çölçimen N. Alp H. H. Akyol M. E. Demir I. et al . (2015). Neuroprotective effects of thymoquinone on the hippocampus in a rat model of traumatic brain injury. World Neurosurg. [Epub ahead of print]. 10.1016/j.wneu.2015.09.052
42
Hamm R. J. Lyeth B. G. Jenkins L. W. O’Dell D. M. Pike B. R. (1993). Selective cognitive impairment following traumatic brain injury in rats. Behav. Brain Res.59, 169–173. 10.1016/0166-4328(93)90164-l
43
Hanell A. Greer J. E. Jacobs K. M. (2015). Increased network excitability due to altered synaptic inputs to neocortical layer v intact and axotomized pyramidal neurons after mild traumatic brain injury. J. Neurotrauma32, 1590–1598. 10.1089/neu.2014.3592
44
Hao S. Tang B. Wu Z. Ure K. Sun Y. Tao H. et al . (2015). Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature526, 430–434. 10.1038/nature15694
45
Harris J. L. Yeh H. W. Choi I. Y. Lee P. Berman N. E. Swerdlow R. H. et al . (2012). Altered neurochemical profile after traumatic brain injury: (1)H-MRS biomarkers of pathological mechanisms. J. Cereb. Blood Flow Metab.32, 2122–2134. 10.1038/jcbfm.2012.114
46
Henry L. C. Tremblay S. Boulanger Y. Ellemberg D. Lassonde M. (2010). Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. J. Neurotrauma27, 65–76. 10.1089/neu.2009.0962
47
Hetherington H. P. Hamid H. Kulas J. Ling G. Bandak F. de Lanerolle N. C. et al . (2014). MRSI of the medial temporal lobe at 7 T in explosive blast mild traumatic brain injury. Magn. Reson. Med.71, 1358–1367. 10.1002/mrm.24814
48
Hicdonmez T. Kanter M. Tiryaki M. Parsak T. Cobanoglu S. (2006). Neuroprotective effects of N-acetylcysteine on experimental closed head trauma in rats. Neurochem. Res.31, 473–481. 10.1007/s11064-006-9040-z
49
Hoffer M. E. Balaban C. Slade M. D. Tsao J. W. Hoffer B. (2013). Amelioration of acute sequelae of blast induced mild traumatic brain injury by N-acetyl cysteine: a double-blind, placebo controlled study. PLoS One8:e54163. 10.1371/journal.pone.0054163
50
Hunt R. F. Scheff S. W. Smith B. N. (2011). Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice. J. Neurosci.31, 6880–6890. 10.1523/JNEUROSCI.0032-11.2011
51
Issar N. M. Hedera P. Phibbs F. T. Konrad P. E. Neimat J. S. (2013). Treating post-traumatic tremor with deep brain stimulation: report of five cases. Parkinsonism Relat. Disord.19, 1100–1105. 10.1016/j.parkreldis.2013.07.022
52
Jia F. Yin Y. H. Gao G. Y. Wang Y. Cen L. Jiang J. Y. (2014). MMP-9 inhibitor SB-3CT attenuates behavioral impairments and hippocampal loss after traumatic brain injury in rat. J. Neurotrauma31, 1225–1234. 10.1089/neu.2013.3230
53
Johnson B. N. Palmer C. P. Bourgeois E. B. Elkind J. A. Putnam B. J. Cohen A. S. (2014). Augmented inhibition from cannabinoid-sensitive interneurons diminishes CA1 output after traumatic brain injury. Front. Cell. Neurosci.8:435. 10.3389/fncel.2014.00435
54
Kang W. H. Cao W. Graudejus O. Patel T. P. Wagner S. Meaney D. F. et al . (2015). Alterations in hippocampal network activity after in vitro traumatic brain injury. J. Neurotrauma32, 1011–1019. 10.1089/neu.2014.3667
55
Kang E. K. Kim D. Y. Paik N. J. (2012). Transcranial direct current stimulation of the left prefrontal cortex improves attention in patients with traumatic brain injury: a pilot study. J. Rehabil. Med.44, 346–350. 10.2340/16501977-0947
56
Kastin A. J. Akerstrom V. (2003). Entry of exendin-4 into brain is rapid but may be limited at high doses. Int. J. Obes. Relat. Metab. Disord.27, 313–318. 10.1038/sj.ijo.0802206
57
Kisely S. Hall K. Siskind D. Frater J. Olson S. Crompton D. (2014). Deep brain stimulation for obsessive-compulsive disorder: a systematic review and meta-analysis. Psychol. Med.44, 3533–3542. 10.1017/s0033291714000981
58
Lawrence D. W. Comper P. Hutchison M. G. Sharma B. (2015). The role of apolipoprotein E episilon (epsilon)-4 allele on outcome following traumatic brain injury: a systematic review. Brain Inj.29, 1018–1031. 10.3109/02699052.2015.1005131
59
Lee D. J. Gurkoff G. G. Izadi A. Berman R. F. Ekstrom A. D. Muizelaar J. P. et al . (2013). Medial septal nucleus theta frequency deep brain stimulation improves spatial working memory after traumatic brain injury. J. Neurotrauma30, 131–139. 10.1089/neu.2012.2646
60
Lee D. J. Gurkoff G. G. Izadi A. Seidl S. E. Echeverri A. Melnik M. et al . (2015). Septohippocampal neuromodulation improves cognition after traumatic brain injury. J. Neurotrauma32, 1822–1832. 10.1089/neu.2014.3744
61
Len T. K. Neary J. P. (2011). Cerebrovascular pathophysiology following mild traumatic brain injury. Clin. Physiol. Funct. Imaging31, 85–93. 10.1111/j.1475-097X.2010.00990.x
62
Leśniak M. Polanowska K. Seniów J. Czlonkowska A. (2014). Effects of repeated anodal tDCS coupled with cognitive training for patients with severe traumatic brain injury: a pilot randomized controlled trial. J. Head Trauma Rehabil.29, E20–E29. 10.1097/HTR.0b013e318292a4c2
63
Levin H. S. Mattis S. Ruff R. M. Eisenberg H. M. Marshall L. F. Tabaddor K. et al . (1987). Neurobehavioral outcome following minor head injury: a three-center study. J. Neurosurg.66, 234–243. 10.3171/jns.1987.66.2.0234
64
Li Y. Chigurupati S. Holloway H. W. Mughal M. Tweedie D. Bruestle D. A. et al . (2012). Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS One7:e32008. 10.1371/journal.pone.0032008
65
Li H. Lee C. H. Yoo K. Y. Choi J. H. Park O. K. Yan B. C. et al . (2010). Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus. Neurosci. Lett.486, 38–42. 10.1016/j.neulet.2010.09.040
66
Li Y. Perry T. Kindy M. S. Harvey B. K. Tweedie D. Holloway H. W. et al . (2009). GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc. Natl. Acad. Sci. U S A106, 1285–1290. 10.1073/pnas.0806720106
67
Li S. Zaninotto A. L. Neville I. S. Paiva W. S. Nunn D. Fregni F. (2015). Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence. Neuropsychiatr. Dis. Treat.11, 1573–1586. 10.2147/NDT.s65816
68
List J. Ott S. Bukowski M. Lindenberg R. Floel A. (2015). Cognitive function and brain structure after recurrent mild traumatic brain injuries in young-to-middle-aged adults. Front. Hum. Neurosci.9:228. 10.3389/fnhum.2015.00228
69
Lowenstein D. H. Thomas M. J. Smith D. H. McIntosh T. K. (1992). Selective vulnerability of dentate hilar neurons following traumatic brain injury: a potential mechanistic link between head trauma and disorders of the hippocampus. J. Neurosci.12, 4846–4853.
70
Lozano A. M. Giacobbe P. Hamani C. Rizvi S. J. Kennedy S. H. Kolivakis T. T. et al . (2012). A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J. Neurosurg.116, 315–322. 10.3171/2011.10.JNS102122
71
Maas A. I. Stocchetti N. Bullock R. (2008). Moderate and severe traumatic brain injury in adults. Lancet Neurol.7, 728–741. 10.1016/s1474-4422(08)70164-9
72
Maller J. J. Thomson R. H. Lewis P. M. Rose S. E. Pannek K. Fitzgerald P. B. (2010). Traumatic brain injury, major depression, and diffusion tensor imaging: making connections. Brain Res. Rev.64, 213–240. 10.1016/j.brainresrev.2010.04.003
73
Mao Q. Jia F. Zhang X. H. Qiu Y. M. Ge J. W. Bao W. J. et al . (2010). The up-regulation of voltage-gated sodium channel Nav1.6 expression following fluid percussion traumatic brain injury in rats. Neurosurgery66, 1134–1139; discussion 1139. 10.1227/01.neu.0000369612.31946.a2
74
Martin B. Golden E. Carlson O. D. Pistell P. Zhou J. Kim W. et al . (2009). Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies and extends survival in a mouse model of Huntington’s disease. Diabetes58, 318–328. 10.2337/db08-0799
75
Merlo L. Cimino F. Angileri F. F. La Torre D. Conti A. Cardali S. M. et al . (2014). Alteration in synaptic junction proteins following traumatic brain injury. J. Neurotrauma31, 1375–1385. 10.1089/neu.2014.3385
76
Miller J. P. Sweet J. A. Bailey C. M. Munyon C. N. Luders H. O. Fastenau P. S. (2015). Visual-spatial memory may be enhanced with theta burst deep brain stimulation of the fornix: a preliminary investigation with four cases. Brain138, 1833–1842. 10.1093/brain/awv095
77
Miller D. M. Wang J. A. Buchanan A. K. Hall E. D. (2014). Temporal and spatial dynamics of nrf2-antioxidant response elements mediated gene targets in cortex and hippocampus after controlled cortical impact traumatic brain injury in mice. J. Neurotrauma31, 1194–1201. 10.1089/neu.2013.3218
78
Munyon C. Eakin K. C. Sweet J. A. Miller J. P. (2014). Decreased bursting and novel object-specific cell firing in the hippocampus after mild traumatic brain injury. Brain Res.1582, 220–226. 10.1016/j.brainres.2014.07.036
79
Nakao K. Ikegaya Y. Yamada M. K. Nishiyama N. Matsuki N. (2003). Fimbrial control of bidirectional synaptic plasticity of medial perforant path-dentate transmission. Synapse47, 163–168. 10.1002/syn.10168
80
Naziroğlu M. Senol N. Ghazizadeh V. Yürüker V. (2014). Neuroprotection induced by N-acetylcysteine and selenium against traumatic brain injury-induced apoptosis and calcium entry in hippocampus of rat. Cell. Mol. Neurobiol.34, 895–903. 10.1007/s10571-014-0069-2
81
Okun M. S. (2012). Deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med.367, 1529–1538. 10.1056/NEJMct1208070
82
Ortiz F. Gutiérrez R. (2015). Entorhinal cortex lesions result in adenosine-sensitive high frequency oscillations in the hippocampus. Exp. Neurol.271, 319–328. 10.1016/j.expneurol.2015.06.009
83
Page S. J. Cunningham D. A. Plow E. Blazak B. (2015). It takes two: noninvasive brain stimulation combined with neurorehabilitation. Arch. Phys. Med. Rehabil.96, S89–S93. 10.1016/j.apmr.2014.09.019
84
Panenka W. J. Lange R. T. Bouix S. Shewchuk J. R. Heran M. K. Brubacher J. R. et al . (2015). Neuropsychological outcome and diffusion tensor imaging in complicated versus uncomplicated mild traumatic brain injury. PLoS One10:e0122746. 10.1371/journal.pone.0122746
85
Park E. Bell J. D. Baker A. J. (2008). Traumatic brain injury: can the consequences be stopped?CMAJ178, 1163–1170. 10.1503/cmaj.080282
86
Paterno R. Metheny H. Xiong G. Elkind J. Cohen A. S. (2015). Mild traumatic brain injury decreases broadband power in area CA1. J. Neurotrauma [Epub ahead of print]. 10.1089/neu.2015.4107
87
Perry T. Lahiri D. K. Chen D. Zhou J. Shaw K. T. Egan J. M. et al . (2002). A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J. Pharmacol. Exp. Ther.300, 958–966. 10.1124/jpet.300.3.958
88
Polanowska K. Seniów J. (2010). [Influence of transcranial direct current stimulation on cognitive functioning of patients with brain injury]. Neurol. Neurochir. Pol.44, 580–590. 10.1016/S0028-3843(14)60156-0
89
Rachmany L. Tweedie D. Li Y. Rubovitch V. Holloway H. W. Miller J. et al . (2013). Exendin-4 induced glucagon-like peptide-1 receptor activation reverses behavioral impairments of mild traumatic brain injury in mice. Age (Dordr.)35, 1621–1636. 10.1007/s11357-012-9464-0
90
Raghupathi R. (2004). Cell death mechanisms following traumatic brain injury. Brain Pathol.14, 215–222. 10.1111/j.1750-3639.2004.tb00056.x
91
Reeves T. M. Lyeth B. G. Phillips L. L. Hamm R. J. Povlishock J. T. (1997). The effects of traumatic brain injury on inhibition in the hippocampus and dentate gyrus. Brain Res.757, 119–132. 10.1016/s0006-8993(97)00170-4
92
Royo N. C. LeBold D. Magge S. N. Chen I. Hauspurg A. Cohen A. S. et al . (2007). Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function. Neuroscience148, 359–370. 10.1016/j.neuroscience.2007.06.014
93
Salcedo I. Tweedie D. Li Y. Greig N. H. (2012). Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br. J. Pharmacol.166, 1586–1599. 10.1111/j.1476-5381.2012.01971.x
94
Samal B. B. Waites C. K. Almeida-Suhett C. Li Z. Marini A. M. Samal N. R. et al . (2015). Acute response of the hippocampal transcriptome following mild traumatic brain injury after controlled cortical impact in the rat. J. Mol. Neurosci.57, 282–303. 10.1007/s12031-015-0626-2
95
Sankar T. Lipsman N. Lozano A. M. (2014). Deep brain stimulation for disorders of memory and cognition. Neurotherapeutics11, 527–534. 10.1007/s13311-014-0275-0
96
Shin S. S. Dixon C. E. Okonkwo D. O. Richardson R. M. (2014). Neurostimulation for traumatic brain injury. J. Neurosurg.121, 1219–1231. 10.3171/2014.7.JNS131826
97
Shirvalkar P. R. Rapp P. R. Shapiro M. L. (2010). Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes. Proc. Natl. Acad. Sci. U S A107, 7054–7059. 10.1073/pnas.0911184107
98
Sick T. J. Pérez-Pinzón M. A. Feng Z. Z. (1998). Impaired expression of long-term potentiation in hippocampal slices 4 and 48 h following mild fluid-percussion brain injury in vivo. Brain Res.785, 287–292. 10.1016/s0006-8993(97)01418-2
99
Sönmez A. Sayin O. Gürgen S. G. Çalişir M. (2015). Neuroprotective effects of MK-801 against traumatic brain injury in immature rats. Neurosci. Lett.597, 137–142. 10.1016/j.neulet.2015.05.001
100
Sours C. George E. O. Zhuo J. Roys S. Gullapalli R. P. (2015). Hyper-connectivity of the thalamus during early stages following mild traumatic brain injury. Brain Imaging Behav.9, 550–563. 10.1007/s11682-015-9424-2
101
Sun D. Daniels T. E. Rolfe A. Waters M. Hamm R. (2015). Inhibition of injury-induced cell proliferation in the dentate gyrus of the hippocampus impairs spontaneous cognitive recovery after traumatic brain injury. J. Neurotrauma32, 495–505. 10.1089/neu.2014.3545
102
Susman M. DiRusso S. M. Sullivan T. Risucci D. Nealon P. Cuff S. et al . (2002). Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. J. Trauma53, 219–224. 10.1097/00005373-200208000-00004
103
Suthana N. Fried I. (2014). Deep brain stimulation for enhancement of learning and memory. Neuroimage85, 996–1002. 10.1016/j.neuroimage.2013.07.066
104
Sweet J. A. Eakin K. C. Munyon C. N. Miller J. P. (2014). Improved learning and memory with theta-burst stimulation of the fornix in rat model of traumatic brain injury. Hippocampus24, 1592–1600. 10.1002/hipo.22338
105
Tabansky I. Quinkert A. W. Rahman N. Muller S. Z. Lofgren J. Rudling J. et al . (2014). Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury. Behav. Brain Res.273, 123–132. 10.1016/j.bbr.2014.07.026
106
Terrio H. Brenner L. A. Ivins B. J. Cho J. M. Helmick K. Schwab K. et al . (2009). Traumatic brain injury screening: preliminary findings in a US Army Brigade Combat Team. J. Head Trauma Rehabil.24, 14–23. 10.1097/htr.0b013e31819581d8
107
Toth Z. Hollrigel G. S. Gorcs T. Soltesz I. (1997). Instantaneous perturbation of dentate interneuronal networks by a pressure wave-transient delivered to the neocortex. J. Neurosci.17, 8106–8117.
108
Tweedie D. Rachmany L. Rubovitch V. Lehrmann E. Zhang Y. Becker K. G. et al . (2013). Exendin-4, a glucagon-like peptide-1 receptor agonist prevents mTBI-induced changes in hippocampus gene expression and memory deficits in mice. Exp. Neurol.239, 170–182. 10.1016/j.expneurol.2012.10.001
109
Ulam F. Shelton C. Richards L. Davis L. Hunter B. Fregni F. et al . (2015). Cumulative effects of transcranial direct current stimulation on EEG oscillations and attention/working memory during subacute neurorehabilitation of traumatic brain injury. Clin. Neurophysiol.126, 486–496. 10.1016/j.clinph.2014.05.015
110
van Bregt D. R. Thomas T. C. Hinzman J. M. Cao T. Liu M. Bing G. et al . (2012). Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat. Exp. Neurol.234, 8–19. 10.1016/j.expneurol.2011.12.003
111
van der Horn H. J. Liemburg E. J. Aleman A. Spikman J. M. van der Naalt J. (2016). Brain networks subserving emotion regulation and adaptation after mild traumatic brain injury. J. Neurotrauma33, 1–9. 10.1089/neu.2015.3905
112
Veeramuthu V. Narayanan V. Kuo T. L. Delano-Wood L. Chinna K. Bondi M. W. et al . (2015). Diffusion tensor imaging parameters in mild traumatic brain injury and its correlation with early neuropsychological impairment: a longitudinal study. J. Neurotrauma32, 1497–1509. 10.1089/neu.2014.3750
113
Wang X. Gao X. Michalski S. Zhao S. Chen J. (2015a). Traumatic brain injury severity affects neurogenesis in adult mouse hippocampus. J. Neurotrauma [Epub ahead of print]. 10.1089/neu.2015.4097
114
Wang W. X. Visavadiya N. P. Pandya J. D. Nelson P. T. Sullivan P. G. Springer J. E. (2015b). Mitochondria-associated microRNAs in rat hippocampus following traumatic brain injury. Exp. Neurol.265, 84–93. 10.1016/j.expneurol.2014.12.018
115
Winson J. (1978). Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. Science201, 160–163. 10.1126/science.663646
116
Witgen B. M. Lifshitz J. Smith M. L. Schwarzbach E. Liang S. L. Grady M. S. et al . (2005). Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation. Neuroscience133, 1–15. 10.1016/j.neuroscience.2005.01.052
117
Yan H. Q. Shin S. S. Ma X. Li Y. Dixon C. E. (2014). Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus. Brain Res.1548, 63–72. 10.1016/j.brainres.2013.12.028
118
Zhang Z. Wang H. Jin Z. Cai X. Gao N. Cui X. et al . (2015). Downregulation of survivin regulates adult hippocampal neurogenesis and apoptosis and inhibits spatial learning and memory following traumatic brain injury. Neuroscience300, 219–228. 10.1016/j.neuroscience.2015.05.025
119
Zhao S. Yu A. Wang X. Gao X. Chen J. (2015). Post-injury treatment of 7,8-dihydroxyflavone promotes neurogenesis in the hippocampus of the adult mouse. J. Neurotrauma [Epub ahead of print]. 10.1089/neu.2015.4036
120
Zlotnik A. Sinelnikov I. Gruenbaum B. F. Gruenbaum S. E. Dubilet M. Dubilet E. et al . (2012). Effect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in rats. Anesthesiology116, 73–83. 10.1097/aln.0b013e31823d7731
Summary
Keywords
hippocampus, mild traumatic brain injury, neurophysiology, neuromodulation, cognitive dysfunction, drug repositioning
Citation
Girgis F, Pace J, Sweet J and Miller JP (2016) Hippocampal Neurophysiologic Changes after Mild Traumatic Brain Injury and Potential Neuromodulation Treatment Approaches. Front. Syst. Neurosci. 10:8. doi: 10.3389/fnsys.2016.00008
Received
18 November 2015
Accepted
25 January 2016
Published
09 February 2016
Volume
10 - 2016
Edited by
Akiva Cohen, University of Pennsylvania & Research Institute of Children’s Hospital of Philadelphia, USA
Reviewed by
Mazyar Fallah, York University, Canada; Trent Anderson, University of Arizona, USA
Updates
Copyright
© 2016 Girgis, Pace, Sweet and Miller.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jonathan P. Miller jonathan.miller@uhhospitals.org
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.