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To investigate the risk of psychiatric disorders following TBI, and to clarify whether the post-TBI rehabilitation was associated with a lower risk of developing psychiatric disorders.
A register-based, retrospective cohort design
Using data from the National Health Insurance Research Database (NHIRD) of Taiwan, we established an exposed cohort with TBI and a nonexposed group without TBI matched by age and year of diagnosis between 2000 and 2015.
This study included 231,894 patients with TBI and 695,682 controls.
Rehabilitation therapies in TBI patients.
A multivariable Cox proportional hazards regression model was used to compare the risk of developing psychiatric disorders.
The incidence rate of psychiatric disorders was higher in the TBI group when compared with the control group. Compared with the control group, the risk of psychiatric disorders in the TBI group was twofold (HR=2.056, 95% CI:1.940- 2.172, p < 0.001). Among the TBI subjects, 49,270 (21.25%) had received rehabilitation therapy and had a lower risk of psychiatric disorders (HR=0.691, 95% CI: 0.679-0.703, p < 0.001). In the subgroup analysis, the medium- to high-level intensity rehabilitation therapy was associated with lower risks of psychiatric disorder (HR=0.712 and 0.568, respectively), but there was no significant finding in the low-intensity group.
We found that TBI was associated with a high risk for developing psychiatric disorders, and that the post-TBI rehabilitation significantly reduced the risk of psychiatric disorders in a dose-dependent manner.
Traumatic brain injury (TBI) causes lifelong cognitive deficits, particularly impairments of executive functioning (EF). Musical training and music-based rehabilitation have been shown to enhance cognitive functioning and neuroplasticity, but the potential rehabilitative effects of music in TBI are still largely unknown. The aim of the present crossover randomized controlled trial (RCT) was to determine the clinical efficacy of music therapy on cognitive functioning in TBI and to explore its neural basis.
Using an AB/BA design, 40 patients with moderate or severe TBI were randomized to receive a 3-month neurological music therapy intervention either during the first (AB, n = 20) or second (BA, n = 20) half of a 6-month follow-up period. Neuropsychological and motor testing and magnetic resonance imaging (MRI) were performed at baseline and at the 3-month and 6-month stage. Thirty-nine subjects who participated in baseline measurement were included in an intention-to-treat analysis using multiple imputation. Results showed that general EF (as indicated by the Frontal Assessment Battery [FAB]) and set shifting improved more in the AB group than in the BA group over the first 3-month period and the effect on general EF was maintained in the 6-month follow-up. Voxel-based morphometry (VBM) analysis of the structural MRI data indicated that gray matter volume (GMV) in the right inferior frontal gyrus (IFG) increased significantly in both groups during the intervention versus control period, which also correlated with cognitive improvement in set shifting. These findings suggest that neurological music therapy enhances EF and induces fine-grained neuroanatomical changes in prefrontal areas.
The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.
Traumatic brain injury accounts for approximately 10 million deaths and/or hospitalizations annually in the world, and approximately 1.5 million annual emergency room visits and hospitalizations in the US (Langlois et al., 2006). Young men are consistently over-represented as being at greatest risk for TBI (Langlois et al., 2006). While half of all traumatic deaths in the USA are due to brain injury (Mayer and Badjatia, 2010), the majority of head injuries are considered mild and often never receive medical treatment (Corrigan et al., 2010). Survivors of TBI are at risk for lowered life expectancy, dying at a 3⋅2 times more rapid rate than the general population (Baguley et al., 2012). Survivors also face long term physical, cognitive, and psychological disorders that greatly diminish quality of life. Even so-called mild TBI without notable cell death may lead to enduring cognitive deficits (Niogi et al., 2008; Rubovitch et al., 2011). A 2007 study estimated that TBI results in $330,827 of average lifetime costs associated with disability and lost productivity, and greatly outweighs the $65,504 estimated costs for initial medical care and rehabilitation (Faul et al., 2007), demonstrating both the long term financial and human toll of TBI.
The development of management protocols in major trauma centers (Brain Trauma Foundation et al., 2007) has improved mortality and functional outcomes (Stein et al., 2010). Monitoring of intracranial pressure is now standard practice (Bratton et al., 2007), and advanced MRI technologies help define the extent of brain injury in some cases (Shah et al., 2012). Current treatment of major TBI is primarily managed through surgical intervention by decompressive craniotomy (Bullock et al., 2006) which involves the removal of skull segments to reduce intracranial pressure. Delayed decompressive craniotomy is also increasingly used for intractable intracranial hypertension (Sahuquillo and Arikan, 2006). The craniotomy procedure is associated with considerable complications, such as hematoma, subdural hygroma, and hydrocephalus (Stiver, 2009). At present, the pathology associated with TBI remains refractive to currently available pharmacotherapies (Meyer et al., 2010) and as such represents an area of great research interest and in need of new potential targets. Effective TBI drug therapies have yet to be proven, despite promising preclinical data (Lu et al., 2007; Mbye et al., 2009; Sen and Gulati, 2010) plagued by translational problems once reaching clinical trials (Temkin et al., 2007; Tapia-Perez et al., 2008; Mazzeo et al., 2009).
The many biochemical events that occur in the hours and months following TBI have yielded preclinical studies directed toward a single injury mechanism. However, an underlying premise of the present review is an important need to address the multiple targets associated with secondary injury cascades following TBI. A growing body of published scientific research indicates that the endogenous cannabinoid (endocannabinoid; eCB) system possesses several targets uniquely positioned to modulate several key secondary events associated with TBI. Here, we review the preclinical work examining the roles that the different components of the eCB system play in ameliorating pathologies associated with TBI.
Originally, “Cannabinoid” was the collective name assigned to the set of naturally occurring aromatic hydrocarbon compounds in the Cannabis sativa plant (Mechoulam and Goani, 1967). Cannabinoid now more generally refers to a much more broad set of chemicals of diverse structure whose pharmacological actions or structure closely mimic that of plant-derived cannabinoids. Three predominant categories are currently in use; plant-derived phytocannabinoids (reviewed in Gertsch et al., 2010), synthetically produced cannabinoids used as research (Wiley et al., 2014) or recreational drugs (Mills et al., 2015), and the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995).
These three broad categories of cannabinoids generally act through cannabinoid receptors, two types of which have so far been identified, CB1 (Devane et al., 1988) and CB2 (Munro et al., 1993). Both CB1 and CB2 receptors are coupled to signaling cascades predominantly through Gi/o-coupled proteins. CB1 receptors mediate most of the psychomimetic effects of cannabis, its chief psychoactive constituent THC, and many other CNS active cannabinoids. These receptors are predominantly expressed on pre-synaptic axon terminals (Alger and Kim, 2011), are activated by endogenous cannabinoids that function as retrograde messengers, which are released from post-synaptic cells, and their activation ultimately dampens pre-synaptic neurotransmitter release (Mackie, 2006). Acting as a neuromodulatory network, the outcome of cannabinoid receptor signaling depends on cell type and location. CB1 receptors are highly expressed on neurons in the central nervous system (CNS) in areas such as cerebral cortex, hippocampus, caudate-putamen (Herkenham et al., 1991). In contrast, CB2 receptors are predominantly expressed on immune cells, microglia in the CNS, and macrophages, monocytes, CD4+ and CD8+ T cells, and B cells in the periphery (Cabral et al., 2008). Additionally, CB2 receptors are expressed on neurons, but to a much less extent than CB1 receptors (Atwood and MacKie, 2010). The abundant, yet heterogeneous, distribution of CB1 and CB2 receptors throughout the brain and periphery likely accounts for their ability to impact a wide variety of physiological and psychological processes (e.g., memory, anxiety, and pain perception, reviewed in Di Marzo, 2008) many of which are impacted following TBI.
Another unique property of the eCB system is the functional selectivity produced by its endogenous ligands. Traditional neurotransmitter systems elicit differential activation of signaling pathways through activation of receptor subtypes by one neurotransmitter (Siegel, 1999). However, it is the endogenous ligands of eCB receptors which produce such signaling specificity. Although several endogenous cannabinoids have been described (Porter et al., 2002; Chu et al., 2003; Heimann et al., 2007) the two most studied are anandamide (Devane et al., 1992) and 2-AG (Mechoulam et al., 1995; Sugiura et al., 1995). 2-AG levels are three orders of magnitude higher than those of anandamide in brain (Béquet et al., 2007). Additionally, their receptor affinity (Pertwee and Ross, 2002; Reggio, 2002) and efficacy differ, with 2-AG acting as a high efficacy agonist at CB1 and CB2 receptors, while anandamide behaves as a partial agonist (Hillard, 2000a). In addition, anandamide binds and activates TRPV1 receptors (Melck et al., 1999; Zygmunt et al., 1999; Smart et al., 2000), whereas 2-AG also binds GABAA receptors (Sigel et al., 2011). As such, cannabinoid ligands differentially modulate similar physiological and pathological processes.
Distinct sets of enzymes, which regulate the biosynthesis and degradation of the eCBs and possess distinct anatomical distributions (see Figure Figure11), exert control over CB1 and CB2 receptor signaling. Inactivation of anandamide occurs predominantly through FAAH (Cravatt et al., 1996, 2001), localized to intracellular membranes of postsynaptic somata and dendrites (Gulyas et al., 2004), in areas such as the neocortex, cerebellar cortex, and hippocampus (Egertová et al., 1998). Inactivation of 2-AG proceeds primarily via MAGL (Dinh et al., 2002; Blankman et al., 2007), expressed on presynaptic axon terminals (Gulyas et al., 2004), and demonstrates highest expression in areas such as the thalamus, hippocampus, cortex, and cerebellum (Dinh et al., 2002). The availability of pharmacological inhibitors for eCB catabolic enzymes has allowed the selective amplification of anandamide and 2-AG levels following brain injury as a key strategy to enhance eCB signaling and to investigate their potential neuroprotective effects.
For people with many neurologic disorders, seeing the neurologist by video may be as effective as an in-person visit, according to a review of the evidence conducted by the American Academy of Neurology (AAN). The evidence review examined all available studies on use of telemedicine for several neurologic conditions – stroke being one of the conditions that is well-validated and highly utilizes telemedicine – and is published in the December 4, 2019, online issue of Neurology®, the medical journal of the AAN. The results indicate that a diagnosis from a neurologist by video for certain neurologic conditions is likely to be as accurate as an in-person visit.
Telemedicine is the use of video conferencing or other technology for doctor visits from another location. The patient could be at home or at a local doctor’s office.
Telemedicine can be especially helpful for people with epilepsy, who may not be able to drive to appointments, people with neurologic disorders like multiple sclerosis and movement disorders, who may have mobility issues that make getting to a clinic difficult, and, of course, for people in rural areas who may not be able to see a neurologist based hours away without making that trip. Another effective use may be for evaluating people with possible concussions, where telemedicine could be used on-site to make an immediate diagnosis. For sports injuries, it could be used to make a decision on whether the athlete is ready to return to the field.”
Jaime Hatcher-Martin, MD, PhD, lead author who was with Emory University in Atlanta while serving on the American Academy of Neurology’s Telemedicine Work Group, is now with the company SOC Telemed and is a member of the American Academy of Neurology
For the evidence review, the researchers analyzed 101 studies on telemedicine use in the areas of concussion and traumatic brain injury, dementia, epilepsy, headache, multiple sclerosis, movement disorders, neuromuscular conditions and general neurology. Hatcher-Martin noted that evidence for the use of telemedicine for stroke has been well-established.
Overall, studies found that patients and their caregivers were just as satisfied with virtual doctor visits as they were with in-person visits. Some studies show that using telemedicine is as effective as in-person visits to make accurate diagnoses and in some cases may show improved health outcomes. However, few randomized, controlled studies have been conducted on telemedicine for neurology, outside of stroke. In many areas, little research has been done.
“This is just the beginning of evaluating the benefits of telemedicine in neurology,” said senior author Raghav Govindarajan, MD, of the University of Missouri, who served as a chair on the American Academy of Neurology’s Telemedicine Work Group and is a Fellow of the American Academy of Neurology.
“We need to conduct further studies to better understand when virtual appointments are a good option for a patient. Keep in mind that telemedicine may not eliminate the need for people to meet with a neurologist in person. Rather, it is another tool that can help increase people’s access to care and also help lessen the burden of travel and costs for patients, providers and caregivers.”
Traumatic brain injury (TBI) –– defined as a bump, blow or jolt to the head that disrupts normal brain function –– sent 2.5 million people in the U.S. to the emergency room in 2014, according to statistics from the U.S. Centers for Disease Control and Prevention. Today, researchers report a self-assembling peptide hydrogel that, when injected into the brains of rats with TBI, increased blood vessel regrowth and neuronal survival.
The researchers will present their results at the American Chemical Society (ACS) Fall 2019 National Meeting & Exposition. ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 9,500 presentations on a wide range of science topics.
“When we think about traumatic brain injuries, we think of soldiers and athletes,” says Biplab Sarkar, Ph.D., who is presenting the work at the meeting. “But most TBIs actually happen when people fall or are involved in motor vehicle accidents. As the average age of the country continues to rise, the number of fall-related accidents in particular will also increase.”
TBIs encompass two types of injuries. Primary injury results from the initial mechanical damage to neurons and other cells in the brain, as well as blood vessels. Secondary injuries, which can occur seconds after the TBI and last for years, include oxidative stress, inflammation and disruption of the blood-brain barrier. “The secondary injury creates this neurotoxic environment that can lead to long-term cognitive effects,” Sarkar says. For example, TBI survivors can experience impaired motor control and an increased rate of depression, he says. Currently, there is no effective regenerative treatment for TBIs.
Sarkar and Vivek Kumar, Ph.D., the project’s principal investigator, wanted to develop a therapy that could help treat secondary injuries.
We wanted to be able to regrow new blood vessels in the area to restore oxygen exchange, which is reduced in patients with a TBI. Also, we wanted to create an environment where neurons can be supported and even thrive.”
Biplab Sarkar, Ph.D., New Jersey Institute of Technology
The researchers, both at the New Jersey Institute of Technology, had previously developed peptides that can self-assemble into hydrogels when injected into rodents. By incorporating snippets of particular protein sequences into the peptides, the team can give them different functions. For example, Sarkar and Kumar previously developed angiogenic peptide hydrogels that grow new blood vessels when injected under the skin of mice.
To adapt their technology to the brain, Sarkar and Kumar modified the peptide sequences to make the material properties of the hydrogel more closely resemble those of brain tissue, which is softer than most other tissues of the body. They also attached a sequence from a neuroprotective protein called ependymin. The researchers tested the new peptide hydrogel in a rat model of TBI. When injected at the injury site, the peptides self-assembled into a hydrogel that acted as a neuroprotective niche to which neurons could attach.
A week after injecting the hydrogel, the team examined the rats’ brains. They found that in the presence of the hydrogel, survival of the brain cells dramatically improved, resulting in about twice as many neurons at the injury site in treated rats than in control animals with brain injury. In addition, the researchers saw signs of new blood vessel formation. “We saw some indications that the rats in the treated group were more ambulatory than those in the control group, but we need to do more experiments to actually quantify that,” Sarkar says.
According to Kumar, one of the next steps will be to study the behavior of the treated animals to assess their functional recovery from TBI. The researchers are also interested in treating rats with a combination of their previous angiogenic peptide and their new neurogenic version to see if this could enhance recovery. And finally, they plan to find out if the peptide hydrogels work for more diffuse brain injuries, such as concussions. “We’ve seen that we can inject these materials into a defined injury and get good tissue regeneration, but we’re also collaborating with different groups to find out if it could help with the types of injuries we see in soldiers, veterans and even people working at construction sites who experience blast injuries,” Kumar says.
Representing approximately 5% of epilepsy in the civilian population and up to 50% in certain military populations, posttraumatic epilepsy warrants both increased clinical attention and research considerations. In this chapter, we will discuss the important definitions when considering posttraumatic epilepsy including the timing of posttraumatic seizures and the severity of head injuries. We will also review the epidemiology and risk factors for posttraumatic epilepsy in both the civilian population and the military and will describe the association of head trauma and psychogenic nonepileptic seizures. Our clinical discussion focuses on the timing of posttraumatic seizures, the utility of diagnostic testing, treatment of posttraumatic epilepsy, and outcomes of these patients. In addition, we elucidate potential pathophysiologic mechanisms underlying posttraumatic epilepsy and consider its role as a model for epileptogenesis in current and future research. We highlight the relevant studies in each section and underscore the theme that more research is certainly needed in most areas of posttraumatic epilepsy.
If you’re new to the term MOOC it is an acronym for Massive Online Open Course and each year Physiopedia has one for you to take part in for free. The courses Physiopedia have hosted have been hugely successful and have covered a diverse range of topics. This year the topic is Traumatic Brain Injury and it starts today!
The 2019 MOOC aims to provide a basic theoretical understanding of the management of traumatic brain injury in order to equip physiotherapists with sufficient knowledge to manage a person following a traumatic brain injury. This includes assessing impairments, activity limitations and participation restrictions, setting appropriate goals of treatment, formulating an evidence-based treatment plan, implementing treatment and evaluating its success.
Check out the video below to find out more!
This is a completely online course which will take place in Physiopedia’s complimentary e-learning platform Physioplus. You will need need to set up a FREE trial account to access the course, you can do that here. The course will become available on the Physioplus site on 21 October 2019, we place the link at the top of this page and also email it to you. If you’d like to know more about the course check out some more details on the PP page dedicated to the MOOC.
The course will be accredited in 32 States in the USA, Australia and South Africa. That’s right this course comes with free CEUs and CPD Credits if you take part and complete the course.
Don’t forget to choose your favourite T-Shirt for our design competition!
Find out more at https://brainlaw.com/invisible-rain-c… A TBI is a life changing event. But traumatic brain injury is often called “The Invisible Injury” as injuries (and symptoms) will not always be obvious to an observer.
And for those suffering from a TBI it can be difficult to explain how they feel inside.
Every 21 seconds, one person in the USA sustains a brain injury.
And each year over 2.5 million Americans visit the emergency room after suffering a traumatic brain injury, with an estimated 282,000 require hospitalization.
While every TBI is different, and everyone will experience their injury in a unique way, “The Invisible Rain Cloud” attempts to explain some of the common symptoms and feelings an individual may face in their life after brain injury.
The video was created by New York brain injury lawyers De Caro & Kaplen, LLP (https://brainlaw.com), who have been advocating on behalf of individuals suffering from a brain injury for over 30 years.
Find out more at https://brainlaw.com/invisible-rain-c…