Disease Etiology and Post Concussion Syndrome

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

Post Concussion Syndrome

Post-concussion syndrome (PCS) is a complex disorder and the complete pathophysiology is still not completely understood. PCS can be subcategorized into physiological PCS, vestibulo-ocular PCS, cervicogenic PCS, and mood-related PCS based on predominant clinical signs and symptoms. Physiological PCS is the most classic type of PCS and is due to global metabolic dysfunction in the brain which affects the autonomic nervous system (ANS) and cerebral blood flow (CBF) autoregulation. This is suspected to be the cause for symptom-limited exercise intolerance which is a characteristic finding in this subtype. In this chapter we discuss the definition of PCS and the main subtypes. We further discuss possible causes for symptoms of PCS based on research that have studied this disorder using advanced imaging, cardiovascular and cerebrovascular metrics, and intracranial pressure. Finally, we discuss the treatment of PCS and the possible long-term effects.

**Keywords:** mild traumatic brain injury, concussion, post-concussion syndrome, autonomic nervous system dysfunction, cervical post traumatic disorder,

Concussions are defined as reversible neurological dysfunction in the absence of gross brain lesions [1], caused by either a direct blow to the head, neck, or elsewhere on the body with an impulsive force transmitted to the head [2]. Although there is some ambiguity in the definitions of mild traumatic brain injury (mTBI) and concussion, the term concussion usually refers to a milder head injury (GCS = 15) and generally used in the context of sport-related injuries while mTBI are a broader term that includes concussion [3]. Concussions have become an international public health concern and it is estimated that about 42 million people suffer from some form of mTBI every year [4]. In the US alone, it is estimated that 1.6–3.8 million mTBI occur each year [5] and approximately 5–10% of the population will experience a concussion in their lives [6]. Some populations, like military personnel, are at a higher risk for concussions and mTBI. It is estimated that approximately 19.5–22.8% of all returning deployed US troops suffer exposure to blast and/or concussive TBI [7]. The pathophysiology of concussion has been studied in great detail, yet it is one of the least understood injuries facing the neuroscience or sports medicine community [8]. It is hypothesized that acceleration/deceleration and rotational forces cause diffuse injury to the neurons, which causes an ionic imbalance and release of a cascade of neurotransmitters [9–11]. To restore homeostasis, membrane pumps become activated which results in a brief hyper-metabolic state. Lactate is produced, which further impairs neuronal function [12]. Intra-axonal alterations within in the subaxolemmal, neurofilament, and microtubular cytoskeleton

vestibulo-ocular post traumatic disorder, exercise treatment

*Mohammad Nadir Haider and Itai Bezherano*

#### **Chapter 1**

## Post Concussion Syndrome

*Mohammad Nadir Haider and Itai Bezherano*

#### **Abstract**

Post-concussion syndrome (PCS) is a complex disorder and the complete pathophysiology is still not completely understood. PCS can be subcategorized into physiological PCS, vestibulo-ocular PCS, cervicogenic PCS, and mood-related PCS based on predominant clinical signs and symptoms. Physiological PCS is the most classic type of PCS and is due to global metabolic dysfunction in the brain which affects the autonomic nervous system (ANS) and cerebral blood flow (CBF) autoregulation. This is suspected to be the cause for symptom-limited exercise intolerance which is a characteristic finding in this subtype. In this chapter we discuss the definition of PCS and the main subtypes. We further discuss possible causes for symptoms of PCS based on research that have studied this disorder using advanced imaging, cardiovascular and cerebrovascular metrics, and intracranial pressure. Finally, we discuss the treatment of PCS and the possible long-term effects.

**Keywords:** mild traumatic brain injury, concussion, post-concussion syndrome, autonomic nervous system dysfunction, cervical post traumatic disorder, vestibulo-ocular post traumatic disorder, exercise treatment

#### **1. Introduction**

Concussions are defined as reversible neurological dysfunction in the absence of gross brain lesions [1], caused by either a direct blow to the head, neck, or elsewhere on the body with an impulsive force transmitted to the head [2]. Although there is some ambiguity in the definitions of mild traumatic brain injury (mTBI) and concussion, the term concussion usually refers to a milder head injury (GCS = 15) and generally used in the context of sport-related injuries while mTBI are a broader term that includes concussion [3]. Concussions have become an international public health concern and it is estimated that about 42 million people suffer from some form of mTBI every year [4]. In the US alone, it is estimated that 1.6–3.8 million mTBI occur each year [5] and approximately 5–10% of the population will experience a concussion in their lives [6]. Some populations, like military personnel, are at a higher risk for concussions and mTBI. It is estimated that approximately 19.5–22.8% of all returning deployed US troops suffer exposure to blast and/or concussive TBI [7].

The pathophysiology of concussion has been studied in great detail, yet it is one of the least understood injuries facing the neuroscience or sports medicine community [8]. It is hypothesized that acceleration/deceleration and rotational forces cause diffuse injury to the neurons, which causes an ionic imbalance and release of a cascade of neurotransmitters [9–11]. To restore homeostasis, membrane pumps become activated which results in a brief hyper-metabolic state. Lactate is produced, which further impairs neuronal function [12]. Intra-axonal alterations within in the subaxolemmal, neurofilament, and microtubular cytoskeleton

network with impairment of axonal transport as well as impaired glucose metabolism have been observed in the acute and subacute phase after mTBI, which support the hypothesis of metabolic and cellular disruptions in the brain [13].

The typical duration of clinical recovery in majority of concussions is 7–10 days, but it is estimated that 10% [14] to 30% [15] of adolescents and 10–15% [16, 17] of adults take much longer to recover. These statistics have ranged from 5% to more than 50% in the published literature; the primary cause of this variation is due to the different criteria used to measure dysfunction [18]. If symptoms persist for more than 2 weeks in adults, or 1 month in adolescents, then the diagnosis of post-concussion syndrome (PCS) is made [19]. However, this terminology is incorrect because technically it is not a *syndrome*. A *syndrome* is a consistent set of findings associated with a condition with symptom linkage and of symptom resolution [20], but currently there is no gold-standard symptom or set of symptoms that are diagnostic of PCS [21] or its recovery [22]. PCS is defined in the World Health Organization's International Classification of Disease 10 (ICD-10) as history of head trauma with or without loss of consciousness preceding at least three of the following symptoms: headache, dizziness, malaise, fatigue, noise tolerance; irritability, depression, anxiety, emotional lability; subjective concentration, memory, or intellectual difficulties without neuropsychological evidence of marked impairment; insomnia; reduced alcohol tolerance; and preoccupation with above symptoms [23].

Self-reported symptom checklist have been used to report the symptoms of a concussion, the most common being the post-concussion symptom scale (PCSS) [24]. It is a list of 22-symptoms, which can be rated on a Likert scale (no symptom to severe symptom), with a maximum possible score of 132. Unfortunately, these symptoms are not specific to concussions or PCS and the healthy population has an average score of 6 out of 132 [25], hence several studies use the cutoff of 7 on the PCSS to diagnose concussion and PCS [22]. However, there is no symptom cutoff limit that can reliably identify people with concussion and/or PCS. One study [26] showed this cutoff criterion (7 out of 132) incorrectly labeled 34% of healthy people with PCS, which is higher than people with a concussive head injury (31%). Self-reported symptom checklists have also been criticized because there is variation in symptom reporting between people. Athletes are known to under-report their symptoms, whereas people with secondary gain are known to over-report them [27]. Another potential downside of symptom checklists is that it is suggested to reinforce illness behavior and encourages over-endorsement of symptoms that might not otherwise have been reported on free recall [28, 29]. Still, this is a useful tool for clinicians because it helps track symptoms longitudinally, so it is always advised to compare symptom reports with previous ones. Another popular symptom checklist is the post-concussion symptom inventory (PCSI), it has an added benefit which allows patients to report symptoms before and after head injury which makes is easier for clinicians to interpret its findings [30].

#### **2. Post-concussion syndrome classification**

PCS have been subcategorized based on their predominant pathophysiology as shown in **Figure 1** [31, 32]. These classifications may overlap as it is possible to have one or more associated conditions after a head injury. Physiological PCS are believed to be true concussions because these patients typically present with minimal physical examination abnormalities but can have signs of oculomotor and/ or vestibular dysfunction. They often complain of cognitive fatigue, headaches, and

**5**

*Post Concussion Syndrome*

in more detail.

*signs and symptoms.*

**Figure 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

balance problems [33], but the most objective biomarker of physiological dysfunction is symptom-limited exercise intolerance at a low heart rate [34]. These patients have worsening of existing symptoms, or onset of new symptoms, when they begin to exercise. This exacerbation occurs at below 70% of their age appropriate maximum heart rate [32]. The pathophysiology of this type of PCS will be discussed later

*Post-concussion syndrome subtypes. Classification of the different types of PCS based on predominant clinical* 

Vestibulo-ocular and cervicogenic PCS are not true concussions since they do not involve global metabolic disturbance of brain function, rather post-traumatic disorders of isolated subsystems from which the symptoms originate, i.e., the central oculomotor and vestibular systems and upper cervical spine respectively [35]. They present with predominantly vestibulo-ocular/cervical signs and symptoms, respectively, and may demonstrate exercise intolerance during graded treadmill testing, but symptom exacerbation typically occurs at a significantly greater workload (beyond 70% of age-predicted maximum heart rate) than in physiological PCS [34]. This late symptom exacerbation is thought to be due to stress on the vestibular/ocular systems or excessive motion of the cervical spine characteristic of walking/running at higher workloads. Abnormal physical examination findings that point towards a vestibular or ocular pathology, such as smooth pursuits, repetitive saccades, vestibulo-ocular reflex, near point convergence (binocular vision), abnormal accommodation (monocular vision), and benign paroxysmal positional vertigo, are present in almost 70% of patient with mTBI [36, 37]. Clinical predictors of vestibulo-ocular PCS include female sex, pre-injury depression, post-traumatic amnesia, history of motion sickness, dizziness, blurred vision, and difficulty focusing at the time of injury [38, 39]. The neck and suboccipital regions are also frequently involved in head injuries and can cause headaches, persistent dizziness, and balance difficulties [40]. Isolated persistent dysfunction (beyond the normal duration of recovery) may suggest lesions in cranial nerves, their nuclei, or the brain stem, and are associated with prolonged recovery [41]. These overlapping symptoms make the diagnosis of PCS difficult and it is possible that patients with physiological PCS can also have isolated dysfunction

in the vestibular, ocular, and cervical systems at the same time.

The last subtype, mood-related PCS, presents with symptoms that are primarily affective and/or cognitive in nature, have minimal physical examination signs, and are capable of exercising to exhaustion without significant symptom exacerbation. The management of this sub-type is challenging, even for an experienced

#### **Figure 1.**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

network with impairment of axonal transport as well as impaired glucose metabolism have been observed in the acute and subacute phase after mTBI, which support

The typical duration of clinical recovery in majority of concussions is 7–10 days, but it is estimated that 10% [14] to 30% [15] of adolescents and 10–15% [16, 17] of adults take much longer to recover. These statistics have ranged from 5% to more than 50% in the published literature; the primary cause of this variation is due to the different criteria used to measure dysfunction [18]. If symptoms persist for more than 2 weeks in adults, or 1 month in adolescents, then the diagnosis of post-concussion syndrome (PCS) is made [19]. However, this terminology is incorrect because technically it is not a *syndrome*. A *syndrome* is a consistent set of findings associated with a condition with symptom linkage and of symptom resolution [20], but currently there is no gold-standard symptom or set of symptoms that are diagnostic of PCS [21] or its recovery [22]. PCS is defined in the World Health Organization's International Classification of Disease 10 (ICD-10) as history of head trauma with or without loss of consciousness preceding at least three of the following symptoms: headache, dizziness, malaise, fatigue, noise tolerance; irritability, depression, anxiety, emotional lability; subjective concentration, memory, or intellectual difficulties without neuropsychological evidence of marked impairment; insomnia; reduced

the hypothesis of metabolic and cellular disruptions in the brain [13].

alcohol tolerance; and preoccupation with above symptoms [23].

which makes is easier for clinicians to interpret its findings [30].

PCS have been subcategorized based on their predominant pathophysiology as shown in **Figure 1** [31, 32]. These classifications may overlap as it is possible to have one or more associated conditions after a head injury. Physiological PCS are believed to be true concussions because these patients typically present with minimal physical examination abnormalities but can have signs of oculomotor and/ or vestibular dysfunction. They often complain of cognitive fatigue, headaches, and

**2. Post-concussion syndrome classification**

Self-reported symptom checklist have been used to report the symptoms of a concussion, the most common being the post-concussion symptom scale (PCSS) [24]. It is a list of 22-symptoms, which can be rated on a Likert scale (no symptom to severe symptom), with a maximum possible score of 132. Unfortunately, these symptoms are not specific to concussions or PCS and the healthy population has an average score of 6 out of 132 [25], hence several studies use the cutoff of 7 on the PCSS to diagnose concussion and PCS [22]. However, there is no symptom cutoff limit that can reliably identify people with concussion and/or PCS. One study [26] showed this cutoff criterion (7 out of 132) incorrectly labeled 34% of healthy people with PCS, which is higher than people with a concussive head injury (31%). Self-reported symptom checklists have also been criticized because there is variation in symptom reporting between people. Athletes are known to under-report their symptoms, whereas people with secondary gain are known to over-report them [27]. Another potential downside of symptom checklists is that it is suggested to reinforce illness behavior and encourages over-endorsement of symptoms that might not otherwise have been reported on free recall [28, 29]. Still, this is a useful tool for clinicians because it helps track symptoms longitudinally, so it is always advised to compare symptom reports with previous ones. Another popular symptom checklist is the post-concussion symptom inventory (PCSI), it has an added benefit which allows patients to report symptoms before and after head injury

**4**

*Post-concussion syndrome subtypes. Classification of the different types of PCS based on predominant clinical signs and symptoms.*

balance problems [33], but the most objective biomarker of physiological dysfunction is symptom-limited exercise intolerance at a low heart rate [34]. These patients have worsening of existing symptoms, or onset of new symptoms, when they begin to exercise. This exacerbation occurs at below 70% of their age appropriate maximum heart rate [32]. The pathophysiology of this type of PCS will be discussed later in more detail.

Vestibulo-ocular and cervicogenic PCS are not true concussions since they do not involve global metabolic disturbance of brain function, rather post-traumatic disorders of isolated subsystems from which the symptoms originate, i.e., the central oculomotor and vestibular systems and upper cervical spine respectively [35]. They present with predominantly vestibulo-ocular/cervical signs and symptoms, respectively, and may demonstrate exercise intolerance during graded treadmill testing, but symptom exacerbation typically occurs at a significantly greater workload (beyond 70% of age-predicted maximum heart rate) than in physiological PCS [34]. This late symptom exacerbation is thought to be due to stress on the vestibular/ocular systems or excessive motion of the cervical spine characteristic of walking/running at higher workloads. Abnormal physical examination findings that point towards a vestibular or ocular pathology, such as smooth pursuits, repetitive saccades, vestibulo-ocular reflex, near point convergence (binocular vision), abnormal accommodation (monocular vision), and benign paroxysmal positional vertigo, are present in almost 70% of patient with mTBI [36, 37]. Clinical predictors of vestibulo-ocular PCS include female sex, pre-injury depression, post-traumatic amnesia, history of motion sickness, dizziness, blurred vision, and difficulty focusing at the time of injury [38, 39]. The neck and suboccipital regions are also frequently involved in head injuries and can cause headaches, persistent dizziness, and balance difficulties [40]. Isolated persistent dysfunction (beyond the normal duration of recovery) may suggest lesions in cranial nerves, their nuclei, or the brain stem, and are associated with prolonged recovery [41]. These overlapping symptoms make the diagnosis of PCS difficult and it is possible that patients with physiological PCS can also have isolated dysfunction in the vestibular, ocular, and cervical systems at the same time.

The last subtype, mood-related PCS, presents with symptoms that are primarily affective and/or cognitive in nature, have minimal physical examination signs, and are capable of exercising to exhaustion without significant symptom exacerbation. The management of this sub-type is challenging, even for an experienced

concussion expert, because of the extensive overlap with symptoms of primary mood disorders. The most recent concussion in sport group (CISG) guidelines recommend a multidisciplinary team approach to treatment that may involve a psychiatrist, a psychologist and/or a neuropsychologist [21]. Other disorders, such as chronic post-traumatic headaches and migraines, are treated in a similar fashion and should be referred to their corresponding specialist, i.e., a neurologist.

#### **3. Sex differences**

The duration of recovery is suggested to be longer for females with males recovering in an average of 7–10 days where as females recovering in an average of 14 days [21]. Healthy females at baseline are also reported to have higher symptom severity on concussion symptom scales than healthy males [42]. A study [43] suggests that adolescent females were more likely to be diagnosed with PCS due to increased symptom load as well as the duration of symptoms because males returned to being asymptomatic by the fourth week of recovery, missing the PCS diagnostic criteria. Another study suggests the female sex to be a significant predictor of prolonged PCS, which they described as symptoms that lasted for more than 3 months [44]. Interestingly, the same study found this association to be more prominent between the ages of 14 and 56, which is characterized by drastic fluctuations of hormone levels. This calls into question the role of female sex hormones in recovery trajectories and symptom resolution. Some critics have suggested that the above theories overestimate sex effect on PCS, suggesting that the increased relative rates of females entering PCS and experiencing PCS symptoms are more often due to differing societal pressures and perceived stigma experienced by the sexes causing many males to perceive their symptoms as resolved [45, 46].

A topic of more recent research is the morphological and structural differences in females that could predict PCS. It has been well established by the literature that female athletes, given equal exposure and risk, are more likely to sustain a concussion [47]. The reasoning behind a female's increased vulnerability is still under debate, with decreased neck girth and differences in play style all seeming to play a role [48, 49]. A recently [50] identified difference in female brains is decreased axon size and density. This decreased axon size complimented with an increased density of axonal fibers could predispose females to having more severe consequences than males when given the same impact. More research in the cellular differences between males and females could address the differences observed in PCS incidence.

#### **4. Imaging**

Currently, the ICD-10 states that no advanced imaging methods can diagnose a concussion [21], but some studies have shown that certain types of PCS have observable differences from each other on advanced imaging. PCS patients with neuropsychiatric complains have significant differences than PCS patients without them. Diffusion tensor imaging (DTI) studies [51] have shown decreased fractional anisotropy (FA) in the superior longitudinal fasciculus, vermis, and white matter around the nucleus accumbens and anterior limb of the internal capsule which correlates to symptoms of depression and anxiety. A larger meta-analysis [52] showed patients who had predominantly cognitive/affective symptoms 1 month post-mTBI had significantly increased FA and reduced mean diffusivity (MD) than those with other symptoms. Increased FA indicates faster unidirectional flow within neurons and decreased MD indicates better axonal integrity [53], which is surprising after the

**7**

*Post Concussion Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

brain is injured. Another way to interpret these findings is that there is more activity within each neuron, which is more consistent with the hypothesized post-mTBI hyper-metabolic state described above. Long-term changes have also been shown to occur after mTBI and PCS. A study [54] that longitudinally assessed regional brain volumes at 1 month post-injury and again at 1 year post-injury. They found significant reductions in the anterior cingulate white matter, left cingulate gyrus isthmus white matter, and right precuneal gray matter. The reduction in left cingulate gyrus isthmus correlated with clinical scores on anxiety and depression, which is a prominent symptom of PCS. Similarly, electrophysiology studies have also provided evidence for this. Electroencephalographic (EEG) studies [55] have shown altered frontal-alpha asymmetry and beta asymmetry in patients who self-reported depression/anxiety and anger post-mTBI respectively. A magneto-encephalography study [56] has reported high accuracy in identifying patients with mTBI, with a much higher reliability for blast injuries. More research is warranted to identify imaging biomarkers that can

diagnose mTBI, the different PCS sub-types, as well as their recovery.

**5. Autonomic nervous system (ANS) dysfunction and PCS**

drive may interfere with the onset and maintenance of sleep [67].

The brain needs a constant perfusion pressure, i.e., the supply of blood and nutrients, irrespective of changes in cerebral blood flow (CBF) or systemic blood pressure. Increases or decreases in CBF are detected by a series of receptors which provide local and systemic responses [68]. Local responses include constriction

**6. Cerebral blood flow and PCS**

The Autonomic Nervous System (ANS) control centers are located in the brainstem and can be damaged when rotational forces are applied to the upper cervical spine [57]. This damage has been confirmed in a recent DTI study [58] in patients with PCS, with PCS patient displaying a significantly higher percent high and low voxels upon follow up scan. The ANS dysfunction could be due to damage to these centers are/or due to uncoupling of these centers and cardiovascular system [8, 59]. This may cause reduced heart rate variability, a measure of sympathovagal reactivity. This stunted reactivity has been documented at rest and during exercise in the acute phase after concussions, as well as several months after [60]. Cardiovascular dysfunction in PCS may manifest as symptoms of orthostatic hypotension, postural orthostatic tachycardia syndrome, and altered heart rate and blood pressure responses at rest and during exercise, all which are common in PCS [31]. Studies have also shown abnormal ANS function, as assessed by heart rate variability metrics, when moving from rest to a state of increased metabolic demand in PCS, and this dysfunction can persist even after the patient is clinically recovered [61]. Patients with acute concussions and PCS have also been found to have higher rates of sympathetic nervous system output than controls, as exemplified by higher resting heart rates [62] and higher heart rates during cognitive [63] and physical exercise [64]. A study done on acutely concussed adults showed a blunted parasympathetic response to stimuli, with concussed athletes showing a stunted mean arterial pressure and first-minute high frequency power rise when compared to controls, as well as altogether lack of significant changes in heart rate upon face cooling [65]. This abnormal sympathovagal imbalance may help explain some of the clinical symptoms of PCS. One example is sleep disturbances in PCS because it involves activation of the parasympathetic drive [66]. This increased sympathetic

#### *Post Concussion Syndrome DOI: http://dx.doi.org/10.5772/intechopen.85432*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

males to perceive their symptoms as resolved [45, 46].

**3. Sex differences**

concussion expert, because of the extensive overlap with symptoms of primary mood disorders. The most recent concussion in sport group (CISG) guidelines recommend a multidisciplinary team approach to treatment that may involve a psychiatrist, a psychologist and/or a neuropsychologist [21]. Other disorders, such as chronic post-traumatic headaches and migraines, are treated in a similar fashion

and should be referred to their corresponding specialist, i.e., a neurologist.

The duration of recovery is suggested to be longer for females with males recovering in an average of 7–10 days where as females recovering in an average of 14 days [21]. Healthy females at baseline are also reported to have higher symptom severity on concussion symptom scales than healthy males [42]. A study [43] suggests that adolescent females were more likely to be diagnosed with PCS due to increased symptom load as well as the duration of symptoms because males returned to being asymptomatic by the fourth week of recovery, missing the PCS diagnostic criteria. Another study suggests the female sex to be a significant predictor of prolonged PCS, which they described as symptoms that lasted for more than 3 months [44]. Interestingly, the same study found this association to be more prominent between the ages of 14 and 56, which is characterized by drastic fluctuations of hormone levels. This calls into question the role of female sex hormones in recovery trajectories and symptom resolution. Some critics have suggested that the above theories overestimate sex effect on PCS, suggesting that the increased relative rates of females entering PCS and experiencing PCS symptoms are more often due to differing societal pressures and perceived stigma experienced by the sexes causing many

A topic of more recent research is the morphological and structural differences in females that could predict PCS. It has been well established by the literature that female athletes, given equal exposure and risk, are more likely to sustain a concussion [47]. The reasoning behind a female's increased vulnerability is still under debate, with decreased neck girth and differences in play style all seeming to play a role [48, 49]. A recently [50] identified difference in female brains is decreased axon size and density. This decreased axon size complimented with an increased density of axonal fibers could predispose females to having more severe consequences than males when given the same impact. More research in the cellular differences between

males and females could address the differences observed in PCS incidence.

Currently, the ICD-10 states that no advanced imaging methods can diagnose a concussion [21], but some studies have shown that certain types of PCS have observable differences from each other on advanced imaging. PCS patients with neuropsychiatric complains have significant differences than PCS patients without them. Diffusion tensor imaging (DTI) studies [51] have shown decreased fractional anisotropy (FA) in the superior longitudinal fasciculus, vermis, and white matter around the nucleus accumbens and anterior limb of the internal capsule which correlates to symptoms of depression and anxiety. A larger meta-analysis [52] showed patients who had predominantly cognitive/affective symptoms 1 month post-mTBI had significantly increased FA and reduced mean diffusivity (MD) than those with other symptoms. Increased FA indicates faster unidirectional flow within neurons and decreased MD indicates better axonal integrity [53], which is surprising after the

**6**

**4. Imaging**

brain is injured. Another way to interpret these findings is that there is more activity within each neuron, which is more consistent with the hypothesized post-mTBI hyper-metabolic state described above. Long-term changes have also been shown to occur after mTBI and PCS. A study [54] that longitudinally assessed regional brain volumes at 1 month post-injury and again at 1 year post-injury. They found significant reductions in the anterior cingulate white matter, left cingulate gyrus isthmus white matter, and right precuneal gray matter. The reduction in left cingulate gyrus isthmus correlated with clinical scores on anxiety and depression, which is a prominent symptom of PCS. Similarly, electrophysiology studies have also provided evidence for this. Electroencephalographic (EEG) studies [55] have shown altered frontal-alpha asymmetry and beta asymmetry in patients who self-reported depression/anxiety and anger post-mTBI respectively. A magneto-encephalography study [56] has reported high accuracy in identifying patients with mTBI, with a much higher reliability for blast injuries. More research is warranted to identify imaging biomarkers that can diagnose mTBI, the different PCS sub-types, as well as their recovery.

#### **5. Autonomic nervous system (ANS) dysfunction and PCS**

The Autonomic Nervous System (ANS) control centers are located in the brainstem and can be damaged when rotational forces are applied to the upper cervical spine [57]. This damage has been confirmed in a recent DTI study [58] in patients with PCS, with PCS patient displaying a significantly higher percent high and low voxels upon follow up scan. The ANS dysfunction could be due to damage to these centers are/or due to uncoupling of these centers and cardiovascular system [8, 59]. This may cause reduced heart rate variability, a measure of sympathovagal reactivity. This stunted reactivity has been documented at rest and during exercise in the acute phase after concussions, as well as several months after [60]. Cardiovascular dysfunction in PCS may manifest as symptoms of orthostatic hypotension, postural orthostatic tachycardia syndrome, and altered heart rate and blood pressure responses at rest and during exercise, all which are common in PCS [31]. Studies have also shown abnormal ANS function, as assessed by heart rate variability metrics, when moving from rest to a state of increased metabolic demand in PCS, and this dysfunction can persist even after the patient is clinically recovered [61].

Patients with acute concussions and PCS have also been found to have higher rates of sympathetic nervous system output than controls, as exemplified by higher resting heart rates [62] and higher heart rates during cognitive [63] and physical exercise [64]. A study done on acutely concussed adults showed a blunted parasympathetic response to stimuli, with concussed athletes showing a stunted mean arterial pressure and first-minute high frequency power rise when compared to controls, as well as altogether lack of significant changes in heart rate upon face cooling [65]. This abnormal sympathovagal imbalance may help explain some of the clinical symptoms of PCS. One example is sleep disturbances in PCS because it involves activation of the parasympathetic drive [66]. This increased sympathetic drive may interfere with the onset and maintenance of sleep [67].

#### **6. Cerebral blood flow and PCS**

The brain needs a constant perfusion pressure, i.e., the supply of blood and nutrients, irrespective of changes in cerebral blood flow (CBF) or systemic blood pressure. Increases or decreases in CBF are detected by a series of receptors which provide local and systemic responses [68]. Local responses include constriction

or dilation of cerebral blood vessels and systemic responses include altering the cardiac contractibility and systemic blood pressure. This protects the brain from changes in sympathetic nerve activity, mean arterial blood pressure, and arterial CO2 levels [69]. Of relevance to physiological PCS, the ANS controls the CBF response to exercise which is suspected to be the cause of symptom exacerbation on physical exertion [70]. Evidence to support this hypothesis includes lower resting global CBF detected beyond symptom recovery using MR-angiography, with 64% of sport-related concussion patients showing CBF improvements within 30 days [71, 72], and regional alterations in resting CBF in patients with PCS [73–75]. Taken together, there is an abundance of evidence that cerebral autoregulation is impaired in PCS, a likely explanation for many physiological PCS symptoms.

Functional magnetic resonance imaging (fMRI) have also been used to assess patients with concussion and PCS. fMRI can assess task-evoked blood-oxygenlevel-dependent (BOLD) responses either during resting state or during cognitive tasks [76]. PCS patients have cognitive intolerance so it logical to assess for differences in activation/inactivation during cognitive tasks. Changes in regional deoxyhemoglobin concentrations can also been assessed using functional near-infrared spectroscopy (fNIRS) [77]. Abnormal CBF regulation should lead to differences in BOLD responses in the PCS brain so research is currently being done to find objective biomarkers for PCS. Unfortunately, the literature is not decisive [78]. Studies have shown decreased BOLD activity in thalamus and hypothalamus as well as frontal/temporal regions but increased functional connectivity in certain brain circuits including enhanced thalami-cortical functional connectivity based on resting-state BOLD responses in TBI patients in comparison to healthy controls. There could be several reasons for these differences, it could be due to the multiple sub-types of PCS, some causing an increases response whereas other causing a decreased response, or due to the time since injury with acute cases showing more activation due to neuro-metabolic activity and chronic cases showing decreased activity. More research is warranted to understand the pathophysiology of CBF autoregulation disturbances in PCS.

#### **7. Intra-cranial pressure (ICP) and PCS**

Intra-cranial pressure (ICP) is the pressure of the cerebrospinal fluid in the subarachnoid space and is between 7 and 15 mmHg in a healthy supine adult and -10 mmHg in the standing position [79]. Since the brain is inside a stiff skull with fixed volume, an increase in ICP could lead to impaired CBF and is an important cause of secondary insult due to ischemia [80, 81]. ICP can be measured using direct and indirect methods. Direct methods, such as intraventricular catheter, are invasive, have high risk of complications and are not justified for mTBI [82]. Indirect methods, like ultrasonographic or ophthalmological, are noninvasive but have a downside of being less sensitive and less reliable [83]. Increased ICP has already been documented in moderate and severe traumatic brain injury (TBI) and their treatment includes monitoring and normalization of the ICP. Due to the mild nature of mTBI, directly measured ICP has not been studied in much detail in this population but there is one systematic review that suggests a prolonged increase in ICP after an mTBI and recommends further research [84]. One particular study [85] of interest used intravenous hypertonic 3% saline on acutely concussed patients. Hypertonic saline is a commonly used pharmacotherapy for treatment of increased ICP and its efficacy has been documented in moderate to severe forms of TBI [81, 86–89]. The study showed a significant decrease in concussion-specific symptoms after an infusion of hypertonic saline but did not measure ICP, hence the

**9**

*Post Concussion Syndrome*

**8. Neuroinflammation**

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

the extent of BBB breach being 0.9mm3

appropriate for mTBI.

**9. Treatment of PCS**

ICP response to hypertonic saline is an assumption. More research needs to be done

Neuroinflammation is the inflammation of nervous tissue and is present in several pathological conditions such as infection, injury, autoimmunity, toxicity and aging [90]. The central nervous system (CNS) has its own native cells, the microglia and astrocytes, capable of initiating the inflammatory response [91–93]. While neuroinflammation is recognized to promote protective and regenerative effects by activating alternative pathways, persistent neuroinflammation is considered detrimental in several diseases and is an area of interest in several neurodegenerative diseases [94]. Among the several inflammatory mediators released after TBI, some of the most researched include tumor necrosis factor-α (TNFα) [95] and interleukin-1β [96]. TNFα has been shown to be produced early after experimental mTBI, generally returning to baseline levels within 24 hours of injury. Mice with dysfunctional TNFα systems have prolonged recovery (2–3 weeks versus >4 weeks), increased cell damage, and increased blood brain barrier permeability (BBB) with

after TBI [97, 98]. However, the literature on TNFα role in mTBI is controversial. Older studies have shown that inhibition of TNFα after mTBI in animal models can be beneficial by improving neurological outcome, motor function recovery, and decreasing edema size [99, 100]. However, a newer study has shown that TNFα knockout mice performed poorly when compared to wild type mice after concussive brain injury [101]. The authors of that study also concluded that TNFα inhibition influence cognitive deficits independent of mTBI so these therapies are not

Treatment of concussion and PCS has changed significantly over that past decade. The previous standard of care used to be complete physical and cognitive rest with a high degree of social isolation until symptoms resolve [102]. This "rest is best" model of care was supported by evidence that showed that the brain is vulnerable immediately after a concussion with cognitive or physical stress [12] and excessing physical activity [103, 104] would prolong the recovery. Forced aerobic exercise imposed upon rodents within 2 weeks of fluid percussion-simulated concussion was shown to be detrimental to recovery of cognitive function. However, exercise administered three or more weeks after injury in rodents was beneficial to both. A recent randomized controlled trial in humans compared prolonged rest to a short period of rest followed by a step-wise return to activity and found that the strict rest group reported more daily symptoms and a prolonged duration of recovery [105]. Another observational study suggests that moderate levels of physical activity, specifically aerobic exercise, within the first week after injury reduces the incidence of PCS in children and adolescents [15]. This growing body of evidence has changed the management of concussions and PCS and the most recent CISG guidelines [21] recommend a short period of rest (24–48 hours) post-injury, followed by a graded return to sub-threshold activity. There have been more studies [106] that have shown the benefits of early sub-threshold aerobic activity in concussion and PCS since guideline came out. A recent randomized controlled trial [107] of over a hundred acutely concussed adolescents showed a significant reduction in

greater in TNFα receptor lacking mice

in PCS to investigate this possible alternate method of treatment.

ICP response to hypertonic saline is an assumption. More research needs to be done in PCS to investigate this possible alternate method of treatment.

### **8. Neuroinflammation**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

or dilation of cerebral blood vessels and systemic responses include altering the cardiac contractibility and systemic blood pressure. This protects the brain from changes in sympathetic nerve activity, mean arterial blood pressure, and arterial CO2 levels [69]. Of relevance to physiological PCS, the ANS controls the CBF response to exercise which is suspected to be the cause of symptom exacerbation on physical exertion [70]. Evidence to support this hypothesis includes lower resting global CBF detected beyond symptom recovery using MR-angiography, with 64% of sport-related concussion patients showing CBF improvements within 30 days [71, 72], and regional alterations in resting CBF in patients with PCS [73–75]. Taken together, there is an abundance of evidence that cerebral autoregulation is impaired

Functional magnetic resonance imaging (fMRI) have also been used to assess patients with concussion and PCS. fMRI can assess task-evoked blood-oxygenlevel-dependent (BOLD) responses either during resting state or during cognitive tasks [76]. PCS patients have cognitive intolerance so it logical to assess for differences in activation/inactivation during cognitive tasks. Changes in regional deoxyhemoglobin concentrations can also been assessed using functional near-infrared spectroscopy (fNIRS) [77]. Abnormal CBF regulation should lead to differences in BOLD responses in the PCS brain so research is currently being done to find objective biomarkers for PCS. Unfortunately, the literature is not decisive [78]. Studies have shown decreased BOLD activity in thalamus and hypothalamus as well as frontal/temporal regions but increased functional connectivity in certain brain circuits including enhanced thalami-cortical functional connectivity based on resting-state BOLD responses in TBI patients in comparison to healthy controls. There could be several reasons for these differences, it could be due to the multiple sub-types of PCS, some causing an increases response whereas other causing a decreased response, or due to the time since injury with acute cases showing more activation due to neuro-metabolic activity and chronic cases showing decreased activity. More research is warranted to understand the pathophysiology of CBF autoregulation

Intra-cranial pressure (ICP) is the pressure of the cerebrospinal fluid in the subarachnoid space and is between 7 and 15 mmHg in a healthy supine adult and -10 mmHg in the standing position [79]. Since the brain is inside a stiff skull with fixed volume, an increase in ICP could lead to impaired CBF and is an important cause of secondary insult due to ischemia [80, 81]. ICP can be measured using direct and indirect methods. Direct methods, such as intraventricular catheter, are invasive, have high risk of complications and are not justified for mTBI [82]. Indirect methods, like ultrasonographic or ophthalmological, are noninvasive but have a downside of being less sensitive and less reliable [83]. Increased ICP has already been documented in moderate and severe traumatic brain injury (TBI) and their treatment includes monitoring and normalization of the ICP. Due to the mild nature of mTBI, directly measured ICP has not been studied in much detail in this population but there is one systematic review that suggests a prolonged increase in ICP after an mTBI and recommends further research [84]. One particular study [85] of interest used intravenous hypertonic 3% saline on acutely concussed patients. Hypertonic saline is a commonly used pharmacotherapy for treatment of increased ICP and its efficacy has been documented in moderate to severe forms of TBI [81, 86–89]. The study showed a significant decrease in concussion-specific symptoms after an infusion of hypertonic saline but did not measure ICP, hence the

in PCS, a likely explanation for many physiological PCS symptoms.

**8**

disturbances in PCS.

**7. Intra-cranial pressure (ICP) and PCS**

Neuroinflammation is the inflammation of nervous tissue and is present in several pathological conditions such as infection, injury, autoimmunity, toxicity and aging [90]. The central nervous system (CNS) has its own native cells, the microglia and astrocytes, capable of initiating the inflammatory response [91–93]. While neuroinflammation is recognized to promote protective and regenerative effects by activating alternative pathways, persistent neuroinflammation is considered detrimental in several diseases and is an area of interest in several neurodegenerative diseases [94]. Among the several inflammatory mediators released after TBI, some of the most researched include tumor necrosis factor-α (TNFα) [95] and interleukin-1β [96]. TNFα has been shown to be produced early after experimental mTBI, generally returning to baseline levels within 24 hours of injury. Mice with dysfunctional TNFα systems have prolonged recovery (2–3 weeks versus >4 weeks), increased cell damage, and increased blood brain barrier permeability (BBB) with the extent of BBB breach being 0.9mm3 greater in TNFα receptor lacking mice after TBI [97, 98]. However, the literature on TNFα role in mTBI is controversial. Older studies have shown that inhibition of TNFα after mTBI in animal models can be beneficial by improving neurological outcome, motor function recovery, and decreasing edema size [99, 100]. However, a newer study has shown that TNFα knockout mice performed poorly when compared to wild type mice after concussive brain injury [101]. The authors of that study also concluded that TNFα inhibition influence cognitive deficits independent of mTBI so these therapies are not appropriate for mTBI.

#### **9. Treatment of PCS**

Treatment of concussion and PCS has changed significantly over that past decade. The previous standard of care used to be complete physical and cognitive rest with a high degree of social isolation until symptoms resolve [102]. This "rest is best" model of care was supported by evidence that showed that the brain is vulnerable immediately after a concussion with cognitive or physical stress [12] and excessing physical activity [103, 104] would prolong the recovery. Forced aerobic exercise imposed upon rodents within 2 weeks of fluid percussion-simulated concussion was shown to be detrimental to recovery of cognitive function. However, exercise administered three or more weeks after injury in rodents was beneficial to both. A recent randomized controlled trial in humans compared prolonged rest to a short period of rest followed by a step-wise return to activity and found that the strict rest group reported more daily symptoms and a prolonged duration of recovery [105]. Another observational study suggests that moderate levels of physical activity, specifically aerobic exercise, within the first week after injury reduces the incidence of PCS in children and adolescents [15]. This growing body of evidence has changed the management of concussions and PCS and the most recent CISG guidelines [21] recommend a short period of rest (24–48 hours) post-injury, followed by a graded return to sub-threshold activity. There have been more studies [106] that have shown the benefits of early sub-threshold aerobic activity in concussion and PCS since guideline came out. A recent randomized controlled trial [107] of over a hundred acutely concussed adolescents showed a significant reduction in

recovery time from a median of 17 days in the placebo group to a median of 13 days in the aerobic exercise group (p = 0.006). This study is a turning point and will affect the approach to concussion treatment worldwide [108].

There are several theories why light to moderate levels of exercise can improve recovery from PCS. The neurocognitive benefits of exercise, such as attenuation of cognitive impairment and reduction of dementia risk in humans, have been known for years [109]. The proposed mechanism of brain health is due to the action of factors that promote neuron growth and repair. Brain derived neurotrophic factor (BDNF) is one of these factors that increase hippocampal volume and improves spatial memory [110]. BDNF levels have been shown to increase after exercise in animals [109] which has provided pre-clinical support for the observation that patients with PPCS recover much faster with sub-threshold aerobic exercise treatment [29]. In humans, studies have shown that exercise increases BDNF level as early as 5–6 weeks after initiation of aerobic training, which has a positive influence on brain neuroplasticity [111, 112]. In regards of CBF regulation, physical deconditioning from prolonged rest has been shown to impair CBF regulation [113], which is already impaired in PCS as discussed above, whereas exercise has been shown to be beneficial in improving CBF regulation [114]. The rapidity of the beneficial effect of exercise on neuroplasticity suggests improved neuronal function rather than reduced cerebrovascular disease risk being the cause for increased brain health and function. An interesting finding is that not all light to moderate exercise causes an increase in BDNF. Rats who were "forced" to exercise after concussion did not increase BDNF levels and showed an increase in stress hormone levels, which was not seen in rats who exercised voluntarily [115, 116]. This emphasizes the benefits of voluntary, sub-symptom threshold exercise during PCS.

Currently, there are no pharmacological therapies that are recommended for PCS [117]. Several pharmacological therapies have been researched but there is not enough empirical evidence to suggest their efficacy. A randomized controlled trial [118] studied the effects of the anti-Parkinson drug, amantadine, in adolescents with PCS and found that it significantly improved symptomology and cognitive function (as assessed by a computerized neurocognitive test). However, more evidence is needed to recommend these therapies. Psychostimulants such as methylphenidate and amphetamines, have been considered as pharmacological therapies for cognitive dysfunction after PCS [117]. This is based on studies that have proven their efficacy in moderate and severe forms of TBI [119–121]. Research is required on patients with mTBI before it can be recommended for PCS.

#### **10. Long-term sequelae**

There has been an increase in the awareness of long-term consequences of repetitive concussions and PCS since the discovery of chronic traumatic encephalopathy (CTE) in a retired American football player in 2005 [122]. CTE is a neurodegenerative disorder characterized by significant emotional disturbances, cognitive decline, and deposition of Tau proteins in the brain [123]. The Tau proteinopathy seen in CTE is different from the Tau proteinopathy seen in Alzheimer's disease because it is found widespread in the frontal and temporal lobes [124], as opposed to localization in the limbic system in Alzheimer's. There is no uncertainty that CTE is caused by repetitive head injuries, and has been described as early at 1928 in boxers [125], and the increased awareness of long-term consequences of repetitive head injuries, concussive or sub-concussive, have made it a popular topic in the media and research. The National Institutes of Health held a consensus meeting in 2016 with the aim of defining the neuropathological criteria for CTE diagnosis [126].

**11**

*Post Concussion Syndrome*

**11. Conclusion**

as therapies for PCS.

**Acknowledgements**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

agreement and improved specificity to the diagnosis of CTE.

They blindly evaluated 25 cases of various tau proteinopathies, including CTE and a number of dementing brain diseases, and the results demonstrated reasonably good

There is some controversy in the incidence rate of CTE and if the presence of tau protein represents trauma-induced CTE versus normal deposits as a result of age and other life factors [127]. Some researchers suggest a very high incidence of CTE in anyone who participated in a contact sport, with rates as high as 75–99% [124, 128]. All of these studies have been done by post-mortem analysis of brain tissue, which is currently the only way to definitely diagnose CTE [129]. However, several studies have been performed since 2017 which have brought uncertainty to the clinical manifestations and incidence of CTE, i.e., the patterns of behavior and cognitive deficits experienced by the living individual affected by CTE. Retired contact-sport athletes have be shown to have no differences in cognition [130, 131], mild cognitive impairment [132], executive function [133], or structural or functional brain differences [134]. This suggests that although Tau proteins may deposit in the brain after headinjuries, they do not causes significant decrease in function unless it is very severe.

PCS is a complex disorder and its pathophysiology is not clearly understood. There are no symptoms, or group of symptoms, that can accurately diagnose PCS. Females may be at a higher risk of developing PCS than male. Although there are no advanced imaging biomarkers for PCS, some studies present differences in those patients who predominantly complain of mood-related or cognitive symptoms when compared with other sub-types of PCS. Longitudinal changes in the brain have been identified in PCS up to 1 year since concussive head injury. ANS dysfunction is observed in PCS, which could be due to damage to the ANS control centers located in the hindbrain or uncoupling of the connections between the central ANS and cardiovascular system. Abnormal cardiovascular metrics suggest ANS dysfunction and impaired CBF regulation, which may explain the characteristic finding of symptom-limited exercise intolerance in physiological PCS. Functional imaging, like fMRI, has shown differences between healthy people and patients with PCS, but these differences are not consistent in the literature. Long term consequences of PCS or repetitive concussions include CTE, but the clinical manifestations of CTE need to be studied in greater detail. Therapies for PCS include sub-threshold aerobic exercise, which may increase neuroplasticity and decrease neuroinflammation through release of BDNF. More research needs to be done to identify objective biomarkers of concussion, PCS, and recovery, as well

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number 1R01NS094444. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The author does not declare any conflicts of interest.

#### *Post Concussion Syndrome DOI: http://dx.doi.org/10.5772/intechopen.85432*

They blindly evaluated 25 cases of various tau proteinopathies, including CTE and a number of dementing brain diseases, and the results demonstrated reasonably good agreement and improved specificity to the diagnosis of CTE.

There is some controversy in the incidence rate of CTE and if the presence of tau protein represents trauma-induced CTE versus normal deposits as a result of age and other life factors [127]. Some researchers suggest a very high incidence of CTE in anyone who participated in a contact sport, with rates as high as 75–99% [124, 128]. All of these studies have been done by post-mortem analysis of brain tissue, which is currently the only way to definitely diagnose CTE [129]. However, several studies have been performed since 2017 which have brought uncertainty to the clinical manifestations and incidence of CTE, i.e., the patterns of behavior and cognitive deficits experienced by the living individual affected by CTE. Retired contact-sport athletes have be shown to have no differences in cognition [130, 131], mild cognitive impairment [132], executive function [133], or structural or functional brain differences [134]. This suggests that although Tau proteins may deposit in the brain after headinjuries, they do not causes significant decrease in function unless it is very severe.

#### **11. Conclusion**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

affect the approach to concussion treatment worldwide [108].

benefits of voluntary, sub-symptom threshold exercise during PCS.

on patients with mTBI before it can be recommended for PCS.

**10. Long-term sequelae**

Currently, there are no pharmacological therapies that are recommended for PCS [117]. Several pharmacological therapies have been researched but there is not enough empirical evidence to suggest their efficacy. A randomized controlled trial [118] studied the effects of the anti-Parkinson drug, amantadine, in adolescents with PCS and found that it significantly improved symptomology and cognitive function (as assessed by a computerized neurocognitive test). However, more evidence is needed to recommend these therapies. Psychostimulants such as methylphenidate and amphetamines, have been considered as pharmacological therapies for cognitive dysfunction after PCS [117]. This is based on studies that have proven their efficacy in moderate and severe forms of TBI [119–121]. Research is required

There has been an increase in the awareness of long-term consequences of repetitive concussions and PCS since the discovery of chronic traumatic encephalopathy (CTE) in a retired American football player in 2005 [122]. CTE is a neurodegenerative disorder characterized by significant emotional disturbances, cognitive decline, and deposition of Tau proteins in the brain [123]. The Tau proteinopathy seen in CTE is different from the Tau proteinopathy seen in Alzheimer's disease because it is found widespread in the frontal and temporal lobes [124], as opposed to localization in the limbic system in Alzheimer's. There is no uncertainty that CTE is caused by repetitive head injuries, and has been described as early at 1928 in boxers [125], and the increased awareness of long-term consequences of repetitive head injuries, concussive or sub-concussive, have made it a popular topic in the media and research. The National Institutes of Health held a consensus meeting in 2016 with the aim of defining the neuropathological criteria for CTE diagnosis [126].

recovery time from a median of 17 days in the placebo group to a median of 13 days in the aerobic exercise group (p = 0.006). This study is a turning point and will

There are several theories why light to moderate levels of exercise can improve recovery from PCS. The neurocognitive benefits of exercise, such as attenuation of cognitive impairment and reduction of dementia risk in humans, have been known for years [109]. The proposed mechanism of brain health is due to the action of factors that promote neuron growth and repair. Brain derived neurotrophic factor (BDNF) is one of these factors that increase hippocampal volume and improves spatial memory [110]. BDNF levels have been shown to increase after exercise in animals [109] which has provided pre-clinical support for the observation that patients with PPCS recover much faster with sub-threshold aerobic exercise treatment [29]. In humans, studies have shown that exercise increases BDNF level as early as 5–6 weeks after initiation of aerobic training, which has a positive influence on brain neuroplasticity [111, 112]. In regards of CBF regulation, physical deconditioning from prolonged rest has been shown to impair CBF regulation [113], which is already impaired in PCS as discussed above, whereas exercise has been shown to be beneficial in improving CBF regulation [114]. The rapidity of the beneficial effect of exercise on neuroplasticity suggests improved neuronal function rather than reduced cerebrovascular disease risk being the cause for increased brain health and function. An interesting finding is that not all light to moderate exercise causes an increase in BDNF. Rats who were "forced" to exercise after concussion did not increase BDNF levels and showed an increase in stress hormone levels, which was not seen in rats who exercised voluntarily [115, 116]. This emphasizes the

**10**

PCS is a complex disorder and its pathophysiology is not clearly understood. There are no symptoms, or group of symptoms, that can accurately diagnose PCS. Females may be at a higher risk of developing PCS than male. Although there are no advanced imaging biomarkers for PCS, some studies present differences in those patients who predominantly complain of mood-related or cognitive symptoms when compared with other sub-types of PCS. Longitudinal changes in the brain have been identified in PCS up to 1 year since concussive head injury. ANS dysfunction is observed in PCS, which could be due to damage to the ANS control centers located in the hindbrain or uncoupling of the connections between the central ANS and cardiovascular system. Abnormal cardiovascular metrics suggest ANS dysfunction and impaired CBF regulation, which may explain the characteristic finding of symptom-limited exercise intolerance in physiological PCS. Functional imaging, like fMRI, has shown differences between healthy people and patients with PCS, but these differences are not consistent in the literature. Long term consequences of PCS or repetitive concussions include CTE, but the clinical manifestations of CTE need to be studied in greater detail. Therapies for PCS include sub-threshold aerobic exercise, which may increase neuroplasticity and decrease neuroinflammation through release of BDNF. More research needs to be done to identify objective biomarkers of concussion, PCS, and recovery, as well as therapies for PCS.

#### **Acknowledgements**

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number 1R01NS094444. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

#### **Conflict of interest**

The author does not declare any conflicts of interest.

### **Author details**

Mohammad Nadir Haider1 \* and Itai Bezherano2

1 Department of Orthopedics and Sports Medicine, Concussion Management Clinic and Research Center, State University of New York at Buffalo, Buffalo, NY, USA

2 Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY, USA

\*Address all correspondence to: haider@buffalo.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**13**

*Post Concussion Syndrome*

2011;**3**(10):S359-S368

Reports. 2016;**20**(6):42

2004;**36**(0):28-60

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

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of concussion and subconcussion: Where we are and where we are going. Neurosurgical Focus.

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2015;**45**(6):893-903

2016;**316**(23):2504-2514

2010;**9**(1):21-26

2011;**24**(3):243-250

[16] Jotwani V, Harmon KG.

Postconcussion syndrome in athletes. Current Sports Medicine Reports.

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[18] Tator CH, Davis HS, Dufort PA, et al. Postconcussion syndrome: Demographics and predictors in 221

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[2] Choe MC. The pathophysiology of concussion. Current Pain and Headache

[3] Anderson T, Heitger M, Macleod A. Concussion and mild head injury. Practical Neurology. 2006;**6**(6):342-357

[4] Cassidy JD, Carroll L, Peloso P, et al. Incidence, risk factors and prevention of mild traumatic brain injury: Results of the WHO collaborating centre task force on mild traumatic brain injury. Journal Rehabilitation Medicine.

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receptor agonist, exendin-4. Alzheimer's

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### **References**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

1 Department of Orthopedics and Sports Medicine, Concussion Management Clinic and Research Center, State University of New York at Buffalo, Buffalo, NY, USA

2 Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY, USA

\* and Itai Bezherano2

**12**

**Author details**

Mohammad Nadir Haider1

provided the original work is properly cited.

\*Address all correspondence to: haider@buffalo.edu

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[3] Anderson T, Heitger M, Macleod A. Concussion and mild head injury. Practical Neurology. 2006;**6**(6):342-357

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[6] Conder RL, Conder AA. Sportsrelated concussions. North Carolina Medical Journal. 2015;**76**(2):89-95

[7] Tweedie D, Rachmany L, Rubovitch V, et al. Blast traumatic brain injuryinduced cognitive deficits are attenuated by preinjury or postinjury treatment with the glucagon-like peptide-1 receptor agonist, exendin-4. Alzheimer's & Dementia. 2016;**12**(1):34-48

[8] Len T, Neary J. Cerebrovascular pathophysiology following mild traumatic brain injury. Clinical Physiology and Functional Imaging. 2011;**31**(2):85-93

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[10] Dashnaw ML, Petraglia AL, Bailes JE. An overview of the basic science

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[12] Giza CC, Hovda DA. The new neurometabolic cascade of concussion. Neurosurgery. 2014;**75**(suppl\_4):S24-S33

[13] Hill CS, Coleman MP, Menon DK. Traumatic axonal injury: Mechanisms and translational opportunities. Trends in Neurosciences. 2016;**39**(5):311-324

[14] Williams RM, Puetz TW, Giza CC, Broglio SP. Concussion recovery time among high school and collegiate athletes: A systematic review and meta-analysis. Sports Medicine. 2015;**45**(6):893-903

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*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

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**18**

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[100] Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. Cytokine production in the brain following closed head injury: Dexanabinol (HU-211) is a novel TNF-α inhibitor and an effective neuroprotectant. Journal of Neuroimmunology. 1997;**72**(2):169-177

[101] Khuman J, Meehan IIIWP, Zhu X, et al. Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice. Journal of Cerebral Blood Flow and Metabolism. 2011;**31**(2):778-789

[102] McCrory P, Meeuwisse WH, Aubry M, et al. Consensus statement on concussion in sport: The 4th international conference on concussion in sport held in Zurich, November 2012. British Journal of Sports Medicine. 2013;**47**(5):250-258

[103] Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F. Voluntary exercise following traumatic brain injury: Brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience. 2004;**125**(1):129-139

[104] Majerske CW, Mihalik JP, Ren D, et al. Concussion in sports: Postconcussive activity levels, symptoms, and neurocognitive performance. Journal of Athletic Training. 2008;**43**(3):265-274

[105] Thomas DG, Apps JN, Hoffmann RG, McCrea M, Hammeke T. Benefits of strict rest after acute concussion: A randomized controlled trial. Pediatrics. 2015;**135**(2):213-223

[106] Leddy JJ, Haider MN, Hinds AL, Darling S, Willer BSA. Preliminary study of the effect of early aerobic exercise treatment for sport-related concussion in males. Clinical Journal of Sport Medicine. 2018; Published Online

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[108] Chrisman SP. Exercise and recovery time for youth with concussions. Journal of the American Medical Association Pediatrics. 2019

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[114] Tan CO, Meehan WP 3rd, Iverson GL, Taylor JA. Cerebrovascular regulation, exercise, and mild traumatic brain injury. Neurology. 2014;**83**(18):1665-1672

[115] Griesbach GS, Tio DL, Nair S, Hovda DA. Recovery of stress response coincides with responsiveness to voluntary exercise after traumatic brain injury. Journal of Neurotrauma. 2014;**31**(7):674-682

[116] Griesbach GS, Tio DL, Vincelli J, McArthur DL, Taylor AN. Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury. Journal of Neurotrauma. 2012;**29**(7):1426-1433

[117] Meehan WP. Medical therapies for concussion. Clinics in Sports Medicine. 2011;**30**(1):115-124

[118] Reddy CC, Collins M, Lovell M, Kontos AP. Efficacy of amantadine treatment on symptoms and neurocognitive performance among adolescents following sports-related concussion. The Journal of head trauma rehabilitation. 2013;**28**(4):260-265

[119] Williams SE, Ris MD, Ayyangar R, Schefft B, Berch D. Recovery in pediatric brain injury: Is psychostimulant medication beneficial? The Journal of Head Trauma Rehabilitation. 1998;**13**(3):73-81

[120] Plenger PM, Dixon CE, Castillo RM, Frankowski RF, Yablon SA, Levin HS. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebocontrolled study. Archives of Physical Medicine and Rehabilitation. 1996;**77**(6):536-540

[121] Pangilinan PH, Giacoletti-Argento A, Shellhaas R, Hurvitz EA, Hornyak JE. Neuropharmacology in pediatric brain injury: A review. PM & R: The

Journal of Injury, Function, and Rehabilitation. 2010;**2**(12):1127-1140

[122] Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a national football league player. Neurosurgery. 2005;**57**(1):128-134

[123] Armstrong RA, McKee AC, Alvarez VE, Cairns NJ. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy. Journal of Neural Transmission. 2017;**124**(2):185-192

[124] McKee AC, Stein TD, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain: A Journal of Neurology. 2013;**136**(1):43-64

[125] Martland HS. Punch drunk. Journal of the American Medical Association. 1928;**91**(15):1103-1107

[126] McKee AC, Cairns NJ, Dickson DW, et al. The first NINDS/ NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathologica. 2016;**131**(1):75-86

[127] Davis GA, Castellani RJ, McCrory P. Neurodegeneration and sport. Neurosurgery. 2015;**76**(6):643-655; discussion 655-646

[128] Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. Journal of the American Medical Association. 2017;**318**(4):360-370

[129] Riley DO, Robbins CA, Cantu RC, Stern RA. Chronic traumatic encephalopathy: Contributions from the Boston University Center for the study of traumatic encephalopathy. Brain Injury. 2015;**29**(2):154-163

[130] Esopenko C, Chow TW, Tartaglia MC, et al. Cognitive and psychosocial

**21**

*Post Concussion Syndrome*

jnnp-2016-315260

2017;**88**(6):505-511

2018;**33**(5):E16-E23

2018;**33**(5):E9-E15

2018;**33**(5):E24-E32

*DOI: http://dx.doi.org/10.5772/intechopen.85432*

function in retired professional hockey players. Journal of Neurology, Neurosurgery, and Psychiatry. 2017;**88**:512-519. DOI: 10.1136/

[131] McMillan TM, McSkimming P, Wainman-Lefley J, et al. Long-term health outcomes after exposure to repeated concussion in elite level: Rugby union players. Journal of Neurology, Neurosurgery, and Psychiatry.

[132] Baker JG, Leddy JJ, Hinds AL, et al. An exploratory study of mild cognitive impairment of retired

professional contact sport athletes. The Journal of Head Trauma Rehabilitation.

[133] Willer BS, Tiso MR, Haider MN,

function and mental health in retired contact sport athletes. The Journal of Head Trauma Rehabilitation.

[134] Zivadinov R, Polak P, Schweser F, et al. Multimodal imaging of retired professional contact sport athletes does not provide evidence of structural and functional brain damage. The Journal of Head Trauma Rehabilitation.

et al. Evaluation of executive

*Post Concussion Syndrome DOI: http://dx.doi.org/10.5772/intechopen.85432*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

Journal of Injury, Function, and Rehabilitation. 2010;**2**(12):1127-1140

[123] Armstrong RA, McKee AC, Alvarez VE, Cairns NJ. Clustering of tau-immunoreactive pathology in chronic traumatic encephalopathy. Journal of Neural Transmission.

[124] McKee AC, Stein TD, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain: A Journal of Neurology. 2013;**136**(1):43-64

[125] Martland HS. Punch drunk. Journal of the American Medical Association.

[126] McKee AC, Cairns NJ, Dickson

NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic

encephalopathy. Acta Neuropathologica.

[127] Davis GA, Castellani RJ, McCrory P. Neurodegeneration and sport. Neurosurgery. 2015;**76**(6):643-655;

[128] Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. Journal of the American Medical Association.

[129] Riley DO, Robbins CA, Cantu RC,

encephalopathy: Contributions from the Boston University Center for the study of traumatic encephalopathy. Brain

[130] Esopenko C, Chow TW, Tartaglia MC, et al. Cognitive and psychosocial

Stern RA. Chronic traumatic

Injury. 2015;**29**(2):154-163

2017;**124**(2):185-192

1928;**91**(15):1103-1107

2016;**131**(1):75-86

discussion 655-646

2017;**318**(4):360-370

DW, et al. The first NINDS/

[122] Omalu BI, DeKosky ST, Minster RL, Kamboh MI, Hamilton RL, Wecht CH. Chronic traumatic encephalopathy in a national football league player. Neurosurgery. 2005;**57**(1):128-134

[114] Tan CO, Meehan WP 3rd, Iverson GL, Taylor JA. Cerebrovascular regulation, exercise, and mild traumatic brain injury. Neurology.

[115] Griesbach GS, Tio DL, Nair S, Hovda DA. Recovery of stress response coincides with responsiveness to voluntary exercise after traumatic brain injury. Journal of Neurotrauma.

[116] Griesbach GS, Tio DL, Vincelli J, McArthur DL, Taylor AN. Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury. Journal of Neurotrauma.

[117] Meehan WP. Medical therapies for concussion. Clinics in Sports Medicine.

[118] Reddy CC, Collins M, Lovell M, Kontos AP. Efficacy of amantadine treatment on symptoms and

neurocognitive performance among adolescents following sports-related concussion. The Journal of head trauma rehabilitation. 2013;**28**(4):260-265

[119] Williams SE, Ris MD, Ayyangar R, Schefft B, Berch D. Recovery in pediatric

brain injury: Is psychostimulant medication beneficial? The Journal of Head Trauma Rehabilitation.

[120] Plenger PM, Dixon CE, Castillo RM, Frankowski RF, Yablon SA, Levin HS. Subacute methylphenidate treatment for moderate to moderately severe traumatic brain injury: A preliminary double-blind placebocontrolled study. Archives of Physical

Medicine and Rehabilitation.

[121] Pangilinan PH, Giacoletti-Argento A, Shellhaas R, Hurvitz EA, Hornyak JE. Neuropharmacology in pediatric brain injury: A review. PM & R: The

1996;**77**(6):536-540

1998;**13**(3):73-81

2014;**83**(18):1665-1672

2014;**31**(7):674-682

2012;**29**(7):1426-1433

2011;**30**(1):115-124

**20**

function in retired professional hockey players. Journal of Neurology, Neurosurgery, and Psychiatry. 2017;**88**:512-519. DOI: 10.1136/ jnnp-2016-315260

[131] McMillan TM, McSkimming P, Wainman-Lefley J, et al. Long-term health outcomes after exposure to repeated concussion in elite level: Rugby union players. Journal of Neurology, Neurosurgery, and Psychiatry. 2017;**88**(6):505-511

[132] Baker JG, Leddy JJ, Hinds AL, et al. An exploratory study of mild cognitive impairment of retired professional contact sport athletes. The Journal of Head Trauma Rehabilitation. 2018;**33**(5):E16-E23

[133] Willer BS, Tiso MR, Haider MN, et al. Evaluation of executive function and mental health in retired contact sport athletes. The Journal of Head Trauma Rehabilitation. 2018;**33**(5):E9-E15

[134] Zivadinov R, Polak P, Schweser F, et al. Multimodal imaging of retired professional contact sport athletes does not provide evidence of structural and functional brain damage. The Journal of Head Trauma Rehabilitation. 2018;**33**(5):E24-E32

**23**

**Chapter 2**

and Sleep

*and Luz Navarro*

**Abstract**

**1. Introduction**

*Marina Martinez-Vargas,* 

GABAergyc, and glutamatergic systems.

*Mercedes Graciela Porras-Villalobos,* 

Neuroprotection, Photoperiod,

*Francisco Estrada-Rojo, Ricardo Jesus Martinez-Tapia,* 

After an acquired brain injury, responses that induce cell death are activated; however, neuroprotective mechanisms are also activated. The relation between these responses determines the destination of the damaged tissue. This relation presents variations throughout the day; numerous studies have shown that the onset of a stroke occurs preferably in the morning. In the rat, ischemia causes more damage when it is induced during the night. The damage caused by a traumatic brain injury (TBI), in the rat, varies depending on the time of day it is induced. Minor behavioral damage has been reported when the TBI occurs during the night, a period that coincides with the wakefulness of the rat. It also has been observed that sleep deprivation accelerates the recovery. Our group has documented that this is due, in part, to a difference in the degree of activation of cannabinergic,

**Keywords:** circadian rhythm, sleep deprivation, traumatic brain injury, stroke,

Recent research on acquired brain injury, the pathophysiological processes involved, as well as the mechanisms of morphological and functional recovery, have led, among other essential aspects, to the concept of neuroprotection [1]. This term refers to the use of any therapeutic modality that prevents or delays cell death resulting from a neuronal injury. In this sense, neuroprotection could be considered as a cytoprotection technique similar to cardioprotection or vasoprotection [2, 3]. Also, the term neuroprotection has been used to refer to self-protective responses

that the body displays when it undergoes an acquired brain injury and tries to maintain the integrity and functionality of the brain [4]. The management of the term neuroprotection, in this sense, is more recent and emphasizes the balance of the body's responses to an event of ischemia and/or traumatic brain injury (TBI). In a TBI, two types of lesions can be identified. The primary lesion, which corresponds to mechanical damage to the parenchyma or the vasculature, occurs

cannabinergic system, glutamatergic system, GABAergyc system

*Adan Perez-Arredondo, Antonio Barajas-Martinez* 

#### **Chapter 2**

## Neuroprotection, Photoperiod, and Sleep

*Marina Martinez-Vargas, Mercedes Graciela Porras-Villalobos, Francisco Estrada-Rojo, Ricardo Jesus Martinez-Tapia, Adan Perez-Arredondo, Antonio Barajas-Martinez and Luz Navarro*

#### **Abstract**

After an acquired brain injury, responses that induce cell death are activated; however, neuroprotective mechanisms are also activated. The relation between these responses determines the destination of the damaged tissue. This relation presents variations throughout the day; numerous studies have shown that the onset of a stroke occurs preferably in the morning. In the rat, ischemia causes more damage when it is induced during the night. The damage caused by a traumatic brain injury (TBI), in the rat, varies depending on the time of day it is induced. Minor behavioral damage has been reported when the TBI occurs during the night, a period that coincides with the wakefulness of the rat. It also has been observed that sleep deprivation accelerates the recovery. Our group has documented that this is due, in part, to a difference in the degree of activation of cannabinergic, GABAergyc, and glutamatergic systems.

**Keywords:** circadian rhythm, sleep deprivation, traumatic brain injury, stroke, cannabinergic system, glutamatergic system, GABAergyc system

#### **1. Introduction**

Recent research on acquired brain injury, the pathophysiological processes involved, as well as the mechanisms of morphological and functional recovery, have led, among other essential aspects, to the concept of neuroprotection [1]. This term refers to the use of any therapeutic modality that prevents or delays cell death resulting from a neuronal injury. In this sense, neuroprotection could be considered as a cytoprotection technique similar to cardioprotection or vasoprotection [2, 3].

Also, the term neuroprotection has been used to refer to self-protective responses that the body displays when it undergoes an acquired brain injury and tries to maintain the integrity and functionality of the brain [4]. The management of the term neuroprotection, in this sense, is more recent and emphasizes the balance of the body's responses to an event of ischemia and/or traumatic brain injury (TBI).

In a TBI, two types of lesions can be identified. The primary lesion, which corresponds to mechanical damage to the parenchyma or the vasculature, occurs at the moment of impact and is not reversible or curable and the secondary lesion, which corresponds to late effects, which occur hours to days post-trauma, involves a series of functional, structural, cellular, and molecular changes that cause neuronal damage. Among the events that occur, ischemia has been described. When the flow of blood to the brain tissue ceases, the entry of oxygen and nutrients and the exit of potentially toxic metabolites are severely damaged, resulting in biochemical changes in the affected brain area. There is a depletion of glucose and glycogen and failure of Na/K ATPase and other pumps, which result in a decrease in excitation threshold, presence of action potentials, release of excitatory neurotransmitters such as glutamate, massive entry of calcium, and activation of proteases, lipases, and nucleases, among other enzymes [5]. However, as mentioned earlier, neuroprotective responses are also induced; for example, the GABAergic and cannabinergic systems are activated [6, 7]. The balance between both responses will determine the outcome of the damaged tissue [4].

Indeed, the release of glutamate and the activation of its ionotropic receptors are the main events that result in cell death as a consequence of a TBI or cerebral ischemic attack with acute hypoxia [8–10]. The increase in GABAergic synaptic transmission may have neuroprotective effects against cerebral ischemia, and its inhibition increases the alterations induced by this event, while the inhibition of excitatory signals or excitatory neurotransmitters results in the cytoprotection of ischemic brain tissue [6, 11]. GABA mimetic drugs have a protective effect. Thus, administration of GABAA agonists such as benzodiazepines or muscimol attenuates the damage produced by a TBI [12, 13], while bicuculline, a GABAA antagonist, increases it [12].

*In vitro* and *in vivo* data suggest that the cannabinergic system is a component of mammalian neuroprotective mechanisms that an organism displays after suffering an insult such as a TBI [7, 14–17]. Endocannabinoid anandamide and 2-arachidonoylglycerol (2-Ag) increase after an acquired brain injury [14, 15] and serve as signaling mediators in integrating inhibitory and excitatory synaptic transmission, as they could regulate glutamate and GABA release [17]. Besides, recently it has been reported that 2-Ag keeps brain homeostasis by exerting anti-inflammatory effects in response to harmful insults [17].

#### **2. Neuroprotection and photoperiod**

The cerebral ischemic attack, similar to the heart attack, has a marked diurnal rhythm. Numerous studies have shown that the time of onset of cerebral vascular accidents, as well as transient ischemic attacks, occurs preferably between 6:00 and 12:00 h in the morning that is, after the subject gets up and begins to present activity [18–20]. Numerous variables have been mentioned as responsible for this circadian pattern, among which are postural changes, circadian variations of platelet aggregation, thrombolysis, blood pressure, cardiac rhythm, and circulating concentrations of catecholamines, whose maximum levels occur just in this period. In the rat, ischemia causes more significant damage if it is induced in the hours of darkness compared to the hours of light [21].

Our group has analyzed the severity of a TBI concerning the photoperiod. Using the rat as a model, we have found that the recovery from a TBI induced by the technique of "closed head injury" presents diurnal variations, recovery being better if the trauma occurs in the hours of darkness concerning daylight hours [22–24]. In other words, there seems to be a greater neuroprotection response in the hours of darkness. The fact that the functionality of the brain is not the same in the hours of light as in the hours of darkness is not surprising; many pieces of

**25**

**Figure 1.**

*from Refs. [4-7, 23, 24, 31-34, 71-86, 92-95].*

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

evidence indicate the importance of rhythms in general, and in particular of the circadian rhythms in physiology. The presence of circadian rhythms has been explained as an adaptive response of the different organisms to the environmental variables. All species from cyanobacteria to humans have these rhythms that serve to anticipate the daily variations of different variables such as temperature, light, or food intake. It is accepted that virtually any physiological parameter that has been measured for a period of 24 h in humans has fluctuations [25, 26]. Several aspects of brain physiology, neuronal activity, and secretion of neurotransmitters, among others, change throughout the day, in such a way that the cerebral functions present circadian variations, dependent on the time of day, although it should be noted that they also depend on the sleep-wake cycle [27, 28]. Circadian rhythms in mammals are generated by the suprachiasmatic nucleus (SCN) of the hypothalamus, and both GABA and glutamate are intimately related to the function of this nucleus. Indeed, the photic information received by the SCN comes directly from the retina through the hypothalamic retinal tract, which releases glutamate, and indirectly through the hypothalamic geniculate tract that releases GABA and neuropeptide Y [29]; besides,

GABA is one of the main neurotransmitters present in the SCN.

The variability in neuroprotection associated with the photoperiod can be explained by considering that the endogenous levels of practically any endogenous molecule present variations during the different phases of photoperiod. Diurnal variations have been reported in the circulating levels of heat shock proteins (HSPs) [30], as well as brain-derived neurotrophic factor (BDNF) and its receptors in the prefrontal cortex [31], of anandamide in cerebrospinal fluid, pons, hippocampus, and hypothalamus [32]. Our group found diurnal variations in CB1 cannabinoid receptor expression in the hippocampus [33], pons [34] and cerebral cortex [23].

*Mechanisms of neuronal damage, endogenous neuroprotection, and its relationship with photoperiod, sleep deprivation for short periods, and sleep rebound. BDNF: brain-derived neurotrophic factor; CB1: cannabinoid receptor type 1; GABA: gamma-aminobutyric acid; HSP: heat shock proteins; NMDA: N-methyl-d-aspartate receptor; 2-Ag: 2-arachidonoylglycerol; and SWS: slow wave sleep. Data obtained* 

#### *Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

outcome of the damaged tissue [4].

effects in response to harmful insults [17].

**2. Neuroprotection and photoperiod**

darkness compared to the hours of light [21].

increases it [12].

at the moment of impact and is not reversible or curable and the secondary lesion, which corresponds to late effects, which occur hours to days post-trauma, involves a series of functional, structural, cellular, and molecular changes that cause neuronal damage. Among the events that occur, ischemia has been described. When the flow of blood to the brain tissue ceases, the entry of oxygen and nutrients and the exit of potentially toxic metabolites are severely damaged, resulting in biochemical changes in the affected brain area. There is a depletion of glucose and glycogen and failure of Na/K ATPase and other pumps, which result in a decrease in excitation threshold, presence of action potentials, release of excitatory neurotransmitters such as glutamate, massive entry of calcium, and activation of proteases, lipases, and nucleases, among other enzymes [5]. However, as mentioned earlier, neuroprotective responses are also induced; for example, the GABAergic and cannabinergic systems are activated [6, 7]. The balance between both responses will determine the

Indeed, the release of glutamate and the activation of its ionotropic receptors are the main events that result in cell death as a consequence of a TBI or cerebral ischemic attack with acute hypoxia [8–10]. The increase in GABAergic synaptic transmission may have neuroprotective effects against cerebral ischemia, and its inhibition increases the alterations induced by this event, while the inhibition of excitatory signals or excitatory neurotransmitters results in the cytoprotection of ischemic brain tissue [6, 11]. GABA mimetic drugs have a protective effect. Thus, administration of GABAA agonists such as benzodiazepines or muscimol attenuates the damage produced by a TBI [12, 13], while bicuculline, a GABAA antagonist,

*In vitro* and *in vivo* data suggest that the cannabinergic system is a component of mammalian neuroprotective mechanisms that an organism displays after suffering an insult such as a TBI [7, 14–17]. Endocannabinoid anandamide and 2-arachidonoylglycerol (2-Ag) increase after an acquired brain injury [14, 15] and serve as signaling mediators in integrating inhibitory and excitatory synaptic transmission, as they could regulate glutamate and GABA release [17]. Besides, recently it has been reported that 2-Ag keeps brain homeostasis by exerting anti-inflammatory

The cerebral ischemic attack, similar to the heart attack, has a marked diurnal rhythm. Numerous studies have shown that the time of onset of cerebral vascular accidents, as well as transient ischemic attacks, occurs preferably between 6:00 and 12:00 h in the morning that is, after the subject gets up and begins to present activity [18–20]. Numerous variables have been mentioned as responsible for this circadian pattern, among which are postural changes, circadian variations of platelet aggregation, thrombolysis, blood pressure, cardiac rhythm, and circulating concentrations of catecholamines, whose maximum levels occur just in this period. In the rat, ischemia causes more significant damage if it is induced in the hours of

Our group has analyzed the severity of a TBI concerning the photoperiod. Using the rat as a model, we have found that the recovery from a TBI induced by the technique of "closed head injury" presents diurnal variations, recovery being better if the trauma occurs in the hours of darkness concerning daylight hours [22–24]. In other words, there seems to be a greater neuroprotection response in the hours of darkness. The fact that the functionality of the brain is not the same in the hours of light as in the hours of darkness is not surprising; many pieces of

**24**

evidence indicate the importance of rhythms in general, and in particular of the circadian rhythms in physiology. The presence of circadian rhythms has been explained as an adaptive response of the different organisms to the environmental variables. All species from cyanobacteria to humans have these rhythms that serve to anticipate the daily variations of different variables such as temperature, light, or food intake. It is accepted that virtually any physiological parameter that has been measured for a period of 24 h in humans has fluctuations [25, 26]. Several aspects of brain physiology, neuronal activity, and secretion of neurotransmitters, among others, change throughout the day, in such a way that the cerebral functions present circadian variations, dependent on the time of day, although it should be noted that they also depend on the sleep-wake cycle [27, 28]. Circadian rhythms in mammals are generated by the suprachiasmatic nucleus (SCN) of the hypothalamus, and both GABA and glutamate are intimately related to the function of this nucleus. Indeed, the photic information received by the SCN comes directly from the retina through the hypothalamic retinal tract, which releases glutamate, and indirectly through the hypothalamic geniculate tract that releases GABA and neuropeptide Y [29]; besides, GABA is one of the main neurotransmitters present in the SCN.

The variability in neuroprotection associated with the photoperiod can be explained by considering that the endogenous levels of practically any endogenous molecule present variations during the different phases of photoperiod. Diurnal variations have been reported in the circulating levels of heat shock proteins (HSPs) [30], as well as brain-derived neurotrophic factor (BDNF) and its receptors in the prefrontal cortex [31], of anandamide in cerebrospinal fluid, pons, hippocampus, and hypothalamus [32]. Our group found diurnal variations in CB1 cannabinoid receptor expression in the hippocampus [33], pons [34] and cerebral cortex [23].

#### **Figure 1.**

*Mechanisms of neuronal damage, endogenous neuroprotection, and its relationship with photoperiod, sleep deprivation for short periods, and sleep rebound. BDNF: brain-derived neurotrophic factor; CB1: cannabinoid receptor type 1; GABA: gamma-aminobutyric acid; HSP: heat shock proteins; NMDA: N-methyl-d-aspartate receptor; 2-Ag: 2-arachidonoylglycerol; and SWS: slow wave sleep. Data obtained from Refs. [4-7, 23, 24, 31-34, 71-86, 92-95].*

Besides, we recently reported diurnal variations in the expression of the NMDA receptor in motor cortex [24] (see **Figure 1**).

On the other hand, it has been reported that the TBI causes circadian dysregulations of blood pressure, heart rate, body temperature [35], hormonal cycles [36], and the sleep-wake cycle [37, 38]. Patients who suffered a severe TBI do not have a perceptible sleep/wake rhythm on the first or second day after the injury, and only half of them will have recovered a consolidated day/night pattern of wakefulness and sleep, 8 days later. The recovery of a circadian organization is a predictive factor of patient wellness [39]. It has been suggested that patients with lesions in the hypothalamus and the SCN will have poor outcomes [40]. Recent data from the literature indicate that even a mild TBI causes damage in hypothalamic structural and functional connectivity [41]. Also, it has been shown that the expression of clock genes such as BMAL1 and Cry1 is disrupted in the SCN and hippocampus of rats that are subjected to TBI [42].

#### **3. Neuroprotection and sleep**

Numerous studies have documented sleep-wake disturbances (SWD) in adults post-TBI, with excessive diurnal somnolence and insomnia being the biggest complaints. However, other sleep disorders such as narcolepsy, restless leg syndrome, parasomnias, and obstructive and central sleep apnea have also been reported [39]. Several studies indicate that hypersomnia following TBI has a prevalence varying between 50 and 85% [39, 43]. If the onset of hypersomnolence is from the traumatic event, it is called posttraumatic hypersomnia (PH) and is a hallmark of severe TBI. It has been reported that PH is related to direct injury to the alerting histaminergic tuberomammillary neurons, which are reduced by approximately 40% after severe TBI [44]. Also documented are fatigue and hypersomnia following mild TBI associated with the injury of the lower portion of the ascending reticular activating system between the pontine reticular formation and the intralaminar thalamic nucleus, using diffusion tensor tractography [45].

Botchway et al. [46] reported that even 20 years after a TBI in childhood, young adulthood present increased risk of SWD and that this is more common after a moderate TBI than after a severe one.

Haboubi et al. [47] found that up to 46% of patients reported insomnia that persisted beyond 6 months after mild TBI. Insomnia is reported more frequently with milder forms of TBI injuries [48] and has been associated with head trauma involving lower frontal and anterior temporal regions, including the basal forebrain as it affects the area involved in sleep initiation [39, 49].

Zhou [41], using advanced quantitative magnetic resonance imaging techniques, showed that disruption of functional and structural hypothalamic connectivity in patients with mild TBI was associated with fatigue and sleep problems.

Hypersomnolence has been associated with a decrease in the number of hypocretin-positive cells in experimental TBI models [50–52]. Also, an increased number of awakenings associated with an increase in reactive microglia in thalamic regions have been reported [53].

On the other hand, there are few data in the literature that support the neuroprotective role of sleep or wakefulness. Although, when a child falls and hits his/ her head, a general recommendation says: "Do not let him sleep"; there is no reliable data in the literature to support that this sleep deprivation will have some protective effect. More informed recommendations indicate that if the child is sleepy, he/ she is allowed to sleep, but that he must be awakened every 2 h to verify that he/she speaks, moves the four extremities and that is oriented [54].

**27**

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

It is worth noting that there is extensive literature that supports that sleep deprivation for prolonged periods impairs many physiological functions and causes death [55–58]. Total sleep deprivation (TSD) in rats causes deterioration in health whose end is death in a period between 11 and 32 days [56], while selectively rapid eye movement sleep deprivation (REMSD) causes death between 16 and 54 days [57]. Nevertheless, recent evidence suggests that sleep deprivation for shorter periods may be neuroprotective. Indeed, several studies in focal and global cerebral ischemia [59, 61, 65–67], cardiac arrest [60] or TBI [64, 68, 69] murine models have documented that both TSD [59, 61, 64–66, 69] and REMSD [60, 64, 67] have neuroprotective effects, whether they are applied before the insult [59–61, 65, 66] or after it [64, 67, 69] as summarized in **Table 1**. However, some studies indicate that sleep deprivation for short periods had no effect [68] or, its effect was deleterious [62, 63] (see **Table 1**).

As can be seen in **Table 1**, in some of the cases, sleep deprivation for short periods of time was applied before the noxious stimulus so it could be considered as a preconditioning stimulus [70], that is, a stimulus that triggers the activation of the endogenous neuroprotection response and prepares the organism against a harmful event of greater wingspan. However, in other studies indicated in **Table 1**, sleep deprivation for short periods was applied after the noxious stimulus, so it would rather act as a neuroprotective factor by delaying and/or decreasing the secondary lesion. In this sense, several reports in the literature suggest that sleep deprivation for short periods increase the expression of neuroprotective molecules like HSP, growth factors, and plasticity-related genes [71–73]. It also has been reported that TSD for short periods

Another factor that could be participating in the neuroprotective role of sleep deprivation for short periods is the balance between glutamatergic and GABAergic systems, which both sleep deprivation and TBI produce. In the literature, there are reports that TBI increases both glutamate [76–78] and GABA [79]. Also, the expression of GABAA receptors [80, 81] and NMDA [82] is modified; there are also several reports that indicate that sleep deprivation for short periods changes the release of both glutamate and GABA. REMSD increases the level of glutamate [83], as well as that of GABA but reduces the glutamate/GABA ratio [84]. These modifications could be significant in events such as TBI or ischemia since they would be regulating the excitotoxicity produced by glutamate. They could also be correlated with reports showing that sleep deprivation for short periods modifies the expression and/or replacement of NMDA receptors [85, 86]. For example, McDermott [87] shows that the REMSD for 72 h increases the intracellular NMDA levels, which could be interpreted as a down-regulation in response to the increase of glutamate; in the same way, several investigations show that the sleep deprivation for short periods can be an event that prevents the glutamate toxicity mediated by NMDA receptors [88]. As for GABAA receptors, there are reports that sleep deprivation for short periods increases their expression [89, 90], and/or modifies the expression of some subunits, which may explain functional changes in GABAergic transmission [91]. The cannabinergic system could also be participating in the neuroprotective effect of sleep deprivation for short periods. It has been reported that circulating

Also, it is worth noting that TSD induces a subsequent increase or rebound in slow-wave or high-amplitude electroencephalographic activity during slow wave sleep (SWS) while REMD induces an increase or rebound in REMS [93], so it is possible that the sleep rebound is the neuroprotective factor. This is in agreement with the findings of Brager et al. [94] who utilized remote preconditioning to prevent damage in a focal brain ischemia model. They found that remote preconditioning was associated with an increase of SWS. Also, sleep rebound appears to reduce the cerebral cortex level of glutamate [83] and increase that of GABA [95]. Besides, we

produces neurogenesis in the hippocampus [74, 75] (see **Figure 1**).

2-Ag increases with sleep deprivation [92].

#### *Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

receptor in motor cortex [24] (see **Figure 1**).

rats that are subjected to TBI [42].

**3. Neuroprotection and sleep**

nucleus, using diffusion tensor tractography [45].

as it affects the area involved in sleep initiation [39, 49].

speaks, moves the four extremities and that is oriented [54].

moderate TBI than after a severe one.

have been reported [53].

Besides, we recently reported diurnal variations in the expression of the NMDA

On the other hand, it has been reported that the TBI causes circadian dysregulations of blood pressure, heart rate, body temperature [35], hormonal cycles [36], and the sleep-wake cycle [37, 38]. Patients who suffered a severe TBI do not have a perceptible sleep/wake rhythm on the first or second day after the injury, and only half of them will have recovered a consolidated day/night pattern of wakefulness and sleep, 8 days later. The recovery of a circadian organization is a predictive factor of patient wellness [39]. It has been suggested that patients with lesions in the hypothalamus and the SCN will have poor outcomes [40]. Recent data from the literature indicate that even a mild TBI causes damage in hypothalamic structural and functional connectivity [41]. Also, it has been shown that the expression of clock genes such as BMAL1 and Cry1 is disrupted in the SCN and hippocampus of

Numerous studies have documented sleep-wake disturbances (SWD) in adults post-TBI, with excessive diurnal somnolence and insomnia being the biggest complaints. However, other sleep disorders such as narcolepsy, restless leg syndrome, parasomnias, and obstructive and central sleep apnea have also been reported [39]. Several studies indicate that hypersomnia following TBI has a prevalence varying between 50 and 85% [39, 43]. If the onset of hypersomnolence is from the traumatic event, it is called posttraumatic hypersomnia (PH) and is a hallmark of severe TBI. It has been reported that PH is related to direct injury to the alerting histaminergic tuberomammillary neurons, which are reduced by approximately 40% after severe TBI [44]. Also documented are fatigue and hypersomnia following mild TBI associated with the injury of the lower portion of the ascending reticular activating system between the pontine reticular formation and the intralaminar thalamic

Botchway et al. [46] reported that even 20 years after a TBI in childhood, young

Zhou [41], using advanced quantitative magnetic resonance imaging techniques, showed that disruption of functional and structural hypothalamic connectivity in

Hypersomnolence has been associated with a decrease in the number of hypocretin-positive cells in experimental TBI models [50–52]. Also, an increased number of awakenings associated with an increase in reactive microglia in thalamic regions

On the other hand, there are few data in the literature that support the neuroprotective role of sleep or wakefulness. Although, when a child falls and hits his/ her head, a general recommendation says: "Do not let him sleep"; there is no reliable data in the literature to support that this sleep deprivation will have some protective effect. More informed recommendations indicate that if the child is sleepy, he/ she is allowed to sleep, but that he must be awakened every 2 h to verify that he/she

adulthood present increased risk of SWD and that this is more common after a

patients with mild TBI was associated with fatigue and sleep problems.

Haboubi et al. [47] found that up to 46% of patients reported insomnia that persisted beyond 6 months after mild TBI. Insomnia is reported more frequently with milder forms of TBI injuries [48] and has been associated with head trauma involving lower frontal and anterior temporal regions, including the basal forebrain

**26**

It is worth noting that there is extensive literature that supports that sleep deprivation for prolonged periods impairs many physiological functions and causes death [55–58]. Total sleep deprivation (TSD) in rats causes deterioration in health whose end is death in a period between 11 and 32 days [56], while selectively rapid eye movement sleep deprivation (REMSD) causes death between 16 and 54 days [57].

Nevertheless, recent evidence suggests that sleep deprivation for shorter periods may be neuroprotective. Indeed, several studies in focal and global cerebral ischemia [59, 61, 65–67], cardiac arrest [60] or TBI [64, 68, 69] murine models have documented that both TSD [59, 61, 64–66, 69] and REMSD [60, 64, 67] have neuroprotective effects, whether they are applied before the insult [59–61, 65, 66] or after it [64, 67, 69] as summarized in **Table 1**. However, some studies indicate that sleep deprivation for short periods had no effect [68] or, its effect was deleterious [62, 63] (see **Table 1**).

As can be seen in **Table 1**, in some of the cases, sleep deprivation for short periods of time was applied before the noxious stimulus so it could be considered as a preconditioning stimulus [70], that is, a stimulus that triggers the activation of the endogenous neuroprotection response and prepares the organism against a harmful event of greater wingspan. However, in other studies indicated in **Table 1**, sleep deprivation for short periods was applied after the noxious stimulus, so it would rather act as a neuroprotective factor by delaying and/or decreasing the secondary lesion. In this sense, several reports in the literature suggest that sleep deprivation for short periods increase the expression of neuroprotective molecules like HSP, growth factors, and plasticity-related genes [71–73]. It also has been reported that TSD for short periods produces neurogenesis in the hippocampus [74, 75] (see **Figure 1**).

Another factor that could be participating in the neuroprotective role of sleep deprivation for short periods is the balance between glutamatergic and GABAergic systems, which both sleep deprivation and TBI produce. In the literature, there are reports that TBI increases both glutamate [76–78] and GABA [79]. Also, the expression of GABAA receptors [80, 81] and NMDA [82] is modified; there are also several reports that indicate that sleep deprivation for short periods changes the release of both glutamate and GABA. REMSD increases the level of glutamate [83], as well as that of GABA but reduces the glutamate/GABA ratio [84]. These modifications could be significant in events such as TBI or ischemia since they would be regulating the excitotoxicity produced by glutamate. They could also be correlated with reports showing that sleep deprivation for short periods modifies the expression and/or replacement of NMDA receptors [85, 86]. For example, McDermott [87] shows that the REMSD for 72 h increases the intracellular NMDA levels, which could be interpreted as a down-regulation in response to the increase of glutamate; in the same way, several investigations show that the sleep deprivation for short periods can be an event that prevents the glutamate toxicity mediated by NMDA receptors [88]. As for GABAA receptors, there are reports that sleep deprivation for short periods increases their expression [89, 90], and/or modifies the expression of some subunits, which may explain functional changes in GABAergic transmission [91].

The cannabinergic system could also be participating in the neuroprotective effect of sleep deprivation for short periods. It has been reported that circulating 2-Ag increases with sleep deprivation [92].

Also, it is worth noting that TSD induces a subsequent increase or rebound in slow-wave or high-amplitude electroencephalographic activity during slow wave sleep (SWS) while REMD induces an increase or rebound in REMS [93], so it is possible that the sleep rebound is the neuroprotective factor. This is in agreement with the findings of Brager et al. [94] who utilized remote preconditioning to prevent damage in a focal brain ischemia model. They found that remote preconditioning was associated with an increase of SWS. Also, sleep rebound appears to reduce the cerebral cortex level of glutamate [83] and increase that of GABA [95]. Besides, we

have documented that the rebound after REMSD increases the expression of the CB1 cannabinoid receptors in the rat pons [34], which could have a neuroprotective effect.

Also, during sleep rebound, the function of the glymphatic system is favored and therefore the elimination of toxic brain substances [96–98].


*SWS, slow wave sleep; REMS, rapid eye movement sleep; TBI, traumatic brain injury; and CSR, Chronic sleep restriction.*

**29**

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

**4. Sleep deprivation in humans**

type 2, and cardiovascular disease [99].

mobilization of ions and water [106].

cerebrovascular disorders [115].

obtained in animal models, but what is known in humans?

The TSD or REMSD data for short periods indicated in the previous section were

However, numerous studies have reported the effectiveness of TSD for one night

Several studies have tried to find the mechanism by which the TSD or REMSD are effective in mood improvement. In this sense, some of the effects of sleep deprivation or the rebound could be considered as neuroprotective; for example, Davies et al. observed that TSD for 24 h increases the serum levels of tryptophan, taurine, and serotonin, which could explain, in part, the antidepressant effect of deprivation [104]. It is worth noting that taurine has been related to cell volume changes triggered by different neurological diseases that produce secondary damage to ischemia [105]. This role is associated with its participation as osmolyte, which has been demonstrated by characterizing the increase in its extracellular concentration and its decrease in the intracellular one. Taurine can regulate the edema induced by the glutamate released during the excitotoxic cascade after a TBI. The nonvesicular release of taurine is an essential protective mechanism to prevent cell lysis, since, upon release to the extracellular environment, there is a change in the direction of

Hefti et al. [107] showed an increased expression of mGluR5 glutamate receptor in the cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala of healthy men after 33 h of TSD. Previously, some authors had reported that the activation of this receptor decreases the damage, using animal

Gorgulu and Caliyurt [110] demonstrated an increase in the concentration of serum BDNF in patients with depression treated with three overnight TSD over a week; nevertheless, in healthy subjects, TSD did not affect the level of BDNF. In the course of TSD, the concentration of cortisol increases considerably as a result of stimulation of the hypothalamic-pituitary-adrenal axis. The rebound after TSD resulted in a significant reduction of cortisol and increase of growth hormone (GH) secretion driven by the increase of SWS [111]. Recently, neuroprotection has

Also, the level of thyroid hormones increases during sleep deprivation. It is the result of the stimulation of the hypothalamic-pituitary-thyroid axis [114]. It has also been described that thyroid hormones play a neuroprotective role in acute

However, some studies show effects of TSD that could not be considered as neuroprotective; for example, Trivedi et al. [116] found that glutathione, ATP, cysteine, and homocysteine levels in plasma were significantly reduced as a result of one night of TSD, while Meier-Ewert et al. [117] reported that one night of TSD

models of cerebral focal ischemia [108] and spinal cord injury [109].

been identified as one of the functions of GH [112, 113].

in patients with depression; the first to report this were Pflug and Tolle, in 1971 [100]. Subsequently, Vogel et al. [101] described that the REMSD was also effective. Gillin [102], in 1983, pointed out that of a total of 852 patients who were TSD or REMSD for one or more nights, 493 (57.9%) were reported to have "improved", but it is recognized that this improvement in mood is transient and it is currently recommended that the TSD or REMSD be combined with sleep phase advance

(SPA), pharmacotherapy, and sometimes also phototherapy [103].

Recent studies indicate that our society is sleeping less and less and that this has a negative impact on health and wellbeing. Between 7 and 8 h/night of sleep is recommended in adults, although this time varies from person to person. Having an insufficient sleep in quantity or quality for multiple nights causes a debt of sleep that cannot be recovered and increases the risk of stroke, obesity, diabetes Mellitus

#### **Table 1.**

*REMSD, rapid eye movement sleep deprivation. TSD, total sleep deprivation.*

#### **4. Sleep deprivation in humans**

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

**Reference Damage** 

Hsu et al. [59] Global

Weil et al. [60] Cardiac

Gao et al. [62] Focal

Moldovan et al. [61]

Zunzunegui et al. [63]

Martinez Vargas et al. [64]

Cam et al. [65] Focal

Pace et al. [66] Focal

Cheng et al. [67] Global

Caron and Stephenson [68]

Morawska et al. [69]

**model**

cerebral ischemia in rat

arrest in mice

Focal cerebral ischemia in rat

cerebral ischemia in rat

Focal cerebral ischemia in rat

cerebral ischemia in rat

cerebral ischemia in rat

cerebral ischemia in rat

and therefore the elimination of toxic brain substances [96–98].

**and schedule)**

ischemia

ischemia

TBI in rat REMSD and TSD for 24 h immediately after a moderate TBI

ischemia

ischemia

6 h of TSD immediately before focal cerebral

6 h of TSD immediately before focal cerebral

REMSD for 12 h/day for 3 days 48 h after global cerebral ischemia and reperfusion

sodium oxybate or TSD (6 h daily/5 d) starting 1 day after TBI

*SWS, slow wave sleep; REMS, rapid eye movement sleep; TBI, traumatic brain injury; and CSR, Chronic sleep restriction.*

TBI in rat TSD for 48 h or chronic sleep restriction (6 h of sleep/ day for 10 days) following

mild TBI

TBI in rat Increased sleep with

*REMSD, rapid eye movement sleep deprivation. TSD, total sleep deprivation.*

**Sleep deprivation (method** 

48 h of REMSD immediately before cardiac arrest

6 h of TSD immediately before focal cerebral

TSD for 12 h, 12 h after focal cerebral ischemia. TSD for 12 h, for consecutive 3 days 12 h after ischemia

TSD for 12 h, for consecutive 3 days 12 h after ischemia

TSD for 5 days before a transient global cerebral

have documented that the rebound after REMSD increases the expression of the CB1 cannabinoid receptors in the rat pons [34], which could have a neuroprotective effect. Also, during sleep rebound, the function of the glymphatic system is favored

**Main findings Outcome**

**⇑**

**⇑**

**⇑**

**⇓**

**⇓**

**⇑**

**⇑**

**⇑**

**⇑**

**=**

**⇑**

Attenuation of the damage of pyramidal cells in the hippocampal

Improved ischemic outcome. Lesser neuronal hippocampal damage and increased gene expression of IL-6

Decreased loss of functions and a

Both sleep deprivation schedules increased the infarct volume and the

Lower recovery of forearm motor skills, reduction in axonal sprouting, and synaptophysin expression

Increase in the neurobehavioral recovery and reduction in the histological damage

Reduction in infarct volume associated with an increase in the amount of SWS and REMS.

and immune response.

Reduction in infarct volume associated with a reduction in up-regulation of genes involved in cell cycle regulation

Improvement in cognitive function, increased number of BrdU- and BrdU/NSE-positive cells as well as hippocampal BDNF expression

TSD or CSR did not exacerbate the neuronal damage induced by TBI

Enhanced encephalographic slowwave activity. Markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved

memory impairment

CA1 and glial reactions

smaller infarct volume

number of damaged cells

and IL-10

**28**

**Table 1.**

The TSD or REMSD data for short periods indicated in the previous section were obtained in animal models, but what is known in humans?

Recent studies indicate that our society is sleeping less and less and that this has a negative impact on health and wellbeing. Between 7 and 8 h/night of sleep is recommended in adults, although this time varies from person to person. Having an insufficient sleep in quantity or quality for multiple nights causes a debt of sleep that cannot be recovered and increases the risk of stroke, obesity, diabetes Mellitus type 2, and cardiovascular disease [99].

However, numerous studies have reported the effectiveness of TSD for one night in patients with depression; the first to report this were Pflug and Tolle, in 1971 [100]. Subsequently, Vogel et al. [101] described that the REMSD was also effective. Gillin [102], in 1983, pointed out that of a total of 852 patients who were TSD or REMSD for one or more nights, 493 (57.9%) were reported to have "improved", but it is recognized that this improvement in mood is transient and it is currently recommended that the TSD or REMSD be combined with sleep phase advance (SPA), pharmacotherapy, and sometimes also phototherapy [103].

Several studies have tried to find the mechanism by which the TSD or REMSD are effective in mood improvement. In this sense, some of the effects of sleep deprivation or the rebound could be considered as neuroprotective; for example, Davies et al. observed that TSD for 24 h increases the serum levels of tryptophan, taurine, and serotonin, which could explain, in part, the antidepressant effect of deprivation [104]. It is worth noting that taurine has been related to cell volume changes triggered by different neurological diseases that produce secondary damage to ischemia [105]. This role is associated with its participation as osmolyte, which has been demonstrated by characterizing the increase in its extracellular concentration and its decrease in the intracellular one. Taurine can regulate the edema induced by the glutamate released during the excitotoxic cascade after a TBI. The nonvesicular release of taurine is an essential protective mechanism to prevent cell lysis, since, upon release to the extracellular environment, there is a change in the direction of mobilization of ions and water [106].

Hefti et al. [107] showed an increased expression of mGluR5 glutamate receptor in the cingulate cortex, insula, medial temporal lobe, parahippocampal gyrus, striatum, and amygdala of healthy men after 33 h of TSD. Previously, some authors had reported that the activation of this receptor decreases the damage, using animal models of cerebral focal ischemia [108] and spinal cord injury [109].

Gorgulu and Caliyurt [110] demonstrated an increase in the concentration of serum BDNF in patients with depression treated with three overnight TSD over a week; nevertheless, in healthy subjects, TSD did not affect the level of BDNF.

In the course of TSD, the concentration of cortisol increases considerably as a result of stimulation of the hypothalamic-pituitary-adrenal axis. The rebound after TSD resulted in a significant reduction of cortisol and increase of growth hormone (GH) secretion driven by the increase of SWS [111]. Recently, neuroprotection has been identified as one of the functions of GH [112, 113].

Also, the level of thyroid hormones increases during sleep deprivation. It is the result of the stimulation of the hypothalamic-pituitary-thyroid axis [114]. It has also been described that thyroid hormones play a neuroprotective role in acute cerebrovascular disorders [115].

However, some studies show effects of TSD that could not be considered as neuroprotective; for example, Trivedi et al. [116] found that glutathione, ATP, cysteine, and homocysteine levels in plasma were significantly reduced as a result of one night of TSD, while Meier-Ewert et al. [117] reported that one night of TSD increased serum C reactive protein concentrations. Also, one night of TSD causes an increase of serum concentration of interleukin 6 (IL-6), a proinflammatory cytokine in depressive patients as in healthy subjects; but in healthy individuals sleep rebound increased the level of interleukin-1-receptor antagonist (IL-1RA) [118], which inhibits the action of the proinflammatory interleukins 1alpha and 1beta.

Some deleterious effects attributed to the TSD may be influenced by the deprivation method; for example, Gil-Lozano et al. [119] reported that overnight TSD with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. These alterations were not observed in TSD participants maintained under dark conditions.

#### **5. Limitations**

Studies on the impact of acute sleep deprivation and its neuroprotective effects in humans against acquired brain damage are scarce. However, studies performed in subjects without brain injury indicate the existence of neuroprotective mechanisms, as long as it is a TSD for short or acute periods (24 h). In order to propose sleep deprivation as a neuroprotective mechanism and incorporate it as part of the treatment against TBI, more studies are still needed.

#### **6. Perspectives**

The importance of the TBI as a public health problem worldwide requires us to understand the pathophysiological changes underlying this neurological event, as well as the processes that favor the activation of endogenous neuroprotection, in order to apply them as a possible therapeutic strategy.

The previous evidence highlights the importance of considering the time of the day when acquired brain injury is established. The alterations found as a consequence of this event are heterogeneous and complex, ranging from molecular changes to behavioral modifications; as pointed before, TBI causes dysregulation of sleep-wake cycle and homeostasis unbalance including many neuropeptide and hormones changes.

In many of the alterations induced by an acquired brain damage, the participation of neurotransmission systems such as GABAergic, glutamatergic, and cannabinergic is fundamental. These, like all endogenous molecules, have a diurnal variation; such variations, in the same way, affect the sleep-wake cycle. Evidence in animal models of the neuroprotective effect of sleep deprivation for short periods encourages us to continue researching this.

Knowing the relationship between neuroprotection, photoperiod, and sleep, as well as the participation of the neurotransmission systems involved in the TBI, opens a window in their study as potential biomarkers or therapeutic targets. With this approach, it will probably benefit a higher number of patients with acquired brain damage.

**31**

**Author details**

of Mexico, Cd. Mx., Mexico

provided the original work is properly cited.

Antonio Barajas-Martinez and Luz Navarro\*

\*Address all correspondence to: lnavarro@unam.mx

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Francisco Estrada-Rojo, Ricardo Jesus Martinez-Tapia, Adan Perez-Arredondo,

Department of Physiology, Faculty of Medicine, National Autonomous University

Marina Martinez-Vargas, Mercedes Graciela Porras-Villalobos,

#### **Acknowledgements**

This work was supported by PAPIIT IN223417.

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

pants maintained under dark conditions.

ment against TBI, more studies are still needed.

order to apply them as a possible therapeutic strategy.

encourages us to continue researching this.

This work was supported by PAPIIT IN223417.

**5. Limitations**

**6. Perspectives**

hormones changes.

brain damage.

**Acknowledgements**

increased serum C reactive protein concentrations. Also, one night of TSD causes an increase of serum concentration of interleukin 6 (IL-6), a proinflammatory cytokine in depressive patients as in healthy subjects; but in healthy individuals sleep rebound increased the level of interleukin-1-receptor antagonist (IL-1RA) [118], which inhibits the action of the proinflammatory interleukins 1alpha and 1beta. Some deleterious effects attributed to the TSD may be influenced by the deprivation method; for example, Gil-Lozano et al. [119] reported that overnight TSD with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. These alterations were not observed in TSD partici-

Studies on the impact of acute sleep deprivation and its neuroprotective effects in humans against acquired brain damage are scarce. However, studies performed in subjects without brain injury indicate the existence of neuroprotective mechanisms, as long as it is a TSD for short or acute periods (24 h). In order to propose sleep deprivation as a neuroprotective mechanism and incorporate it as part of the treat-

The importance of the TBI as a public health problem worldwide requires us to understand the pathophysiological changes underlying this neurological event, as well as the processes that favor the activation of endogenous neuroprotection, in

In many of the alterations induced by an acquired brain damage, the participation of neurotransmission systems such as GABAergic, glutamatergic, and cannabinergic is fundamental. These, like all endogenous molecules, have a diurnal variation; such variations, in the same way, affect the sleep-wake cycle. Evidence in animal models of the neuroprotective effect of sleep deprivation for short periods

Knowing the relationship between neuroprotection, photoperiod, and sleep, as well as the participation of the neurotransmission systems involved in the TBI, opens a window in their study as potential biomarkers or therapeutic targets. With this approach, it will probably benefit a higher number of patients with acquired

The previous evidence highlights the importance of considering the time of the day when acquired brain injury is established. The alterations found as a consequence of this event are heterogeneous and complex, ranging from molecular changes to behavioral modifications; as pointed before, TBI causes dysregulation of sleep-wake cycle and homeostasis unbalance including many neuropeptide and

**30**

### **Author details**

Marina Martinez-Vargas, Mercedes Graciela Porras-Villalobos, Francisco Estrada-Rojo, Ricardo Jesus Martinez-Tapia, Adan Perez-Arredondo, Antonio Barajas-Martinez and Luz Navarro\* Department of Physiology, Faculty of Medicine, National Autonomous University of Mexico, Cd. Mx., Mexico

\*Address all correspondence to: lnavarro@unam.mx

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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iub.98

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

[10] Gouix E, Lèveillè F, Nicole O, Melon C, Had-Aissouni L, Buisson A. Reverse glial glutamate uptake triggers neuronal

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after brain injury. Nature.

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2008;**14**:S11-S14

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Research. 2002;**67**(6):781-786

nbd.2010.03.012

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

[73] Elliott AS, Huber JD, OíCallaghan JP, Rosen CL, Miller DB. A review of sleep deprivation studies the brain transcriptome. Springerplus. 2014;**3**:728

[74] Grassi Zucconi G, Cipriani S, Balgkouranidou I, Scattoni R. One night sleep deprivation stimulates hippocampal neurogenesis. Brain Research Bulletin. 2006;**69**:375-381

[75] Junek A, Rusak B, Semba K. Shortterm sleep deprivation may alter the dynamics of hippocampal cell proliferation in adult rats. Neuroscience.

[76] Faden AI, Demediuk P, Panter SS, Vink R. The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science.

[77] Katayama Y, Becker DP, Tamura T, Hovda DA. Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. Journal of Neurosurgery. 1990

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[79] Zhong C et al. NAAG peptidase inhibitor increases dialysate NAAG and reduces glutamate, aspartate and GABA levels in the dorsal hippocampus following fluid percussion injury in the rat. Journal of Neurochemistry.

2010;**170**:1140-1152

1989;**244**(4906):798-800

Dec;**73**(6):889-900

2006;**97**(4):1015-1025

1999;**816**:234-237

[80] Neumann-Haefelin T et al.

Upregulation of GABA-receptor a1- and a2-subunit mRNAs following a ischemic cortical lesions in rats. Brain Research.

[81] Mtchedlishvili Z, Lepsveridze E, Xu H, Kharlamov EA, Lu B, Kelly KM.

before stroke is neuroprotective: A pre-ischemic conditioning related to sleep rebound. Experimental Neurology.

2013;**247**:673-679. DOI: 10.1016/j.

[66] Pace M, Baracchi F, Gao B, Bassetti C. Identification of sleep-modulated pathways involved in neuroprotection from stroke. Sleep. 2015;**38**(11): 1707-1718. DOI: 10.5665/sleep.5148

[67] Cheng O, Li R, Zhao L, Yu L, Yang B, Wang J, et al. Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion. PLoS One. 2015;**10**(6):e0125877. DOI: 10.1371/

[68] Caron AM, Stephenson R. Sleep deprivation does not affect neuronal susceptibility to mild traumatic brain injury in the rat. Nature and Science of Sleep. 2015;**7**:63-72. DOI: 10.2147/NSS.

[69] Morawska MM, Büchele F, Moreira CG, Imbach LL, Noain D, Baumann CR. Sleep modulation alleviates axonal damage and cognitive decline after rodent traumatic brain injury. The Journal of Neuroscience. 2016;**36**(12):3422-3429. DOI: 10.1523/

JNEUROSCI.3274-15.2016

STROKEAHA.117.018796

2001;**25**(Suppl):S28-S35

[70] Pincherle A, Pace M, Sarasso S, Facchin L, Dreier JP, Bassetti CL. Sleep, preconditioning and stroke. Stroke. 2017;**48**(12):3400-3407. DOI: 10.1161/

[71] Tononi G, Cirelli C. Modulation of brain gene expression during sleep and wakefulness: A review of recent findings. Neuropsychopharmacology.

[72] Cirelli C, Gutierrez CM, Tononi G. Extensive and divergent effects of sleep and wakefulness on brain gene expression. Neuron. 2004;**41**(1):35-43

expneurol.2013.03.003

journal.pone.0125877

S82888

**36**

Increase of GABAA receptormediated tonic inhibition in dentate granule cells after traumatic brain injury. Neurobiology of Disease. 2010;**38**(3):464-475. DOI: 10.1016/j. nbd.2010.03.012

[82] Kumar A, Zou L, Yuan X, Long Y, Yang K. N-methyl-d-aspartate receptors: Transient loss of NR1/NR2A/NR2B subunits after traumatic brain injury in a rodent model. Journal of Neuroscience Research. 2002;**67**(6):781-786

[83] Dash MB, Douglas CL, Vyazovskiy VV, Cirelli C, Tononi G. Long-term homeostasis of extracellular glutamate in the rat cerebral cortex across sleep and waking states. The Journal of Neuroscience. 2009;**29**(3):620-629. DOI: 10.1523/JNEUROSCI.5486-08.2009

[84] Wang SX, Li QS. Effects of sleep deprivation on gamma-amino-butyric acid and glutamate contents in rat brain. Di Yi Jun Yi Da Xue Xue Bao. 2002;**22**(10):888-890

[85] Longordo F et al. Consequences of sleep deprivation on neurotransmitter receptor expression and function. The European Journal of Neuroscience. 2009;**29**(9):1810-1819

[86] Longordo F et al. NR2A at CA1 synapses is obligatory for the susceptibility of hippocampal plasticity to sleep loss. The Journal of Neuroscience. 2009;**29**(28):9026-9041

[87] McDermott CM et al. Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus. The Journal of Physiology. 2006;**570** (Pt 3):553-565

[88] Novati A, Hulshof HJ, Granic I, Meerlo P. Chronic partial sleep deprivation reduces brain sensitivity to glutamate N-methyld-aspartate receptor-mediated neurotoxicity. Journal of Sleep

Research. 2012;**21**(1):3-9. DOI: 10.1111/j.1365-2869.2011.00932.x

[89] Pokk P et al. Is upregulation of benzodiazepine receptors a compensatory reaction to reduced GABAergic tone in the brain of stressed mice? Naunyn-Schmiedeberg's Archives of Pharmacology. 1996;**354**(6):703-708

[90] Cirelli C, Tononi G. Gene expression in the brain across the sleep-waking cycle. Brain Research. 2000;**885**(2):303-321

[91] Modirrousta M, Mainville L, Jones BE. Dynamic changes in GABAA receptors on basal forebrain cholinergic neurons following sleep deprivation and recovery. BMC Neuroscience. 2007;**8**:15

[92] Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, de Wit H, et al. Sleep restriction enhances the daily rhythm of circulating levels of endocannabinoid 2-arachidonoylglycerol. Sleep. 2016;**39**(3):653-664. DOI: 10.5665/sleep.5546

[93] Rechtschaffen A, Bergmann BM, Gilliland MA, Bauer K. Effects of method, duration, and sleep stage on rebounds from sleep deprivation in the rat. Sleep. 1999;**22**(1):11-31

[94] Brager AJ, Yang T, Ehlen JC, Simon RP, Meller R, Paul KN. Sleep is critical for remote preconditioninginduced neuroprotection. Sleep. 2016;**39**(11):2033-2040

[95] Bettendorff L et al. Paradoxical sleep deprivation increases the content of glutamate and glutamine in rat cerebral cortex. Sleep. 1996;**19**(1):65-71

[96] Jessen NA, Munk AS, Lundgaard I, Nedergaard M. The glymphatic system: A Beginner's guide. Neurochemical Research. 2015;**40**(12):2583-2599. DOI: 10.1007/s11064-015-1581-6

[97] Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathway in neurological disorders. Lancet Neurology. 2018;**17**(11):1016-1024. 10.1016/S1474-4422(18)30318-1

[98] Eugene AR, Masiak J. The neuroprotective aspects of sleep. MEDtube Science. 2015;**3**(1):35-40

[99] Abrams RM. Sleep deprivation. Obstetrics and Gynecology Clinics of North America. 2015;**42**(3):493-506. DOI: 10.1016/j.ogc.2015.05.013

[100] Pflug B, Tőlle R. Therapie endogener depressionen durch schlafentzug. Nervenarzt. 1971;**42**:117-124

[101] Vogel GW, Vogel F, McAbee RS, Thurmond AJ. Improvement of depression by REM sleep deprivation, new findings and a theory. Archives of General Psychiatry. 1980;**37**:247-253

[102] Gillin JC. The sleep therapies of depression. Progress in Neuro-Psychopharmacology & Biological Psychiatry. 1983;**7**:351-364

[103] Dopierała E, Rybakowski J. Sleep deprivation as a method of chronotherapy in the treatment of depression. Psychiatria Polska. 2015;**49**(3):423-433. DOI: 10.12740/ PP/30455

[104] Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, et al. Effect of sleep deprivation on the human metabolome. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(29):10761-10766. DOI: 10.1073/pnas.1402663111

[105] Nilsson P, Hillered L, Pontén U, Ungerstedt U. Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. Journal of Cerebral Blood Flow and Metabolism. 1990;**10**(5):631-637

[106] Stover JF, Unterberg AW. Increased cerebrospinal fluid glutamate and taurine concentrations are associated with traumatic brain edema formation in rats. Brain Research. 2000;**875**(1-2):51-55

[107] Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM, et al. Increased metabotropic glutamate receptor subtype 5 availability in human brain after one night without sleep. Biological Psychiatry. 2013;**73**(2):161-168. DOI: 10.1016/j. biopsych.2012.07.030

[108] Bao WL, Williams AJ, Faden AI, Tortella FC. Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Research. 2001;**922**(2):173-179

[109] Byrnes KR, Stoica B, Riccio A, Pajoohesh-Ganji A, Loane DJ, Faden AI. Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents. Annals of Neurology. 2009;**66**(1):63-74. DOI: 10.1002/ana.21673

[110] Gorgulu Y, Caliyurt O. Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Research Bulletin. 2009;**80**(3):158-162

[111] Vgontzas AN, Mastorakos G, Bixler EO, Kales A, Gold PW, Chrousos GP. Sleep deprivation effects on the activity of the hypothalamicpituitary-adrenal and growth axes: Potential clinical implications. Clinical Endocrinology. 1999;**51**(2):205-215

[112] Arce VM, Devesa P, Devesa J. Role of growth hormone (GH) in the treatment on neural diseases: From neuroprotection to neural repair. Neuroscience Research. 2013;**76**(4):179-186. DOI: 10.1016/j. neures.2013.03.014

**39**

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

[113] Arámburo C, Alba-Betancourt C, Luna M, Harvey S. Expression and function of growth hormone in the nervous system: A brief review. General and Comparative Endocrinology. 2014;**203**:35-42. DOI: 10.1016/j.

American Journal of Physiology. Endocrinology and Metabolism. 2016;**310**(1):E41-E50. DOI: 10.1152/

ajpendo.00298.2015

[114] Pereira JC Jr, Andersen ML. The role of thyroid hormone in sleep deprivation. Medical Hypotheses.

ygcen.2014.04.035

2014;**82**(3):350-355

[115] Bunevicius A, Iervasi G, Bunevicius R. Neuroprotective actions of thyroid hormones and low-T3 syndrome as a biomarker in acute cerebrovascular disorders. Expert Review of Neurotherapeutics.

2015;**15**(3):315-326. DOI: 10.1586/14737175.2015.1013465

journal.pone.0181978

2004;**43**(4):678-683

[118] Voderholzer U, Fiebich BL, Dersch R, Feige B, Piosczyk H, Kopasz M, et al. Effects of sleep deprivation on nocturnal cytokine concentrations in depressed patients and healthy control subjects. The Journal of Neuropsychiatry and Clinical Neurosciences. 2012;**24**(3):354-366

[119] Gil-Lozano M, Hunter PM, Behan LA, Gladanac B, Casper RF, Brubaker PL. Short-term sleep deprivation with nocturnal light exposure alters timedependent glucagon-like peptide-1 and insulin secretion in male volunteers.

[116] Trivedi MS, Holger D, Bui AT, Craddock TJA, Tartar JL. Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status. PLoS One. 2017;**12**(7):e0181978. DOI: 10.1371/

[117] Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. Journal of the American College of Cardiology.

*Neuroprotection, Photoperiod, and Sleep DOI: http://dx.doi.org/10.5772/intechopen.85013*

*Traumatic Brain Injury - Neurobiology, Diagnosis and Treatment*

[106] Stover JF, Unterberg AW. Increased cerebrospinal fluid glutamate and taurine concentrations are associated

with traumatic brain edema formation in rats. Brain Research.

[107] Hefti K, Holst SC, Sovago J, Bachmann V, Buck A, Ametamey SM, et al. Increased metabotropic glutamate

receptor subtype 5 availability in human brain after one night without sleep. Biological Psychiatry. 2013;**73**(2):161-168. DOI: 10.1016/j.

[108] Bao WL, Williams AJ, Faden AI, Tortella FC. Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Research.

[109] Byrnes KR, Stoica B, Riccio A, Pajoohesh-Ganji A, Loane DJ, Faden AI. Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents. Annals of Neurology. 2009;**66**(1):63-74.

[110] Gorgulu Y, Caliyurt O. Rapid antidepressant effects of sleep deprivation therapy correlates with serum BDNF changes in major depression. Brain Research Bulletin.

[111] Vgontzas AN, Mastorakos G, Bixler EO, Kales A, Gold PW, Chrousos

GP. Sleep deprivation effects on the activity of the hypothalamicpituitary-adrenal and growth axes: Potential clinical implications. Clinical Endocrinology. 1999;**51**(2):205-215

[112] Arce VM, Devesa P, Devesa J. Role of growth hormone (GH) in the treatment on neural diseases: From neuroprotection to neural repair. Neuroscience Research. 2013;**76**(4):179-186. DOI: 10.1016/j.

2000;**875**(1-2):51-55

biopsych.2012.07.030

2001;**922**(2):173-179

DOI: 10.1002/ana.21673

2009;**80**(3):158-162

neures.2013.03.014

[97] Rasmussen MK, Mestre H,

in neurological disorders. Lancet Neurology. 2018;**17**(11):1016-1024. 10.1016/S1474-4422(18)30318-1

[98] Eugene AR, Masiak J. The neuroprotective aspects of sleep. MEDtube Science. 2015;**3**(1):35-40

[99] Abrams RM. Sleep deprivation. Obstetrics and Gynecology Clinics of North America. 2015;**42**(3):493-506. DOI: 10.1016/j.ogc.2015.05.013

[100] Pflug B, Tőlle R. Therapie endogener depressionen durch schlafentzug. Nervenarzt.

[101] Vogel GW, Vogel F, McAbee RS, Thurmond AJ. Improvement of depression by REM sleep deprivation, new findings and a theory. Archives of General Psychiatry. 1980;**37**:247-253

[102] Gillin JC. The sleep therapies of depression. Progress in Neuro-Psychopharmacology & Biological

Psychiatry. 1983;**7**:351-364

PP/30455

[103] Dopierała E, Rybakowski J. Sleep deprivation as a method of chronotherapy in the treatment of depression. Psychiatria Polska. 2015;**49**(3):423-433. DOI: 10.12740/

[104] Davies SK, Ang JE, Revell VL, Holmes B, Mann A, Robertson FP, et al. Effect of sleep deprivation on the human metabolome. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(29):10761-10766. DOI: 10.1073/pnas.1402663111

[105] Nilsson P, Hillered L, Pontén U, Ungerstedt U. Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. Journal of Cerebral Blood Flow and Metabolism.

1971;**42**:117-124

Nedergaard M. The glymphatic pathway

**38**

1990;**10**(5):631-637

[113] Arámburo C, Alba-Betancourt C, Luna M, Harvey S. Expression and function of growth hormone in the nervous system: A brief review. General and Comparative Endocrinology. 2014;**203**:35-42. DOI: 10.1016/j. ygcen.2014.04.035

[114] Pereira JC Jr, Andersen ML. The role of thyroid hormone in sleep deprivation. Medical Hypotheses. 2014;**82**(3):350-355

[115] Bunevicius A, Iervasi G, Bunevicius R. Neuroprotective actions of thyroid hormones and low-T3 syndrome as a biomarker in acute cerebrovascular disorders. Expert Review of Neurotherapeutics. 2015;**15**(3):315-326. DOI: 10.1586/14737175.2015.1013465

[116] Trivedi MS, Holger D, Bui AT, Craddock TJA, Tartar JL. Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status. PLoS One. 2017;**12**(7):e0181978. DOI: 10.1371/ journal.pone.0181978

[117] Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. Journal of the American College of Cardiology. 2004;**43**(4):678-683

[118] Voderholzer U, Fiebich BL, Dersch R, Feige B, Piosczyk H, Kopasz M, et al. Effects of sleep deprivation on nocturnal cytokine concentrations in depressed patients and healthy control subjects. The Journal of Neuropsychiatry and Clinical Neurosciences. 2012;**24**(3):354-366

[119] Gil-Lozano M, Hunter PM, Behan LA, Gladanac B, Casper RF, Brubaker PL. Short-term sleep deprivation with nocturnal light exposure alters timedependent glucagon-like peptide-1 and insulin secretion in male volunteers.

American Journal of Physiology. Endocrinology and Metabolism. 2016;**310**(1):E41-E50. DOI: 10.1152/ ajpendo.00298.2015

Section 2

Imaging Diagnosis and

Biomarkers

41

Section 2
