\r\n\tEqually important are the consequences deriving from the extraordinary nature of the present times. The COVID-19 pandemic and the restrictive measures to contain the infection (lockdown and "physical distancing" in primis) have revolutionized the lives, and a distortion/modification of habits, rhythms, arrangements will continue to be necessary.
\r\n\tGovernments have implemented a series of actions to mitigate the spread of infections and alleviate the consequent pressure on the hospital system. On the other hand, the Covid-19 pandemic has caused a series of other cascading effects that will probably be much more difficult to mitigate and which expose to complex consequences. The past two years have brought many challenges, particularly for healthcare professionals, students, family members of COVID-19 patients, people with mental disorders, the frail, the elderly, and more generally those in disadvantaged socio-economic conditions, and workers whose livelihoods have been threatened. Indeed, the substantial economic impact of the pandemic may hinder progress towards economic growth as well as progress towards social inclusion and mental well-being.
\r\n\t
\r\n\tAlthough in all countries the knowledge on the impact of the pandemic on mental health is still limited and mostly derived from experiences only partially comparable to the current epidemic, such as those referring to the SARS or Ebola epidemics, it is likely that the demand for intervention it will increase significantly in the coming months and years. The extraordinary growth of scientific research in the field of neuroscience now offers the possibility of a new perspective on the relationship between mind and brain and generates new scenarios in understanding the long wave of the pandemic and in the prospects for treatment. Moreover, the pandemic also has led to opportunities to implement remote monitoring and management interventions.
\r\n\t
\r\n\tOverall this volume will address the complex relationship existing between COVID-19, mental health, acquired knowledge, and possible interventions taking a highly multidisciplinary approach; from physiological and psychobiological mechanisms, and neuromodulation through medical treatment, psychosocial interventions, and self-management.
Anxiety is a term often used to encompass feelings of apprehension, dread, unease or similarly unpleasant emotions. Trait anxiety defines the affect of an organism over time and across situations, whereas state anxiety is the response or adaptation to a given situation [1]. Anxiety can be differentiated from fear, both biologically and behaviorally [see 1 for an extensive review]. Converging theories and evidence from clinical psychology and comparative neuroscience suggest that fear can be considered a negatively-valenced emotion that is brief, focused on the present, occurs in situations of specific threat, and aids in avoidance or escape [1,2]. Anxiety, on the other hand, is a negatively-valenced emotion that is characterized by sustained hyperarousal in response to uncertainty, is thus future-focused, and aids in defensive approach or risk assessment [1,2]. Both anxiety and fear are emotions experienced by all individuals and can serve to be adaptive in shaping decisions and behaviors related to survival of an organism [1,3]. However, when excessive, or pathological, or triggered inappropriately, fear and anxiety form the basis of a variety of anxiety disorders [3,4,5; Table 1]. As illustrated by Table 1, some anxiety disorders such as generalized anxiety disorder (GAD) or obsessive-compulsive disorder (OCD) are characterized by excessive anxiety as defined above [1]. However, other anxiety disorders are characterized, at least in part, by excessive and inappropriate fear, such as posttraumatic stress disorder (PTSD), specific phobias and social anxiety disorder [1,3; Table 1]. Thus, it is important to understand the neurobiology of both anxiety and fear to obtain a comprehensive picture of the physiological basis of anxiety disorders.
One in three people will develop one of the anxiety disorders outlined by Table 1 within their life-time, with the life-time prevalence at least two times more likely for women [5,6]. Furthermore, individuals may present with one or more comorbid anxiety disorders, and anxiety disorders are highly likely to be comorbid with other psychiatric illnesses, such as major depressive disorder, psychosis, mania, and substance abuse disorder [4-6]. Several non-psychiatric disorders are also associated with anxiety disorders, and these include hyperthyroidism, Cushing’s disease and mitral value prolapse [4,5]. Thus, anxiety disorders are one of the most prevalent psychiatric disorders, posing great personal, economic, and societal burdens [4-6].
Generalized Anxiety Disorder (GAD) |
Excessive worry occurring more days than not over at least a 6 month period, accompanied by restlessness, fatigue, sleep disturbances, muscle tension or irritability. |
Posttraumatic Stress Disorder (PTSD) |
Characterized by a history of trauma and symptoms related to avoidance, re-experiencing, and physiological hyperarousal in the face of triggering cue. |
Obsessive-Compulsive Disorder (OCD) |
Compulsions (repeated actions) produced to reduce anxiety associated with obsessions (unwanted, intrusive thoughts). |
Panic Disorder |
Characterized by panic attacks; a period of intense fear or discomfort accompanied by a variety of physiological symptoms (e.g. sweating, trembling, chest pains, tachycardia). |
Agoraphobia |
Fear and avoidance of situations from which escape would be difficult in the event of having panic-like symptoms. |
Specific Phobia |
Excessive or unreasonable fear in anticipation or in response to a specific object or situation. |
Social Anxiety Disorder (Social Phobia) |
Excessive/unreasonable fear and avoidance of social situations (including performances) in which the person is exposed to unfamiliar people or possible scrutiny by others. |
The neurobiological bases of anxiety and fear appear to be very similar across species [1], thus complementary findings from both animal models (most often rodents) and human studies can contribute to theories of the neurobiological basis of anxiety disorders. State fear within animal models is most often studied by measures of freezing and fear-potentiated startle, both acquired via classical conditioning of rodents [1,8]. State anxiety, on the other hand, is most often studied using apparatus such as an open field, elevated plus maze, or light-dark box, which all take advantage of the rodent’s preference for familiar, dark, and/or enclosed areas [1,9]. Notably, these paradigms do not rely on the processes underlying classical conditioning, although McNaughton and Corr [2] caution against defining fear verses anxiety as conditioned versus unconditioned responses. While trait fear is not well-defined by animal studies [1], trait anxiety is often examined in animal models by the use of selective breeding, resulting in high- and low-anxiety strains and lines of rodents [for example, see 1, 10]. However, one can argue that experimental manipulations (such as early-life stress or amphetamine withdrawal) that drive a group of animals towards greater fear- and anxiety-like phenotypes also examine the underlying basis of trait fear or anxiety [e.g. 11, 12]. As noted by Sylver et al [1] clinical studies most often examine trait anxiety, whereas experiments involving animal models most often focus on state anxiety and fear, and then relate these findings to concepts associated with trait anxiety. Regardless, both human and animal studies suggest an important role for the amygdala, and subregions within, in mediating fear and anxiety, and in the manifestation of anxiety disorders (Sections 2 and 3). Therefore, the goals of this review are to first evaluate and integrate classical and recent findings from human studies and relevant animal models that reveal the specific role the amygdala plays in fear and anxiety, and then to elucidate how anxiolytic drugs may affect the amygdala function to ameliorate heightened fear and/or anxiety. This is important, given that traditional drug and cognitive behavioral therapy (CBT) are effective in reducing symptoms of the various anxiety disorders for many individuals, but often do not provide long-term relief, and relapse is a common post-treatment outcome [as reviewed by 3]. Therefore, the final goal of the current review is to identify future potential therapeutic targets for the treatment of anxiety disorders.
Human imaging studies that explore the neurobiological bases of anxiety or fear processing typically use functional magnetic resonance imaging (fMRI) or positron emission tomography (PET) as measures of neural activity or cerebral blood flow. Imaging experiments that are designed to study neural reactivity to fearful stimuli utilize either conditioned fear paradigms similar to those used in animal models, or involve the presentation of unconditioned stimuli such as fearful faces [1]. It has become clear that masked stimuli can elicit conditioned and unconditioned fear responses from human subjects, suggesting unconscious, implicit processing of these cues [as reviewed by 1]. Similarly, increased activity of the amygdala is observed in response to both conditioned and unconditioned fearful stimuli, independent of whether the subject is aware of the stimulus [1,13-16].
Comparable studies that have examined neural correlates of anxiety in healthy controls are limited. One of the reasons for this is that many studies use fearful stimuli, such as the fearful faces or conditioned fear paradigms [1], blurring the distinction between fear and anxiety. Therefore, conclusions regarding neural bases of anxiety are better drawn from studies that include trait anxiety as a variable while utilizing fearful stimuli, or those fewer studies in which an anxiogenic situation is created within the experimental design. Like for studies of fear processing, the majority of these studies show a relationship between trait anxiety and greater amygdala reactivity [as reviewed by 17]. For example, a study of healthy subjects found that reactivity of the amygdala was positively correlated with anticipatory anxiety, and when the anticipated event was imminent, amygdala activation positively correlated with the degree of trait anxiety [18]. Furthermore, college students who scored in the upper 15th percentile for trait anxiety show greater amygdala reactivity to emotional faces as compared to students who scored in the normative range, suggesting that anxiety-prone individuals have greater amygdala reactivity [19]. A similar hyperactivity of the amygdala in high trait anxiety participants is noted when a masked emotional faces or unattended faces paradigm are used [20,21], suggesting the individual does not need to be aware of the stimulus to exhibit heightened amygdala activity. Interestingly, Etkin et al., [21] differentiate between different subregions of the amygdala (see Section 3.1 for more details on amygdala subregions), with the basolateral amygdala activated during masked presentations of emotional faces while the dorsal/central amygdala was activated during unmasked presentations. Thus, there may be subregion specificity within the amygdala when processing unconscious versus conscious emotionally-valenced stimuli.
When gender has been examined as a factor in populations of healthy subjects, higher trait anxiety is associated with greater amygdala responses to unattended fearful faces in female but not male participants [22]. A further factor potentially mediating the relationship between trait anxiety and amygdala reactivity appears to be perceived social support. To illustrate, Hyde et al. [17] show a positive correlation between the degree of trait anxiety and amygdala reactivity to fearful faces in subjects that report below-average social support, but not in those who report above average support. Related, it is also thought that the degree of social anxiety rather than trait anxiety may be more closely related to amygdala reactivity to emotional faces [23]. These factors, and other similar considerations, may explain why some, but not all, studies show a positive correlation between trait anxiety and amygdala reactivity in non-patient populations [18-21,23].
Hyperactivity of the amygdala in response to negatively-valenced stimuli also appears to be a common finding from a variety of clinical anxiety populations [16]. For example, individuals suffering from social anxiety disorder show heightened amygdala responses to both social and non-social highly emotive stimuli as compared to healthy control groups, with the degree of social anxiety positively correlated with amygdala reactivity [24-27]. Furthermore, activation of the amygdala by non-social stimuli has been correlated with trait anxiety in social anxiety disorder, leading to the conclusion that social anxiety disorder is characterized by a more general dysfunction in emotional processing in addition to altered processing of social stimuli and situations [26]. Importantly, reduced symptoms in a public speaking situation following either CBT or antidepressant treatment was associated with reduced amygdala reactivity [24], further suggesting a tight link between symptomology and amygdala reactivity in social anxiety disorder.
Like social anxiety disorder, a commonly replicated finding from various PTSD populations is hyperactivity of the amygdala in response to masked fearful faces or trauma-related stimuli [3,28,29]. This manifests as higher amygdala reactivity as compared to non-PTSD groups and/or a positive correlation between severity of PTSD symptoms and amygdala reactivity [28,30-33]. Furthermore, in a group of unmedicated acute PTSD subjects (1 month post trauma), the degree of PTSD symptoms also positively correlated with activity of the amygdala in response to masked fearful faces [34]. Thus, amygdala hyperactivity observed in chronic PTSD appears early in the disorder. However, it should be noted that in these same individuals, the degree of PTSD symptoms negatively correlated with activity in the amygdala in response to unmasked fearful faces [34]. This suggests amygdala hypoactivity in response to consciously-processed fearful stimuli in the early stages of PTSD, further implying a dissociation in amygdala activity in response to consciously-processed versus unconsciously-processed fearful stimuli. Interestingly, activity of the amygdala in response to fearful stimuli might not only be characteristic of PTSD, but might predict treatment outcome. Bryant et al [33] show that individuals diagnosed with PTSD that do not respond to CBT (8 one weekly sessions) show significantly greater pre-treatment amygdala activation in response to masked fearful faces as compared to those PTSD subjects who did respond to CBT, as defined by a 50% or more reduction in scores on the Clinician-Administered PTSD Scale (CAPS). Therefore, hyper-function of the amygdala might provide a useful tool for future selections of treatment options for PTSD.
Similar to PTSD and social anxiety disorder, amygdala hyperactivity as a result of highly emotional stimuli presentation or symptom provocation has been observed in specific phobia, panic disorder, and OCD [35-38]. Given the prevalence of GAD, it is surprising that few studies have assessed amygdala reactivity in GAD participants. Somewhat more surprising is that of those studies that have determined amygdala activity in response to emotive stimuli in adult GAD populations, a lack of amygdala hyperactivity has been observed [27,39,40]. This stands in contrast to findings from pediatric GAD, where hyperactivity of the amygdala is apparent in response to emotional stimuli and positively correlated with symptom severity [41,42]. However, recent findings examining amygdala function within paradigms that elicit anticipatory anxiety or emotional conflict have implicated a role for amygdala hyper-reactivity in adult GAD populations. For example, Nitschke et al. [43] report greater anticipatory amygdala activation in response to both emotional and neutral images in adult GAD subjects. Furthermore, Etkin et al [44] found that adult participants with GAD exhibited poor performance on a task that involved emotional conflict (incongruent visual emotional stimuli), accompanied by a failure of the frontal cortex to exert negative top-down control of amygdala activity (see Section 3.1 for more on top-down control of the amygdala). Therefore, amygdala hypofunction in adult GAD might be better revealed by imaging studies that create anxiogenic or conflict situations, rather than the standard presentation of fearful stimuli. While this conclusion requires direct testing, the findings that anxiogenic but not fearful stimuli reveal hypofunction of the amygdala in GAD, whereas fearful stimuli consistently elicit amygdala hyper-reactivity in other anxiety disorders (such as social anxiety disorder, PTSD and also pediatric GAD), suggests a neural dichotomy between GAD and other anxiety disorders on the anxiety to fear continuum.
In summary, there appears to be reasonable overlap across various experimental paradigms and study populations to conclude that the amygdala is reactive to fearful stimuli and anxiogenic situations, and exhibits hyper-function to emotive stimuli, anxiogenic situations and/or symptom provocation in anxiety disorders. However, which neurotransmitters and subregions of the amygdala mediate these responses if often better answered by animal studies, where spatial and neurochemical resolution is greatly improved over human imaging studies.
As discussed above, hyper-function of the amygdala appears to be a key component of human anxiety disorders. However, the contribution of particular amygdalar subregions in the development and maintenance of this hyperactive state in humans is still being established. Only very recently have refinements in the acquisition and analysis of fMRI data allowed subregion function to be segregated effectively during emotional tasks such as avoidance learning [45] and facial expression recognition [21,46]. Similarly, effective structural identification of human amygdalar subregions and assessment of their functional connectivity using imaging techniques is still fairly new [for example, see 47-51]. Therefore, most of our understanding of causal neurochemical pathways in amygdalar circuitry related to fear and anxiety has derived from extensive studies using rodent and non-human primate models [for example, see 9,52-58].
Anatomical arrangement of the mammalian amygdala appears to have been evolutionarily conserved, with particular subregions being connected to homologous brain structures across species [as reviewed by 59]. The lateral (LA) nucleus of the amygdala is reciprocally connected with the auditory, somatosensory and visual sensory association centers in the temporal and insular cortices [59], and in rats also receives further auditory information via projections from the posterior thalamus [59,60]. The medial amygdala (MeA) is reciprocally connected with the accessory olfactory bulb and many hypothalamic and preoptic nuclei [59,61], creating a locus for assimilation of olfactory stimuli and information regarding internal hormonal state [62,63]. Information summated within the LA and MeA is then conveyed to the adjacent basal (B) and accessory basal (AB) nuclei [64], which also receive projections from the CA1 and subiculum areas of the ventral hippocampus [65-67]. The B/AB nuclei send excitatory and inhibitory projections back to the LA and MeA [64,68], creating a localized circuit that may assist in fine-tuning the filtering of sensory input into these regions [64]. Excitatory projections from this basolateral (BLA) complex target the central nucleus of the amygdala (CeA) either directly or via a series of GABAergic interneurons known as intercalated (ITC) cells located between the BLA and CeA [69], providing an effective means of gating CeA activity and output through a combination of direct excitation and feed-forward inhibition [64,70,71]. The CeA itself, principally the medial sector, sends GABAergic projections to brainstem, hypothalamic and basal forebrain regions that control expression of autonomic, hormonal and behavioral responses to emotive situations 72,73]. It should also be noted that in addition to activating the CeA, the BLA projects to the adjacent bed nucleus of the stria terminalis (BNST), which in turn targets many of the same regions as the CeA to produce similar behavioral and physiological responses [73]. The MeA is also able to regulate these responses not only via its influence on hypothalamic nuclei and brainstem targets, but by modulating activity in the BNST and CeA [61,64].
The functional connectivity between the BLA, MeA and CeA ensures that sensory and contextual information associated with emotional situations, such as fearful or anxiogenic circumstances, is channeled to effector regions to produce appropriate responses necessary for survival. The BLA and CeA, unlike the MeA, do not appear necessary for expression of unconditioned fear responses to olfactory stimuli in rodents, e.g., to novel presentation of predator odor [74-76], although the BLA does appear to play a role in responses to other types of unconditioned stimuli [77,78]. However, the functional arrangement of the BLA and CeA with other regions facilitates learning about the situation, such that appropriate reactions are maintained if cues associated with initial exposure are experienced again. The BLA in particular appears to play a crucial role in encoding positive or negative salience to relevant stimuli for future reference, as indicated by numerous studies showing that the BLA is required for fear learning and acquisition of conditioned fear responses [see 56,60]. Once fear conditioning is acquired, the CeA is necessary for expression of the conditioned response [56,60], the magnitude of which will be influenced by BLA gating of CeA activity and output. Similarly, the BLA is needed for acquisition and expression of fear extinction [79,80], which requires a subject to learn that expression of a previously conditioned fear response is no longer necessary when the conditioned stimulus no longer predicts an aversive event [57,81]. To achieve this, the BLA must integrate new sensory information (absence of the unconditioned aversive stimulus) that will result in a dampening of CeA excitation. This may result from increased BLA excitation of ITC cells during fear extinction acquisition to enhance feed-forward inhibition of the CeA [79,82,83], followed by structural remodeling within the BLA during consolidation of the extinction memory to inhibit later BLA output [79]. However, while the roles of the BLA and CeA in fear behaviors are well established, their contribution to anxiety is less clear, especially for the CeA. Animal studies suggest that changes in BLA and CeA activity can alter state anxiety [9; also see Section 3.2.]. However, most investigations have focused on the BLA with the exact role of the CeA remaining ill-defined [for example, see 84,85], although it appears that BLA to CeA circuitry can directly regulate anxiety-like behavior as measured on the elevated plus maze [EPM, 86]. This direct control is thought to result from BLA excitation of GABAergic neurons in the lateral CeA to induce feed-forward inhibition of output from the medial CeA [86], similar to that induced by BLA excitation of ITC cells during fear extinction. Thus, suppression of CeA output may be equally important for mediating expression of both fear and anxiety. Alternatively, some studies have suggested that it is BLA activation of the BNST, not of the CeA, that is responsible for mediating anxiety-like behavior as measured using light-potentiated startle responses in rodents [56,87,88]. Startle responses are also potentiated by corticotropin releasing factor (CRF) infused into the BNST [56]. This effect is presumed to result through facilitation of glutamate release from BLA afferents by CRF neurons that originate in the lateral CeA [88,89], implying that even if BNST is the principal output center for certain types of anxiety-like behaviors, the CeA may still play some modulatory role. Furthermore, the MeA has been strongly implicated in animal models of state anxiety [for example, see 90-93 and see Section 3.2], but whether its effects involve modulation of CeA activity is unknown. To direct translational research into the neurological underpinning of anxiety disorders more effectively, animal studies employing as wide a range of state anxiety paradigms as possible, along with animal models that generate trait anxiety, are required to establish the exact nature of CeA involvement and of amygdala subregion interplay in mediating anxiety-like behavior.
It is important to remember that while the amygdala can mediate fear and anxiety-like behavior, other brain regions play a major role in expression of these states, presumably by influencing activity in particular amygdalar subregions to alter the balance of output from the CeA. For example, input from the ventral hippocampus to the B/AB nuclei within the BLA is required for expression of conditioned fear responses to contextual cues in rodents and humans [60,94,95], and so receipt of this information presumably increases BLA activity, to in turn enhance CeA output in the aversive context. In rodents, the ventromedial prefrontal cortex (vmPFC) also appears to be crucial in regulating amygdalar activity, especially during fearful experiences [79]. The prelimbic (PL) subregion of the vmPFC can enhance conditioned fear expression via excitatory projections to the BLA and CeA [96-98]. In contrast, expression of conditioned fear appears to be decreased by activation of the infralimbic (IL) subregion of the vmPFC [99, but see 100]. The IL cortex is also required for effective consolidation and recall of fear extinction memories [79,98]. Both decreased conditioned fear responding and fear extinction require suppression of CeA output, which is thought to result in part via IL cortex stimulation of the series of inhibitory ITC cells that project to the CeA [71,79,96,101]. The bidirectional roles of the PL and IL cortices in regulating conditioned fear through opposing influences on CeA activity and output imply that imbalance in the influence of either cortical structure could contribute to amygdala hyperactivity seen in anxiety disorders characterized by excessive and inappropriate fear (see Table 1). This is supported by fMRI studies investigating neural correlates of impaired fear extinction in PTSD patients, who compared to healthy subjects show hyperactivity of the amygdala during extinction learning [102]. This enhanced amygdala function in PTSD patients is accompanied by greater activation of the dorsal anterior cingulate cortex (dACC, functionally equivalent to the rodent PL cortex, [3,57], which is also present during recall of the extinction memory [102]. This is in line with rodent studies demonstrating potentiated fear conditioning upon PL cortex activation [98]. However, PTSD individuals exhibit hypoactivation of the ventral portion of the vmPFC (equivalent to rodent IL cortex, [3,57]) during extinction learning and recall [102,103]. Human imaging studies also suggest that impaired regulation of amygdala activity by the ventral vmPFC may contribute to anxiety disorders characterized by hypervigilance in the absence of conditioned stimuli, such as in GAD. Specifically, the strength of the connection between the vmPFC and the amygdala, as measured using diffusion tensor imaging, predicts levels of self-reported trait anxiety, such that weaker connections are seen in more anxious individuals [104]. As mentioned earlier (Section 2.2), participants with GAD exhibited a failure of the vmPFC to exert negative top-down control of amygdala activity during a task that involved emotional conflict [44]. Further, resting state fMRI revealed that in anxious individuals, vmPFC activity was negatively correlated with amygdala activity, while a positive relationship was observed for low anxious subjects [105]. The combination of animal and human studies strongly indicates that inadequate suppression by the ventral portion of the vmPFC, most likely of the CeA, is a key factor in amygdala hyperactivity underlying the emergence of excessive fear and anxiety states.
The monoamine neurotransmitters (serotonin, dopamine and norepinephrine) have long been associated with fear and anxiety, and drugs that alter monoaminergic function are often effective across the range of anxiety disorders [8, 9, 52, 55]. Animal studies suggest a variety of anxiogenic stressors or fearful stimuli increase monoamine levels in the amygdala. To illustrate, increased serotonin (5-HT) release or increased activity of 5-HT neurons in the amygdala have been observed in response to restraint or footshock, or in association with expression of conditioned fear behavior [106-110]. Similarly, dopamine (DA) and norepinephrine (NE) levels in the amygdala are increased following restraint, handling stress, footshock or during the expression of conditioned fear behavior [107,111-118]. The source of monoamines to the amygdala arise from monoaminergic cell body regions in the brainstem. Specifically, the dorsal raphe nucleus (dRN) provides 5-HT innervation to the amygdala, while NE and DA innervation of the amygdala arise from the locus coeruleus (LC) and ventral tegmental area (VTA) respectively [55,119,120]. Regulation of monoaminergic activity in the amygdala thus can occur at the level of these brainstem cell body regions, or within the terminal regions of the amygdala.
One of the important mediators of amygdala monoaminergic activity in response to anxiogenic or fearful stimuli is CRF. A strong body of evidence implicates central CRF in mediating fear and anxiety [12,121-128], and recent clinical studies suggest an important role for CRF in anxiety disorders [129]. Like anxiogenic and fearful stimuli, central infusion of CRF or CRF receptor agonists increases 5-HT, NE and DA levels in the amygdala [130-133], and stress-induced increases in monoamine levels in the amygdala are prevented by CRF receptor antagonists [108,111]. It is thought that CRF regulation of monoaminergic activity in the amygdala occurs at the level of the monoaminergic cell bodies. The monoaminergic cell body regions receive CRF innervation from the CeA and BNST, and CRF type 1 and 2 (CRF1 and CRF2) receptors are localized to the dRN, LC and VTA [134-140]. Direct infusion of CRF or CRF receptor agonists into the dRN stimulates 5-HT release in the CeA or BLA [131-133]. Interestingly, CRF-induced 5-HT release in the amygdala appears to be dependent on CRF2 receptor activation in the dRN [131,133], and CRF2 receptors are known to increase 5-HT neuronal firing rates in the dRN [141]. Importantly, increased neuronal surface expression of CRF2 receptors occurs in the dRN as a result of stress [142], and increased expression of CRF2 receptors in the dRN has been observed in rat models of high anxiety [11,128,137,143]. Furthermore, CRF2 receptor antagonists infused directly into the dRN reduce heightened anxiety-like behavior in rat models of amphetamine withdrawal or early life stress [12,128]. Combined, these findings suggest that CRF2 receptor modulation of 5-HT activity in the amygdala may play an important role in heightened anxiety. While similar studies have not been performed to elucidate the role of CRF receptors in the LC and VTA in mediating NE and DA activity in the amygdala and anxiety states, some indirect evidence suggests an important role for CRF receptors in the LC and VTA stress responses [136,138,144]. Overall, it is clear that further investigations are needed to ascertain the role of CRF receptors in mediating NE and DA activity in the amygdala and how CRF modulation of this activity could relate to fear or anxiety.
Studies demonstrating increased monoamine activity in the amygdala in response to anxiogenic or fearful stimuli, and CRF modulation of these responses (as described above) do not allow conclusions to be made about the specific role of each monoamine in mediating anxiety or fear. Direct manipulation of monoaminergic activity within the amygdala or specific amygdala subregions, and the measurement of resultant anxiety-like or fear-related behaviors, have gone some way to providing a picture of how monoamine function in the amygdala might translate to anxiety or fear. Table 2 summarizes such studies directly manipulating 5-HT levels or 5-HT receptor activity in the amygdala. When 5-HT or 5-HT activity is decreased in the entire amygdala [145,146], a consistent increase in anxiety-like behavior is observed (Table 2). This would suggest that increased 5-HT activity in the amygdala would thus be associated with decreased anxiety, implying an anxiolytic role of 5-HT. However, this does not appear to be supported by experiments that directly manipulate 5-HT receptor activity in the amygdala with 5-HT receptor ligands (Table 2). For example, activation of postsynaptic excitatory 5-HT2 or 5-HT3 receptors in the amygdala decreases social interaction and increases anxiety-like behavior, whereas antagonism of 5-HT3 receptors in particular increases social interaction and decreases anxiety-like behaviors, suggesting that 5-HT actions on postsynaptic receptors is anxiogenic (Table 2), although, see [147] for an exception to this pattern. Similarly, activation of excitatory 5HT2 receptors in the BLA generally increases anxiety-like behavior (Table 2), suggesting an anxiogenic role for postsynaptic 5-HT receptors in the BLA (although an exception to this is observed, [148]). In contrast, inhibitors of 5-HT2 receptors in the MeA increase anxiety-like behavior while activation of these receptors increases social interaction and decreases anxiety behavior (Table 2). Thus like the some findings from the amygdala as a whole (Table 2), 5-HT activity in the MeA appears to play an anxiolytic role. The role of 5-HT or 5-HT receptors has not been well studied in the CeA. However, rats undergoing amphetamine withdrawal that exhibit greater anxiety-like behavior have greater 5-HT release in the CeA [12,133], suggesting a similar anxiogenic relationship between 5-HT and anxiety as for the BLA. Future work should determine whether 5-HT in the CeA reduces anxiety-like behaviors as is suggestive for the MeA, or in contrast, increases anxiety-like behaviors as appears to be the case for the BLA. Overall, the findings summarized in Table 2 suggest a dichotomy in the potential role of 5-HT in the amygdala in mediating anxiety depending on whether the entire amygdala or a specific subregion is targeted. Potential confounds in comparing the studies listed in Table 2 could be the different paradigms used to measure anxiety-like behaviors and the relative selectivity of 5-HT receptor ligands across different experiments. Future studies directly comparing the effects of 5-HT manipulations within the different amygdala subregions across several well-validated tests of anxiety-like behaviors will better elucidate the role of amygdala 5-HT in mediating anxiety.
Amygdala Subregion | Monoamine or Receptor Involvement | Behavioral Outcome | Citation |
Amygdala | Decreased 5-HT (induced by MDMA) | Increased anxiety behavior | Faria et al. [145] |
Amygdala | Decreased 5-HIAA (induced by stress) | Increased anxiety behavior | Niwa et al. [146] |
Amygdala | 5-HT1A agonist | No change in anxiety behavior | Zangrossi and Graeff [149] |
Amygdala | 5-HT2B/2C agonist | Increased anxiety behavior | Cornelio and Nunes-De-Souza [150] |
Amygdala | 5-HT3 agonist | Decreased social interaction | Higgans et al. [151] |
Amygdala | 5-HT3 agonist | Decreased anxiety behavior | Costall et al. [147] |
Amygdala | 5-HT3 antagonist | Increased social interaction | Higgans et al. [151] |
Amygdala | 5-HT3 antagonist | Decreased anxiety behavior | Costall et al. [147] |
Amygdala | 5-HT3 antagonist | Decreased anxiety behavior | Tomkins et al. [152] |
BLA | 5-HT1A agonist | Decreased social interaction | Gonzalez et al. [153] |
BLA | 5-HT1A agonist | No change in anxiety behavior | Gonzalez et al. [153] |
BLA | 5-HT2A agonist | Increased anxiety behavior | Zangrossi and Graeff [149] |
BLA | 5-HT2A/2C agonist | No change in anxiety behavior | Cruz et al [148] |
BLA | 5-HT2C agonist | Increased anxiety behavior | Vincente et al. [154] |
MeA | 5-HT2A antagonist | Increased anxiety behavior | Zangrossi and Graeff [149] |
MeA | 5-HT2 agonist | No change in anxiety behavior | Duxon et al. [155] |
MeA | 5-HT2B agonist | Increased social interaction | Duxon et al. [156] |
MeA | 5-HT2B agonist | Decreased anxiety behavior | Duxon et al. [155] |
MeA | 5-HT2B/2C agonist | No change in anxiety behavior | Duxon et al. [155] |
CeA | Increased 5-HT | Increased unconditioned freezing | Forster et al. [132] |
BLA | Increased 5-HT | Decreased conditioned freezing | Inoue et al. [157] |
BLA | Increased 5-HT | Decreased unconditioned tonic immobility | Leite-Panissi et al. [158] |
BLA | 5-HT1A agonist | Decreased conditioned freezing | Li et al. [159] |
BLA | 5-HT1A agonist | Decreased acquisition and expression of conditioned defeat | Morrison et al. [160] |
BLA | 5-HT1A/2 agonist | Decreased unconditioned tonic immobility | Leite-Panissi et al. [158] |
The Role of Serotonin in Anxiety-Like and Fear-Related Behaviors
Determining the role of amygdala 5-HT in fear-related behavior has mainly utilized studies of freezing or immobility responses in rodents, and of 5-HT manipulation in the BLA (Table 2). From these studies, it seems clear that 5-HT in the BLA decreases the expression of unconditioned and conditioned fear responses, likely via activation of the inhibitory postsynaptic 5-HT1A receptor (Table 2). Thus, it has been suggested that 5-HT in the BLA/amygdala ameliorates fear [8]. This conclusion is in contrast to the apparent role for BLA 5-HT in enhancing anxiety (Table 2), suggesting a fear versus anxiety dissociation for the role of 5-HT in the BLA. This dissociation, if upheld by more in-depth future work, could prove important information for the development of treatment strategies for the various anxiety disorders that differ in the degree of anxiety-like and fear-like symptomology (as discussed in Section 1.1).
A role for amygdala DA in anxiety has not been as well explored as for 5-HT. However, a summary of studies that have manipulated DA function in the amygdala provides a consistent picture of the role of amygdala DA in mediating anxiety in animal models (Table 3). Indirect evidence suggests that decreased DA in the amygdala leads to increased anxiety, and this is supported by direct manipulation of the CeA (Table 3). For example, decreased DA or DA receptor antagonism within the CeA all increase anxiety-like behavior (Table 3), suggesting that DA activity in the CeA is anxiolytic. This role for DA in the CeA is in direct contrast to the BLA, where converging evidence suggests that decreased DA function in the BLA decreases anxiety-like behaviors while increased DA receptor activity in the BLA increases anxiety (Table 3). Thus, DA activity in the BLA is anxiogenic, revealing an opposite role for DA activity in the CeA and BLA in mediating anxiety-like behaviors in animal models.
Amygdala Subregion | Monoamine or Receptor Involvement | Behavioral Outcome | Citation |
Amygdala | Decreased DA | Decreased rearing in open field indicative of increased anxiety behavior | Summavielle et al. [163] |
CeA | Decreased DA | Decreased voluntary activity indicative of increased anxiety behavior | Izumo et al. [164] |
CeA | D1 antagonist | Increased anxiety behavior | Rezayof et al. [165] |
CeA | D2/3 antagonist | Increased anxiety behavior | de la Mora et al. [166] |
BLA | DA depletion | Decreased anxiety in males but not females | Sullivan et al. [167] |
BLA | D1 agonist | Increased anxiety behavior | Banaej et al. [168] |
BLA | D2 agonist | Increased anxiety behavior | Banaej et al. [168] |
BLA | D1 antagonist | Decreased anxiety behavior | Banaej et al. [168] |
BLA | D1 antagonist | Decreased anxiety behavior | de la Mora et al. [169] |
BLA | D2 antagonist | Decreased anxiety behavior | Banaej et al. [168] |
Amygdala | D2 antagonist | Decreased acquisition and retention of fear conditioning | Greba et al. [170] |
CeA | D1 agonist | Increased conditioned fear behavior | Guarraci et al. [171] |
CeA | D1 antagonist | Inhibited conditioned fear behavior | Guarraci et al. [171] |
CeA | D2 antagonist | Decreased conditioned fear behavior | Guarraci et al. [172] |
BLA | DA depletion | Decreased fear conditioning | Seldon et al. [173] |
BLA | D1 antagonist | Inhibited acquisition of fear conditioning | Greba and Kokkinidis [174] |
BLA | D2 antagonist | Inhibited fear potentiated startle | De Oliveira et al. [175] |
The Role of Dopamine in Anxiety-Like and Fear-Related Behaviors
In contrast, the role of DA in mediating fear-related behaviors does not appear to differ based on amygdala subregion (Table 3). Reducing DA function in the amygdala reduces or inhibits processes associated with fear conditioning, while increasing DA receptor activity increases conditioned fear (Table 3). Thus, DA in the amygdala is required for fear conditioning, and enhanced DA levels in the amygdala as elicited by fearful stimuli and conditioned cues [107,112] would thus facilitate fear conditioning. It should be noted that the studies summarized by Table 3 indicate a role for both excitatory D1 receptors and inhibitory D2 receptors. Dopamine D2 receptors are localized both pre- and post-synaptically, with pre-synaptic D2 autoreceptors limiting DA neuronal activity and DA release [161,162]. Thus, antagonism of presynaptic D2 receptors would actually increase DA within the amygdala. Since the effects of D2 receptor antagonism on fear-related behaviors is characteristic of reduced, not enhanced, DA function in the amygdala, it may be concluded that the results of D2 receptor antagonism summarized by Table 3 are due to postsynaptic D2 receptor effects. However, this conclusion requires direct testing.
Very few studies have examined the role of amygdala NE in mediating anxiety-like behavior in animal models, surprising given that anxiogenic stimuli increase NE in this region [for example, see 111,115,116] and drugs that alter NE neurotransmission are used to treat anxiety disorders [8]. There appears to be little role for NE receptors in the CeA in mediating anxiety-like behavior, although infusion of a α1 antagonist can increase social interaction following an anxiogenic stimulus [restraint; 176; Table 4]. It is clear that more experiments are required to delineate the role of amygdala NE in mediating anxiety.
Studies determining the role of NE in fear-related behaviors have concentrated on the BLA, due to the importance of this amygdala subregion in conditioned fear responses (see Section 3.1.). The major focus of the studies summarized by Table 4 has been on the role of NE in fear conditioning and reconsolidation of fear memories in conditioned fear paradigms. Taken as a whole, findings suggest that NE in the BLA facilitates fear conditioning and fear memory, via activation of adrenergic β receptors (Table 4). Recent evidence suggests a role for α1 receptors in the BLA in mediating fear memory, in this case, activation of α1 receptors by NE would appear to decrease fear memory (Table 4). Thus, it is possible that NE in the BLA could have opposing effects on reconsolidation of fear memory based on the balance of α1 versus β receptor activity – a hypothesis that requires direct testing. The role of NE in the BLA (and β receptors in particular) in fear memory has generated interest in targeting this NE system for the treatment of anxiety disorders where enhancement in fear memory is apparent, such as PTSD [for example, see 177]. Whether NE within the BLA plays a role in other aspects of fear processing (e.g. unconditioned fear responses to non-olfactory based stimuli) or NE within other amygdala subregions mediate fear should be subjects of future investigations to fully elucidate the role of amygdala NE in fear.
Amygdala Subregion | Monoamine or Receptor Involvement | Behavioral Outcome | Citation |
CeA | α1 antagonist | Increased social interaction | Cecchi et al. [176] |
CeA | α1 antagonist | No effect on anxiety behavior | Cecchi et al. [176] |
CeA | β1/2 antagonist | No effect on social interaction | Cecchi et al. [176] |
CeA | β1/2 antagonist | No effect on anxiety behavior | Cecchi et al. [176] |
BLA | Increased NE | Increased memory and retention of fear conditioning | LaLumiere et al. [178] |
BLA | Decreased NE | Impaired fear conditioning | Seldon et al. [173] |
BLA | Decreased NE | Impaired fear memory | Debiec and LeDoux [177] |
BLA | α1 antagonist | Increased fear memory | Lazzaro et al. [179] |
BLA | β1/2 antagonist | Impaired of fear memory | Debiec and LeDoux [180] |
BLA | β1 antagonist | Impaired fear memory (as enhanced by glucocorticoids) | Roozendaal et al. [181] |
The Role of Norepinephrine in Anxiety-Like and Fear-Related Behaviors
In summary, it is clear that more work is required to fully understand the role of amygdala monoamines in mediating fear and anxiety. However, several patterns of interest emerge from the current literature, namely that there are distinct subregion differences in the role each monoamine plays in mediating anxiety and fear, with the one monoamine possibly playing opposing roles depending on subregion or depending on whether anxiety or fear measures are employed. Therefore, these findings suggest neurochemical dissociations between amygdala subregions and monoamines in mediating fear or anxiety.
Psychopharmacological management of anxiety disorders includes the benzodiazepines, antidepressants, 5-HT1A agonists and various “off-label” drugs such as β-blockers, mood stabilizers and antipsychotics. The mechanism by which these drugs produce anti-anxiety effects has yet to be definitively established and represents a frequently updated field of research. Because these drugs bind to target receptors throughout the brain, it is unlikely that their efficacy can be attributed to action in one particular region. However, given the role that the amygdala plays in fear and anxiety, modification of amygdala function by pharmacological agents represents a likely mechanism of action as well as a target to guide future drug development. The evidence for amygdala involvement in anxiolytic action comes from both human imaging studies as well as work in animal models.
Given the highly complex and subjective nature of anxiolytic drug response in humans, neuroimaging represents an invaluable tool for drug evaluation and discovery.
Various studies have utilized healthy volunteers undergoing experimental challenges in an attempt to elucidate the neurobiology underlying the anxiolytic effect of benzodiazepines. These studies have found that benzodiazepines have the ability to impair functions related to amygdala activity including fear conditioning [184-186], recognition of fearful emotional faces [187], and memory for emotional stimuli relative to neutral stimuli [188,189].
Neuroimaging work appears to support a role for the amygdala in benzodiazepine action, although this may be dependent upon the nature of the accompanying neuropsychological challenge. Specifically, lorazepam was found to decrease amygdala activation during an emotional face assessment task without modifying baseline levels of anxiety or task recognition [190]. A similar finding was found with diazepam, which decreased amygdala response to fearful faces, and also impaired fearful face recognition [191]. However, during anticipation of aversive electrical stimulation, lorazepam failed to produce changes in amygdala activity [192]. Thus, while there is support for benzodiazepine induced modulation of the amygdala during processing of threatening/emotional stimuli, further studies are needed to clarify the neural correlates of benzodiazepine-induced anxiolysis.
Most antidepressants are unique from benzodiazepines and β-blockers in that a time lag exists between initial treatment and onset of anxiolytic effects. In line with a potential anxiogenic role of serotonin in the amygdala (see Table 2 and associated text), some patients have reported an initial exacerbation of anxiety upon acute dosing of SSRIs [203]. In studies on healthy subjects, acute dosing of the SSRI citalopram can enhance recognition of fearful faces as well as increase emotion-potentiated startle response [204-206]. These effects are reversed when citalopram treatment is continued for 7 days [207,208].
Attempts to correlate the acute versus sub-chronic effects of SSRIs with neural activation have resulted in unexpected findings. On one hand, sub-chronic citalopram treatment was found to decrease amygdala activation to unconscious fearful stimuli [209], suggesting a relationship between repeated SSRI treatment, changes in emotional processing, and decreased amygdala activity. However, acute doses of citalopram have also been found to decrease amygdala activation to fearful faces [208,210,211]. Divergent effects of acute versus sub-chronic citalopram on emotional recognition but similar effects on amygdala response could suggest that the amygdala does not play a core role in acute SSRI-induced anxiety or chronic SSRI-induced anxiolysis. However, it has been emphasized that the effects of serotonergic challenge on fear recognition and amygdala activation appear to be dependent upon the individual’s baseline sensitivity to threat [212], gender [213] and genotype [214]. Thus differences in subject profiles both between and within studies could have confounded results.
Overall, it appears that pharmacotheraputics commonly used to treat anxiety disorders may modulate amygdala function. In particular, it appears that anxiolytics can reduce amygdala reactivity to highly emotive or fearful stimuli. Given that amygdala hyper-reactivity to similar stimuli is the most common finding across all anxiety disorders (with the exception of adult GAD – see Section 2.2), it is possible that the anxiolytic effects of these drugs may be in part, mediated by dampening amygdala function.
As discussed in the human studies in Section 4.1 above [184,188,189], a key aspect of benzodiazepine action may be the ability to modulate emotional memory. Here the BLA once again appears to be a main site of benzodiazepine action. Lesions of the BLA, but not the CeA, block the benzodiazepine induced deficits in inhibitory avoidance memory [225,226]. Similar impairments were seen by direct injection of benzodiazepine into the BLA and not the CeA [227]. Enhancement of memory consolidation could be induced by BLA infusion of a benzodiazepine antagonist [228]. Given that individuals with anxiety disorders may be hypervigilant to cues associated with threatening stimuli and biased to form memories regarding such stimuli [229,230], the pro-amnestic effects of benzodiazepines in the BLA may represent a putative mechanism of action.
Despite the action of β-blockers within the amygdala to modulate fear conditioning (see Table 4), attempts at testing propranolol in other animal models of PTSD have met with mixed results, echoing the mixed efficacy seen thus far in humans [199,200,239,240]. One such model is exposure to predator odor in rodents, which produces long lasting increases in anxiety like behavior [241-243]. The increases in anxiety like behavior following exposure to predator odor is influenced by a long lasting potentiation in BLA activity [243], supporting the role of the amygdala in mediating the consequences of fear and trauma. Propranolol administered 1 minute following exposure to predator odor to rats blocks the development of anxiogenesis in various tests, including the EPM, one week later [241]. However, when propranolol administration is delayed to 1 hour following predator odor exposure, no effects are seen when rats are subsequently tested on the EPM 30 days later [242]. These results highlight once again a potential key role of timing if propranolol is to be effectively implemented in clinical patients. Similarly, findings that propranolol seems most effective in blocking the
Much evidence suggests that enhanced activity at 5-HT2C within the BLA by SSRIs produces acute anxiogenic effects, while the eventual downregulation of these receptors by chronic treatment leads to eventual anxiolysis. For example, amygdala or BLA 5-HT2C receptors have been found to produce anxiety-like responses in a variety of tests [249,250] (see Table 2). Blockade of 5-HT2C receptors within the BLA prevents the acute anxiogenic effect of the SSRI fluoxetine on the Vogel conflict test [251]. Systemic 5-HT2C antagonism also prevents the increase in fear conditioning [252], decrease in social interaction [247,253], and escape response to airjet [254] following acute SSRI treatment. Following chronic treatment with SSRIs, 5-HT2C agonists have attenuated anxiogenic effects on the exacerbation of OCD symptoms in humans [255,256], on social interaction [257] and hyperlocomotion [258], suggesting down-regulation of the ability to 5-HT2C receptors in the amygdala to produce anxiogenic responses following chronic SSRI treatment. Thus, the amygdala (BLA in particular) may be an important locus of action for the long-term effects of SSRIs on anxiety.
The literature reviewed above suggests that in part, the effects of anxiolytic drugs may be mediated by altering amygdala function – either global dampening of the amygdala by benzodiazepines, or specific actions on 5-HT and NE receptors within particular amygdala subregions. However, to improve therapeutic efficacy and reduce relapse, several aspects of amygdala pharmacology discussed above might provide useful potential anxiolytic targets in the future.
Findings suggesting down-regulation of anxiogenic 5-HT2C receptors in the amygdala following chronic SSRI treatment (Section 4.2.) present a potential strategy of reducing onset latency of SSRIs as well as enhancing their effects. Specifically, blocking 5-HT2C receptors at the initiation of SSRI treatment would be expected to produce a faster onset of anxiolytic action. Currently, there are no selective 5-HT2C antagonists available for human use. However, atypical antipsychotics [259] as well as atypical antidepressants such as mirtazapine [260] possess 5-HT2C antagonist activity. While there is evidence that antipsychotic augmentation of SSRIs may improve anxiolytic efficacy, their use has been limited by poor tolerability [for review see 261]. Although research is lacking, mirtazapine and the melatonin receptor agonist/5-HT2C receptor antagonist agomelatine [262] may provide the advantage of targeting anxiogenic 5-HT2C in the amygdala with less side effects.
Furthermore, the recent observation that β-adrenoreceptor activation within the BLA results in decreased of GABAA receptor surface expression necessary for fear reinstatement [234] (and see Section 4.2.) suggests that the combination of propranolol and a benzodiazepine may have unique benefit for PTSD. By blocking β-adrenoreceptors with propranolol, one might be able to enhance benzodiazepine receptor availability, and increase benzodiazepine-induced inhibition of fear circuits within the amygdala. While currently speculative, the use of propranolol to enhance benzodiazepine action in the amygdala may represent a potential creative treatment strategy in a population that is traditionally refractory to benzodiazepine treatment.
While current pharmacotherapeutic strategies for the treatment of anxiety disorders target monoamine function, this has predominantly been related to altering 5-HT or NE levels or receptor activity [8]. However, Table 3 clearly shows a role for DA in the amygdala in mediating both fear and anxiety, and the role for DA and both D1 and D2 receptors in acquisition and retention of conditioned fear in particular appears quite robust. Thus, reducing DA function might serve as means by which to treat anxiety disorders in which fear plays a major component. The obvious disadvantage of dopaminergic-based pharmacotheraputics is potential for major cognitive and motoric side-effects, limiting the treatment options with the currently available dopaminergic agents. Atypical antipsychotic drugs incorporate DA receptor blocking activity while avoiding many of the motoric and cognitive issues of traditional agents. There is evidence that atypical agents possess anxiolytic activity [261], but metabolic side effects make them poorly tolerated. Furthermore, because atypical antipsychotics also have high affinity for 5-HT receptors, the contribution of DA modulation to their anxiolytic effects in humans is currently unknown. One potential strategy may be the use of partial agonists to reduce DA activity in the amygdala via activation of inhibitory presynaptic D2 autoreceptors. While non-selective for DA, the D2 partial agonist aripiprazole has demonstrated anxiolytic efficacy similar to other atypical antipsychotic drugs [263]. In the future, more selective DA partial agonists may have additional benefit without unwanted side-effects.
Finally, CRF has been identified as an important neuropeptide in the regulation of monoaminergic activity in the amygdala in response to anxiogenic or fearful stimuli (Section 3.2). Furthermore, CRF and its receptors (CRF1 and CRF2) are implicated in fear and anxiety within animal models and in the development of anxiety disorders [12,121-129]. Upon the development of non-peptide CRF1 receptor antagonists that cross the blood-brain barrier, there was great interest in the use of CRF1 receptor antagonist in the treatment of anxiety disorders. To date, there have been limited phase II clinical trials published regarding the use of CRF1 receptor antagonists in anxiety disorders [264]. Of those, preliminary findings suggest the CRF1 receptor antagonist-treated groups did not differ from placebo-treated groups in anxiety symptomology in both social anxiety disorder and GAD [264]. However, it has been suggested that efficacious concentrations have not been established for the various CRF1 receptor antagonists, and it is clear that further clinical trials are necessary. One potential promising area in the treatment of anxiety disorders may actually lie in CRF2 receptor antagonists. As outlined in Section 3.2, CRF2 receptors mediate 5-HT activity in the amygdala, are up-regulated in animal models of anxiety, and an antagonist of this receptor reduces heightened anxiety in rats [11,12,127,128,131,132,137]. The challenge lies in developing non-peptide CRF2 receptor antagonists that cross the blood-brain barrier, so that the efficacy of such ligands can be determined for anxiety disorders.
Human imaging studies in non-patient populations suggest amygdala activation in response to fearful stimuli, and that the magnitude of this response is positively correlated with trait anxiety. Furthermore, individuals suffering from an anxiety disorder (with the possible exception of adult GAD) show exaggerated amygdala responses to fearful or emotive stimuli, which again is positively correlated with the severity of symptoms. Moreover, reactivity of the amygdala to fearful stimuli is reduced by anxiolytic drugs in healthy subjects, and long-term pharmacotherapy or CBT reduces amygdala hyper-reactivity in anxiety disorders. Animal studies corroborate an important role for the amygdala in fear and anxiety, with specific subregions mediating acquisition and expression of fear, fear memories and anxiety, and the monoamines within each of these regions often playing a very specific role in facilitating or attenuating fear or anxiety. Both human and animal studies suggest dysfunction of the amygdala might arise in part, from inadequate top-down control by regions such as the medial prefrontal cortex, and in part, from altered neuropeptide regulation of amygdala monoaminergic systems. Overall, the amygdala plays a critical role in anxiety disorders, and understanding the function of this region in fear and anxiety states and how dysfunction of the amygdala results in anxiety disorders is critical to improving long-term treatment outcomes.
AcknowledgementThis work was supported by National Institutes of Health grant R01 DA019921, and Department of Defense grants W81XWH-10-1-0925 and W81XWH-10-1-0578.
Air pollution is one of the major global public health concerns. This has been reflected in the recently published report by the World Health Organization (WHO) that, only 10% of people live in cities, which conforms with the WHO air quality guideline. What is shocking is that air pollution causes death of one person in every nine people annually, and outdoor air pollution on its own is causing deaths of 3 million people every year [1]. It is also worth noting that, air pollutants in urban areas can be contributed by local sources and long-range transport of air masses [2, 3, 4], for instance, transport of dust mass from Gobi desert to East Asia [5, 6, 7] and from Sahara desert to Europe [8, 9]. These urban aerosols have been reported by a number of authors [10, 11] to have ecotoxicities that are potential for causing health problems [12, 13, 14].
So far, China is the fastest-growing country in the world with a pace which has never been seen before. This growth is partially contributed by heavy investments in manufacturing industries for different kinds of products. This has got an impact on air pollution as most of these industries to use coal as one of the major sources of power; the habitual use of coal for heating in the households by rural dwellers also contributes to the impacts [15, 16]. Besides, lifestyle changes caused by the change of economic status like the increase in the number of vehicles as it can be seen in most of the Chinese cities, to a greater extent worsen the air quality for the country. This has reinforced the Chinese government to make efforts in mitigating air pollution problems, which include the enactment of a stringent law (National Ambient Air Quality Standard (NAAQS)) in 2012 to curb the emission of air pollutants. The NAAQS stipulates the hourly, daily, and annual standards of NO2, SO2, CO, O3, PM10, and PM2.5; the PM10 and PM2.5 stand for particulate matter with the aerodynamic diameter of less than 10 microns and 2.5 microns, respectively. So far, a number of studies on boundary layer structure, which is the main determinant of air pollutants, are available online [3, 4, 17, 18, 19, 20, 21]. Apart from the pioneer studies [22, 23, 24, 25] on pollutants forecast by using large-scale circulations, little has been done on this area which is the key for planning and in managing pollutants. This chapter aims at highlighting the linkage between urban aerosol distribution and large-scale circulation, which are potential for forecasting pollutants.
In order to establish the relationship between the pollutants and the AAOI, Singular Value Decomposition (SVD) analysis was used to determine covariance of Geopotential height (GPH) and BLSI. The study by Bretherton
The leading mode of the singular value decomposition (SVD) of geopotential height (GPH) and boundary layer structure index (BLSI) showing (a) Average boundary layer structure index from December 2014 to February 2015 (DJF
Based on the established covariance of GPH–SVD and BLSI–SVD on the subsection above, it is evident that the AAOI has significant influence on the BLSI which at the end determines pollutants distribution. This subsection, therefore, correlated the average of June and July AAOI (JJ–AAOI) (i.e. boreal summer) with the average dust surface mass concentration of PM2.5 of November to February (boreal winter). This dust mass concentration of PM2.5 is the product of MERRA-2 atmospheric reanalysis which has been assimilated with ground and satellite observation. An assessment study on MERRA-2 surface dust mass concentration of PM2.5 by He et al. [31] reveals a significant correlation with surface measured PM2.5 over the Yangtze River Basin (YRB). Similar consistent observation between surface measured and MERRA-2 data (dust surface mass concentration of PM2.5) has also been reported in North China by Song et al. [32]. Therefore, MERRA-2 data are reliable for studying air pollution. It is also worth noting that, November is not a winter month but during this period of time the concentration of PM2.5 is higher, similar to what is experienced during the winter months (December, January, and February (DJF)). Therefore, November was included in the analysis as the winter month to capture its feedback mechanism of AAOI. A previous study by Fan and Wang [30] on the Antarctic oscillation (AAO) and dust weather frequency found that there was a significant correlation between AAO of DJF and surface air temperature in North China.
The average dust surface mass concentration of PM2.5 over the area (115° E–125° E and 30°N–40° N) which showed a significant correlation with the AAOI was determined and used to develop the time series of pollutants with the AAOI. The determined correlation coefficient on this area was 0.42, which is significant at a 95% confidence level. A closer look at the time series of AAOI (Figure 2), showed a consistent lead–lag effect except in the two scenarios (from 1988/1989 to 1993/1994 and 2013/2014 to 2017/2018) where the trends were not obvious. The observed trends which were not obvious are thought to be so because pollutants distribution over the area is determined by more than one system thus there is a possibility that other influential systems were stronger during this period of time than the effect of AAOI. For instance, a study by Chen and Wang [33] suggested the weakened northerly winds and the growth of inversion anomalies in the lower part of the troposphere and the weakened trough over East Asia to be the reason for haze occurrence. So, whenever one of the factors of this inter-dependable system changes, the whole system will behave differently from its normal behavior.
Time series of average dust mass surface concentration of PM2.5 over the area (115°E–125° E and 30°N–40°N) during winter (November to February of the following year) and the average of June and July Antarctic oscillation index (JJ–AAOI) from the year 1980 to 2018. The lead–lag relationship is consistent except in the two scenarios (1988/1989 to 1993/1994 and 2013/2014 to 2017/2018).
Further, the ability of the June and July AAOI (JJ–AAOI) in describing the changes in winter dust mass concentration of PM2.5 and its potential for forecasting pollutants were tested. The linear regression method was used to develop the prediction equation for the dust surface mass concentration of PM2.5 over the region which showed a positive correlation with the AAOI. The dust surface mass concentration of PM2.5 of zonal (115° E–125° E, 30° N–40° N) region was de-trended and used to develop the anomaly time series of PM2.5 concentration. The data set of thirty years [30] from 1980 to 2009 was used to train the system and to formulate the forecasting equation while the data from 2010 to 2007 was used to run the prediction eq. Among the different models (linear, quadratic, cubic, exponential, and logarithmic) which were tested, the linear equation model was found to be the best model (Figure not shown). The developed linear regression equation was modified by adding a percentage error to the training data set and generating a new regression equation. This procedure was repeated several times until the percentage error was reduced, and a more convincing equation was generated. Note that, whenever the process is repeated, new coefficients were generated for the forecast Equation. A number of studies have also used the linear regression equation to forecast weather and climate parameters [34, 35, 36]. The best linear regression equation was;
The dependent variable (
The predicted trend was almost the same with the measured values of the anomaly of dust surface mass concentration of PM2.5 (Figure 3), even though the magnitude of the values differs. The forecast equation predicted higher values in 3 cases than the anomaly of the actual values. The developed regression equation shows the potential of prediction as it can explain about 60% of the anomaly of the surface dust mass concentration over northeast China. Nevertheless, there was a difference between observed and predicted anomaly values (see Figure 3) because the dust surface mass concentration of PM2.5 does not entirely depend on one factor, thus, small discrepancies suggest the influence of other determining factors. Not only that but also the region (115° E–125° E, 30° N–40° N) covered by the average data is huge, so small changes in the dust mass concentration can result in a large discrepancy. Nevertheless, the correlation coefficient (
Prediction ability test of the linear regression equation for the anomaly of average dust surface mass concentration of PM2.5 for winter (November to February) using the average of June and July Antarctic oscillation index (JJ–AAOI) from the year 2010 to 2017.
For obtaining some more insights and the possible mechanisms that may be the causative agents, the AAOI, and the Antarctic Sea ice were studied. The correlation results of the AAOI and the Antarctic Sea ice concentration show that there is a significant correlation (at 90% confidence level) between them even though the area which shows a significant correlation decreases as the lead–lag time increases (Figure 4a–g). This is because the Antarctic Sea ice distribution is significantly influenced by atmospheric pressure than other factors such as temperature and wind [37, 38, 39, 40]. It is worth noting that, the AAO is also defined based on the GPH anomalies. Nevertheless, the area which shows significant correlation changes with the time of the year (i.e. each month) shows different correlation results. Results from Figure 4a and b suggest that August and September are the most significant months because large areas over the Antarctica region show a significant correlation during these two months.
Correlation map between the average of June and July Antarctic oscillation index (JJ–AAOI) and the Antarctic Sea ice over for the months (a) August (b) September (c) October (d) November (e) December (f) January (g) February for the period of 36 years (i.e. the year 1982–2017). The red (blue) color shows the area with a positive (negative) correlation with JJ–AAOI at a 90% confidence level.
Similarly, previous studies [41, 42] showed that the AAO signal normally tends to lead the climate anomalies by two to three months (one season). Likewise, a study by Carleton [39] revealed that the indices (Southern Oscillation Index (SOI), Trans-Polar Index (TPI)) over SH leads the Antarctic Sea ice for more than four months. The key areas identified in August and September were five [5]; the first area was between 30°E–50°E and 59.5°S–62°S, the second area was between 90°E–110°E and 57.5°S–61.5°S, the third area was between 110°E–170°E and 61°S–64°S, the fourth area was between 110°W–140°W and 65°S–68°S, and the fifth area was between 40°W–60°W and 59°S–65°S. Similar areas of Sea ice were determined in the study by Wu and Zhang [43] to have a strong influence on the atmosphere. The first, second, and fourth key areas showed a positive correlation with AAOI while the third and fifth areas showed a negative correlation. Interestingly, Figure 4c and d show that, during the austral spring season (October and November), the size of the areas which showed a significant correlation (positive and negative) has been reduced. The reduced areas indicate that the influence of stored signals is reduced with time. Similarly, Figure 4e–g show the austral summer season (December, January, and February), in which the areas were further reduced and reached their minimum level at the end of February (Figure 4g). Concurrent results have been reported by Gupta and England [38] on their study of coupled ocean–atmosphere−ice response to variation in SAM (AAO) and by Hall and Visbeck [40] on their study on variability of SH Sea ice from AAO. The finding suggests that the anomalies of the AAOI in June and July can be stored at Antarctic Sea ice before it influences the ABLS which at the end determines the distribution and concentration of dust surface mass concentration of PM2.5 over East and North China. The signal of the AAOI can be imprinted and transmitted through the ice-sea-air system. Since the atmosphere on itself cannot store long memory due to the nature of atmospheric waves which most of the time are chaotic [42, 44, 45, 46], there is a need for the medium which can store this memory, such as the Sea ice. Therefore, the AAOI influences the boundary layer through the ice−sea−atmosphere interaction. Similar interaction of the ice−sea−atmosphere has been revealed by Yuan and Li [37] to be the most important interaction, which affects the atmospheric pressure and temperature. This lead–lag phenomenon is feasible because the observed atmospheric feedback mechanism is shorter than the atmospheric circulation of Rossby waves to travel from the Southern Hemisphere (SH) to the Northern Hemisphere (NH). Similar lead–lag time has been reported by Shen and Mickley [47] in the study of the effects of ENSO on summertime ozone pollution in the eastern United States. The subsection below used the key areas of Antarctic Sea ice to define a new ice index aiming at quantifying the influence of ice concentration on dust surface mass concentration.
In order to encounter the weight contribution of different areas within the same month, the regression analysis was performed. Figure 5 shows the weight contribution of five key areas, where the highest contribution was found to be originated at 30°E–50°E and 59.5°S–62°S with the weight of eight-folds, while the lowest contribution originated at 40°W–60°W and 59°S–65°S with the contribution of negative three folds.
The average weight contribution of five key different regions for August to October for 36 years (i.e. the year 1982–2017). The red (blue) color shows the area with positive (negative) weight contribution of the key areas.
This weighting contribution was used to develop the ice index which was then correlated with AAOI; the correlation coefficient found was 0.6 and it was significant at a 99% confidence limit. The observed correlation is reasonable as AAOI has the tendency of regulating Sea ice through atmospheric, oceanic, and dynamic forcing over the Antarctica area [37, 38, 48]. Also, the difference in weight contribution suggests that the anomalies over the five correlated areas of Antarctica did not contribute equally to the observed trend of PM2.5 distribution. Moreover, the ice index developed showed a significant correlation at a 90% confidence limit with the dust surface mass concentration of PM2.5 around East and North China (Figure not shown). These observed results imply that, apart from other contributing factors, the Antarctic Sea ice plays a key role in determining the distribution of the pollutants over East and North China. At this juncture, one of the difficult questions that could arise is how does the dynamics over the Antarctic influence the pollutants on the other side of the hemisphere? One of the possible reasons that could be used to explain the occurrence of this mechanism is through the actions of wind. Furthermore, the correlation map of zonal and meridional winds with the ice index also showed a significant correlation over East and North China (Figure 6).
The correlation map between the average of August to October Antarctic Sea ice index and the average zonal and meridional wind (average of November to February) at 850 hPa from 1981 to 2018. The marked areas passed the significance correlation test at a 90% confidence level.
Moreover, Figure 6 shows that the eastern and northern parts of China acted as the center of the cyclone, which favors the accumulation of pollutants from the high-pressure zone. A similar observation was reported by Liang and Wang [49] that, East Asia Jetstream (EAJ) is the dominant wind field in China. Therefore, this area acted as the convergence zone of pollutants from different areas. It was found that in this area, wind was originated from far areas such as the northern part of India. Likewise, as presented in Figure 6, this region is under the influence of southerly anomalies which resulted in the decline of clean and moist wind from the northern part. Moreover, the stronger southerly and weaker northerly anomaly has been reported to weaken East Asia winter monsoon [50]. This condition is thought to generate stable atmospheric conditions; a favorable condition for pollutants accumulation. This observation indicates that the higher August to October Sea ice index causes the southerly wind to be stronger while the northerly wind becomes weaker. A similar observation was reported by a number of authors [24, 33] that, higher August, September, and October AAO (ASO–AAO) cause weaker northerly winds over North China.
The correlation coefficient between the JJ–AAOI and the average zonal (80° E–130° E) zonal wind shows significant zonal dipole pattern, with the positive phase in mainland China. The selection of a small area is done purposely in order to capture the detailed information at a fine-scale from the global data. The averaging of these data is intended to minimize the effect which may be caused by the mesoscale phenomena. At the altitudes of 1000 hPa and 850 hPa, there are positively correlated areas over the Taklamakan desert; the size of the correlated area is decreasing with the altitude (Figure 7a and b). This observation suggests that the zonal wind at lower altitudes up to 500 hPa at the area around desert regions was decreasing with the altitude. That means, the higher JJ–AAOI corresponds to the higher low-level wind speeds which may result in the generation of dust and therefore increase the dust surface mass concentration of PM2.5. Different from what was observed at 1000 hPa, the East China Sea was observed to have a significant negative correlation at the altitude of 200 hPa (Figure 7d). Therefore, this shows that the zonal wind from East China Sea decreased, hence little moist and cleaner air was allowed to enter mainland China.
Correlation coefficient between averaged zonal (80°E–130°E) zonal wind at (a) 1000 hPa (b) 850 hPa (c) 500 hPa (d) 200 hPa and average of June and July Antarctic oscillation index (JJ
The lead–lag timescale of two months is feasible as revealed in the previous study by Fan and Wang [22] which also found that, dust-related circulations have a timescale of 30 to 60 days from SH to North China. Yuan and Li [37] reported a delayed response of two months from the Sea ice to large-scale atmospheric circulations. Not only these studies but also a study by Qin et al. [51] found a good correlation between April–May AAOI and summer (July–August) rainfall over North China. Similarly, the study by Yuan et al. [48] reveals that the positive phase of AAO during boreal spring can determine the late summer precipitation over North China. The lead–lag time between the positive phase of AAO and summer precipitation is about six months. Therefore, these previous studies further complement the feasibility of two months lead–lag mechanism between the pollutants and the anomaly over SH i.e. the anomalies of the Antarctic Sea ice and the JJ–AAOI. These results signify the need to further contemplate the potential of predicting the status of PM2.5 dust surface mass concentration at least two months in advance; for the purpose of air quality management. Similar suggestion of using AAO in predicting the following season was unveiled by a number of authors [41, 42, 46, 52].
Moreover, the latitude−altitude section for slopes of average zonal (80°E–130°E) meridional wind over mainland China and the average of September and October AAOI (SO–AAOI) (Figure 8a), shows a similar scenario to what has been portrayed in Figure 7. There is AAO like structure below the altitude of 850 hPa and positive anomalies at the altitude between 600 hPa and 70 hPa in SH at around 40°S and 60°S of the Equator (Figure 8a). Over the mainland China, there were positive anomalies below the altitude of 500 hPa with the center at around 850 hPa. At the equator, negative anomalies were observed below the altitude of 400 hPa. Similarly, the slope of zonal wind shows AAO like structure between 40°S and 60°S throughout the troposphere, with the positive anomalies area extending to the stratosphere (Figure 8b). Over the NH, there was a dipole like structure from 10° N to 80° N. As it has been the case for zonal and meridional winds, the slope of AAOI and GPH also show an AAO like structure (Figure 9) in the SH and the dipole like structure in the NH. The positive anomalies over mainland China were found between the pressure level of 700 hPa and 100 hPa. It is worth noting that, the dipole-like structure observed in NH was centered at around 200 hPa in almost all cases i.e. the height of the dominant EAJ. As it has been put forward by previous studies [48, 49], EAJ is important in determining the weather condition for mainland China.
Latitude-altitude section for slopes of September and October Antarctic oscillation index (SO–AAOI) and mean zonal (80°E–130°E) of (a) meridional (v) wind (b) zonal (u) wind. The abscissa represents latitude while the ordinate represents pressure levels. The marked areas passed the significance test at a 90% confidence level.
Latitude-altitude section for slopes of September and October Antarctic oscillation index (SO−AAOI) and mean zonal (80°E–130°E) geopotential height. The abscissa represents latitude while the ordinate represents pressure levels. The marked areas passed the significance test at a 90% confidence level.
The observed characteristics of the slope of AAOI with the GPH, zonal and meridional winds are clearly seen in Figure 6, which shows the correlation map indicating the most significant area being between 20°N and 50°N, and 100°E and 125°E. Therefore, this implies that the actions of winds and the influence of AAOI can potentially affect the distribution of pollutants over most parts of mainland China. Corroborated results have been reported by Fan and Wang [22, 30] study on dust in North China, Zheng et al. [42] study on the seasonal influence of AAOI on precipitation, and Wang and Fan [53] study on the linkage between southern hemisphere zonal wind and East Asian summer monsoon circulation. In general, these studies indicate that the possible mechanism of the linkage between Antarctic and NH is based mainly on meridional teleconnection.
It is well established in the literature that, large-scale circulation in both, SH and NH affects the climate and weather patterns of China and Asia as well. So in order to get an insight into the possible mechanisms as to how the climatic factors influence the distribution of the pollutants over China, empirical orthogonal functions (EOFs) was used to decompose the variability of winter dust surface mass concentration of PM2.5 (November, December, January and February) from 1980 to 2018. As it has been pointed out in the previous subsection, November is also included in the analysis because it was found to be highly polluted during the winter months, therefore, its inclusion is necessary for capturing the broader picture of what is happening during the high pollutants periods. Figure 10a and b show the first EOF (EOF1) and second EOF (EOF2) loading of the dust mass surface concentration of PM2.5, respectively. The EOF1 explains 40% of the original loading of surface dust mass concentration of PM2.5 anomaly which shows a swath of a positive anomaly over the northwest and eastern part of China (Figure 10a). A previous study by Bian et al. [5] linked the dust pollution in eastern China with this high loading area identified by EOF1 as in this area, there is the largest desert in China (i.e. Taklamakan desert) and the Gobi desert. A study on the estimates of the ground concentration of PM2.5 based on satellite-derived aerosol optical depth by Ma et al. [54] also indicated the Tarim Basin (i.e. Taklamakan desert) and Gobi desert similar to what has been identified by EOF1 as the potential sources of PM2.5 in China. Elsewhere, Galindo et al. [8] found a high concentration of crustal element in PM10 samples in Italy during dust outbreaks in Sahara desert. Therefore, this substantiates that, these deserts can generate both coarse and fine particles causing high loading of PM2.5 dust mass concentration. A different scenario was observed on EOF2 which explains 29% of the total variance of dust mass concentration of PM2.5 because some parts of the central and northern areas showed a negative correlation (Figure 10b). That is, the area which was identified to explain much of the loading by EOF1 showed a negative correlation in EOF2 different from what was reported in the previous studies [5, 54]. This finding can be partially contributed by the small variance explained by EOF2 as compared to the one of EOF1. The maximum spatial loadings of EOF1 are found at 35°N–42°N and 75°E–110°E and the average spatial loading are found at around 22°N–40°N and 110°E–125°E. Time series of decomposed surface dust mass concentration of PM2.5 for the leading principal component (PC1) and second principal component (PC2) are as shown in Figure 11a and b, respectively. Before 1992, the time series of PC1 showed the four years wave train of negative and positive values (+, −, +) before it maintained the decadal negative value from 1997 to 2007. A different scenario was observed in the time series of PC2 as it showed a bi-decadal mode of negative values before the year 2000 and positive values after the year 2000 except in the year 2008 when it was negative. The value of PC2 post the year 2000 and the year 2009 have a time scale of eight and nine years of consecutive positive values, respectively. With due consideration to scant information from the variation trend of EOF2, this study did not consider EOF2 for further analysis. This is, therefore, suggested to provide the area of focus for other researchers to explore further on what is the possible association between EOF2 and the distribution of the pollutants.
The loading of Empirical orthogonal function (EOF) of average dust surface mass concentration of PM2.5 during winter season (November to February) from 1980 to 2018 across China (a) EOF1 (b) EOF2.
Normalized detrended time series of decomposed average dust surface mass concentration of PM2.5 during the winter season (November to February) from 1980 to 2018 (a) Leading principal component (PC1) (b) Second principal component (PC2).
Since, EOF1 explains much variance of dust mass concentration of PM2.5 during winter (Figure 10a), the correlation amongst climatic factors of boreal autumn (September and October) and PC1 were used to identify key areas with the influence on pollutants distribution in China. Figure 12 shows the correlation coefficient results between averaged zonal (80°E–130°E) zonal wind at different altitudes (1000 hPa, 850 hPa, 500 hPa, and 200 hPa) and PC1. The analysis of the results from the correlation map of PC1 and zonal wind showed significant zonal positive and negative tripole (+, −, +) patterns in the meridional direction. The center of negative correlation at 1000 hPa and 850 hPa is at East China Sea around 22°N and 125°E (Figure 12a and b). The negatively correlated area which was around East China Sea was observed to shift inland at 500 hPa and disappeared at 200 hPa (Figure 12c and d). The positive correlation in mainland China at 1000 hPa and 850 hPa was centered on the position of Taklamakan desert (40°N and 95°E) while for the upper level (500 hPa and 200 hPa) it was centered at 30°N and 95°E (Figure 12c and d). Observed significant zonal positive and negative dipole propagation suggests the influence of zonal wind in propagating the signals to mid-latitude.
Correlation map of the leading principal component (PC1) and averaged zonal (80°E–130°E) zonal wind at (a) 1000 hPa (c) 850 hPa (e) 500 hPa (g) 200 hPa. The marked areas passed the significant test at 90% confidence level.
Figure 13a shows the composite difference of meridional circulation between the years of high and low-AAOI. The high and low years were selected after multiplying the standard deviation by 0.5 of standardized JJ–AAOI. The year 1979, 1984, 1985, 1989, 1993, 1998, 2004, 2010, 2015, and 2016 were selected as the years of high positive JJ–AAOI, while the years 1991, 1992, 1996, 1997, 2005, 2007, and 2009 were selected as the years of low negative JJ–AAOI. Similarly, Figure 13b shows the composite difference of meridional circulation between high and low PC1 years. The high and low years were also selected after multiplying the standard deviation by 0.5 of standardized PC1. The years with positive high (negative low) PC1 were 1983, 1985, 1991, 1992, 1995, 2008, 2009, 2011, and 2012 (1979, 1980, 1988, 1990, 1997, 1998, 2000, 2004, and 2005). The shadings which are seen on these figures (i.e. Figure 13a and b) denote the climatology average of June and July vertical velocity (i.e. omega). A careful look at these figures show the ascending motions are from the equator to around 40°N and descending motion at around 60°S and 20°N. The observed intensification of the westerlies at around 60°S and 75°S during the high AAOI years has been reported in previous studies [40, 52]. Since the global meridional circulations in both SH and NH are connected and share ascending air mass branches, therefore, the meridional circulation changes in SH will also affect the circulations in NH. The results from these figures show that the significant ascending and southerly anomalies exhibit around 25°N and 35°N during the positive JJ–AAOI years. That is to say, the higher PC1 is concurrent with the overlaying ascending southerly anomaly which is in one way or another endorsed by the positive phase of JJ–AAO. These observed scenarios during the positive phase of AAO are favorable for pollutant accumulation.
Composite difference of September and October meridional circulation between high and low (a) June and July AAOI years (b) PC1. The shaded area represents the climatology vertical velocity (omega) with the units of 1% Pa/s while the black vector represents the composite difference which reaches 90% confidence level for student t-test.
The linkage between large-scale circulation and the pollutants distribution was studied using the correlation map of AAOI and dust surface mass concentration of PM2.5 over mainland China. The area which was found to have a significant correlation was normalized and used to develop a time series of dust mass concentration. The correlation coefficient between time series of dust mass concentration of PM2.5 and AAOI was 0.42; significant at 95% confidence level. The lead–lag trend of the time series of pollutants and the JJ–AAOI was consistent except on two occasions (1988/89 to 1993/94 and 2013/14 to 2017/18). The inconsistency in these two occasions indicates that another prominent system was leading the AAO. On top of this, most of the high and low AAOI years did not fall within these two occasions which also support the existence of other influencing system signifying that pollutants distribution does not depend on only one factor. Moreover, the JJ–AAOI was found to have a good correlation with the Antarctic Sea ice concentration in the leading months over the key areas which were: 30°E–50°E and 59.5°S–62°S, 90°E–110°E and 57.5°S–61.5°S, 110°E–170°E and 61°S–64°S, 110°W–140°W and 65°S–68°S, and 40°W–60°W and 59°S–65°S. The correlation coefficient of ice index developed from the regression analysis of the key areas with AAOI was 0.6 and significant at 99% indicating that the signals of AAOI are imprinted on Antarctic Sea ice before affecting the ABL and dust mass concentration. It should be noted that mainland China acts as the center of the cyclone (convergence zone). The persistence of the positive phase of J
Moreover, EOF1 was found to explain 40% of the total variability of dust mass concentration of PM2.5 over mainland China. This is indicated by a swath of positive anomaly over the northeast particularly over the Taklamakan and Gobi Desert as well as eastern part of the country. The maximum spatial loading of EOF1 centered at around 35°N–42°N and 75°E–110°E and 22°N–40°N and 110°E–125°E; these areas are potential sources for dust mass before they find their way to the atmosphere through wind. Contrary, EOF2 which explains 29% of the total variability showed a negative correlation with dust mass concentration of PM2.5 over potential sources identified by EOF1 which indicates that different mechanisms control dust mass concentration. EOF2 results could be partially contributed by its small variance. Furthermore, time series of decomposed dust mass concentration of PM2.5 for the PC1 revealed a four years wave train of positive and negative values (+, −, +) before the year 1992 and the decadal negative train after the year 1997; the trend is concurrent with the calculated high and low year of PC1. The time series of PC2 indicates the existence of a bi-decadal mode of negative values before the year 2000, and a positive value after, except in the year 2008 where there was a negative value. PC1 showed a significant zonally positive correlation with the zonal wind and negative tripole (+, −, +) pattern in the meridional direction. The positively correlated regions over mainland China were centered at Taklamakan desert (40°N and 95°E) as was the case for AAOI analysis. The zonal positive and negative pattern indicates that zonal wind influenced the propagation of signals to mid-latitude. Moreover, the composite difference of meridional wind among the years of high and low June AAOI and also the year of high and low PC1, showed that the significant ascending and southerly anomalies exhibit at around 25°N and 35°N during the years with high J
Edited by Jan Oxholm Gordeladze, ISBN 978-953-51-3020-8, Print ISBN 978-953-51-3019-2, 336 pages,
\nPublisher: IntechOpen
\nChapters published March 22, 2017 under CC BY 3.0 license
\nDOI: 10.5772/61430
\nEdited Volume
This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\\n\\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\\n\\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\\n\\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\\n\\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\\n\\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\\n\\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\\n\\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\\n\\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\\n\\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\\n\\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\\n\\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
\\n"}]'},components:[{type:"htmlEditorComponent",content:'This book serves as a comprehensive survey of the impact of vitamin K2 on cellular functions and organ systems, indicating that vitamin K2 plays an important role in the differentiation/preservation of various cell phenotypes and as a stimulator and/or mediator of interorgan cross talk. Vitamin K2 binds to the transcription factor SXR/PXR, thus acting like a hormone (very much in the same manner as vitamin A and vitamin D). Therefore, vitamin K2 affects a multitude of organ systems, and it is reckoned to be one positive factor in bringing about "longevity" to the human body, e.g., supporting the functions/health of different organ systems, as well as correcting the functioning or even "curing" ailments striking several organs in our body.
\n\nChapter 1 Introductory Chapter: Vitamin K2 by Jan Oxholm Gordeladze
\n\nChapter 2 Vitamin K, SXR, and GGCX by Kotaro Azuma and Satoshi Inoue
\n\nChapter 3 Vitamin K2 Rich Food Products by Muhammad Yasin, Masood Sadiq Butt and Aurang Zeb
\n\nChapter 4 Menaquinones, Bacteria, and Foods: Vitamin K2 in the Diet by Barbara Walther and Magali Chollet
\n\nChapter 5 The Impact of Vitamin K2 on Energy Metabolism by Mona Møller, Serena Tonstad, Tone Bathen and Jan Oxholm Gordeladze
\n\nChapter 6 Vitamin K2 and Bone Health by Niels Erik Frandsen and Jan Oxholm Gordeladze
\n\nChapter 7 Vitamin K2 and its Impact on Tooth Epigenetics by Jan Oxholm Gordeladze, Maria A. Landin, Gaute Floer Johnsen, Håvard Jostein Haugen and Harald Osmundsen
\n\nChapter 8 Anti-Inflammatory Actions of Vitamin K by Stephen J. Hodges, Andrew A. Pitsillides, Lars M. Ytrebø and Robin Soper
\n\nChapter 9 Vitamin K2: Implications for Cardiovascular Health in the Context of Plant-Based Diets, with Applications for Prostate Health by Michael S. Donaldson
\n\nChapter 11 Vitamin K2 Facilitating Inter-Organ Cross-Talk by Jan O. Gordeladze, Håvard J. Haugen, Gaute Floer Johnsen and Mona Møller
\n\nChapter 13 Medicinal Chemistry of Vitamin K Derivatives and Metabolites by Shinya Fujii and Hiroyuki Kagechika
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Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. 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Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"13",type:"subseries",title:"Plant Physiology",keywords:"Plant Nutrition, Plant Hormone, Photosynthesis, Respiration, Plant Stress, Multi-omics, High-throughput Technology, Genome Editing",scope:"Plant Physiology explores fundamental processes in plants, and it includes subtopics such as plant nutrition, plant hormone, photosynthesis, respiration, and plant stress. In recent years, emerging technologies such as multi-omics, high-throughput technologies, and genome editing tools could assist plant physiologists in unraveling molecular mechanisms in specific critical pathways. The global picture of physiological processes in plants needs to be investigated continually to increase our knowledge, and the resulting technologies will benefit sustainable agriculture.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/13.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11409,editor:{id:"332229",title:"Prof.",name:"Jen-Tsung",middleName:null,surname:"Chen",slug:"jen-tsung-chen",fullName:"Jen-Tsung Chen",profilePictureURL:"https://mts.intechopen.com/storage/users/332229/images/system/332229.png",biography:"Dr. Jen-Tsung Chen is currently a professor at the National University of Kaohsiung, Taiwan. He teaches cell biology, genomics, proteomics, medicinal plant biotechnology, and plant tissue culture. Dr. Chen\\'s research interests include bioactive compounds, chromatography techniques, in vitro culture, medicinal plants, phytochemicals, and plant biotechnology. 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