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Oliveira is a postdoctoral research fellow associate member of CICECO, Aveiro Institute of Materials (Portugal), and HMRI, Hunter Medical Research Institute (Australia). She has received 7 awards and/or honors and is a member of international scientific societies.",coeditorOneBiosketch:"Maria de Lourdes Pereira is an Associate Professor at the University of Aveiro, Portugal. She published over 80 peer-reviewed papers in scientific journals and over 23 book chapters.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"323848",title:"Ph.D.",name:"Sonia",middleName:null,surname:"Oliveira",slug:"sonia-oliveira",fullName:"Sonia Oliveira",profilePictureURL:"https://mts.intechopen.com/storage/users/323848/images/system/323848.jpg",biography:"Sonia M Oliveira is a postdoctoral research fellow associate member of CICECO, Aveiro Institute of Materials (Portugal), and HMRI, Hunter Medical Research Institute (Australia). Completed a Doctor of Philosophy in Human Physiology in 2018 by The University of Newcastle (Australia) and License in Research Animal Use in 2012 by The University of Newcastle. She holds a MSc in Molecular and Cellular Biology (2010) and Licenciatura in Biology (pre-Bologna) (2008) by the University of Aveiro (Portugal). Published ~ 20 original works including 2 book chapters. She edited 1 book and is Invited Guest Editor to a Special Issue in a peer-reviewed International Journal. Participated in several national and international event(s). Supervised MSc and LSc/BSc student(s) and, work(s) of course completion, and tutored and lectured different Life Sciences subjects in Portugal and in Australia. She has received 7 awards and/or honors and is member of international scientific societies. Works in the area(s) of Life sciences with emphasis on Biological Sciences, Cellular and Molecular Biology, Medical and Health Sciences, Neurosciences, Cancer Biology, Reproduction Biology and Stem Cells, Toxicology and Biomimetic systems.",institutionString:"University of Aveiro",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Aveiro",institutionURL:null,country:{name:"Portugal"}}}],coeditorOne:{id:"79715",title:"Prof.",name:"Maria De Lourdes",middleName:null,surname:"Pereira",slug:"maria-de-lourdes-pereira",fullName:"Maria De Lourdes Pereira",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpOwQAK/Profile_Picture_1592568232161",biography:"Maria de Lourdes Pereira is Associate Professor with Habilitation since 2003 at the University of Aveiro, Portugal. 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1. Introduction
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The cerebellum is traditionally thought of as the neural structure responsible for motor control, voluntary movement, balance and associative learning. However, there is a growing awareness that the cerebellum plays a role in higher cognitive functions such as sensory processing [1,2], attention [3,4], verbal working memory [5-8] and emotion [9-11]. Converging evidence suggests that the cerebellum may play a role in anxiety disorders. With the greater appreciation that anxiety disorders are best conceptualized by diathesis models of risk, cerebellar activation may represent an endophenotype contributing to anxiety etiology.
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This chapter will present the role of a normal functioning cerebellum and outline instances in which abnormal functioning underlies a variety of pathologies including anxiety disorders. We will begin by describing historically accepted roles of the cerebellum in motor control, timing, and learning and memory. We will then present research relating to less appreciated roles such as executive processing and emotional control to demonstrate less recognized cognitive and emotional capacities of the cerebellum.
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Key to our theory is that individual differences in cerebellar activity underlie vulnerability to develop anxiety disorders. This argument will be presented by providing an overview of pre-existing vulnerabilities contributing to a diathesis approach of anxiety. We will discuss recent research in which individual differences in cerebellar modulated activities is present, such as during associative learning, avoidance or image processing tasks. Finally, a diathesis model which incorporates cerebellar activation into the etiology and expression of anxiety disorders will be presented with a discussion of its implications and future directions.
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2. Historically accepted roles of the cerebellum
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The cerebellum is a unique neural structure that accounts for approximately 10% of the total brain volume and contains nearly half of all the neurons of the brain [12,13]. The cerebellum is highly organized, with distinct inputs and outputs. It is made up of an outer region of gray matter (the cerebellar cortex), an inner region of white matter, and three pairs of deep nuclei responsible for cerebellar output; the dentate, the fastigial, and the interposed[13]. The cerebellum is made up of two hemispheres that are structural mirror images, each containing three deep nuclei. The two hemispheres are connected medially by the vermis. For specificity, the cerebellum is segregated into sections: Crus I, Crus II, and lobules I-X ([14].
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Motor Functioning. The traditional view of the cerebellum is that of a motor comparator. Muscle movement, especially coordinated and smooth motions, are the product of a feedback loop involving the cerebellum and frontal cortex. Afferent connections via the cortico-pontine-cerebellar tract with the premotor and motor cortex carry a “copy” of motor demands to the cerebellum. The cerebellum then compares feedback from the muscle spindles, joints, and tendons via the cerebellar peduncles to modify motor behavior, maintain coordination and perform skilled movements [15-17].
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The essential role of the cerebellum in motor behavior is especially evident following cerebellar insult. Unlike lesions of the motor cortex, a cerebellar lesion does not eliminate movement entirely. Instead, it disrupts initiation, coordination, and timing of movements. Movement deficits following cerebellar lesions can be very precise. Some lesions affect certain muscle groups, but not others, depending on the location, revealing a precise topography in the cerebellum. For example, deterioration of the anterior cerebellum affects the lower limbs, causing a wide staggering gait, while largely sparing arm and hand movements [18-21]. Cerebellar lesions often lead to a lack of coordination, affecting the ability to perform directed movements. Damage to the vestibulocerebellum, which receives input from the vestibular nuclei, affects gross movements, such as standing upright, to fine movements, such as maintaining fixation of gaze. Spinocerebellar lesions disrupt signals from the spinal cord and affect coordination interfering with movement regulation. The spinocerebellum uses a feed-forward process to make on-line updates to ensure accurate coordinated movements. Lesions of the cerebellum cause a variety of movement disorders such as overshooting or undershooting of targets (referred to as dysmetria), poor path correction caused by poorly coordinated joint motions (known as ataxia), tremors at the end of actions [13,18,22]. Finally, insult of the cerebrocerebellum, which has afferents from the cerebral cortex, impairs planned movements and sensory input, affecting reaction time. Individuals with lesions to the cerebrocerebellum report difficulty performing directed actions. Instead of a smooth integration of movements toward a target, their actions take place as a series of several movements strung together, known as decomposition of movement [18]. Altogether, the profound and specific outcomes of cerebellar insult indicate its critical role in coordinated motor behavior, enabling smooth and accurate performance of highly specific fine motor movements.
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Timing. Given its role in motor behaviors outlined above, it is not surprising that the cerebellum is essential in motor timing, which produces timed movements by coordinating velocity, acceleration and deceleration [15,23-28]. A simple way of measuring motor timing is through repetitive finger tapping tasks. Participants are asked to tap in time with a pacing device (e.g., metronome). After synchronization, the training device is removed and the individual is asked to continue tapping at the same interval. Variability in timing can then be measured in the inter-tap intervals. This simple task elucidates the essential role of the cerebellum in motor timing. Healthy participants demonstrate a significant increase in cerebellar activity (in addition to other areas related to motor timing such as the supplementary motor area and basal ganglia) during timed finger tapping [28]. Patients with lateral cerebellar lesions demonstrate increased variability when performing rhythmic tapping with the affected (ipsilateral) finger, but not when tapping with the unaffected (contralateral) finger. Interestingly, those with medial cerebellar lesions did not show timing errors, but had a greater number of motor errors, supporting involvement of the cerebellum specifically in timing and not just in producing the behavioral motor output [23].
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Timing is also essential in higher cognitive functions such as stimulus processing, expectations, language, and attention. Sensory timing is often measured by duration judgment tasks, which presents two stimuli of either the same or different duration. Here, participants are required to attend to a stimulus, maintain it in working memory, compare it to a second stimulus and make a judgment. Significant increases in cerebellar activity are present during timing tasks in healthy human participants [29,30]. Additionally, the use of repetitive transcranial magnetic stimulation (rTMS), which induces inhibition and causes a “temporary lesion” in the stimulated region, of the lateral cerebellum impaired short interval time perception in a similar task (400-600 ms) [31]. Comparable sensory timing deficits are seen in children with Ataxia Telangiectasia, a disease involving cortical degeneration affecting Purkinje and granular cell layers [32]. A similar deficit in duration judgment is seen in patients with cerebellar tumors [33]. Furthermore, the effect of cerebellar lesions on sensory timing is not specific to duration judgment tasks. Patients with cerebellar lesions display deficits in a variety of other tasks requiring sensory processing including interval discrimination [24,34], speed judgments [35,36] and verbal timing [37-41].
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Eyeblink conditioning. Although the cerebellum has long been acknowledged as a motor integrator and modulator, associative learning was assumed to be accomplished by higher cortical regions. Over the latter quarter of the 20th century, Thompson and colleagues presented a body of work that the cerebellum is part of the intrinsic circuitry for eyeblink conditioning, a form of new motor learning [42-45]. The foundation of eyeblink conditioning is the simple reflex pathway; the unconditional stimulus (US) produces an unconditional response (UR). Introduction of a second stimulus (conditioned stimulus or CS) that is temporally paired with the US gives rise to a conditioned response (CR), which precedes or significantly modifies the UR. In delay conditioning, the CS precedes and coterminates with the US. Thompson recognized that the simplicity of eyeblink conditioning coupled with the ability to explicitly assess reactivity to the CS, to the US, or its combination under various conditions provided an excellent platform to understand the nature of the engram – the storage and location of a memory trace [42,46,47].
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The intrinsic cerebellar circuitry demonstrates why damage to the cerebellar cortex, cerebellar nuclei, or major afferent pathways abolishes or impairs acquisition of the CR during eyeblink conditioning [48-53]. Using rats and rabbits, the neurobiology of eyeblink conditioning has been reduced to two pathways that converge in the cerebellum (For detailed reviews see [45,54]). The basic essential pathway is presented in Figure 1. Simplified, the CS pathway transmits auditory, visual, and somatosensory information via the pontine nuclei to the cerebellar cortex and interpositus nucleus via mossy fiber connections. The US pathway takes two routes from the trigeminal nucleus: a reflexive route that bypasses the cerebellum and a learning route that integrates the relationship between the CS and US. From there, climbing fibers synapse at the cerebellar cortex and interpositus nucleus. The CS and US pathways converge in the cerebellar cortex and anterior interpositus. It is here where the memory trace is stored by changes in the firing patterns of purkinje cells during the development of the CR [47,55-57]. The CR is produced by release of inhibition of the interpositus, which increases activity to the red nucleus, in turn causing the cranial motor nuclei to induce an eye blink response [58,59].
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Figure 1.
Intrinsic delay eyeblink conditioning pathway. Adapted from Christian & Thompson, 2003.
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Another benefit of the eyeblink conditioning paradigm is that the same parameters can be used across animal species, in humans, and even in early infancy. Consistent with the animal literature, intact cerebellar structures are necessary for the acquisition of the CR in eyeblink conditioning in humans [48-50,60]. Furthermore, imaging studies indicate that activity in the cerebellum is significantly greater during eyeblink conditioning in humans [61-65].
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Given the advanced understanding of neurosubstrates and its amenability for cross species comparisons, eyeblink conditioning has been a platform for understanding clinical abnormalities and cerebellar dysfunction. Therefore, a more detailed review will be presented for eyeblink conditioning, as well as a selection of clinical examples in which a cerebellar role is revealed by eyeblink conditioning.
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Cerebellar abnormalities and eyeblink conditioning. The cerebellum is particularly affected by ethanol alcohol, with alcohol-related diseases causing serious damage to its development and cells. For example, impaired delay eyeblink conditioning has been observed in Korsakoff patients, recovered alcoholics, and children with Fetal Alcohol Syndrome [66-69]. However, not all disorders cause deficits in eyeblink conditioning. For example, individuals with autism acquire eyeblink conditioning faster than matched controls, although the form of the CR is altered [70,71]. Schizophrenia also alters cerebellar functioning, with facilitated eyeblink conditioning observed in schizophrenics compared to healthy controls [72]. Some interventions can also rescue or improve cerebellar functioning. For example, improved performance in eyeblink conditioning has been observed in mice following an antioxidant rich diet over a standard diet [73].
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Regardless of etiology, cerebellar abnormalities affect eyeblink conditioning. The well-documented pathways, substrates, and lesion studies makes eyeblink conditioning a simple, yet sensitive tool to understand the cerebellar role in various neuropathologies.
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3. Higher cognitive and emotional capacities
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Recently, the cerebellum has garnered greater attention for its higher cognitive capabilities. Reviews such as those from Courchesne and colleagues [3,74], Schmahmann and colleagues [75,76] and others [77-79] establish the cognitive role of the cerebellum, which will be briefly summarized here.
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Anatomy. In order to have a role in higher cognitive processing the cerebellum must maintain connections with neural structures known to influence cognition. As such, cerebellar efferents have been traced to both motor and non-motor areas of the frontal cortex [80-85]. Tract-tracing studies with primates indicate that cerebellar output to the dorsolateral prefrontal cortex (DLPFC) places it in a position to modulate higher cognitive processing. Transneuronal retrograde virus tracers injected into multiple areas of the DLPFC (Brodmann areas 9, 46 and 12) labeled neurons in the dentate nucleus, indicating that the dentate has output channels to prefrontal regions [84]. The DLPFC plays an important role in many aspects of executive functioning including organization [86,87], behavioral control [87] working memory [88,89], reasoning and decision making [90], reward and expectancy [91], and emotion and motivation [92]. Follow up studies were able to pinpoint lateral dentate projections to the prefrontal cortex (PFC), with separate dorsal dentate projections terminating in the motor and premotor regions, suggesting a topographic organization of the dentate nucleus with both motor and non-motor output to the cortex [93].
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Functional connectivity. Cerebellar connectivity to non-motor cognitive areas in human imaging research reflects pathways implicated in primate studies. Functional connectivity MRI correlates signal fluctuations in one brain area with activity in another, implying a relationship between the two areas. Using this method, Allen et al. [94] found that activity in the dentate nucleus of the cerebellum correlated with changes in activity in non-motor regions such as the limbic system, parietal lobes, and prefrontal cortex. Connectivity between the cerebellum and anterior cingulate cortex, a region typically associated with error detection, anticipation, attention, and emotional responses, has also been reported in resting state paradigms [95]. Furthermore, there is evidence that the cerebellum contributes to the intrinsic connectivity networks, a series of brain structures that correspond to basic functions such as vision, audition, language, episodic memory, executive functioning, and salience detection [11]. Distinct contributions of the neocerebellum to the default mode network, the executive network, and the salience network substantiate the assertion that there is functional connectivity between the cerebellum and non-motor cognitive regions.
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Clinical support for a cerebellar role in non-motor cognitive processes is established by the work of Schmahmann and colleagues. Schmahmann recognized that not all patients with cerebellar strokes present with motor deficits. By assessing motor impairments alongside stroke location, he found that individuals with posterior lobe lesions presented with minor if at any motor impairments. Instead, they suffered from behavioral changes affecting executive functioning, verbal fluency, working memory, abstract reasoning, spatial memory, personality, and language deficits; recently coined as cerebellar cognitive affective syndrome [96,97].
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Loss of function in lesions is supported by activational studies in healthy humans. Using functional MRI, significant changes in cerebellar activity is present during tasks that are considered largely cognitive or to involve executive processing. Significant increases in cerebellar activity have been recorded during sensory timing [29,30], spatial attention [98-101], and verbal working memory tasks [5,6,102].
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Anatomical and functional connectivity, specific activation during executive processing tasks, and impairments concomitant with lesions is convincing evidence that the cerebellum plays a critical role in higher cognitive processing.
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Emotions. In addition to connections with prefrontal and frontal cortex, the cerebellum also has direct anatomical connections to the amygdala, the brain region typically associated with emotion and fear [103]. Functional support for this connectivity comes from imaging studies that demonstrate judging emotional intonation, feeling empathy, experiencing sadness, and viewing emotional pictures all correlate with increased activity in the cerebellum [9,76,104-106].
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If the cerebellum has important connections to the limbic system, then it follows that stimulation of the cerebellum should result in changes of emotional behaviors. As such, electrical stimulation of the cerebellum in animals demonstrates that it is an important modulator of behaviors classically attributed to limbic functioning including grooming, eating, and sham rage [107-109]. Bernston et al. [107] reported that stimulating the cerebellum of cats induced grooming and eating behaviors, in addition to similar findings with rats [108,109]. The cerebellum, specifically the vermis, plays a role in fear and avoidant behaviors. For example, lesioning the vermis alters fear responses by decreasing freezing and increasing open field exploration [110]. On other other hand, stimulating the vermis induces fear responses, such as increased amplitude of the acoustic startle response [111], indicating cerebellar modulation of species-specific behaviors beyond coordination of muscle movements.
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Reports from the clinical literature also support cerebellar modulation of emotion. Attempts to treat severe seizure disorders by stimulating the cerebellum provide unique case reports of observations about cerebellar functioning. Heath et al. [112] placed electrodes in the fastigial nucleus of an emotionally disturbed patient and observed increased activity in the region when the patient reported being angry or fearful. Descriptions of unpleasant sensations and the feeling of being scared were reported following stimulation of the dentate nucleus [113]. In a larger study of cerebellar stimulation as a treatment for chronic epilepsy, Cooper et al. [114] reported marked behavioral changes from sullen mood, dangerous, and aggressive behaviors to open, pleasant, responsive, and sociable affect in patients. More recently, descriptions of highly specific lesions to the cerebellar vermis includes personality changes, especially emotional effects such as flattening of affect [97,115]. Observations from these case studies suggest that the cerebellum may utilize its reciprocal connections with the prefrontal cortex and limbic system to modulate emotional processing.
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\n\t\t\t\tCerebellum and Anxiety Disorders\n\t\t\t
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Anxiety. Anxiety is the most prevalent disorder in the United States with one quarter of the population estimated to develop an anxiety disorder at some time in their lives [116,117]. On the other hand, three quarters of the population does not suffer from clinical anxiety, raising the question what is it about an individual that makes them more likely to develop an anxiety disorder? Unfortunately, there is no single vulnerability increasing risk for anxiety. Instead, anxiety disorders are best represented by diathesis models, that is, preexisting conditions enhance risk such that individuals are vulnerable to environmental insults or challenges. A stress-diathesis model for anxiety disorders emphasizes changes in stress reactivity from the convergence of a variety of factors such as genetics, biology, sex, and prior experience [118]. Current research efforts heavily focus on the higher cortical areas (e.g., prefrontal cortex, cingulate cortex, hippocampus, amygdala) as areas critical to development of anxiety. However, the cerebellum is also intimately involved in emotional processing, learning and memory – all of which are represented as risk factors in diathesis models. The following sections will describe how cerebellar activity is related to the signs and symptoms of anxiety and provide often overlooked evidence of cerebellar involvement from imaging research. This will form the basis for speculations regarding individual differences in cerebellar activity as a risk factor for anxiety disorders.
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Avoidance. Avoidance is the core feature in the otherwise varied symptomology of anxiety disorders [119]. Therefore, it is essential to understand the role abnormal expressions of avoidance plays in the development and maintenance of anxiety. First, avoidance is acquired and reinforced over time. The essence of anxiety is concern over a potential threatening event in the future, typically one which the individual feels they have no control over and could not cope with. Rather than deal with uncontrollable events, anxious individuals choose to exert their control by substituting other negative thoughts or feelings that are avoidable, providing short term relief and a feeling of temporary control. Avoidance can either be active or passive. In active avoidance, the individual learns to control their environment by alleviating or removing a noxious stimulus. In passive avoidance, the individual learns not to place themselves in a situation that previously contained a noxious stimulus. In anxiety, both forms of avoidance are present, and over time, become pervasive and uncontrollable such that normal functioning becomes impossible.
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Avoidance is a learned process. Therefore, it is possible to measure the differences in acquisition of the negative reinforcement learning seen in active-avoidance. Differences in the speed and strength of acquisition in active-avoidance may contribute to risk or resiliency. Some individuals may be more susceptible to acquire and repeatedly express active-avoidance behaviors, leading to development of behavioral and cognitive avoidance symptoms associated with anxiety disorders.
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Although the cerebellum is typically associated with associative learning using classical conditioning protocols, a cerebellar role in operant learning such as avoidance has also been suggested. For example, lever press avoidance paradigms places a rat in an operant chamber and presents a stimulus (e.g., tone) that precedes and overlaps with an aversive stimulus (e.g., a shock). Over time, the rat learns to make a lever press response to the tone, avoiding the shock. Lesioning the cerebellum prevents acquisition of the avoidance response in this task [120] and in other measures of active-avoidance [121]. Furthermore, cerebellar involvement may play a role in human avoidance as well [122].
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Neuropharmacology. Given the role of the cerebellum and associative learning in anxiety vulnerability, it would be useful to consider treatment approaches that target the cerebellum. Among others, the cerebellum maintains a large density of corticotrophin-releasing hormone (CRH) receptors and cannabinoid receptors. Here, we will outline how these receptors relate to anxiety and eyeblink conditioning.
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The influence of CRH on various behavioral markers of anxiety demonstrates its role in modulating stress reactivity. CRH has anxiogenic properties, with a dysregulation of CRH systems playing a role in anxiety disorders. The cerebellum contains a high density of CRH1 receptors, the receptor linked to stress responding, anxious behavior and cognitive functioning [123]. The effects of CRH receptor activation have been thoroughly outlined using animal models, including its influence on anxiety (for a review see [124]). For example, an injection of corticotropin releasing factor (CRF), which induces corticosterone release (the animal analog of cortisol), has been shown to decrease open field exploration, time spent in open arms in the elevated plus maze, exploration in novel environments, and social interaction in rats at certain doses. Furthermore, injections of CRF increase startle amplitude, and improve acquisition in both active and passive avoidance paradigms. Additionally, CRH receptors are adaptive to environmental demands, with a variety of stressors upregulating CRH1 receptors specifically, suggesting a relationship to chronic stress that may feed forward into anxiety disorders [125,126]. Eyeblink conditioning is also influenced by CRH, with studies demonstrating facilitated acquisition in trace paradigms of both humans and rats [127-129]. Humans treated with metyrapone, which decreases initial cortisol response to stress (although not long term effects of stress [130], acquired trace eyeblink conditioning faster than placebo treated controls. While there were no acquisition differences between the groups in delay-type conditioning, metyrapone treated individuals were significantly slower to extinguish, a difference not seen in the trace group [128]. Altogether, it appears that stress reactivity in the brain impacts cerebellar functioning and may play a role in modulating learning and memory, feeding into anxious behavior and increased vulnerability to anxiety disorders.
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Cannabinoid receptors, which have their highest densities in the frontal cortex and cerebellum, have also been linked to anxiety [131-133]. Low doses of cannabinoid compounds induce anxiolitic effects, with high doses causing anxiety-like reactions in laboratory rats, suggesting interplay between cannabinoid receptor activity and anxiety [134-136]. These findings are in conjunction with subjective reports that exposure to cannabis derivatives can induce feelings of placid relaxation or panic [137]. For example, low doses of a cannabinoid synthetic reduces behaviors linked to stress in rats with high doses of the same drug causing the opposite pattern, inducing anxiety to novelty and increasing corticosterone [135]. Aside from synthetic activation, endogenous cannabinoid receptor activity is related to anxiety as well. Pharmacological blockage of the CB1 cannabinoid receptor increased anxiety-like behaviors in rats including reduced open arm exploration in the elevated plus maze and increased withdrawal-related behaviors [132]. Cannabinoids influence anxiety and have a high density of receptors in the cerebellum, suggesting that cannabinoid receptor activation would influence eyeblink conditioning as well. As such, animal models have demonstrated that CB1 knockout mice demonstrate disrupted eyeblink conditioning [138] In conjunction, humans who report chronic cannabis use (but not at the time of the study) exhibit fewer and poorly timed CRs during delay eyeblink conditioning compared to non-users [139].
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Temperament differences contributes to anxiety vulnerability
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Diathesis models suggest that the interplay between risk factors increases vulnerability to develop anxiety disorders. Personality is among the many risk factors suggested to play a role in anxiety, with certain personality types at increased risk to develop anxiety disorders. Support for a personality risk factor in anxiety is supported by the low success rates in treating anxiety disorders, which would require the alteration of stable character traits. Of the few studies that have assessed long-term treatment outcomes of anxiety disorders, 30%-50% still have moderate to severe anxiety six years post treatment [140,141].
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An understanding of how personality interacts with anxiety is essential. Here, we will discuss an innate feature of personality known as temperament. Temperament is a core feature of personality, often evident early in childhood and remains stable throughout the lifespan. By measuring temperaments related to anxiety such as behavioral inhibition (BI) and trait anxiety, we are able to differentiate at-risk individuals and assess individual differences on cerebellar modulated tasks.
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Behavioral inhibition. Similar to anxiety disorders, a core feature of behavioral inhibition is avoidance. Additionally, the behavioral and physiological functioning of an individual with behavioral inhibition is comparable to that seen in anxiety including withdrawal, apprehension, and slow latency to approach unfamiliar people or objects [142]. Kagan and colleagues have provided an extensive behavioral profile of BI using longitudinal methods, reporting that children classified as inhibited at 21-months demonstrate avoidance of social interactions [143], reported more phobias, and had a higher incidence of anxiety disorders [144-147]. As with anxiety disorders, it appears that inhibited temperament is a heritable trait [148]. Parents and siblings of those children classified as inhibited were more likely to have anxiety disorders, social phobia, avoidant and overanxious disorders compared to the families of uninhibited children [149-151].
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So far, we have provided evidence supporting that cerebellar differences underlie higher cognitive processes including anxiety disorders. We have outlined the essential role avoidance has in the development and maintenance of anxiety disorders and how learning processes may underlie increased avoidance. We then introduced behaviorally inhibited temperament, a risk factor with many similarities to anxiety. In the next section we will combine individual differences in cerebellar functioning, avoidance, learning, and temperament to provide a cerebellar diathesis theory of anxiety vulnerability.
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As described above, avoidance in the development of anxiety disorders is a feed-forward process, such that the expression of avoidance reduces stress in the present while simultaneously increasing the aversiveness of the undesired stimulus or state in the future, increasing the likelihood of continued avoidance behaviors. Both adaptive and pathological avoidance can be described in terms of the degree and rigidity of expression, the sensitivity to acquire stimulus to stimulus associations, and inflexibility to change. Multiple processes underlie avoidance acquisition, making it difficult to tease out the essential factors in anxiety. It is possible that increased sensitivity to the cues and contingencies in the environment are learned faster in anxiety, resulting in better performance on avoidance tasks. One way to measure these associations is through the classically conditioned eyeblink response. The use of eyeblink conditioning allows multiple measures to be taken into account including reactivity, acquisition of the relationship between the CS and US, and rate of extinction.
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Learning. The inbred Wistar-Kyoto rat (WKY) provides a model of inherent anxiousness and vulnerability to stress, similar to what is seen in a behaviorally inhibited personality profile [152-160]. Furthermore, the WKY demonstrates enhanced active avoidance in lever-press paradigms, reinforcing the relationship between anxiety vulnerability and avoidance [161,162]. Comparisons of WKY male rats to outbred Sprague-Dawley male rats demonstrate significantly faster acquisition and greater asymptotic performance of the WKY [163,164]. Moreover, avoidance perseverates in WKY during extinction training in the presence of safety signals [159] or avoidance acquisition with more intense stressors [165]. As reviewed by Jiao [166], the WKY provides an animal model of inhibited temperament, faster associative learning, enhanced sensitivity to acquire avoidance, and resistance to extinction. Moreover, the reactivity increases in the face of avoidance acquisition, reminiscent of increased reactivity in PTSD [167].
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Striking parallels are evident between rat models of anxiety vulnerable temperament and humans with self-reported inhibited temperament, suggesting a common neural substrate. One way to assess at-risk temperament is through self-report scales such as those that measure behavioral inhibition [168,169] or trait anxiety [170]. Using these measures, our lab has found that at-risk individuals acquire the relationship between the CS and US the faster, demonstrating more CRs earlier in the training period than those who are low scoring [171,172]. For example, a recent study with a large sample of 117 healthy college-age students found that those scoring high on the Adult Measure of Behavioural Inhibition [169] and Trait Anxiety [170] acquired standard delay eyeblink conditioning faster than those who scored below the median on these measures (see Figure 2). Considering the intimate relationship between associative learning of cues as predictors of aversive events, enhanced classical conditioning may reflect increased sensivity to acquire avoidance responses.
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These and other similar results [171,173,174] suggest that individual differences in acquisition of learning tasks may reflect processes underlying increased risk for anxiety disorders.
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Figure 2.
A comparison of temperament on delay eyeblink acquisition of healthy college-aged students. Those who score above the median on the AMBI and STAI-Trait are considered high scorers, those below are considered low scorers Anxiety vulnerable individuals acquired eyeblink conditioning faster and to a greater degree over the 45 trial training period (blocks 1-9). There were no observed differences in extinction (E1-E3).
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Heart Rate. In addition to higher cortical pathways, the cerebellum also has direct reciprocal connections to the hypothalamus. Studies in rats and primates show projections from the deep cerebellar nuclei to the lateral hypothalamus, posterior hypothalamic area, dorsal hypothalamic area, the paraventricular nucleus, and the dorsomedial hypothalamic nucleus (For a review see [175]), some of which may be related to heart rate reactivity.
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Research in behaviorally inhibited children indicate that a high and stable heart rate (compared to uninhibited children) is indicative of long-term inhibited temperament. Reduced resting heart rate variability has been revealed as a feature of perceived stress [176] and anxiety disorders such as PTSD [177]. The presentation of novel or negative stimuli in healthy populations results in large bradycardic response, with greater bradycardia to more negatively valenced images [178,179]. While there appears to be a relationship between heart rate and anxiety, few studies have looked at heart rate reactivity in behaviorally inhibited adults. Studies that manipulate heart rate typically do so with negatively valenced pictures, assessing reactivity to extreme stimuli (i.e., trauma images for a PTSD patient). In order to disentangle individual reactivity from heart rate changes during high-arousal image processing, which can cause large responses in everyone, a recent study from our lab assessed heart rate change in high and low BI individuals when viewing images that were low in arousal across positive negative and neutral valence. Using this design, we could better understand how BI influences reactivity to everyday stimuli normally encountered in the environment to see if inhibition is related to aberrant parasympathetic or sympathetic activation. Recordings of 6 seconds before, 6 seconds during, and 6 seconds after image presentation suggest a sustained bradycardia in inhibited individuals compared to their non-inhibited counterparts. It is possible that greater vagal tone in high BI could also be related to the enhanced eyeblink acquisition seen in behaviorally inhibited individuals in across studies in Veterans, high school aged students, as well as college aged individuals (See Figure 3).
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Figure 3.
Heart rate change from baseline for positive, neutral, and negative images in high and low behavioral inhibition. Each block represents 20 trials. Behaviorally inhibited individuals showed sutained bradycardia over the neutral picture viewing session. Bradycardia lasted only through the first block of 20 trials in the positive condition, and appeared in the second block (trials 21-40) in the negative condition.
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Cerebellar reactivity. Despite being largely ignored and generally not discussed, imaging studies repeatedly indicate significant changes in cerebellar activity of patients with anxiety disorders compared to healthy controls. Close examination of the reported data reveals significant changes in the cerebellum during resting state and anxiety-provoking tasks in social anxiety disorder [180-182], post-traumatic stress disorder [183-187], obsessive compulsive disorder [188] and generalized anxiety disorder [189,190].
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Individual differences in cerebellar reactivity have recently been extended to include anxiety vulnerability. Numerous studies assess the correlation between measures of anxiety vulnerability, most often trait anxiety, and brain activity [191]. Mostly, these studies report that individual differences in amygdala and PFC activity underlies trait anxiety, modulating stimulus processing and increasing hypervigilance [192-195]. What is often overlooked is that reciprocal connections between the cerebellum, prefrontal cortex, and amygdala position the cerebellum to modulate reactivity in anxiety vulnerable individuals. In the only published study to date to our knowledge that discusses cerebellar activity and temperament, Blackford and colleagues [10] compared behaviorally inhibited to uninhibited individuals when viewing familiar and novel faces and found significant increases in BOLD activation in the right cerebellum of the inhibited individuals when viewing novel faces. Specifically, they reported significant increases in the right Crus 1/Lobule VI region of the cerebellum, which may be related to processing the valence of emotional cues, salience detection, and in sensory processing and expectation; especially pain-related processes like fear and startle reactions [2,11,76].
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The cerebellar differences found in the Blackford study were the result of a full-brain analysis; importantly, standard imaging procedures often incompletely image the cerebellum, so it is possible that the entire structure is not included in typical analyses. Recent research in our lab has explored the relationship of cerebellar activity and anxious temperament as measured by behavioral inhibition and trait anxiety. To extend the Blackford study we again used familiar faces and novel faces. Additionally, we used familiar and novel scenes, allowing us to differentiate the effect of social stimuli and novelty. Furthermore, we used the cerebellum as our region of interest, ensuring complete coverage during imaging. Finally, participants underwent eyeblink conditioning in addition to imaging (outside of the scanner). Given what is known about the behavioral profile of behaviorally inhibited individuals and in light of previous research, we hypothesized that high behavioral inhibition would correlate with changes in cerebellar activity, with the strongest differences occurring to novel faces. We found that the group with higher scores on measures of behavioral inhibition [168,169] had greater cerebellar reactivity to the novel faces compared to baseline than those with lower scores, a difference not seen with familiar faces. Additionally, we observed greater activity of the high BI group when viewing novel scenes, suggesting that the cerebellum may be sensitive to novel stimuli in general. Differences in percent signal change and BOLD signal activations can be seen in figure 4. In eyeblink conditioning, individuals with high BI scores acquired delay eyeblink faster than those with low scores, replicating previous work in our lab.
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Figure 4.
Increased cerebellar reactivity to novel stimuli in anxiety vulnerable individuals. Healthy, college-aged students who scored high on measures of behavioral inhibition demonstrated increased reactivity to multiple areas of the cerebellum in response to novel faces compared to baseline. A similar differential increase in activity was seen for novel scenes. Significant differences in cerebellar activity from baseline were not seen in the familiar face or familiar scene conditions. Left is Right.
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We have demonstrated individual differences in cerebellar reactivity and behavior in cerebellar-modulated tasks related to anxiety and anxiety vulnerability. By modulating the signal from higher cortical areas, the cerebellum may be involved in processes related to emotion and anxiety. Figure 5 outlines the cerebrocerebellar and corticopontinecerebellar circuitry as well as the cerebellar outputs for eyeblink conditioning, heart rate responsivity, and higher cognitive process. Cerebellar outputs to prefrontal regions such as the DLPFC and ACC would allow it to modulate incoming signals to these areas regarding higher cognitive functioning including emotion and anxiety. The anatomical pathways, functional connectivity, and individual differences observed of both clinical anxiety and anxiety vulnerable individuals suggest a cerebellar role in anxiety disorders. We propose that cerebellar functioning is another risk factor that needs to be added to the diathesis of anxiety vulnerability. Continued research of individual differences in both cerebellar-modulated tasks (e.g., eyeblink) and the cerebellar role in higher cognitive tasks (e.g., stimulus processing, attention; emotional regulation) will shed light on the interplay of vulnerabilities contributing to the development of anxiety disorders.
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Figure 5.
Cerebellar functional connectivity. Reciprocal connectivity with the cortex puts the cerebellum in a position to modulate higher cognitive processes via connections with the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Many functions altered by at-risk temperament may be modulated by the cerebellum including eyeblink conditioning, heart rate reactivity, and executive functioning such as emotional regulation, motivation and avoidance.
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\n\t\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41031.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41031.xml",downloadPdfUrl:"/chapter/pdf-download/41031",previewPdfUrl:"/chapter/pdf-preview/41031",totalDownloads:2989,totalViews:708,totalCrossrefCites:2,totalDimensionsCites:16,totalAltmetricsMentions:1,impactScore:12,impactScorePercentile:98,impactScoreQuartile:4,hasAltmetrics:1,dateSubmitted:"April 24th 2012",dateReviewed:"September 1st 2012",datePrePublished:null,datePublished:"March 20th 2013",dateFinished:"November 15th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41031",risUrl:"/chapter/ris/41031",book:{id:"3295",slug:"new-insights-into-anxiety-disorders"},signatures:"Meghan D. Caulfield and Richard J. Servatius",authors:[{id:"31564",title:"Prof.",name:"Richard",middleName:null,surname:"Servatius",fullName:"Richard Servatius",slug:"richard-servatius",email:"Richard.Servatius@va.gov",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"158609",title:"MSc.",name:"Meghan",middleName:null,surname:"Caulfield",fullName:"Meghan Caulfield",slug:"meghan-caulfield",email:"davisml@umdnj.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Historically accepted roles of the cerebellum",level:"1"},{id:"sec_3",title:"3. Higher cognitive and emotional capacities",level:"1"}],chapterReferences:[{id:"B1",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGao\n\t\t\t\t\t\t\tH. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParsons\n\t\t\t\t\t\t\tL. 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W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1989\n\t\t\t\t\tDisrupted eyelid conditioning in a patient with damage to cerebellar afferents.\n\t\t\t\t\tBehavioral Neuroscience\n\t\t\t\t\t103\n\t\t\t\t\t4\n\t\t\t\t\t898\n\t\t\t\t\t902\n\t\t\t\t\n\t\t\t'},{id:"B49",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDaum\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchugens\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAckermann\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLutzenberger\n\t\t\t\t\t\t\tW.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDichgans\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBirbaumer\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993\n\t\t\t\t\tClassical conditioning after cerebellar lesions in humans.\n\t\t\t\t\tBehavioral Neuroscience\n\t\t\t\t\t107\n\t\t\t\t\t5\n\t\t\t\t\t748\n\t\t\t\t\t56\n\t\t\t\t\n\t\t\t'},{id:"B50",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTopka\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tValls-Solé\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMassaquoi\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHallett\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993\n\t\t\t\t\tDeficit in classical conditioning in patients with cerebellar degeneration.\n\t\t\t\t\tBrain\n\t\t\t\t\t116\n\t\t\t\t\t961\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B51",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSears\n\t\t\t\t\t\t\tL. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteinmetz\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1990\n\t\t\t\t\tAcquisition of classically conditioned-related activity in the hippocampus is affected by lesions of the cerebellar interpositus nucleus.\n\t\t\t\t\tBehavioral Neuroscience\n\t\t\t\t\t104\n\t\t\t\t\t5\n\t\t\t\t\t681\n\t\t\t\t\t92\n\t\t\t\t\n\t\t\t'},{id:"B52",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteinmetz\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLavond\n\t\t\t\t\t\t\tD. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvkovich\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLogan\n\t\t\t\t\t\t\tC. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1992\n\t\t\t\t\tDisruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit?\n\t\t\t\t\tThe Journal of Neuroscience\n\t\t\t\t\t12\n\t\t\t\t\t11\n\t\t\t\t\t4403\n\t\t\t\t\t26\n\t\t\t\t\n\t\t\t'},{id:"B53",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIvkovich\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLockard\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993\n\t\t\t\t\tInterpositus lesion abolition of the eyeblink conditioned response is not due to effects on performance.\n\t\t\t\t\tBehavioral Neuroscience\n\t\t\t\t\t107\n\t\t\t\t\t3\n\t\t\t\t\t530\n\t\t\t\t\t2\n\t\t\t\t\n\t\t\t'},{id:"B54",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSteinmetz\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2000\n\t\t\t\t\tBrain substrates of classical eyeblink conditioning: a highly localized but also distributed system.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t110\n\t\t\t\t\t13\n\t\t\t\t\t24\n\t\t\t\t\n\t\t\t'},{id:"B55",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Cormick\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tClark\n\t\t\t\t\t\t\tG. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLavond\n\t\t\t\t\t\t\tD. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1982\n\t\t\t\t\tInitial localization of the memory trace for a basic form of learning.\n\t\t\t\t\tProceedings of the National Academy of Sciences\n\t\t\t\t\t79\n\t\t\t\t\t8\n\t\t\t\t\t2731\n\t\t\t\t\t5\n\t\t\t\t\n\t\t\t'},{id:"B56",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Cormick\n\t\t\t\t\t\t\tD. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1984\n\t\t\t\t\tCerebellum: essential involvement in the classically conditioned eyelid response.\n\t\t\t\t\tScience\n\t\t\t\t\t223\n\t\t\t\t\t4633\n\t\t\t\t\t296\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B57",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tR. F.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1986\n\t\t\t\t\tThe neurobiology of learning and memory.\n\t\t\t\t\tScience\n\t\t\t\t\t233\n\t\t\t\t\t4767\n\t\t\t\t\t941\n\t\t\t\t\t47\n\t\t\t\t\n\t\t\t'},{id:"B58",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenfield\n\t\t\t\t\t\t\tM. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoore\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1983\n\t\t\t\t\tRed nucleus lesions disrupt the classically conditioned nictitating membrane response in rabbits.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t10\n\t\t\t\t\t2-3\n\t\t\t\t\t393\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B59",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRosenfield\n\t\t\t\t\t\t\tM. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMoore\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1985\n\t\t\t\t\tRed nucleus lesions impair acquisition of the classically conditioned nictitating membrane response but not eye-to-eye savings or unconditioned response amplitude.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t17\n\t\t\t\t\t1\n\t\t\t\t\t77\n\t\t\t\t\t81\n\t\t\t\t\n\t\t\t'},{id:"B60",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchugens\n\t\t\t\t\t\t\tM. 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T.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1995\n\t\t\t\t\tFunctional anatomy of human eyeblink conditioning determined with regional cerebral glucose metabolism and positron-emission tomography.\n\t\t\t\t\tProceedings of the National Academy of Sciences\n\t\t\t\t\t92\n\t\t\t\t\t16\n\t\t\t\t\t7500\n\t\t\t\t\t4\n\t\t\t\t\n\t\t\t'},{id:"B62",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlaxton\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZeffiro\n\t\t\t\t\t\t\tT. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGabrieli\n\t\t\t\t\t\t\tJ. D. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBookheimer\n\t\t\t\t\t\t\tS. Y.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCarrillo\n\t\t\t\t\t\t\tM. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTheodore\n\t\t\t\t\t\t\tW. 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S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGitelman\n\t\t\t\t\t\t\tD. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParrish\n\t\t\t\t\t\t\tT. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMesulam\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tNeuroanatomic overlap of working memory and spatial attention networks: a functional MRI comparison within subjects.\n\t\t\t\t\tNeuroimage\n\t\t\t\t\t10\n\t\t\t\t\t6\n\t\t\t\t\t695\n\t\t\t\t\t704\n\t\t\t\t\n\t\t\t'},{id:"B102",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMarvel\n\t\t\t\t\t\t\tC. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDesmond\n\t\t\t\t\t\t\tJ. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tThe contributions of cerebro-cerebellar circuitry to executive verbal working memory.\n\t\t\t\t\tCortex\n\t\t\t\t\t46\n\t\t\t\t\t7\n\t\t\t\t\t880\n\t\t\t\t\t95\n\t\t\t\t\n\t\t\t'},{id:"B103",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHeath\n\t\t\t\t\t\t\tR. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHarper\n\t\t\t\t\t\t\tJ. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1974\n\t\t\t\t\tAscending projections of the cerebellar fastigial nucleus to the hippocampus, amygdala, and other temporal lobe sites: evoked potential and histological studies in monkeys and cats.\n\t\t\t\t\tExperimental NeurolologyJun. 13;\n\t\t\t\t\t45\n\t\t\t\t\t268\n\t\t\t\t\t87\n\t\t\t\t\n\t\t\t'},{id:"B104",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLee\n\t\t\t\t\t\t\tG. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMeador\n\t\t\t\t\t\t\tK. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLoring\n\t\t\t\t\t\t\tD. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAllison\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrown\n\t\t\t\t\t\t\tW. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPaul\n\t\t\t\t\t\t\tL. K.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tNeural substrates of emotion as revealed by functional magnetic resonance imaging.\n\t\t\t\t\tCognitive Behavioral Neurology\n\t\t\t\t\t17\n\t\t\t\t\t9\n\t\t\t\t\t17\n\t\t\t\t\n\t\t\t'},{id:"B105",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBermpohl\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPascual-Leone\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmedi\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMerabet\n\t\t\t\t\t\t\tL. B.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFregni\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGaab\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2006\n\t\t\t\t\tDissociable networks for the expectancy and perception of emotional stimuli in the human brain\n\t\t\t\t\tNeuroimage\n\t\t\t\t\t30\n\t\t\t\t\t588\n\t\t\t\t\t600\n\t\t\t\t\n\t\t\t'},{id:"B106",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHofer\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSiedentopf\n\t\t\t\t\t\t\tC. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tIschebeck\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRettenbacher\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVerius\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFelber\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tSex differences in brain activation patterns during processing of positively and negatively valenced emotional words.\n\t\t\t\t\tPsychological Medicine\n\t\t\t\t\t37\n\t\t\t\t\t1\n\t\t\t\t\t109\n\t\t\t\t\t19\n\t\t\t\t\n\t\t\t'},{id:"B107",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerntson\n\t\t\t\t\t\t\tG. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPotolicchio\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMiller\n\t\t\t\t\t\t\tN. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1973\n\t\t\t\t\tEvidence for higher functions of the cerebellum: eating and grooming elicited by cerebellar stimulation in cats.\n\t\t\t\t\tProceedings of the National Academy of Sciences\n\t\t\t\t\t70\n\t\t\t\t\t9\n\t\t\t\t\t2497\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'},{id:"B108",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBall\n\t\t\t\t\t\t\tG. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMicco\n\t\t\t\t\t\t\tD. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBerntson\n\t\t\t\t\t\t\tG. G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1974\n\t\t\t\t\tCerebellar stimulation in the rat: complex stimulation-bound oral behaviors and self-stimulation.\n\t\t\t\t\tPhysiology & Behavior\n\t\t\t\t\t13\n\t\t\t\t\t1\n\t\t\t\t\t123\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B109",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWatson\n\t\t\t\t\t\t\tP. 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G.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1969\n\t\t\t\t\tEffects of stimulating or destroying the deep cerebellar regions in man\n\t\t\t\t\tJournal of Neurosurgery\n\t\t\t\t\t31\n\t\t\t\t\t172\n\t\t\t\t\t86\n\t\t\t\t\n\t\t\t'},{id:"B114",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCooper\n\t\t\t\t\t\t\tI. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAmin\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRiklan\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWaltz\n\t\t\t\t\t\t\tJ. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tTung\n\t\t\t\t\t\t\tPui.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPoon\n\t\t\t\t\t\t\tM. 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P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1989\n\t\t\t\t\tStress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats.\n\t\t\t\t\tPhysiology & Behavior\n\t\t\t\t\t46\n\t\t\t\t\t6\n\t\t\t\t\t993\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B154",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParé\n\t\t\t\t\t\t\tW. P.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1993\n\t\t\t\t\tPassive-avoidance behavior in Wistar-Kyoto (WKY), Wistar, and Fischer-344 rats.\n\t\t\t\t\tPhysiology & Behavior\n\t\t\t\t\t54\n\t\t\t\t\t5\n\t\t\t\t\t845\n\t\t\t\t\t52\n\t\t\t\t\n\t\t\t'},{id:"B155",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tParé\n\t\t\t\t\t\t\tW. 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P.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAird\n\t\t\t\t\t\t\tF.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKluczynski\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1994\n\t\t\t\t\tStrain differences in hypothalamic-pituitary-adrenal activity and stress ulcer.\n\t\t\t\t\tAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology\n\t\t\t\t\t266\n\t\t\t\t\t2\n\t\t\t\t\tR353\n\t\t\t\t\t60\n\t\t\t\t\n\t\t\t'},{id:"B157",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tArmario\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGavaldà\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMartí\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1995\n\t\t\t\t\tComparison of the behavioural and endocrine response to forced swimming stress in five inbred strains of rats.\n\t\t\t\t\tPsychoneuroendocrinology\n\t\t\t\t\t20\n\t\t\t\t\t8\n\t\t\t\t\t879\n\t\t\t\t\t90\n\t\t\t\t\n\t\t\t'},{id:"B158",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRittenhouse\n\t\t\t\t\t\t\tP. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLópez-Rubalcava\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStanwood\n\t\t\t\t\t\t\tG. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLucki\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2002\n\t\t\t\t\tAmplified behavioral and endocrine responses to forced swim stress in the Wistar-Kyoto rat\n\t\t\t\t\tPsychoneuroendocrinology\n\t\t\t\t\t27\n\t\t\t\t\t3\n\t\t\t\t\t303\n\t\t\t\t\t18\n\t\t\t\t\n\t\t\t'},{id:"B159",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinor\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tRapid avoidance acquisition in Wistar-Kyoto rats.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t192\n\t\t\t\t\t2\n\t\t\t\t\t191\n\t\t\t\t\t7\n\t\t\t\t\n\t\t\t'},{id:"B160",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMcAuley\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStewart\n\t\t\t\t\t\t\tA. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWebber\n\t\t\t\t\t\t\tE. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCromwell\n\t\t\t\t\t\t\tH. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2009\n\t\t\t\t\tWistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t204\n\t\t\t\t\t1\n\t\t\t\t\t162\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B161",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tRapid avoidance acquisition in Wistar-Kyoto rats\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t192\n\t\t\t\t\t2\n\t\t\t\t\t191\n\t\t\t\t\t97\n\t\t\t\t\n\t\t\t'},{id:"B162",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tVulnerability factors in anxiety determined through differences in active-avoidance behavior\n\t\t\t\t\tProgress in Neuro-Psychopharmacology and Biological Psychiatry\n\t\t\t\t\t34\n\t\t\t\t\t6\n\t\t\t\t\t852\n\t\t\t\t\t60\n\t\t\t\t\n\t\t\t'},{id:"B163",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRicart\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tClassical and instrumental conditioning of eyeblink responses in Wistar-Kyoto and Sprague-Dawley rats\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t216\n\t\t\t\t\t1\n\t\t\t\t\t414\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B164",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRicart\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDe Niear\n\t\t\t\t\t\t\tM. A.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tDeficient proactive interference of eyeblink conditioning in Wistar-Kyoto rats.\n\t\t\t\t\tBehavioural Brain Research\n\t\t\t\t\t216\n\t\t\t\t\t1\n\t\t\t\t\t59\n\t\t\t\t\t65\n\t\t\t\t\n\t\t\t'},{id:"B165",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tJiao\n\t\t\t\t\t\t\tX.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tPang\n\t\t\t\t\t\t\tK. C. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBeck\n\t\t\t\t\t\t\tK. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMinor\n\t\t\t\t\t\t\tT. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tServatius\n\t\t\t\t\t\t\tR. 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J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tResting brain perfusion in social anxiety disorder: a voxel-wise whole brain comparison with healthy control subjects\n\t\t\t\t\tProgress in Neuro-Psychopharmacology and Biological Psychiatry\n\t\t\t\t\t32\n\t\t\t\t\t5\n\t\t\t\t\t1251\n\t\t\t\t\t6\n\t\t\t\t\n\t\t\t'},{id:"B183",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShin\n\t\t\t\t\t\t\tL. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Nally\n\t\t\t\t\t\t\tR. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKosslyn\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tThompson\n\t\t\t\t\t\t\tW. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRauch\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAlpert\n\t\t\t\t\t\t\tN. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tRegional Cerebral Blood Flow During Script-Driven Imagery in Childhood Sexual Abuse-Related PTSD: A PET Investigation.\n\t\t\t\t\tAmerican Journal of Psychiatry\n\t\t\t\t\t156\n\t\t\t\t\t575\n\t\t\t\t\t84\n\t\t\t\t\n\t\t\t'},{id:"B184",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBremner\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tNarayan\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStaib\n\t\t\t\t\t\t\tL. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSouthwick\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Glashan\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCharney\n\t\t\t\t\t\t\tD. S.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t1999\n\t\t\t\t\tNeural Correlates of Memories of Childhood Sexual Abuse in Women With and Without Posttraumatic Stress Disorder.\n\t\t\t\t\tThe American journal of psychiatry\n\t\t\t\t\t156\n\t\t\t\t\t1787\n\t\t\t\t\t95\n\t\t\t\t\n\t\t\t'},{id:"B185",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBremner\n\t\t\t\t\t\t\tJ. D.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVythilingam\n\t\t\t\t\t\t\tM.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVermetten\n\t\t\t\t\t\t\tE.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSouthwick\n\t\t\t\t\t\t\tS. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMc Glashan\n\t\t\t\t\t\t\tT.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStaib\n\t\t\t\t\t\t\tL. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tNeural correlates of declarative memory for emotionally valenced words in women with posttraumatic stress disorder related to early childhood sexual abuse.\n\t\t\t\t\tBiological Psychiatry\n\t\t\t\t\t53\n\t\t\t\t\t10\n\t\t\t\t\t879\n\t\t\t\t\t89\n\t\t\t\t\n\t\t\t'},{id:"B186",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBonne\n\t\t\t\t\t\t\tO.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tGilboa\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLouzoun\n\t\t\t\t\t\t\tY.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBrandes\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYona\n\t\t\t\t\t\t\tI.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tLester\n\t\t\t\t\t\t\tH.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2003\n\t\t\t\t\tResting regional cerebral perfusion in recent posttraumatic stress disorder.\n\t\t\t\t\tBiological Psychiatry\n\t\t\t\t\t54\n\t\t\t\t\t10\n\t\t\t\t\t1077\n\t\t\t\t\t86\n\t\t\t\t\n\t\t\t'},{id:"B187",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tYang\n\t\t\t\t\t\t\tP.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWu\n\t\t\t\t\t\t\tT. M.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHsu-C\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKer-H\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tEvidence of early neurobiological alternations in adolescents with posttraumatic stress disorder: a functional MRI study.\n\t\t\t\t\tNeuroscience Letters\n\t\t\t\t\t370\n\t\t\t\t\t1\n\t\t\t\t\t13\n\t\t\t\t\t8\n\t\t\t\t\n\t\t\t'},{id:"B188",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tMenzies\n\t\t\t\t\t\t\tL.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAchard\n\t\t\t\t\t\t\tS.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChamberlain\n\t\t\t\t\t\t\tS. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tFineberg\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen-H\n\t\t\t\t\t\t\tC.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tdel Campo\n\t\t\t\t\t\t\tN.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2007\n\t\t\t\t\tNeurocognitive endophenotypes of obsessive-compulsive disorder.\n\t\t\t\t\tBrain\n\t\t\t\t\t130\n\t\t\t\t\t12\n\t\t\t\t\t3223\n\t\t\t\t\t36\n\t\t\t\t\n\t\t\t'},{id:"B189",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlair\n\t\t\t\t\t\t\tK.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShaywitz\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSmith\n\t\t\t\t\t\t\tB. W.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tResponse to emotional expressions in generalized social phobia and generalized anxiety disorder: evidence for separate disorders\n\t\t\t\t\tAmerican Journal of Psychiatry\n\t\t\t\t\t165\n\t\t\t\t\t9\n\t\t\t\t\t1193\n\t\t\t\t\t1202\n\t\t\t\t\n\t\t\t'},{id:"B190",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tChen\n\t\t\t\t\t\t\tJ.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2011\n\t\t\t\t\tA review of neuroimaging studies of anxiety disorders in China\n\t\t\t\t\tNeuropsychiatric Disease and Treatment\n\t\t\t\t\t7\n\t\t\t\t\t241\n\t\t\t\t\t249\n\t\t\t\t\n\t\t\t'},{id:"B191",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchwartz\n\t\t\t\t\t\t\tC. E.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRauch\n\t\t\t\t\t\t\tS. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tTemperament and its implications for neuroimaging of anxiety disorders.\n\t\t\t\t\tCNS Spectrums\n\t\t\t\t\t9\n\t\t\t\t\t4\n\t\t\t\t\t284\n\t\t\t\t\t91\n\t\t\t\t\n\t\t\t'},{id:"B192",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tEtkin\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKlemenhagen\n\t\t\t\t\t\t\tK. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tDudman\n\t\t\t\t\t\t\tJ. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tRogan\n\t\t\t\t\t\t\tM. T.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tHen\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tKandel\n\t\t\t\t\t\t\tE. R.\n\t\t\t\t\t\t\n\t\t\t\t\t\tet al.\n\t\t\t\t\t\n\t\t\t\t\t2004\n\t\t\t\t\tIndividual differences in trait anxiety predict the response of the basolateral amygdala to unconsciously processed fearful faces.\n\t\t\t\t\tNeuron\n\t\t\t\t\t44\n\t\t\t\t\t1043\n\t\t\t\t\t55\n\t\t\t\t\n\t\t\t'},{id:"B193",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBishop\n\t\t\t\t\t\t\tS. J.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2008\n\t\t\t\t\tTrait anxiety and impoverished prefrontal control of attention.\n\t\t\t\t\tNature Neuroscience\n\t\t\t\t\t12\n\t\t\t\t\t1\n\t\t\t\t\t92\n\t\t\t\t\t98\n\t\t\t\t\n\t\t\t'},{id:"B194",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchienle\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tSchäfer\n\t\t\t\t\t\t\tA.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tStark\n\t\t\t\t\t\t\tR.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tWalter\n\t\t\t\t\t\t\tB.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tVaitl\n\t\t\t\t\t\t\tD.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2005\n\t\t\t\t\tRelationship between disgust sensitivity, trait anxiety and brain activity during disgust induction\n\t\t\t\t\tNeuropsychobiology\n\t\t\t\t\t51\n\t\t\t\t\t2\n\t\t\t\t\t86\n\t\t\t\t\t92\n\t\t\t\t\n\t\t\t'},{id:"B195",body:'\n\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tBlackford\n\t\t\t\t\t\t\tJ. U.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tAvery\n\t\t\t\t\t\t\tS. N.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tCowan\n\t\t\t\t\t\t\tR. L.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tShelton\n\t\t\t\t\t\t\tR. C.\n\t\t\t\t\t\t\n\t\t\t\t\t\t\n\t\t\t\t\t\t\tZald\n\t\t\t\t\t\t\tD. H.\n\t\t\t\t\t\t\n\t\t\t\t\t\n\t\t\t\t\t2010\n\t\t\t\t\tSustained amygdala response to both novel and newly familiar faces characterizes inhibited temperament.\n\t\t\t\t\tSocial Cognitive and Affective Neuroscience\n\t\t\t\t\t6\n\t\t\t\t\t5\n\t\t\t\t\t621\n\t\t\t\t\t9\n\t\t\t\t\n\t\t\t'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Meghan D. Caulfield",address:null,affiliation:'
Stress & Motivated Behavior Institute, New Jersey Medical School, New Jersey, U. S. A.
'},{corresp:"yes",contributorFullName:"Richard J. Servatius",address:"Richard.Servatius@va.gov",affiliation:'
Stress & Motivated Behavior Institute, New Jersey Medical School, New Jersey, U. S. A.
'}],corrections:null},book:{id:"3295",type:"book",title:"New Insights into Anxiety Disorders",subtitle:null,fullTitle:"New Insights into Anxiety Disorders",slug:"new-insights-into-anxiety-disorders",publishedDate:"March 20th 2013",bookSignature:"Federico Durbano",coverURL:"https://cdn.intechopen.com/books/images_new/3295.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:null,printIsbn:"978-953-51-1053-8",pdfIsbn:"978-953-51-7118-8",reviewType:"peer-reviewed",numberOfWosCitations:55,isAvailableForWebshopOrdering:!0,editors:[{id:"157077",title:"Dr.",name:"Federico",middleName:null,surname:"Durbano",slug:"federico-durbano",fullName:"Federico Durbano"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1057"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"43757",type:"chapter",title:"An Evolutionary Perspective on Anxiety and Anxiety Disorders",slug:"an-evolutionary-perspective-on-anxiety-and-anxiety-disorders",totalDownloads:4131,totalCrossrefCites:1,signatures:"John Scott Price",reviewType:"peer-reviewed",authors:[{id:"156695",title:"Dr.",name:"John",middleName:"Scott",surname:"Price",fullName:"John Price",slug:"john-price"}]},{id:"43733",type:"chapter",title:"Anxiety: An Adaptive Emotion",slug:"anxiety-an-adaptive-emotion",totalDownloads:3508,totalCrossrefCites:2,signatures:"Ana G. Gutiérrez-García and Carlos M. Contreras",reviewType:"peer-reviewed",authors:[{id:"158560",title:"Dr.",name:"Carlos M.",middleName:null,surname:"Contreras",fullName:"Carlos M. Contreras",slug:"carlos-m.-contreras"}]},{id:"41031",type:"chapter",title:"Focusing on the Possible Role of the Cerebellum in Anxiety Disorders",slug:"focusing-on-the-possible-role-of-the-cerebellum-in-anxiety-disorders",totalDownloads:2989,totalCrossrefCites:2,signatures:"Meghan D. Caulfield and Richard J. 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“If you do not change direction, you may end up where you are heading”,
Lao Tsu, Chinese philosopher.
1. Introduction
Squamous cell carcinoma of the anus (SCCA) is a rare tumor with an increasing incidence over the last decades [1]. It originates from the basal cells of the epithelial layer of the anal canal, which extends from the anorectal junction to the anal orifice, or anal margin, which extends from the anal orifice to a radius of 5 cm laterally [2]. Tumors arising from the anal margin have a different biological behavior, and this will be briefly discussed later in this chapter. Most, but not all, SCCA are causally related with high-risk human papillomavirus (HPV-HR), mainly subtypes 16 and 18 [3, 4]. These tumors develop from high grade anal intraepithelial neoplasia (AIN3) through a number of consecutive oncogenic steps, which are only partially understood [5]. Radical surgery, which usually implies an abdominoperineal resection with a permanent end colostomy, has been shown to yield 5-year survival rates of only 20–70%, depending on stage and resection margins [6]. Radiation therapy has demonstrated superior survival rates with a high probability of organ preservation. The seminal papers of Nigro and colleagues have shown that the combination of radiation and chemotherapy resulted in even better survival rates, at least for locally advanced cases [7, 8]. This has been confirmed in two landmark randomized phase III trials [9, 10]. Hence, chemoradiation therapy (CRT) has largely replaced radical surgery in the treatment of SCCA.
The focus of this chapter is to highlight the evolving concepts toward individualized treatment of patients with SCCA, based upon prognostic parameters. Emphasis will be given to improved radiation treatment techniques, concurrent and (neo) adjuvant chemotherapy regimens, the role of HPV status, molecular markers and immune response. In addition, the role of surgery will be addressed.
2. Improved treatment of SCCA
2.1 Technical improvement of radiation treatment of SCCA
2.1.1 Radiation dose and target volume
The efficacy of (chemo)radiation treatment for SCCA has been known for several decades. The acute and late toxicity, however, was considerable with the large, non-conformal treatment fields, which often resulted in moderate functional outcome and quality of life [11]. With the development of more powerful computers, algorithms and treatment machines, more sophisticated treatment techniques became available. This has resulted in a shift from standard opposed anterior-posterior fields (AP-PA) or a four-field technique in the fifties through eighties of the previous century to 3D-conformal radiotherapy (3D-CRT) in the nineties and intensity-modulated radiotherapy (IMRT) in the early years of this century and volumetric modulated arc therapy (VMAT) in the last decade.
The difference in toxicity between 3D-CRT and IMRT or VMAT has never been compared in a prospective randomized trial, but several retrospective studies and one recent prospective study have reported an improved toxicity profile with the newer techniques [12, 13, 14, 15, 16, 17]. A recent national audit in the UK comparing these techniques confirmed the reduced toxicity with IMRT (Table 1) [18]. A few studies also claim a better disease-free survival (DFS) and locoregional control (LRC) with IMRT [12, 14, 19].
Table 1.
UK National Audit of anal cancer radiotherapy 2015 [18]. Reproduced with permission of Elsevier.
Toxicity is largely related to the radiation dose and the volume of normal tissues exposed to radiation, which in turn is related to the gross tumor volume (GTV) and clinical and planning target volume (CTV and PTV). The GTV is determined by the macroscopic local tumor extent and documented macroscopically involved regional lymph nodes, whereas the CTV is dependent on the site of regional lymph nodes that are considered to be at risk for microscopic metastatic disease. In addition, the PTV is determined by the set-up error of patient positioning. With the advent of magnetic resonance imaging (MRI) and fluor-18-deoxyglucose positron emission tomography (18F FDG-PET), much improvement is made over the years in visualizing the primary tumor and involved regional lymph nodes and, hence, delineating GTV. In contrast, the estimation of microscopic metastatic disease remains poor and is largely based upon a few studies with documented locoregional recurrence in relation to tumor size and irradiated volumes [20, 21, 22]. The CTV for SCCA is notoriously complex, given the potential involvement of inguinal, iliac, mesorectal and presacral lymph nodes. Consensus contouring guidelines have been developed to assist radiation oncologists in setting up a treatment plan [23, 24]. With respect to the radiation dose, a two or three dose level for microscopic and macroscopic disease has emerged form clinical trials. For instance, in the Radiation Therapy Oncology Group (RTOG) 87-11 trial, a radiation dose of 30.6 Gy was given to the common iliac lymph nodes whereas a dose of 45 Gy was delivered to the lower iliac lymph nodes and 50.4 Gy to the primary tumor [25]. In contrast, in the United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (UKCCCR-ACT) I and the European Organization For Research and Treatment of Cancer Radiotherapy (EORTC) 22861 trial the common iliac lymph nodes were not included in the elective radiation field, whereas a dose of 45 Gy was given to the lower iliac and inguinal lymph nodes with a boost to 60–65 Gy to the primary tumor [9, 10]. In the subsequent UKCCCR-ACT II the dose to the iliac and inguinal lymph nodes was limited to 30.6 Gy and the boost to the primary tumor to 50.4 Gy [26]. Despite these differences in radiation dose and volume, no striking difference in LRC was observed between these trials [9, 10, 25]. A number of retrospective studies have reported a better LRC with a higher radiation dose, at least in the locally advanced tumors [27, 28, 29, 30]. This was confirmed in a systematic literature review [31] and a recent retrospective study from a large Scandinavian database [32]. However, in the French prospective randomized ACCORD-03 trial, which included only locally advanced cases, a marginal, non-significant increase in colostomy-free survival (CFS), a surrogate endpoint for LRC, was observed after 70 Gy, as compared with 60 Gy [33]. Consequently, in the absence of definitive evidence, current clinical guidelines do not advocate a higher radiation dose for larger tumors [34, 35].
2.1.2 The treatment gap
In the initial trials, a treatment gap of 6 weeks was included at an intermediate radiation dose [9, 10, 25]. This was done to allow for recovery from acute radiation toxicity, but also to give the tumor time to regress and to assess whether a radiation boost should be given with external beam irradiation or with brachytherapy. As results matured and further insight in tumor radiobiology was gained, this long treatment gap was considered to be potentially hazardous, due to the likelihood of tumor repopulation during the treatment gap. In the subsequent studies, the treatment gap was shortened to 2 weeks, which not only seemed to be feasible, but also resulted in better LRC in some studies [36, 37, 38, 39, 40] but not in others [41, 42]. With the advent of IMRT and VMAT, the entire radiation course could be administered without a treatment break. Today, most modern radiotherapy centers have implemented IMRT or VMAT for SSCA.
2.2 Chemotherapy and radiation for SCCA
2.2.1 Landmark studies
In June 1973, Dr. Nigro presented 3 cases with SCCA at a meeting of the American Proctologic Society in Detroit, that were treated with radiation therapy (RT) and concurrent Mitomycin C (MMC) and 5-fluorouracyl (5-FU) in a preoperative setting [7]. The rationale for this approach was to improve the LRC and overall survival (OS) of SSCA, since the results with radical surgery alone were modest, at best. Dr. Nigro realized that, in contrast with rectal cancer, SCCA originates from an organ which has an abundant lymphatic vessel supply, that allows rapid lymphatic tumor spread. In addition, there is limited space in the lower pelvis for radical surgery. The radiation dose was 30 Gy in 3–5 weeks via two large anterior-posterior opposed fields, and 30 mg of MMC was given on day 1 in a single bolus infusion and 1500 mg per day of 5-FU on days 2–6 in a continuous infusion. Six to 8 weeks later, two of them underwent an abdominoperineal resection, as planned. No tumor was found on microscopic examination of the operation specimen in these two cases. The third patient refused surgery and remained free of disease 1 year later [7]. This treatment regimen was expanded in a larger series, which confirmed the excellent results [43]. This pioneering work formed the basis for definitive CRT with higher, therapeutic radiation doses.
The superiority of this regimen compared with RT alone was established in two randomized phase III trials, the UKCCCR-ACT I and the EORTC 22861 [9, 10]. These trials were executed almost parallel in time and their design was strikingly similar, except for the eligibility criteria: in the EORTC trial only locally advanced patients were eligible, whereas in the ACT I all stages were accepted for inclusion. Despite this imbalance in patient selection, no major difference in the treatment outcome was observed between these two trials. Both studies showed a significant improvement in LRC control with CRT as compared with RT alone [9, 10]. In the ACT I, 3-year LRC increased from 47% after RT alone to 70% after CRT with concurrent 5-FU and MMC [9]. The corresponding figures in the EORTC 22861 trial were 55 and 68%, respectively [10]. The difference in LRC and progression-free survival (PFS) in the ACT I remained up to 12 years after treatment [44]. However, no difference in OS was found in either of these trials [10, 44].
The value of MMC, in addition to 5-FU, was established in the phase III RTOG 87-04 study [25]. In this trial, however, MMC was given twice in the first and fifth week of the radiation treatment, as opposed to only once in the ACT I and EORTC 22861 trial. It resulted in considerably more grade 4-5 hematological toxicity than was seen in the European trials.
2.2.2 Subsequent pivotal studies
In the subsequent phase III RTOG 98-11 trial, the role of neo-adjuvant and concurrent cisplatin and 5-FU was addressed by comparing it with concurrent MMC and 5-FU [45]. While the combination of cisplatin and 5-FU was less toxic than MMC and 5-FU, the disease-free survival (DFS) and OS was significantly worse with the new regimen [46]. In the UKCCCR-ACT II, concurrent cisplatin, 5-FU and RT was compared with concurrent MMC, 5-FU and RT, with or without adjuvant cisplatin and 5-FU, in a 2 × 2 factorial design [26]. In this trial, which is the largest phase III trial carried out to date for anal cancer, no difference in PFS (Figure 1) and toxicity was observed between the four treatment arms [26]. The French phase III ACCORD 03 trial investigated the value of neo-adjuvant and concurrent cisplatin, 5-FU and RT, and radiation dose intensification, also in a 2 × 2 factorial design [33]. Whereas a marginal, non-significant increase in CFS was observed in the group that received the higher radiation dose, no difference in CFS was found between the patients with and without neo-adjuvant chemotherapy. Acute and late toxicity were similar between the four groups [33]. The EORTC 22011-40014 randomized phase II trial compared concurrent MMC, cisplatin and RT with MMC, 5-FU and RT [47]. The new combination proved to be highly effective, but more toxic, with a compliance of only 49% as opposed to 79% for the standard arm [47].
Figure 1.
MMC or cisplatin+5FU and radiation + or—adjuvant cisplatin/5-FU for SSCAC [26]. Reproduced with permission of Elsevier.
2.2.3 Variant schedules
In the UKCCCR-ACT I, EORTC 22861 and RTOG 87-04 trials, MMC was given once on day 1 [9, 10] or twice on day 1 and 29 of the radiation treatment [25], whereas 5-FU was administered in a continuous infusion day 1–4 or 5 and day 29–32 or 33. Variants of this treatment schedule have been explored with 5-FU given continuously in lower daily doses over the entire split-course radiation treatment [37], or by replacing 5-FU with capecitabine, an oral prodrug of 5-FU, given twice daily during the radiation treatment [48, 49, 50, 51]. These schedules seemed feasible and equally effective as the standard schedule. In addition, capecitabine has the advantage of being able to be given on an outpatient basis.
Taken together, the original regimen of MMC and 5-FU remains the standard of care in CRT for SCCA, 45 years after its inception. There is a trend of using capecitabine instead of 5-FU because it is more patient friendly and equally effective. Arguably, MMC is more toxic than cisplatin in combination with 5-FU or capecitabine and RT [37], but this is dose dependent and seems to be equally effective in a single bolus of 10 mg/m2 as 12 or 15 mg/m2 or twice 10 mg/m2 [9, 10, 25]. Furthermore, the combination of cisplatin and 5-FU is not more effective than MMC and 5-FU, but requires hospitalization for hydration procedures to prevent renal toxicity [26].
3. Prognostic factors in anal carcinoma
Well-known clinical prognostic factors in SCCA are age (>55 years better than ≤55 years), sex (female better than male), tobacco smoking (worse), primary tumor size and site (anal margin better than anal canal), T- and N-stage, tumor ulceration (worse if present) and histological differentiation grade [32, 52, 53]. Other prognostic factors include HPV-HR and certain genetic alterations.
3.1 Human papillomavirus
HPV-HR is causally related with the onset and progression of SCCA [5]. Once integrated into the host DNA, the main viral oncoproteins E6 and E7 interact with the tumor suppressor proteins p53 and retinoblastoma protein (pRb), respectively. P53 has a key role in maintaining DNA integrity, whereas pRb is a negative regulator of the cyclin-dependent kinase inhibitor p16. Upon persistent HPV-HR infection, p53 becomes permanently inactivated, disrupting DNA repair processes, and pRb inactivation induces upregulation of p16. As such, p16 is sometimes used as a surrogate marker of HPV-HR infection. These and other oncogenic processes lead to genomic instability, carcinogenesis and tumor progression. As a result, HPV-HR+ SCCA have a number of unique features, some of which have a prognostic or even a predictive value (Figure 2) [5].
Figure 2.
Molecular features in HPV positive tumors [5]. Reproduced with permission of Elsevier.
Patients with HPV-HR+ SCCA have a significantly better outcome after CRT than HPV-HR-tumors [54, 55, 56]. Absolute difference in LRC/PFS varies from 32 to 67%, whereas the difference in OS varies from 22 to 52%. Interestingly, within the HPV-HR+ tumors, LRC and OS after CRT are significantly better in patients with tumors carrying a high HPV-HR DNA load than in those with a low HPV-HR DNA load [57]. Intratumoral p16 expression is also correlated with LRC and PFS after CRT for SCCA [58]. An even stronger discriminating effect on LRC and PFS is observed by combining p16 expression and HPV DNA tumor load [57].
P53 and p16 expression/HPV-HR+ are inversely correlated in SCCA [56, 58]. In addition, p53 expression and disruptive TP53 mutations are associated with a significantly worse outcome after CRT [56, 58].
3.2 Epidermal growth factor receptor
The epidermal growth factor receptor (EGFR) is frequently overexpressed in SCCA and this may confer a growth and survival advantage. In a subgroup analysis of the RTOG 98-11 trial, overexpression of EGFR and a downstream proliferation marker Ki67 was associated with a significantly worse DFS and OS [59]. In a recent small series of recurrent SCCA, high levels of alterations in the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, which is a growth and survival promoting pathway downstream of EGFR, were associated with poor OS [60].
3.3 Immune response
Persistent intratumoral HPV-HR infection can elicit a host immune response, which is mediated by immune checkpoint proteins such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), expressed on activated T-cells and programmed cell death ligand 1 (PD-L1), expressed on tumors and various host cells [5, 61]. This can attract CD8+ T-lymphocytes into the tumor, so-called tumor-infiltrating lymphocytes (TILs). HPV-mediated intratumoral immune response has a significant influence on LRC and DFS, as illustrated by the amount of CD8+ TILs and PD-1 and PD-L1 expression levels after CRT in SCCA (Figure 3) [62].
Figure 3.
Prognostic impact of CD8+/PD1 and DC8+/PD-L1 expression on LRC and DFS after CRT in SSCAC [62]. Reproduced with permission of Taylor and Francis.
4. Biological agents
Although the standard regimen of CRT with MMC and 5-FU is effective in SCCA, there is still room for improvement, in particular in the locally advanced cases and tumors that carry poor prognostic factors. Attempts have been made to investigate newer, promising agents. Here we focus on two avenues that have been explored.
Cetuximab is a chimeric IgG1 monoclonal antibody with a high affinity for EGFR. It has been tested in a few phase II trials in combination with concurrent CRT in SSCA, and turned out to be very toxic and probably also less effective than the standard regimen [63, 64, 65, 66, 67].
Two phase II trials have been published on the use of anti-PD-1 monoclonal antibodies in recurrent and/or metastatic SCCA, that is nivolumab [68] and pembrolizumab [69]. Objective responses were observed in 24 and 17%, respectively, and stable disease in 42% of the latter [68, 69]. Adverse events were acceptable.
5. The role of surgery in anal carcinoma
5.1 Salvage abdominoperineal resection
Radical surgery for SCCA is restricted to locoregional recurrent, non-metastasized and resectable tumors after CRT. The standard operation procedure is an abdominoperineal resection (APR), sometimes extended with resection of parts of the vagina or prostate, if involved, in order to obtain clear surgical margins [6]. This leaves a large pelvic floor defect, which preferably should be closed with a vertical rectus abdominis myocutaneous flap (VRAM). Patients are left with a permanent colostomy. After APR, 5-year OS varies between 30 and 75%, depending upon whether or not clear resection margins have been obtained [6, 70]. Morbidity can be substantial, such as wound infections and poor healing of previously heavily irradiated organs and tissues. Wide resections into non-irradiated tissues and reconstructions with plastic flap techniques reduce these serious complications [6].
5.2 Curative local excision
A particular role for curative surgery in first line treatment of SCCA is reserved for small, T1N0 tumors of the anal margin, suitable for local excision (LE). This is not a trivial decision to make and these patients deserve to be seen by an experienced multidisciplinary team. Based on a recent pattern of care study in Australia, there is a wide variety in management of these small T1 tumors, depending upon the findings after a (non)excisional biopsy (Figure 4) [71]. In accordance with the guidelines and expert opinion, it is safe to say that T1N0 tumors < 1 cm, located in the anal margin, are good candidates for LE [34, 35]. This will probably account for only 4% of all anal cancers [72]. If pathological examination of the surgical specimen reveals that the resection is not radical, some form of additional treatment is warranted and should be discussed in a multidisciplinary team. If located in the anal canal, LE carries a risk of sphincter damage and is therefore relatively contraindicated. Nevertheless, a recent retrospective cohort study of the US National Cancer Database on 2243 cases with T1 N0 SCCA has shown that over the period 2004–2012 LE was increasingly used in the more recent years, also for tumors of the anal canal [73]. Although criticized for its lack of information on the exact tumor location, LRC and DFS [74, 75], this study and the Australian survey [71] illustrate that clinicians are reluctant to treat these small tumors with standard CRT.
Figure 4.
Reported management of T1N0 anal cancer [71]. Reproduced with permission of Springer.
6. Treatment strategy
Today’s clinical research on SCCA is focused on individualizing treatment as a function of estimated prognosis. A good example, for instance, is the UK trial “PersonaLising rAdioTherapy dOse in anal cancer” (PLATO), which offers a platform of 3 trials, ACT3, 4 and 5, for 3 different risk groups of SCCA [76].
ACT3 is a non-randomized trial for patients with low-risk T1N0 tumors of the anal margin, that undergo LE, followed by active surveillance if the resection margin is >1 mm. If the margin is ≤1 mm, postoperative reduced dose CRT is given locally (41.4 Gy in 23 fractions). In the Netherlands Cancer Institute, we use a somewhat different treatment policy for these tumors, taking a relatively new entity for SCCA into account, known as superficially invasive squamous cell carcinoma (SISCCA). SISCCA is defined as an invasive squamous cell carcinoma with an invasive depth of ≤3 mm and a horizontal spread of ≤7 mm that has been completely excised [77]. In the cervix, SISCCA is known to bear a minimal risk of microscopic lymph node metastasis and it is assumed to be similar for SISCCA of the anus, although the data supporting this are scarce [77]. We therefore have adopted a close surveillance policy for SISCCA of the anal margin. If the resection margin is too close or involved, a wider excision is performed, if possible. If not, postoperative reduced dose RT alone is given to the anus (45 Gy in 25 fractions). For T1N0 tumors that are microscopically >3 mm in invasive depth or >7 mm in horizontal spread, we also irradiate the inguinal lymph nodes to 45 Gy in 25 fractions. We do not advocate CRT in these cases, because the results with RT alone are excellent [35, 78, 79]. Furthermore, CRT is associated with an absolute increase of 9% of non-cancer related deaths compared with RT alone, mainly from cardiovascular cause and secondary tumors [44].
ACT4 is a randomized phase II trial for intermediate-risk tumors, T1–2 (≤4 cm) N0 or Nx, comparing LRC at 3 year after standard-dose CRT (50.4 Gy in 28 fractions) versus a reduced-dose CRT (41.4 Gy in 23 fractions). In the French guidelines, the advice for T1 and small T2 tumors is to treat them with RT alone [35]. In the Netherlands Cancer Institute, we follow the Dutch National guidelines, which advocate RT alone for T1N0 tumors and CRT for all other stages [80].
ACT5 is a randomized seamless pilot/phase II/phase III trial for high-risk SCCA, T1-2N1-3 or T3-4Nany, comparing 3-years’ LRC after standard-dose CRT (53.2 Gy in 28 fractions) with that after 2 higher dose levels (58.8 and 61.2 Gy in 28 fractions) [76]. In the Netherlands Cancer Institute, we use CRT for these tumors with a relatively high radiation dose of 59.4 Gy in 30 fractions. We do not consider a lower radiation dose, because with VMAT the toxicity profile is acceptable [79].
7. Conclusions and future prospects
The treatment of SCCA has evolved over the last 5 decades from a mutilating radical surgical treatment with a modest survival probability to an individualized radiation treatment with or without concurrent chemotherapy with good survival outcome and acceptable morbidity. Important improvements in radiation treatment techniques have been made, modern guidelines have been implemented and quality assurance is provided. However, there is still room for improvement. Quality of life analyses have infrequently been performed and are rarely taken into account in treatment decision making (e.g. [11, 81, 82, 83]). A good step forward in this respect is the development of a core outcome set of data, which should be the minimal information required in future clinical trials for anal cancer [84]. Radiation dose de-escalation and omitting concurrent chemotherapy for early tumors with good prognosis are important avenues to explore. On the other hand, new treatment modalities are needed for poor prognostic cases, such as HPV-HR negative SCCA. Immunotherapy seems to be a promising modality, either alone [68, 69] or in combination with chemotherapy [85]. Exploring the molecular profile of SCCA may reveal new potentially therapeutic targets and prognostic and predictive markers [60, 86, 87]. Circulating tumor DNA at baseline and in follow-up may become an important tool in treatment decision making [88]. These new insights and therapeutic avenues may eventually change the landscape of anal cancer treatment in the near future.
Conflict of interest
The authors have declared no potential conflict of interest.
Nomenclature
clinical target volume (CTV)
the microscopic tumor volume, based upon the estimated microscopic lymphatic tumor spread
CTLA-4
a member of the immunoglobulin superfamily, expressed on the cell surface of activated T-cells. It binds to B7-1 and B7-2 molecules of antigen presenting cells, which down-regulates the immune response, a process frequently occurring in cancer
3D-conformal radiotherapy (3D-CRT)
a 3-dimensional radiation treatment technique, which allows to shape the radiation dose distribution “conformal” to the shape of the planning target volume
epidermal growth factor receptor (EGFR)
a transmembrane protein, which is frequently overexpressed in a number of cancers. When activated, either by ligand binding (normal) or mutations (abnormal), it stimulates downstream signaling pathways, which promote DNA synthesis, cell growth and cell migration
gross tumor volume (GTV)
the macroscopic tumor volume as visualized with CT, MRI and/or PET
intensity-modulated radiotherapy (IMRT)
a refined version of 3D-conformal radiotherapy, where various segments within a radiation field allow to modulate the radiation fluency, in order to obtain conformity to irregularly shaped volumes
P16
a tumor suppressor protein, which slows down the cell cycle by inhibiting cyclin-dependent kinases
P53
a tumor suppressor protein, that plays an essential role in maintaining DNA integrity by various mechanisms. It can activate DNA repair proteins and induce cell cycle arrest to allow DNA repair, or, alternatively, initiate programmed cell death if DNA damage appears to be irreparable
PD-1
a member of the immunoglobulin superfamily, expressed on T-cells and pro-B-cells. It binds to PD-L1 on macro phages and dendritic cells, which down-regulates the immune system and promotes self-tolerance, a protective mechanism against auto-immune disease. PD-L1 is frequently overexpressed in many tumors, which promotes tumor tolerance
PI3K/AKT/mTOR pathway
an intracellular signaling pathway involved in cell cycle regulation. It is frequently overactive in many cancers, eliciting a growth and survival advantage
planning target volume (PTV)
the extension of CTV needed to account for systematic and random set up variation of the patient positioning
retinoblastoma protein (pRb)
a tumor suppressor protein, which prevents excessive cell growth by inhibiting DNA synthesis
volumetric modulated arc therapy (VMAT)
a refined version of IMRT, in which the radiation dose is delivered by rotating the gantry around the patient. The collimator head also rotates and contains moving leaves. The dose rate is also variable
\n',keywords:"anal carcinoma, radiotherapy, chemoradiation therapy, prognostic factors, surgery, biological agents",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/66356.pdf",chapterXML:"https://mts.intechopen.com/source/xml/66356.xml",downloadPdfUrl:"/chapter/pdf-download/66356",previewPdfUrl:"/chapter/pdf-preview/66356",totalDownloads:798,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 28th 2018",dateReviewed:"February 28th 2019",datePrePublished:"March 25th 2019",datePublished:"March 18th 2020",dateFinished:"March 25th 2019",readingETA:"0",abstract:"Treatment of squamous cell carcinoma of the anus has evolved over the last 5 decades from radical surgery to combined chemoradiation therapy. Radiation treatment techniques have dramatically improved with the development of more powerful computers, algorithms and treatment machines. The clinical impact of the modern radiation treatment techniques, such as intensity-modulated radiotherapy and volumetric modulated arc therapy, is discussed. The standard-of-care regimen still is concurrent Mitomycin C, 5-fluorouracil and high-dose radiation, as was conceived 45 years ago. Variants of this schedule are discussed in this chapter. International guidelines have been generated and implemented. Whereas concurrent chemoradiation therapy is the treatment of choice for locally advanced tumors, early tumors are probably adequately controlled with either reduced dose chemoradiation therapy or radiation therapy alone. Prognostic factors, such as high-risk human papillomavirus, epidermal growth factor receptor and immune response, will be highlighted. The role of surgery in primary care is limited to local excision of T1N0 tumors ≤ 1 cm of the anal margin. Salvage radical surgery is limited to locoregional recurrent, non-metastasized and resectable tumors after chemoradiation therapy. In addition, new treatment modalities, such as targeted therapy and immunotherapy, will be discussed. Current research aims at refining prognostic subgroups to further individualize treatment strategy, implementing quality assurance protocols in international trials and investigating the molecular profile of squamous cell carcinoma of the anus, in order to identify new treatment avenues. This will hopefully change the landscape of anal cancer treatment in the future.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66356",risUrl:"/chapter/ris/66356",signatures:"Luc Dewit, Annemieke Cats and Geerard Beets",book:{id:"8211",type:"book",title:"Squamous Cell Carcinoma",subtitle:"Hallmark and Treatment Modalities",fullTitle:"Squamous Cell Carcinoma - Hallmark and Treatment Modalities",slug:"squamous-cell-carcinoma-hallmark-and-treatment-modalities",publishedDate:"March 18th 2020",bookSignature:"Hamid Elia Daaboul",coverURL:"https://cdn.intechopen.com/books/images_new/8211.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78984-324-8",printIsbn:"978-1-78984-323-1",pdfIsbn:"978-1-78985-592-0",isAvailableForWebshopOrdering:!0,editors:[{id:"214249",title:"Prof.",name:"Hamid",middleName:"Elia",surname:"Daaboul",slug:"hamid-daaboul",fullName:"Hamid Daaboul"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"287467",title:"Dr.",name:"Luc",middleName:null,surname:"Dewit",fullName:"Luc Dewit",slug:"luc-dewit",email:"l.dewit@nki.nl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"294887",title:"Dr.",name:"Annemieke",middleName:null,surname:"Cats",fullName:"Annemieke Cats",slug:"annemieke-cats",email:"a.cats@nki.nl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"294888",title:"Prof.",name:"Geerard",middleName:null,surname:"Beets",fullName:"Geerard Beets",slug:"geerard-beets",email:"g.beets@nki.nl",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"",level:"1"},{id:"sec_2",title:"1. Introduction",level:"1"},{id:"sec_3",title:"2. Improved treatment of SCCA",level:"1"},{id:"sec_3_2",title:"2.1 Technical improvement of radiation treatment of SCCA",level:"2"},{id:"sec_3_3",title:"Table 1.",level:"3"},{id:"sec_4_3",title:"2.1.2 The treatment gap",level:"3"},{id:"sec_6_2",title:"2.2 Chemotherapy and radiation for SCCA",level:"2"},{id:"sec_6_3",title:"2.2.1 Landmark studies",level:"3"},{id:"sec_7_3",title:"2.2.2 Subsequent pivotal studies",level:"3"},{id:"sec_8_3",title:"2.2.3 Variant schedules",level:"3"},{id:"sec_11",title:"3. Prognostic factors in anal carcinoma",level:"1"},{id:"sec_11_2",title:"3.1 Human papillomavirus",level:"2"},{id:"sec_12_2",title:"3.2 Epidermal growth factor receptor",level:"2"},{id:"sec_13_2",title:"3.3 Immune response",level:"2"},{id:"sec_15",title:"4. Biological agents",level:"1"},{id:"sec_16",title:"5. The role of surgery in anal carcinoma",level:"1"},{id:"sec_16_2",title:"5.1 Salvage abdominoperineal resection",level:"2"},{id:"sec_17_2",title:"5.2 Curative local excision",level:"2"},{id:"sec_19",title:"6. Treatment strategy",level:"1"},{id:"sec_20",title:"7. Conclusions and future prospects",level:"1"},{id:"sec_24",title:"Conflict of interest",level:"1"},{id:"sec_23",title:"Nomenclature",level:"1"}],chapterReferences:[{id:"B1",body:'Nelson R, Levine A, Bernstein L, Smith D, Lai L. Changing patterns of anal canal carcinoma in the United States. Journal of Clinical Oncology. 2013;31:1569-1575. DOI: 10.1200/JCO.2012.45.2524'},{id:"B2",body:'Amin M, Edge S, Greene F, Byrd D, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017'},{id:"B3",body:'Daling J, Weiss N, Klopfenstein L, Cochran L, Chow W, Daifuku R. Correlates of homosexual behaviour and the incidence of anal cancer. Journal of the American Medical Association. 1982;247:1988-1990. 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Initial results from the Royal College of Radiologists’ UK National Audit of Anal Cancer radiotherapy 2015. Clinical Oncology. 2017;29:188-197. DOI: 10.1016/j.clon.2016.10.005'},{id:"B19",body:'Mitra D, Hong T, Horick N, Rose B, Drapek L, Blaszkowsky L, et al. Long-term outcomes and toxicities of a large cohort of anal cancer patients treated with dose-painted IMRT per RTOG 0529. Advances in Radiation Oncology. 2017;2:110-117. DOI: 10.1016/j.adro.2017.01.009'},{id:"B20",body:'Das P, Bhatia S, Eng C, Ajani JA, Skibber JN, Rodriguez-Bigas MA, et al. Predictors and patterns of recurrence after definitive chemoradiation for anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2007;68:794-800. DOI: 10.1016/j.ijrobp.2006.12.052'},{id:"B21",body:'Wright JL, Patil SM, Temple LKF, Minsky BD, Slatz LB, Goodman KA. Squamous cell carcinoma of the anal canal: Patterns and predictors of failure and implications for intensity-modulated radiation treatment planning. International Journal of Radiation Oncology, Biology, Physics. 2010;78:1064-1072. DOI: 10.1016/j.ijrobp.2009.09.029'},{id:"B22",body:'Matthews J, Burmeister B, Borg M, Capp A, Joseph D, Thompson K, et al. T1-2 anal carcinoma requires elective inguinal radiation treatment—The results of trans tasman radiation oncology group study TROG 99.02. Radiotherapy and Oncology. 2011;98:93-98. DOI: 10.1016/j.radonc.2010.10.005'},{id:"B23",body:'Myerson R, Garofalo M, El Naqa I, Abrams R, Apte A, Bosch W, et al. Elective clinical target volumes for conformal therapy in anorectal cancer; a Radiation Therapy Oncology Group consensus panel contouring atlas. International Journal of Radiation Oncology, Biology, Physics. 2009;74:824-830. DOI: 10.1016/j.ijrobp.2008.08.070'},{id:"B24",body:'Ng M, Leong T, Chandler S, Kneebone A, Carroll S, Wiltshire K, et al. Australasian Gastrointestinal Trials Group (AGITG) contouring atlas and planning guidelines for intensity-modulated radiotherapy in anal cancer. 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Mitomycin C with continuous fluorouracil or with cisplatin in combination with radiotherapy for locally advanced anal cancer (European Organisation for Research and Treatment of Cancer phase II study 22011-40014). European Journal of Cancer. 2009;45:2782-2791. DOI: 10.1016/j.ejca.2009.06.020'},{id:"B48",body:'Glynne-Jones R, Meadows H, Wan S, Gollins S, Leslie M, Levine E, et al. EXTRA-a multicenter phase II study of chemoradiation using a 5 day per week oral regimen of capecitabine and intravenous mitomycin C in anal cancer. International Journal of Radiation Oncology, Biology, Physics. 2008;72:119-126. DOI: 10.1016/j.ijrobp.2007.12.012'},{id:"B49",body:'Meulendijks D, Dewit L, Tomasoa B, van Tinteren H, Beijnen J, Schellens J, et al. Chemoradiotherapy with capecitabine for locally advanced anal carcinoma: An alternative treatment option. British Journal of Cancer. 2014;111:1726-1733. 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Abdominoperineal resection for squamous cell anal carcinoma: Survival and risk factors for recurrence. Annals of Surgical Oncology. 2012;19:4186-4192. DOI: 10.1245/s10434-012-2485-1'},{id:"B71",body:'Jones M, Carroll S, Martin J, Hillman R, Grulich A, O’Connell D, et al. Management of early anal cancer: Need for guidelines and standardization. International Journal of Colorectal Disease. 2017;32:1719-1724. DOI: 10.1007/s00384-017-2913-6'},{id:"B72",body:'Renehan A, Muirhead R, Berkman L, McParland L, Sebag-Montefiore D. Early stage anal margin cancer: Towards evidence-based management. Colorectal Disease. 2019. DOI: 10.1111/codi.14571. CDI-00875-2018.R2. [Epub ahead of print]'},{id:"B73",body:'Chai C, Cao H, Awad S, Massarweh N. Management of stage I squamous cell carcinoma of the anal canal. JAMA Surgery. 2018;153(3):209-215. DOI: 10.1001/jamasurg.2017.3151'},{id:"B74",body:'Leeds I, Fang S. Limitations of the National Cancer Data Base to evaluate early-stage Anal Cancer treatment outcomes. JAMA Surgery. 2018;153:690-691. DOI: 10.1001/jamasurg.2018.0391'},{id:"B75",body:'Renehan A, Muirhead R, Sebag-Montefiore D. Limitations of the National Cancer Data Base to evaluate early-stage Anal Cancer treatment outcomes. JAMA Surgery. 2018;153:691. DOI: 10.1001/jamasurg.2018.0394'},{id:"B76",body:'Plato. Personalising Anal Cancer Radiotherapy Dose. DOI: 10.1186/ISRCTN88455282'},{id:"B77",body:'Darragh T, Colgan T, Cox T, Heller D, Henry M, Luff R, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: Background and consensus recommendations from the college of American pathologists and the American Society for Colposcopy and Cervical Pathology. International Journal of Gynecological Pathology. 2012;32:76-115. DOI: 10.1097/PGP.0b013e31826916c7'},{id:"B78",body:'Cummings B, Keane T, O’Sullivan B, Wong C, Catton C. Epidermoid anal cancer: Treatment by radiation alone or by radiation and 5-fluorouracil with and without mitomycin C. International Journal of Radiation Oncology, Biology, Physics. 1991;21:1115-1125. DOI: 10.1016/0360-3016(91)90265-6'},{id:"B79",body:'Tomasoa N, Meulendijks D, Nijkamp J, Cats A, Dewit L. Clinical outcome in patients treated with simultaneous integrated boost—Intensity modulated radiation therapy (SIB-IMRT) with and without concurrent chemotherapy for squamous cell carcinoma of the anal canal. Acta Oncologica. 2016;55:760-766. DOI: 10.3109/0284186X.2015.1124141'},{id:"B80",body:'IKNL Oncoline. Landelijke Richtlijn Anuscarcinoom, Versie 2. Consensus Based. 2012. Available from: https://www.oncoline/gastroenterologie/anuscarcinoom'},{id:"B81",body:'Tournier-Rangeard L, Mercier M, Peiffert D, Gerard J, Romestaing P, Lemanski C, et al. Radiochemotherapy of locally advanced anal canal carcinoma: Prospective assessment of early impact on the quality of life (randomized trial ACCORD 03). Radiotherapy and Oncology. 2008;87:91-97. DOI: 10.1016/j.radonc.2007.12.004'},{id:"B82",body:'Bentzen A, Balteskard L, Wanderås E, Frykholm G, Wilsgaard T, Dahl O, et al. Impaired health-related quality of life after chemoradiotherapy for anal cancer: Late effects in a national cohort of 128 survivors. Acta Oncologica. 2013;52:736-744. DOI: 10.3109/0284186X.2013.770599'},{id:"B83",body:'Sodergren S, Vassiliou V, Dennis K, Tomaszewski K, Gilbert A, Glynne-Jones R, et al. Systematic review of the quality of life issues associated with anal cancer and its treatment with radiochemotherapy. Support Care Cancer. 2015;23:3613-3623. DOI: 10.1007/s00520-015-2879-2'},{id:"B84",body:'Fish R, Caroline Sanders C, Williamson P, Renehan A. Core outcome research measures in anal cancer (CORMAC): Protocol for systematic review, qualitative interviews and Delphi survey to develop a core outcome set in anal cancer. BMJ Open. 2017;7:e018726. DOI: 10.1136/bmjopen-2017-018726'},{id:"B85",body:'Kim S, François E, André T, Samalin E, Jary M, Hajbi F, et al. Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (epitopes-HPV02): A multicentre, single-arm, phase 2 study. The Lancet Oncology. 2018;19:1094-1106. DOI: 10.1016/S1470-2045(18)30321-8'},{id:"B86",body:'Smaglo B, Tesfaye A, Halfdanarson T, Meyer J, Wang J, Gatalica Z, et al. Comprehensive multiplatform biomarker analysis of 199 anal squamous cell carcinomas. Oncotarget. 2015;6:43594-43604. Available from: https://www.impactjournals.com/oncotarget'},{id:"B87",body:'Chung J, Sanford E, Johnson A, Klempner S, Schrock A, Palma N, et al. Comprehensive genomic profiling of anal squamous cell carcinoma reveals distinct genomically defined classes. Annals of Oncology. 2016;27:1336-1341. DOI: 10.1093/annonc/mdw152'},{id:"B88",body:'Cabel L, Jeannot E, Bieche I, Vacher S, Callens C, Bazire L, et al. Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal squamous cell carcinoma. Clinical Cancer Research. 2018;24:5767-5771. DOI: 10.1158/1078-0432.CCR-18-0922'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Luc Dewit",address:"l.dewit@nki.nl",affiliation:'
Department of Radiation Oncology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), The Netherlands
Department of Surgical Oncology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek), The Netherlands
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Proven world leader in Open Access book publishing with over 10 years experience
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Most competitive prices in the market
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Compliant with OA funding requirements
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+184,650 citations in Web of Science databases
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\r\n\t
\r\n
\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
\r\n\t
\r\n
\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
\r\n
\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
\r\n
\r\n\t
\r\n
\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null}]},subseriesFiltersForPublishedBooks:[{group:"subseries",caption:"Bacterial Infectious Diseases",value:3,count:2},{group:"subseries",caption:"Parasitic Infectious Diseases",value:5,count:4},{group:"subseries",caption:"Viral Infectious Diseases",value:6,count:7}],publicationYearFilters:[{group:"publicationYear",caption:"2022",value:2022,count:2},{group:"publicationYear",caption:"2021",value:2021,count:4},{group:"publicationYear",caption:"2020",value:2020,count:3},{group:"publicationYear",caption:"2019",value:2019,count:3},{group:"publicationYear",caption:"2018",value:2018,count:1}],authors:{paginationCount:249,paginationItems:[{id:"274452",title:"Dr.",name:"Yousif",middleName:"Mohamed",surname:"Abdallah",slug:"yousif-abdallah",fullName:"Yousif Abdallah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/274452/images/8324_n.jpg",biography:"I certainly enjoyed my experience in Radiotherapy and Nuclear Medicine, particularly it has been in different institutions and hospitals with different Medical Cultures and allocated resources. Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"18",type:"subseries",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11414,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. 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. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. 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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