\r\n\tEnvironmental Chemoinformatics aims to avoid animal testing, with respect of REACH (Registration, Evaluation, Authorisation, and restriction of Chemicals) regulations, using QSAR models to prioritize compounds by environmental hazard and risk assessment. \r\n\tOptimization of process parameters in various chemical process and operations can carried out by simulation programs (separation: simulation of a fractional distillation column; transport properties; penetration trough membranes; coatings; fermentative process, etc.).
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Amalia Stefaniu has a background in chemical engineering, acquiring her Bachelor’s degree at University POLITEHNICA of Bucharest, Faculty of Chemical Engineering (in French). \r\nShe completed her studies with Postgraduate Academic Advanced Studies, Drugs and Cosmetics specialization and with a masters degree in Biotechnologies and food safety at University of Agricultural Sciences and Veterinary Medicine Bucharest, Faculty of Biotechnologies. \r\n\r\nShe obtained her Ph.D. degree in Exact Sciences - Chemistry (2011) at University POLITEHNICA of Bucharest, Romania, Faculty of Applied Chemistry and Materials Science, Department of Inorganic Chemistry, Physical Chemistry and Electrochemistry.\r\n\r\nHer current position is Senior research scientist at National Institute for Chemical-Pharmaceutical Research and Development, Bucharest, Laboratory of molecular design and molecular docking. 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1. Introduction
Irritable bowel syndrome (IBS) is a functional digestive disorder characterized by abdominal pain, bloating and altered bowel habits without any organic cause (Drossman 1999b; Mulak and Bonaz 2004). Patients with IBS exhibit enhanced perception of visceral sensation to colonic distension which is associated with hypervigilance at the origin of visceral hypersensitivity (VHS) (Ritchie 1973; Bradette, et al. 1994; Elsenbruch, et al. 2010). VHS is a clinical marker of IBS considered to play a major role in its pathophysiology. The exact cause of VHS is unknown but a number of mechanisms are evoked as represented by neuroplastic changes in primary afferent terminals (peripheral sensitization) due to peripheral inflammation or infection of the gut (i.e. post-infectious IBS) but also in the spinal cord (central sensitization) and in the brain (supraspinal pain modulation) or in descending pathways that modulate spinal nociceptive transmission (Bonaz 2003; Mulak and Bonaz 2004). In addition, stress is able to increase visceral sensitivity either at the central and/or peripheral level (Mulak and Bonaz 2004; Larauche, et al. 2011).
There is a bidirectional communication between the central nervous system (CNS) and the gastrointestinal (GI) tract, i.e. the brain-gut axis, such as signals from the brain can modify the motor, sensory, secretory, and immune functions of the GI tract and, conversely, visceral messages from the GI tract can influence brain functions in a top-down and bottom-up relation. Numerous data argue for a dysfunction of this brain-gut axis in the pathophysiology of IBS (Mulak and Bonaz 2004; Bonaz and Sabate 2009; Tillisch, et al. 2011).
Stress, through the corticotrophin-releasing factor (CRF) system (CRF, urocortins and their receptors CRF1,2), is a key factor involved in the pathophysiology of IBS. Indeed, stress is able to modify visceral sensitivity as well as GI motility, permeability, intestinal microbiota, and immunity of the GI tract, all mechanisms that are involved in the pathophysiology of IBS. In addition, stress is able to modulate the hypothalamic pituitary adrenal (HPA) axis and the autonomic nervous system (ANS) which is the link between the gut and the CNS and an imbalance of the ANS is observed in IBS patients (Pellissier, et al. 2010a; Mazurak, et al. 2012). The main brain areas involved in stress are the prefrontal cortex, the limbic system (e.g. the hippocampus and the amygdala) and the hypothalamus. Relations between the prefrontal cortex and the limbic system are important in the management of stress response.
The amygdala is a key structure involved in the stress effect on the GI tract. Indeed, the amygdala is involved in brain-gut and gut-brain interactions. i) The amygdala receives informations from the gut through the parabrachial (PB) nucleus, a sensitive nucleus, and the dorsal vagal complex. The latter, composed of the nucleus tractus solitaries (NTS), is the main entrance of the vagus nerve (vagal afferents) and sends projections to the amygdala. The amygdala is therefore a relay of somatic and visceral nociceptive and non-nociceptive afferents through ascending inputs from the spinal cord and the NTS to the insula which is the main cortical area involved in sensitive information processing. ii) The amygdala controls the ANS which is a key element in the neuro-endocrine and autonomic responses to stress of the organism to maintain homeostasis. On the one hand, the amygdala projects to the dorsal motor nucleus of the vagus nerve (DMNV) at the origin of the parasympathetic branch of the vagus nerve (vagal efferents); this makes the amygdala able to modulate the functioning of the parasympathetic system through the vagus nerve. On the other hand, the amygdala projects to the intermediolateral column cells of the spinal cord, at the origin of the sympathetic nerves, and locus coeruleus (LC) in the pons. It makes the amygdala able to modulate the sympathetic nervous system, the other branch of the ANS, and thus to modulate the sympatho-vagal balance, a marker of brain-gut interactions (Mazurak, et al. 2012). iii) The amygdala controls the HPA axis activation either directly or indirectly via the hippocampus (i.e. inhibition), known to inhibit the HPA axis, and thus to decrease stress response. iv) The amygdala is also involved in childhood psycho-traumatic experiences which are key elements in the pathophysiology of IBS. Indeed, early life stress, as represented by sexual abuse in infancy or adolescence, is present in 30 to 50% of IBS patients (Chitkara, et al. 2008; Bradford, et al. 2012). The amygdala is particularly vulnerable to stressors in early life. The amygdala contains all the elements of the CRFergic system (e.g. CRF, Ucns, CRF1,2) and early life stress induces persistent changes of the CRFergic system in the amygdala leading to an increased stress sensitivity in adulthood. This has been well modelled in the maternally separated (MS) rat model where morphological modifications of the amygdala (e.g. enlarged amygdala volumes and increases in CRF-containing neurons) are induced. v) The amygdala (central nucleus; CeA) and the bed nucleus of the stria terminalis (BNST) are highly interconnected with limbic regions (Bienkowski and Rinaman 2012). These two regions are frequently referred as a “central extended amygdala”, which shares similar connectivity with other brain regions (e.g. hypothalamus and brainstem) that coordinate behavioural and physiological responses to interoceptive and exteroceptive stressors. It makes the amygdala able to link pain and emotional processings. Furthermore, the amygdala is sensitive to stress-induced increase in glucocorticoids since the existence of elevated glucocorticoid level in the amygdala is associated with anxiety-like behavior and visceral hypersensitivity (Myers and Greenwood-Van Meerveld 2007b; 2010). The amygdala is therefore at the cross-road of anxiety, stress, and visceral sensitivity. The role of the amygdala in IBS is therefore crucial since IBS patients reported higher score of state and trait anxiety than healthy volunteers or in inflammatory bowel disease (IBD) patients in remission with IBS symptoms (Drossman 1999b; Pellissier, et al. 2010a). vi) The prefrontal cortex (PFC), and particularly its medial part (mPFC), is able to modulate the functioning of the amygdala. Indeed, the mPFC involvement in fear extinction process (Sotres-Bayon, et al. 2004; Quirk, et al. 2006a) has been shown to be indirectly mediated by its inhibitory action on the amygdala output (Vidal-Gonzalez, et al. 2006). vii) Brain imaging techniques (fMRI, PET) have contributed to a better understanding of the pathophysiology of IBS. During rectal distention, an activation of most of the brain structures referenced above, and in particular the amygdala, have been observed in healthy volunteers (Baciu, et al. 1999) while an abnormal brain processing (i.e. abnormal loci of cerebral activation) of pain was observed in IBS patients (Bonaz, et al. 2002; Agostini, et al. 2011). In addition, brain structural changes of the HPA axis and limbic structures have been recently reported in IBS patients (Blankstein, et al. 2010; Seminowicz, et al. 2010).
At the present time, the only medical treatment of IBS is directed at GI motor/sensory or CNS processing. Unfortunately, this treatment is poorly effective and often associated with high placebo effects, thus revealing the importance of the overlap between pain and placebo neurobiological pathways. The therapeutic approach is essentially focused on the symptoms as represented by anti-spasmodics for pain, laxatives or bulking agents, 5-HT4 agonists and guanylate cyclase-C agonist for intestinal transit regulation and anti-depressives/anxiolytics drugs. Placebo has a ≈ 40% efficacy in IBS patients (Patel, et al. 2005) and pronounced placebo analgesia is coupled with prominent changes of brain activity in visceral pain matrix, as represented by the amygdala (Lu, et al. 2010). Non-pharmacological therapies are of special interest. Cognitive behavioral therapy is associated with reduced limbic activity (e.g. reduced neural activity in the amygdala), GI symptoms, and anxiety (Lackner, et al. 2006). Hypnosis has shown efficacy in IBS (Whorwell, et al. 1984) and is known to modify the activity of the amygdala (Drossman 1999b). All methods focused on stress reduction such as mindfulness-based stress reduction should reduce pain perception (Drossman 1999a). Repetitive transcranial magnetic stimulation of the PFC that decreases the activity of the amygdala (Baeken, et al. 2010) would also be of interest in IBS patients. In this context, vagal nerve stimulation, used for the treatment of refractory epilepsy and depression, should be of interest in the treatment of IBS by modulating the amygdala. Indeed, an inhibitory action of vagal nerve stimulation on amygdala-mPFC neurotransmission, probably due to the deactivation of the amygdala, has been described under VNS (Kraus, et al. 2007). Consequently, new methods aimed at modifying the activity of the amygdala represent a therapeutic challenge in the management of IBS patients.
2. Irritable bowel syndrome
2.1. Definition-background
The irritable bowel syndrome (IBS) is the most common disorder encountered by gastroenterologists. IBS is defined as “a functional bowel disorder in which abdominal pain is associated with defecation or a change in bowel habit with features of disordered defecation and distension”(Drossman 1999b). Classically the syndrome is considered as functional since biological as well as morphological (e.g. colonoscopy) investigations are not able to evidence any detectable organic lesions or anatomical abnormalities (colonic polyps or diverticulosis…) relative to symptomatology of the affected patients. The syndrome has been defined according to Rome III criteria (Longstreth, et al. 2006). There is a female predominance in a ratio of 2:1 (Drossman, et al. 1993). IBS affects up to 10–15% of the population with an estimated 1.7 billion dollars in annual direct cost (Talley, et al. 1991). Generally patients suffer from the absence of a real diagnostic and from the consideration that they have a psychosomatic disease. Pain is perceived by patients as the most distressing symptom and constitutes their major reason for consulting a physician (Sandler, et al. 1984). Extra-intestinal manifestations are also frequently described by the patients (e.g. headache, low back pain, chronic fatigue, interstitial cystitis…) (Whitehead, et al. 2002).
2.2. Pathophysiology
The pathophysiology of IBS is multifactorial. Altered bowel motility, sensory disorders, psychosocial factors are evoked (Drossman, et al. 1999c; Gaynes and Drossman 1999; Bonaz and Sabate 2009). Local features have also been considered as important. The role of food is often evoked by patients and a number of them are intolerant to lactose, fructose, gluten, polyols (Dapoigny, et al. 2004; Morcos, et al. 2009) with an enhancement of their symptoms following an eviction of such foods from diet. There is also good evidence for a role of the GI microbiota in its pathogenesis (Parkes, et al. 2008). Neuroimmune interactions are also involved, based on the development of IBS after infectious gastroenteritis (i.e. post-infectious IBS) (Gwee 2001) or in patients with IBD in clinical remission (i.e. post-inflammatory IBS) (Long and Drossman 2010). A low grade inflammation has been observed in IBS patients with a predominance of mastocytes in close contact with neural fibers explaining why IBS is assimilated to an IBD by some authors (Ford and Talley 2011).
Sensory disorders, and especially VHS, have also been evoked in the pathophysiology of IBS. VHS, represented by the increased sensation of pain when the pelvic colon is distended with an inflated rectal balloon, is a clinical marker of IBS which is observed in most of IBS patients. The exact location of the abnormal processing of visceral pain is unknown, and can have a peripheral origin, i.e. in the digestive tract by altered peripheral functioning of visceral afferents (i.e. bottom-up model), a spinal origin, e.g. spinal hyperalgesia by a defect of the gate control, or a defect of descending inhibitory controls or an altered central processing of afferent information from the gut, i.e. top-down model or a combination of all these hypotheses. IBS patients have an alteration in the spinal modulation of nociceptive process by the inhibitory descending pain modulation systems (Wilder-Smith, et al. 2004) in which the amygdala could be involved.
Psychosocial factors are often found in IBS patients. Among 20 to 50% of IBS patients have psychiatric disorders, such as major depression, anxiety, and somatoform disorders (Garakani, et al. 2003). Low dose of tricyclic antidepressants have shown efficacy in ameliorating the symptoms in patients (Rahimi, et al. 2009). IBS is also frequently associated with fibromyalgia in 30% to 70% of the cases. This syndrome is characterized by somatic hyperalgesia, the physiopathology of which is close to IBS (Mathieu 2009). IBS and fibromyalgia are classified by some authors as central sensitization syndromes (Woolf 2011). A majority of IBS patients associate stressful life events with initiation or exacerbation of their symptoms (Whitehead, et al. 1992) and stress is able to act at all levels of the physiopathology of IBS (see below). Globally, a concept has emerged that IBS is the result of a dysfunction of the brain-gut interplay, as conceptualized in the brain-gut axis. The ANS is, with the HPA axis, the link between the CNS and the gut and an autonomic dysfunction is observed in IBS patients which could be of top-down or bottom-up origin, as observed for VHS.
3. The brain-gut axis
3.1. Definition
The brain talks to the gut and conversely through a bidirectional communication under normal conditions and especially during perturbations of homeostasis. The CNS and the gut communicate through the ANS and the circumventricular organs and the gut contains a “little brain” as represented by the enteric nervous system which is a target of the ANS.
3.2. The enteric nervous system
The enteric nervous system can control functions of the intestine even when it is completely separated from the CNS (Bayliss and Starling 1899). The enteric nervous system contains three categories of neurons, identified as sensory, associative, and motor neurons (both excitatory and inhibitory) which are the final common pathways for the control of signals to the musculature, submucosa, mucosa, and vasculature, both blood and lymphatic. The enteric nervous system contains as many neurons as in the spinal cord (400–600 million) and confers an autonomy to the digestive tract such as the enteric nervous system can function independently of the CNS for the programming of motility and secretion (Furness 2012). Some neuropeptides and receptors are present in both the enteric nervous system and the CNS. The function of the GI tract is modulated by both the enteric nervous system and the ANS.
3.3. The autonomic nervous system (The afferent system)
The ANS is composed of the sympathetic (i.e. the splanchnic nerves) and parasympathetic nervous system (i.e. the vagus nerves and the sacral parasympathetic nucleus represented by the pelvic nerves) which are mixed systems.
The vagus nerve contains essentially 80-90% of afferent fibers vehiculating informations from the abdominal organs to the brain (Altschuler, et al. 1989) with the exception of the pelvic viscera for which informations are vehiculated to S2-S4 levels of the spinal cord by the pelvic nerves with central projections similar to other spinal visceral afferents. The vagus nerve carries mainly mechanoreceptor and chemosensory informations from the gut. If classically vagal afferents do not encode painful stimuli, they are able to modulate nociceptive processing in the spinal cord and the brain (Randich and Gebhart 1992).
The sympathetic nerves contain 50% afferent fibers. Visceral afferents that enter via spinal nerves (i.e; splanchnic and pelvic nerves), at thoracic 5 - lumbar 2 segments of the spinal cord, carry information concerning temperature as well as nociceptive visceral inputs related to mechanical, chemical, or thermal stimulation through C and Aδ fibers, which will reach conscious perception.
The afferent informations of the ANS reach the CNS at the spinal cord level, for the splanchnic nerves, the nucleus tractus solitarius (NTS) level in the dorsal medulla for the vagus nerve, and the sacral parasympathetic (S2-S4) level for the pelvic nerves. At the level of the spinal cord, sympathetic afferents are integrated at the level of laminae I, II outer, V, VII (indirectly) and X. Then the information is sent to the upper level through the spino-thalamic and spino-reticular tracts, the dorsal column with projection to the thalamus (ventral posterolateral nucleus, intralaminar nucleus) and the cerebral cortex (insular, anterior-cingulate, dorsolateral PFC…). Neurons from laminae I, IV, and V responding to visceral stimuli also receive nociceptive cutaneous inputs (Foreman 1999).
At the level of the NTS, vagal afferents are integrated in subnuclei according to visceral somatotopy (e.g. medial, commissural, gelatinosus) (Altschuler, et al. 1993) and then projections to the PB nucleus, in the pons, according to a viscerotopic organization, which in turn projects to numerous structures in the brainstem, hypothalamus, basal forebrain, thalamus, and cerebral cortex (Fulwiler and Saper 1984). In the cerebral cortex, the insular cortex acts as a visceral (e.g. GI) cortex through a NTS-PB-thalamo-cortical pathway according to a viscerotopic map. The insular cortex is connected with the limbic system (bed nucleus of the stria terminalis and CeA) and with the lateral frontal cortical system (Saper 1982). The NTS also sends projections to the ventrolateral medulla, the hypothalamus, and the amygdala/bed nucleus of the stria terminalis contributing to visceral perception. The NTS receives convergent afferents from both the spinal cord (i.e. laminae I, V, VII, and X) and the vagus nerve; some of these afferents probably being at the origin of autonomic reflex responses. This convergence is also observed at the level of the PB and ventrolateral medulla (Saper 2002) thus arguing for a relationship of pain with visceral sensations.
At the forebrain level, the spinal visceral sensory system constitutes a postero-lateral continuation of the cranial nerve to the visceral sensory thalamus and cortex (Saper 2000). There is also a spino-PB pathway since about 80% of lamina I spinothalamic axons send collaterals to the PB (Hylden, et al. 1989) and a spino–parabrachio–amygdaloid pain pathway which implicates the transmission of nociceptive information to the amygdala. Spinal nociceptive neurons in laminae I, IV, V, VII, and X directly innervate the hypothalamus and medial prefrontal cortex (Cliffer, et al. 1991; Burstein 1996). The messages coming from the gut are integrated in the central autonomic network (see below), which, in turn, adapts the response of the digestive tract through the efferent ANS through reflex loops which are essentially unconscious or become conscious in pathological conditions such as VHS observed in IBS. There is also descending pathways that control somatic as well as visceral pain by modulating visceral informations at the spinal cord level. These pathways are both inhibitory, thus producing analgesia as represented by projections from the periaqueductal gray to the rostroventral medulla, and LC descending fibers to the spinal cord as well as facilitatory producing hyperalgesia (rostroventral medulla and OFF and ON cells) (Tsuruoka, et al. 2010).
3.4. The circumventricular organs
The circumventricular organs are highly vascularized structures with fenestrated capillaries located around the 3rd and 4th ventricles. They are characterized by the lack of a blood–brain barrier and represent points of communication between the blood, the brain, and the cerebrospinal fluid (Benarroch 2011). They are represented by the subfornical organ, median eminence, pineal gland, area postrema, organum vasculosum of the lamina terminalis. The circumventricular organs are sensitive to the vascular content (e.g. circulating interleukins, electrolytes). They activate dendritic cells releasing prostaglandins acting on PGE2 receptor of neurons located closely to these circumventricular organs. These neurons send projections to the hypothalamus, activating the HPA axis, and to the central autonomic network represented by the DMNV and the sympathetic pre-ganglionar neurons of the intermediolateralis column. The circumventricular organs are consequently involved in the central integration of a peripheral message to maintain homeosthasis. For example, they are involved in sodium and water balance, cardiovascular regulation, metabolic and energetic balance, immune function, regulation of body temperature, vomiting, reproduction. During an immune challenge represented by systemic inflammation, cytokines released in the circulation talk to the brain through two routes i.e. neural (vagal afferents) and humoral (circumventricular organs) to activate the HPA axis.
3.5. The central autonomic nervous system
The central autonomic nervous system integrates and modulates afferent informations from the gut and sends reversible inputs to the gut. In the CNS, visceral informations are integrated in the central autonomic nervous system via brain regions involved in the autonomic, endocrine, motor, and behavioral responses (Saper 2002). The brain network can be roughly divided into executive structures, mainly hypothalamic, coordinating structures, mainly included in the limbic system, and high level control structures, mainly the frontal cortex.
The hypothalamus e.g. paraventricular nucleus (PVN), lateral hypothalamus, arcuate nucleus and adjacent retrochiasmatic area innervate the parasympathetic and sympathetic preganglionic neurons. The principal neuromediators are oxytocin and vasopressin (Hallbeck, et al. 2001). Through the release of CRF, the neuromediator of stress, the PVN is involved in the HPA axis response to stress. The limbic system is represented by the amygdala and its nuclei, the bed nucleus of the stria terminalis, considered as the extended amygdala, the septum and the hippocampus. The limbic system modulates the endocrine system and the ANS, two major components of the brain-gut axis. Classically, the amygdala is involved in the integration of emotions and the emotional conditioning which is represented by the association of a conditioned stimulus (i.e. a sound) with an unconditioned stimulus (the reinforcement) (Henke, et al. 1991; Benarroch 2006; LeDoux 2007). The amygdala receives afferents from the NTS, PB nucleus, frontal cortex, and LC and sends projection to the ANS, the frontal cortex and the hippocampus. The amygdala inhibits the DMNV, stimulates the sympathetic nervous system and the stress response through the HPA axis. The amygdala is a CRF-containing nucleus.
The prefrontal, insular, and anterior cingulate cortices are involved in the integration of visceral informations, attention, emotions and in the regulation of humor. The anterior cingulate cortex is divided in a cognitive dorsal part and an affective ventral part i.e. the perigenual part which has been frequently activated in brain imaging by numerous emotional stimuli. Most of these structures (ANS, HPA axis, limbic system, endogenous pathways that modulate pain and discomfort…) are part of the emotional motor system that mediates the effect of emotional states on the GI function, modulates gut functions and communicates emotional changes via the ANS to the gut. The threshold for visceral perception is dependent on the individual’s emotional and cognitive state (Mayer 2000; Mayer 2011).
Visceral as well as stressful informations activate the LC, a nucleus belonging to central noradrenergic system localized in the pons. The LC is the largest group of noradrenergic neurones. It is involved in emotional arousal, autonomic, and behavioural responses to stress and attention-related processes through its dense projections to most areas of the cerebral cortex and alertness-modulating nuclei (e.g. majority of the cerebral cortex, cholinergic neurones of the basal forebrain, cortically-projecting neurones of the thalamus, serotoninergic neurones of the dorsal raphe and cholinergic neurones of the pedunculopontine and laterodorsal tegmental nucleus). The LC also exerts an indirect action on autonomic activity via projections to the PVN and to the cerebral cortex and amygdala, structures which are known to influence the activity of premotor sympathetic neurones in the PVN. LC activation leads to anxiety through an activation of the amygdala (Tasan, et al. 2010).
4. Stress and the gut
4.1. Background
Stress is defined as the response of the organism to a solicitation of the challenging environment. The body engages a “fight or flight” response when exposed to an acute challenge with a sympathetic activation leading to an increase of heart rate and respiration, increased arousal, alertness, and inhibition of acutely non adaptive vegetative functions (feeding, digestion, growth and reproduction). The time course of the reaction corresponds to the general syndrome of adaptation defined by Hans Selye in 1950 (Selye 1950). The reaction of stress is physiological but may become pathological following an unbalance between the capacities of adaptation and the requirement of the environment, thus leading to functional, metabolic, and even lesional disorders.
4.2. The CRFergic system
CRF is a 41-amino acid peptide derived from a 191-amino acid preprohormone. CRF is secreted by the paraventricular nucleus (PVN) of the hypothalamus in response to stress (Vale et al. in 1981) as well as its related peptides the urocortines (Ucn) i.e. Ucn 1, Ucn 2 (also known as stresscopin-related peptide), and Ucn 3 (also known as stresscopin). CRF and the Ucns exert their biological actions on target cells through activation of two 7–transmembrane-domain G protein–coupled receptors, known as CRF receptor type 1 (CRF1) and CRF receptor type 2 (CRF2) which are encoded by 2 distinct genes [for review (Gravanis and Margioris 2005)]. CRF and Ucn 1 have equal affinity for the CRF1 receptor, although Ucn 1 is 40 times more potent than CRF in binding CRF2. In contrast, Ucns 2 and 3 bind selectively to CRF2. The population of CRF synthetizing neurons is predominantly expressed in the parvocellular part of the PVN of the hypothalamus and projects via the external zone of the median eminence to the anterior pituitary. In addition to its role as a hypothalamic hypophysiotropic hormone, CRF acts as a neurotransmitter in several brain areas. CRF has predominantly excitatory actions on neurons in the hippocampus, cortex, LC, and hypothalamic nuclei (Siggins, et al. 1985). CRF1 mediates anxiety-like behaviors whereas CRF2 mediates anxiolytic effects in the defensive withdrawal test (Heinrichs, et al. 1997). Competitive CRF receptor antagonists have been developed to determine the functions of CRF receptors under basal and stress conditions (Bonaz and Tache 1994b). The CRF system plays a critical role in coordinating the autonomic, endocrine, and behavioural responses to stress (Dunn and Berridge 1990).
The effect of stress on the GI tract is now well characterized. Stress induces modifications of motility, secretion, visceral sensitivity, local inflammatory responses (Delvaux 1999; Mawdsley and Rampton 2006; Tache and Bonaz 2007) through a central and/or peripheral action through CRF1,2 related receptors. Alterations of this complex system in humans are linked to a variety of anxiety-related psychiatric disorders and stress-sensitive pain syndromes, including IBS. Dysfunction in the HPA axis regulation attributable to overactivation of CRF/CRF1 signaling in response to chronic stress has been implicated in the pathophysiology of IBS symptoms (Chang, et al. 2009).
4.3. Stress effect on GI functions
4.3.1. Motility and secretion
Stress is known to decrease gastric emptying, lengthen small bowel motility and increase colonic motility (Tache and Bonaz 2007). The effects of stress on gut function are mediated by the ANS represented by the sympathetic, vagal and pelvic parasympathetic innervation of the enteric nervous system (Grundy 2006). At the central level, stress inhibits the parasympathetic nervous system and activates the sympathetic nervous system through the effect of PVN projections on the DMNV and intermediolateral column cells of the spinal cord.
CRF signaling is a key component in the alterations of gut motor function in response to stress in both the brain and the gut. The CRF/CRF1 signalling pathway is involved in stress-induced anxiety/depression (Holsboer and Ising 2008) and alterations of colonic motor and visceral pain while both central and peripheral CRF2 receptor activation may exert a counteracting influence (Tache, et al. 2005; Million, et al. 2006). At the level of the GI tract, stress delays gastric emptying through CRF2 while increasing colonic motility and secretion through CRF1 (Tache and Bonaz 2007). In the small bowel, CRF-like peptides stimulate the contractile activity of the duodenum through CRF1 receptor while inhibiting phasic contractions of the ileum through CRF2 receptor (Porcher, et al. 2005).
Stress also induces an activation of the sacral parasympathetic nucleus through the projections of the Barrington nucleus through CRF activation thus stimulating recto-colonic motility (Tache and Bonaz 2007). Numerous data have established the involvement of peripheral CRF signalling in the modulation of secretory function under stress conditions via activation of both CRF1 and CRF2 receptors, activation of cholinergic enteric neurons, mast cells and possibly serotonergic pathways (Larauche, et al. 2009).
4.3.2. Intestinal permeability
An increase of intestinal permeability is observed in the colon of IBS patients, associated with visceral or somatic hypersensitivity (Zhou and Verne 2011). Stress is able to disrupt the intestinal epithelial barrier thus increasing the penetration of luminal antigens into the lamina propria, leading to nociceptors sensitization and favoring the development of visceral hypersensitivity (Ait-Belgnaoui, et al. 2005). This increase of intestinal permeability is due to an activation of peripheral CRF signaling involving both CRF2 and CRF1 (Buckinx, et al. 2011) as well as mast cell activation (Santos, et al. 2001).
4.4. Stress effect on intestinal inflammation
Stress is able to increase intestinal inflammation by increasing intestinal permeability (see above) thus activating mast cells and visceral afferents in a local loop. Stress favours intestinal inflammation by stimulating the sympathetic nervous system and inhibiting the vagus nerve thus decreasing the cholinergic anti-inflammatory pathway. Stress, through its immune-suppressive function also favours inflammation (Ghia, et al. 2006; Mawdsley, et al. 2006; Bonaz 2010).
4.5. Stress effect on the microbiota
Bacteria in the gut (400–1,000 different bacterial species) have an important role in the immune response, including inflammation (Lee and Mazmanian 2010). Stress is able to modify the intestinal microbiota (Bailey, et al. 2010). Alteration of the microbiota favors translocation of bacteria from the intestinal lumen to the interior of the body where they can stimulate the immune system (Clarke, et al. 2010). This can in turn have significant impact on the host and affect behavior, visceral sensitivity and inflammatory susceptibility (Collins and Bercik 2009).
4.6. Stress effect on visceral sensitivity
Stress is known to increase visceral sensitivity [(Larauche, et al. 2012) for review]. Either acting at the central and/or peripheral (e.g. digestive) level, stress is able to increase visceral perception and emotional response to visceral events by a disturbance of the brain-gut axis at its different levels, central, gut and the ANS. Genetic model of depression or anxiety, such as the high-anxiety Wistar-Kyoto (WKY) rats or Flinders Sensitive Line rats have shown increased sensitivity to colorectal distension (Overstreet and Djuric 2001). In the same way genetic models deleting CRF1 exhibit a decrease in colonic sensitivity to colonic distension (Trimble, et al. 2007) while models overexpressing CRF1 exhibit enhanced response to colonic distension (Million, et al. 2007). These data argue for the filiation stress-anxiety-inflammation and visceral hypersensitivity.
Again, the CRF signalling, at both the central and peripheral level, is a key element involved in stress-induced visceral hypersensitivity. Recent data argue for an equally important contribution of the peripheral CRF/CRF1 signalling pathway locally expressed in the gut to the GI stress response (Larauche, et al. 2009). At the peripheral level, mast cells degranulation observed in the colon following stress and peripheral administration of CRF (Wallon, et al. 2008) induces visceral hypersensitivity via the release of mediators (histamine, tryptase, prostaglandin E2, nerve growth factor) that can stimulate or sensitize sensory afferents (van den Wijngaard, et al. 2009; 2010). Intravenous administration of CRF increases GI motility and visceral pain sensitivity in IBS patients compared with healthy controls, whereas administration of a non-selective CRF receptor antagonist improved these responses (Million, et al. 2005; Tache, et al. 2005; Tsukamoto, et al. 2006).
4.7. Gut pathologies are engineered by stress
The GI tract is a sensitive target to stress. Numerous data argue for a role of stress in the pathophysiology of IBS. Patients with IBS report more stressful life events than medical comparison groups or healthy subjects (Drossman, et al. 1996; 2000; Drossman 2011). Stress is strongly associated with symptom onset and symptom severity in IBS patients. Illness experience, health care-seeking behavior, and treatment outcome are adversely affected by stressful life events, chronic social stress, anxiety disorders, maladaptive coping style. A history of emotional, sexual, or physical abuse is often found in IBS patients [(Chitkara, et al. 2008) for review]. For example, there is a significantly higher prevalence (i.e. 44%) of sexual or physical abuse in patients with functional GI disorders than in controls with organic GI disorders (Drossman, et al. 1990). Psychiatric comorbidity, especially major depression, anxiety, and somatoform disorders, occur in 20 to 50% of IBS patients (Garakani, et al. 2003) and more likely precede the onset of the GI symptoms, thus suggesting a role for psychiatric disorders in functional GI disorder development (Sykes, et al. 2003).
Functional brain imaging studies have shown that there is a major influence of cognitive-affective processes on GI sensations and its CNS correlates in health and functional digestive disorders as IBS (Mayer, et al. 2006; Van Oudenhove, et al. 2007). Cognitive-affective processes including arousal, attention and negative emotions strongly influence visceral pain perception through modulation of its neural correlates (Mayer 2011). Feeling emotions requires the participation of brain regions, such as the somatosensory cortices and the upper brainstem nuclei that are involved in the mapping and/or regulation of internal organism states (Damasio, et al. 2000). This has led to the biopsychosocial concept of IBS (Drossman 1996b). These data are in agreement with the role of hypervigilance in the visceral hypersensitivity observed in IBS patients (Naliboff, et al. 2008). Spence et al. (Spence and Moss-Morris 2007) have characterized predictors of post-infectious IBS such as perceived stress, anxiety, somatisation and negative illness beliefs at the time of infection in favor of a cognitive-behavioural model of IBS. The importance of psychosocial factors and somatisation compared to gastric sensorimotor function is most pronounced in hypersensitive patients with functional dyspepsia, another functional GI disorder (Van Oudenhove, et al. 2008).
5. Gut and emotional memories
Early life trauma (neglect, abuse, loss of caregiver or life threatening situation) increases susceptibility to develop later affective disorders such as depression, anxiety, and is a key factor in the development of IBS (Bradford, et al. 2012). Traumatic events, such as war, environmental disasters, physical abuse or a bad accident in adulthood can induce post-traumatic stress disorder (PTSD) with increased prevalence of GI symptoms, such as IBS (Cohen, et al. 2006).
The role of stress sensitization is also reproduced in preclinical studies. Adults rats previously subjected to neonatal maternal separation (MS) exhibit visceral hypersensitivity to colorectal distension in basal conditions (Ren, et al. 2007). This visceral hypersensitivity is exacerbated in acute stress (e.g. water avoidance stress: WAS; Avoidance to water for 1 h by standing on a small platform; Bonaz & Taché 1994b) conditions (Coutinho, et al. 2002). Chronic exposure to repeated WAS is used to study visceral hypersensitivity and is very close to clinical conditions. However, habituation of the CRFergic system is observed in chronic conditions (Bonaz and Rivest 1998) and may induce analgesia. It seems that these conflicting data are influenced by the basal state conditions of the animals before applying the repeated stressor (surgery and single housing) (Larauche, et al. 2010).
6. The amygdala in IBS pathophysiology
The amygadala is a key element in the pathogeny of IBS.
6.1. Anatomical and functional basis
6.1.1. Amygdala structures
The amygdala is divided into a primitive group of nuclei associated with the olfactory system (central, medial and cortical nuclei, and nucleus of the lateral olfactory tract), and a phylogenetically new group of nuclei (lateral and basal) (Knapska, et al. 2007). The lateral (LA), basolateral (BLA), and central nuclei (CeA) are important for sensory processing (Neugebauer 2006; LeDoux 2007). The amygdala is part of the central autonomic nervous system that is involved in the brain-gut axis. The amygdala is a key element in emotional/affective behavior (LeDoux 2007), including the emotional responses to pain such as anxiety and fear of pain (Gauriau and Bernard 2002; Neugebauer, et al. 2004; Neugebauer 2006) as well as in the reciprocal relationship between pain and affective state (Meagher, et al. 2001; Rhudy and Meagher 2003). Affective content is attached to sensory information through associative processing in the LA–BLA circuitry and is then transmitted to the CeA which is the output nucleus for major amygdala functions (Maren 2005; Phelps and LeDoux 2005). The CeA serves to attach emotional significance to afferent nociceptive transmission and coordinates appropriate autonomic, affective and motor behavioral responses through its outputs to the hypothalamus, cortex and brainstem (Neugebauer, et al. 2004).
6.1.2. Amygdala inputs
The CeA receives numerous sensory informations from descending cortical, thalamic (perigeniculate, paraventricular) and brainstem inputs (Whalen and Kapp 1991), as well as from the olfactory system, medial PFC, insula, brainstem viscerosensory and nociceptive centers (NTS, PB), and from all parts of the amygdala. The amygdala increases the excitability of CNS sites regulating behavioral, neuroendocrine, and autonomic responses to stress (LeDoux, et al. 1988) and thus is able to modify GI functions. The amygdala is involved in the affective processing of sensory information and in the generation of anxiety and fear (Davis 1997), elements which are involved in the pathogeny of IBS.
6.1.3. CRF as a key mediator in amygdala
The amygdala, and particularly the CeA, is a major site of extrahypothalamic CRF, in cell bodies and terminals as well as CRF1 and, to a lesser extent, CRF2 receptors. The amygdala is a key element of the extrahypothalamic circuits through which CRF contributes to anxiety-like behavior and affective disorders (Aguilera, et al. 1987; Sajdyk, et al. 1999; Reul and Holsboer 2002; Fu and Neugebauer 2008). Excepting the hypothalamus, the amygdala is the major site of urocortin III (the endogenous ligands for CRF2 receptors) expression (Li, et al. 2002). In particular, activation of CRF neurons in the CeA that project to the LC increase its firing thus resulting in a noradrenaline release in the structures it is projecting to (Bouret, et al. 2003). LC activation leads to anxiety through the activation of the amygdala and, conversely, anxiety producing stimuli (stressful and fear-inducing stimuli) that increase the activity of the amygdala lead to LC activation (Samuels and Szabadi 2008).
6.1.4. Amygdala output to gut
The CEA is involved in the modulation of the ANS because of its brainstem projections to the DMNV, NTS, PB and the periaqueductal gray (Rizvi, et al. 1991), known to modulate the spinal cord processing of noxious information through descending inhibitory controls (Le Bars, et al. 1992). The CEA innervates hypothalamic nuclei, modulating the HPA axis (Rodrigues, et al. 2009). The CeA also projects to the medial peri-LC dendritic region, resulting in increased norepinephrine release and other monoamine systems in the brainstem and forebrain (Gray 1993; Fudge and Emiliano 2003; Pare 2003) which are involved in arousal and hypervigilance.
6.1.5. Modulators of amygdala
The LC has an inhibitory effect on the BLA and the activation of this pathway leads to a disinhibition of the CeA, since the BLA has a predominantly inhibitory influence over the CeA (Rosenkranz, et al. 2006). The LC is involved in the stress response through CRF1 receptors as well as CRF afferent fibers from the Barrington nucleus which is ventro-laterally located to the LC. The Barrington nucleus projects to the sacral parasympathetic nucleus to increase the motility of the distal recto-colon (Valentino, et al. 1993). Colorectal distension increases the firing of the LC through CRF1 through a LC-Barrington nucleus pathway (Rouzade-Dominguez, et al. 2001). In addition, the LC is involved in the brain noradrenergic modulation of the GI tract motility (Bonaz, et al. 1992a; 1992b; 1995). Consequently, the Barrington-LC-amygdalo complex is ideally positioned to bidirectionally coordinate brain-gut interactions.
6.2. Amygdala and the pathophysiology of IBS
6.2.1. Amygdala and visceral hyperalgesia
The use of C-Fos expression as a marker of neuronal activation has shown that somato-visceral (Bonaz and Fournet 2000; Sinniger, et al. 2004; 2005), and visceral (Wang, et al. 2009) pain as well as stress- or abdominal surgery-induced GI disturbances (Bonaz and Tache 1994a; 1994b; 1997; Bonaz and Rivest 1998) and colitis (Porcher, et al. 2004) induced the activation of the amygdala. In addition, the amygdala is one of the central areas from where digestive sensations are elicited in epileptic patients (Mulak, et al. 2008) during intracerebral electrical stimulations. In a model of visceral pain induction such as inflating a balloon into the rectum, an activation of the amygdala is observed in healthy volunteers (Baciu, et al. 1999) while aberrant functional responses (e.g. deactivation of the amygdala) to noxious rectal stimulation was observed in areas of the brain involved in emotional sensory processing, particularly the amygdala, insula, and prefrontal cortex in IBS patients (Bonaz, et al. 2002; Elsenbruch, et al. 2010; Tillisch, et al. 2011) thus arguing for an abnormal brain processing of visceral pain following rectal distension.
Activation of corticosteroid receptor (both glucocorticoid and mineralocorticoid receptors) in the CeA is involved in the induction of anxiety and visceral hypersensitivity (Myers and Greenwood-Van Meerveld 2007b). High levels of glucocorticoids result in CRF mRNA level increases in the amygdala (Makino, et al. 1994). The group of Greenwood-Van Meerveld ) have shown that implants of corticosterone micropellets in the CeA increase anxiety-like behavior as well as visceral hypersensitivity to colonic distension and increased responsiveness of viscera-sensitive lumbosacral spinal neurons that mediate visceromotor reflexes to colo-rectal distension (Greenwood-Van Meerveld, et al. 2001; Myers, et al. 2005; Greenwood-van Meerveld, et al. 2006; Myers and Greenwood-Van Meerveld 2007a). Indeed, exposure of the amygdala to corticosterone-releasing micropellets caused an increase in action potential frequency in the dorsal horn neurons in the L6-S1 spinal segments suggesting that a descending neuronal pathway, originating in the amygdala, could be triggered by continuous activation by corticosterone. The neurons responding with excitation to colorectal distension were short-lasting and long-lasting excitatory neurons based on the duration of the reponse (Venkova et al. 2009). Mineralocorticoid receptors but not glucocorticoid receptors in the amygdala trigger descending pathways facilitating viscero-nociceptive processing in the spinal cord (Venkova, et al. 2009). In addition, a WAS known to activate the amygdala (Bonaz and Tache 1994b), performed during 7 consecutive days induced VHS that was abolished by glucocorticoid receptor and mineralocorticoid receptor antagonists in the amygdala. These results argue for a role of amygdaloid glucocorticoid receptor and mineralocorticoid receptor in IBS.
The CRF signaling is also involved in pain processing. WKY is a rat strain for studying anxiety and IBS. WKY express a greater amount of CRF and CRF1 mRNA in the CeA and the PVN (Bravo, et al. 2011). In this model, it has been shown that colonic hypersensitivity to luminal distension is reversed by peripheral administration of a CRF1 antagonist (O\'Malley, et al. 2011). Infusion of CRF1 antagonist into the CeA attenuates the hypersensitivity to colonic distension in the WKY rats, thus confirming the role of CRF1 receptor in the amygdala in VHS mechanism (Johnson, et al. 2012). The basal expression of CRF in the LC is increased in WKY rats and a selective CRF1 receptor antagonist abolished the activation of LC neurons by colorectal distension and intracisternal CRF in rats (Kosoyan, et al. 2005). These data strengthen the role of the CeA and LC in VHS through CRF1 which is in agreement with the interactions between both nuclei involved in emotional-arousal circuit. Indeed, CRF neurons in the CeA project directly to the LC and increase the firing rate of LC neurons thus increasing noradrenaline release in the vast terminal fields of this ascending noradrenergic system. In humans, oral administration of a selective CRF1 antagonist (GW876008) is followed by a significant BOLD signal reductions within the amygdala during pain expectation in IBS patients (Hubbard, et al. 2011). CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is suppressed in the arthritis pain model. Thus, due to the opposing effect of CRF1 and CRF2 receptors, CRF can induce a dual effect in the amygdala. The differential effects of CRF1 and CRF2 receptor antagonists on pain-related processing in the amygdala have reciprocal opposing influences on anxiety-like behaviors. CRF1 and CRF2 receptors in the amygdala mediate opposing effects on nociceptive processing (Ji and Neugebauer 2007). Numerous data argue for a role of CRF1 and CRF2 to mediate pro- and anti-nociceptive effects of CRF respectively. It has been shown that low concentrations of CRF facilitate nociceptive processing in the CeA neurons through CRF1 while higher concentrations of CRF have inhibitory effects through CRF2 receptors. This is in agreement with the concept that CRF2 receptors serve to dampen or reverse CRF1-initiated responses (Tache and Bonaz 2007). These results clarify the controversial role of CRF in pain modulation and show that the CRFergic system in the amygdala may be a key link between pain and affective states and disorders.
6.3. Amygdala and stress conditioning
6.3.1. The synchronic stress engineering
Systemic cortisol is a classical marker of the HPA axis activation. The amygdala and hippocampus have numerous receptors for cortisol and are consequently highly susceptible to the products of the HPA axis. Glucocorticoid occupation of hippocampal receptors has a suppressive effect on the HPA axis (van Haarst, et al. 1997) whereas glucocorticoid occupation of amygdala receptors have a facilitating effect on the HPA axis, often increasing CRF expression within the amygdala (Makino, et al. 1994). CRF receptors are greatly expressed in the amygdala and hippocampus early in development (Baram and Hatalski 1998), thus explaining why young animals are especially vulnerable to threat. In agreement, early-life stress induces a decrease of hippocampal volume and functional alterations when measured in adulthood (Nemeroff, et al. 2006). Structural changes have also been observed in IBS patients using brain imaging (Blankstein, et al. 2010; Seminowicz, et al. 2010). Also, circulating glucocorticoids can have contrasting effects in the amygdala and hippocampus, and these two structures can play contrasting roles in the activity of the HPA axis. In the context of an overactivity of the HPA axis due to an enhanced stress responsiveness, greater basal levels of systemic cortisol have been reported in IBS patients (Chang, et al. 2009). Circulating cortisol regulates the HPA axis and is also able to act within the amygdala by binding to selective glucocorticoid and mineralocorticoid receptors, highly expressed in the amygdala (Sapolsky, et al. 1983) to facilitate behavioral and psychological stress responses including GI motility.
6.3.2. Amygdala and stress memorisation
Functional imaging studies indicate that the mPFC is engaged in fear extinction process in relation with the amygdala (Phelps, et al. 2004). The amygdala is an important region involved in the acquisition of fear conditioning, a learning that corresponds to the association between a conditioned stimulus andan unconditioned stimulus. The infralimbic region of the mPFC participates in the mechanism of fear extinction (Rosenkranz, et al. 2003; Quirk and Vidal-Gonzalez 2006b) and also in the recall of fear extinction with an active inhibition of the previous fear condition responses. This is mediated by a down regulation of amygdala outputs with mPFC neurons exciting (glutamate) inhibitory neurons (GABA) within the BLA or in the intercalated region inhibiting in turn amygdala outputs from the CeA (Vidal-Gonzalez, et al. 2006). The activity of intentional regulation of treat related-cues by the PFC is decreased in anxious patients and the conditioned fear extinction is also less active, in PTSD-anxious patients and this is associated with symptoms provocations (Bradette, et al. 1994). The amygdala is also activated by uncertainty and the capacity of the PFC to regulate attention, (re) interpretation of the situation will modulate the level of the response of amygdala to uncertainty. In IBS, uncertainty plays an important role in the perception of pain. Therefore it seems important to study the fronto-amygdalar relations in IBS patients. The inhibitory control of the mPFC on CeA would maintain an homeostatic state with an equilibrated sympatho-vagal balance and low glucocorticoids circulating levels. In the case of a deficit in PFC activity with a lack of inhibitory regulatory communications with the amygdala, a chronic imbalance of the ANS with an increase sympathetic activity should appear as we have observed in IBS patients exhibiting a low heart rate variability and a high score of anxiety (Pellissier, et al. 2010a). Moreover, there is a strong relation between the activity of the ANS and the immune system as recently shown by the cholinergic anti-inflammatory pathway (Huston and Tracey 2011). Hence, when the parasympathetic system is hypoactive as a consequence of anxiety for instance, it could facilitate inflammation which could be deleterious for health and well-being (Bonaz 2003). The hypoactivity of the PFC and the enhancement of amygdala (re)-activity are strongly influenced by stress as demonstrated by a number of studies. It has recently been shown an increase in the dendritic arborization, and synaptic connectivity in the LA/B neurons under chronic stress conditions (Vyas, et al. 2002; Vyas, et al. 2006). LA/B neurons from stressed animals display increased firing rates and greater responsiveness (Kavushansky and Richter-Levin 2006) since the mediators of stress i.e. norepinephrine, and glucocorticoids decrease GABA inhibition (Rodriguez Manzanares, et al. 2005), thereby allowing for increased excitability in LA/B. In the meantime, an atrophy and spine loss of neurons in the mPFC following stress and glucocorticoid exposition is observed (Czeh, et al. 2008) allowing an over-activation of amygdala under chronic stress exposition.
6.3.3. Amygdala and early stress
Environmental events during early postnatal life can influence the formation of neural circuits that provide limbic and cortical control over autonomic emotional motor output since a differential timing of hypothalamic and limbic forebrain synaptic inputs to autonomic neurons has been observed during the first 1–2 weeks postnatal (Rinaman, et al. 2011). This provides a potential structural correlate for early experience-dependent effects on later responsiveness to emotionally evocative stimuli and an enhanced risk for the development of psychopathologies such as mood and aggressive disorders. MS is classically used as a model of brain-gut axis dysfunction (O\'Mahony, et al. 2011) and early life trauma are often observed in IBS patients (Bradford, et al. 2012). The amygdala is functionally active early in life and demonstrates continued refinement, through increased cortical connections, throughout childhood and adolescence. The amygdala is particularly vulnerable to stressors early in life. Reduced hippocampal volumes (Woon, et al. 2010) and increased amygdala volumes (Tottenham, et al. 2010) have been associated with early life stress.
6.3.4. The maternal separation model (MS)
Numerous studies have shown that the HPA axis of MS rodents shows hyperactivity in the PVN and amygdala (Plotsky and Meaney 1993; Coutinho, et al. 2002; Plotsky, et al. 2005; Schwetz, et al. 2005). Offspring of mothers that exhibit more licking and grooming of pups show reduced plasma ACTH and corticosterone responses to acute stress and decreased levels of hypothalamic CRF mRNA in correlation with the frequency of maternal licking and grooming during the first 10 days of life (Plotsky, et al. 2005). Thus, it is likely that a major part of the alterations associated with early life stress are related to CRF hyperproduction that account for amygdala hyperactivity. Maternal care during the first week of life is associated with increased GABAergic inhibition of amygdala activity (Diorio and Meaney 2007). These data reflect the importance of early environmental factors in regulating the development of the hypothalamic CRF system in relation with amygdala activity and the vulnerability to stress. Moreover, there is a sex-specific difference in the effects of early life stress on HPA axis activity consistent with the higher prevalence of major depression with hypercortisolism in women than in men. Moreover, women who experienced early life stress are more likely to develop depression as well as IBS (Bradford, et al. 2012). Sex-hormones influence amygdala development in human populations (Rose, et al. 2004). An alteration in the central CRF system has been evidenced in two different rat models of comorbid depression and functional GI disorders (e.g. IBS) represented by neonatal MS and the WKY rat, a genetically stress-sensitive rat strain, that display increased visceral hypersensitivity and alterations in the HPA axis. These rat strains express a greater amount of CRF and CRF1 mRNA in the amygdala (CeA) as well as in the PVN (Bravo, et al. 2011). They also present a positive correlation between increased central CRF and CRF1 receptor expression, with elevated anxiety-like behavior and colonic hypersensitivity (Gunter, et al. 2000; Shepard and Myers 2008). An increase of CRF1 mRNA was observed in the PVN and amygdala while CRF2 mRNA, classically counteracting CRF1 in the CNS, was lower in the amygdala of MS rats. Such modifications, by affecting the HPA axis regulation, may contribute to behavioral changes associated with stress-related disorders, and alter the affective component of visceral pain modulation, which is enhanced in IBS patients (Bravo, et al. 2011).
6.4. The alteration of amygdala control in IBS
The amygdala has interconnections with the anterior cingulate cortex, the PFC, the hippocampus, the hypothalamus (e.g. PVN), the bed nucleus of the stria terminalis, the lateral septum, the thalamus, the periacqueductal gray, the PB, the LC, the raphe nuclei, and the dorsal vagal complex (area postrema, nucleus tractus solitarius and DMNV) (Knapska, et al. 2007). All these regions have been shown to be activated in experimental models of stress, inflammation, and pain as represented by c-fos expression and/or CRF receptor mRNA induction (Bonaz and Tache 1994a; Bonaz and Rivest 1998; Bonaz, et al. 2000; Porcher, et al. 2004; Sinniger, et al. 2004; 2005) or electrical stimulations (Mulak, et al. 2008). In addition, brain imaging techniques (fMRI, PET), have contributed to the better understanding of IBS. An activation of most of the brain structures referenced above, and particularly the amygdala, has been observed in healthy volunteers following rectal pain while an abnormal brain processing of pain was observed in IBS and IBD patients (Baciu, et al. 1999; Bonaz, et al. 2002; Agostini, et al. 2011). In addition, brain structural changes of the HPA axis and limbic structures have been recently reported in IBS patients (Blankstein, et al. 2010; Seminowicz, et al. 2010). Because psycho- or pharmacotherapy tends to result in normalization of activity of key structures such as the PFC including anterior cingulate cortex, hippocampus, or amygdala, either through a top-down or bottom-up effect (Quide, et al. 2012), the determination of psycho-physiological vulnerability in IBS patients should be a flag to consider the psychological needs in the follow-up of such patients in the prevention of relapses of such diseases (Pellissier, et al. 2010b).
7. Therapeutic implications-treatment targeting amygdala activity reduction in IBS
The effect of stress on amygdala functioning has therapeutic implications both with non-pharmacological and pharmacological treatment to reduce stress perception. Psychological mind-body interventions including psychotherapy, cognitive behavioral therapy, hypnotherapy, relaxation exercises or mindfulness mediation have been shown to improve symptoms of IBS patients (Kearney and Brown-Chang 2008; Ford 2009; Whorwell 2009). Repetitive transcranial magnetic stimulation of the PFC, based on the central role of the mPFC in cognitive theory of mind, can cause changes in acute pain perception and has been used in a model of central sensitization syndrome such as fibromyalgia (Mhalla, et al. 2011; Short, et al. 2011) but no data have been currently published in IBS patients. Modulation of the ANS by restoring the sympatho-vagal balance (DeBenedittis, et al. 1994; Nishith, et al. 2003; Gemignani, et al. 2006) as well as modifying coping strategies vigilance state and globally the restoration of a functional brain-gut axis, are at the origin of the efficacy of these treatments. Brain imaging techniques have shown modulation of brain activation, as for example in the amygdala, by such treatments (Goldin and Gross 2010; Lawrence, et al. 2011). Conventional treatment as represented by anti-depressives, anxiolytics, drug targeting the central sensitization syndrome [α2δ ligand (pregabalin, gabapentin); tachykinin receptor antagonists] either directly and/or indirectly are supposed to target the hyperfunctioning of the amygdala (Ghaith, et al. 2010; Gale and Houghton 2011; Trinkley and Nahata 2011; Larauche, et al. 2012). In the context of the microbiota-brain-gut axis, probiotics, prebiotics, antibiotics such as rifaximin, an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects, are of interest (Bercik, et al. 2011; Fukudo, et al. 2011; Fukudo and Kanazawa 2011). If targeting CRF signaling with CRF1 receptor antagonists, based on pre-clinical and/or clinical data (brain imaging) has been used successfully in humans to treat depression and anxiety (Kunzel, et al. 2003) their efficacy is still matter of debate in the treatment of IBS patients (Sweetser, et al. 2009).
8. Conclusion
A growing body of evidence argues for an important role of stress, through the HPA axis, limbic system activity (e.g. the amygdala), and the ANS, i.e. the sympathetic and the parasympathetic (e.g. the vagus nerve) nervous system, in the initiation and perpetuation of IBS. Stress, pain, and immune activation are common risk factors involved in the pathogenesis of IBS which are able to act through this neuro-endocrine-immune axis. The amygdala, through its connections with the PFC, LC, hippocampus, HPA axis, and ANS is a key structure involved in the pathogeny of IBS. Animal models of activation of the CRFergic system in the amygdala, as represented by maternal separation stress or WKY rats, developed VHS as observed in most of IBS patients. Thereofore, a therapeutic targeting of the amygdala either through pharmacological or non-pharmacological approach should be of interest for the treatment of IBS.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/41592.pdf",chapterXML:"https://mts.intechopen.com/source/xml/41592.xml",downloadPdfUrl:"/chapter/pdf-download/41592",previewPdfUrl:"/chapter/pdf-preview/41592",totalDownloads:3505,totalViews:576,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:1,dateSubmitted:"December 13th 2011",dateReviewed:"August 2nd 2012",datePrePublished:null,datePublished:"December 19th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/41592",risUrl:"/chapter/ris/41592",book:{slug:"the-amygdala-a-discrete-multitasking-manager"},signatures:"Bruno Bonaz, Sonia Pellissier, Valérie Sinniger, Didier Clarençon, André Peinnequin and Frédéric Canini",authors:[{id:"147575",title:"Prof.",name:"Bruno",middleName:null,surname:"Bonaz",fullName:"Bruno Bonaz",slug:"bruno-bonaz",email:"bbonaz@chu-grenoble.fr",position:null,institution:null},{id:"149208",title:"Dr.",name:"Sonia",middleName:null,surname:"Pellissier",fullName:"Sonia Pellissier",slug:"sonia-pellissier",email:"sonia.pellissier@univ-savoie.fr",position:null,institution:null},{id:"149211",title:"Dr.",name:"Valérie",middleName:null,surname:"Sinniger",fullName:"Valérie Sinniger",slug:"valerie-sinniger",email:"valerie.sinniger@ujf-grenoble.fr",position:null,institution:null},{id:"149213",title:"Dr.",name:"Didier",middleName:null,surname:"Clarençon",fullName:"Didier Clarençon",slug:"didier-clarencon",email:"didierclarencon@crssa.net",position:null,institution:null},{id:"149215",title:"Dr.",name:"André",middleName:null,surname:"Peinnequin",fullName:"André Peinnequin",slug:"andre-peinnequin",email:"andrepeinnequin@crssa.net",position:null,institution:null},{id:"149216",title:"Dr.",name:"Frédéric",middleName:null,surname:"Canini",fullName:"Frédéric Canini",slug:"frederic-canini",email:"fredericcanini@crssa.net",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Irritable bowel syndrome",level:"1"},{id:"sec_2_2",title:"2.1. Definition-background",level:"2"},{id:"sec_3_2",title:"2.2. Pathophysiology",level:"2"},{id:"sec_5",title:"3. The brain-gut axis",level:"1"},{id:"sec_5_2",title:"3.1. Definition",level:"2"},{id:"sec_6_2",title:"3.2. The enteric nervous system",level:"2"},{id:"sec_7_2",title:"3.3. The autonomic nervous system (The afferent system)",level:"2"},{id:"sec_8_2",title:"3.4. The circumventricular organs",level:"2"},{id:"sec_9_2",title:"3.5. The central autonomic nervous system",level:"2"},{id:"sec_11",title:"4. Stress and the gut",level:"1"},{id:"sec_11_2",title:"4.1. Background",level:"2"},{id:"sec_12_2",title:"4.2. The CRFergic system",level:"2"},{id:"sec_13_2",title:"4.3. Stress effect on GI functions",level:"2"},{id:"sec_13_3",title:"4.3.1. Motility and secretion",level:"3"},{id:"sec_14_3",title:"4.3.2. Intestinal permeability",level:"3"},{id:"sec_16_2",title:"4.4. Stress effect on intestinal inflammation",level:"2"},{id:"sec_17_2",title:"4.5. Stress effect on the microbiota",level:"2"},{id:"sec_18_2",title:"4.6. Stress effect on visceral sensitivity",level:"2"},{id:"sec_19_2",title:"4.7. Gut pathologies are engineered by stress",level:"2"},{id:"sec_21",title:"5. Gut and emotional memories",level:"1"},{id:"sec_22",title:"6. The amygdala in IBS pathophysiology",level:"1"},{id:"sec_22_2",title:"6.1. Anatomical and functional basis",level:"2"},{id:"sec_22_3",title:"6.1.1. Amygdala structures",level:"3"},{id:"sec_23_3",title:"6.1.2. Amygdala inputs",level:"3"},{id:"sec_24_3",title:"6.1.3. CRF as a key mediator in amygdala",level:"3"},{id:"sec_25_3",title:"6.1.4. Amygdala output to gut",level:"3"},{id:"sec_26_3",title:"6.1.5. Modulators of amygdala",level:"3"},{id:"sec_28_2",title:"6.2. Amygdala and the pathophysiology of IBS",level:"2"},{id:"sec_28_3",title:"6.2.1. Amygdala and visceral hyperalgesia",level:"3"},{id:"sec_30_2",title:"6.3. Amygdala and stress conditioning",level:"2"},{id:"sec_30_3",title:"6.3.1. The synchronic stress engineering",level:"3"},{id:"sec_31_3",title:"6.3.2. Amygdala and stress memorisation",level:"3"},{id:"sec_32_3",title:"6.3.3. Amygdala and early stress",level:"3"},{id:"sec_33_3",title:"6.3.4. The maternal separation model (MS)",level:"3"},{id:"sec_35_2",title:"6.4. The alteration of amygdala control in IBS",level:"2"},{id:"sec_37",title:"7. Therapeutic implications-treatment targeting amygdala activity reduction in IBS",level:"1"},{id:"sec_38",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'AgostiniANFilippiniDCevolaniRAgatiCLeoniRTambascoCCalabreseFRizzelloPGionchettiMErcolaniMLeonardiand MCampieri2011Brain functional changes in patients with ulcerative colitis: a functional magnetic resonance imaging study on emotional processing.Inflammatory bowel diseases17817691777'},{id:"B2",body:'AguileraGM. AMillanR. LHaugerand K. 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NPappasand TTakahashi2006Peripherally administered CRF stimulates colonic motility via central CRF receptors and vagal pathways in conscious ratsThe American Journal of PhysiologyR1537R1541.'},{id:"B200",body:'TsuruokaMDWangJTamakiand TInoue2010Descending influence from the nucleus locus coeruleus/subcoeruleus on visceral nociceptive transmission in the rat spinal cordNeuroscience165410191024'},{id:"B201",body:'ValeWJSpiessCRivierand JRivier1981Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin.Science 213451413941397\n\t\t\t'},{id:"B202",body:'ValentinoR. JS. LFooteand M. EPage1993The locus coeruleus as a site for integrating corticotropin-releasing factor and noradrenergic mediation of stress responses.Annals of the New York Academy of Sciences697173188'},{id:"B203",body:'van den WijngaardR.M., T.K. Klooker, O. Welting, O.I. Stanisor, M.M. Wouters, D. van der Coelen, D.C. Bulmer, P.J. Peeters, J. Aerssens, R. de Hoogt, K. Lee, W.J. de Jonge and G.E. Boeckxstaens (2009Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated ratsNeurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 21101107e1194.'},{id:"B204",body:'van den WijngaardR.M., T.K. Klooker, W.J. de Jonge and G.E. Boeckxstaens (2010Peripheral relays in stress-induced activation of visceral afferents in the gutAutonomic neuroscience : basic & clinical 153(1-2): 99 EOF105 EOF'},{id:"B205",body:'Van HaarstA. DM. SOitzland E. RDe Kloet1997Facilitation of feedback inhibition through blockade of glucocorticoid receptors in the hippocampus.Neurochemical research221113231328'},{id:"B206",body:'Van OudenhoveLS. JCoenand QAziz2007Functional brain imaging of gastrointestinal sensation in health and disease.World journal of gastroenterology : WJG132534383445'},{id:"B207",body:'Van OudenhoveLJVandenbergheBGeeraertsRVosPPersoonsBFischlerKDemyttenaereand JTack2008Determinants of symptoms in functional dyspepsia: gastric sensorimotor function, psychosocial factors or somatisation?Gut 571216661673'},{id:"B208",body:'VenkovaKR. DForemanand BGreenwood-vanMeerveld (2009Mineralocorticoid and glucocorticoid receptors in the amygdala regulate distinct responses to colorectal distensionNeuropharmacology562514521'},{id:"B209",body:'Vidal-gonzalezIBVidal-gonzalezS. LRauchand G. JQuirk2006Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fearLearn Mem 136728733'},{id:"B210",body:'VyasARMitraB. SShankaranarayanaRao and S. Chattarji (2002Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons.The Journal of neuroscience: the official journal of the Society for Neuroscience 221568106818'},{id:"B211",body:'VyasASJadhavand SChattarji2006Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdalaNeuroscience1432387393'},{id:"B212",body:'WallonCP. CYangA. VKeitaA. CEricsonD. MMckayP. MShermanM. HPerdueand J. DSoderholm2008Corticotropin-releasing hormone (CRH) regulates macromolecular permeability via mast cells in normal human colonic biopsies in vitroGut5715058'},{id:"B213",body:'WangLVMartinezMLaraucheand YTache2009Proximal colon distension induces Fos expression in oxytocin-, vasopressin-, CRF- and catecholamines-containing neurons in rat brainBrain Res 12477991'},{id:"B214",body:'WhalenP. Jand B. SKapp1991Contributions of the amygdaloid central nucleus to the modulation of the nictitating membrane reflex in the rabbit.Behavioral neuroscience1051141153'},{id:"B215",body:'WhiteheadW. EM. DCrowelland J. CRobinson1992Effects of stressful life events on bowel symptoms: subjects with irritable bowel syndrome compared with subjects without bowel dysfunction.Gut 33825830'},{id:"B216",body:'WhiteheadW. EOPalssonand K. RJones2002Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?Gastroenterology122411401156'},{id:"B217",body:'WhorwellP. JAPriorand E. BFaragher1984Controlled trial of hypnotherapy in the treatment of severe refractory irritable-bowel syndrome.Lancet2841412321234'},{id:"B218",body:'WhorwellP. J2009Behavioral therapy for IBSNature clinical practice. Gastroenterology & hepatology 63148149'},{id:"B219",body:'Wilder-smithC. HDSchindlerKLovbladS. MRedmondand ANirkko2004Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controlsGut 5315951601'},{id:"B220",body:'WoolfC. J2011Central sensitization: implications for the diagnosis and treatment of painPainSuppl): S215'},{id:"B221",body:'WoonF. LSSoodand D. WHedges2010Hippocampal volume deficits associated with exposure to psychological trauma and posttraumatic stress disorder in adults: a meta-analysisProgress in neuro-psychopharmacology & biological psychiatry 34711811188'},{id:"B222",body:'ZhouQand G. NVerne2011New insights into visceral hypersensitivity- clinical implications in IBS." Nature Reviews Gastroenterology & Hepatology 8349355'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Bruno Bonaz",address:null,affiliation:'
Clinique Universitaire d’Hépato-Gastroentérologie, CHU de Grenoble, BP217, France
Stress et Interactions Neuro-Digestives, Grenoble Institut des Neurosciences (GIN), Centre de Recherche INSERM U836-UJF-CEA-CHU, CHU de Grenoble, BP217, France
Clinique Universitaire d’Hépato-Gastroentérologie, CHU de Grenoble, BP217, France
Département de Psychologie, Université de Savoie, France
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\n
1. Introduction
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From the last decade, nanotechnology has established a bridge among all the fields of science and technology. Low-dimensional materials and structures have exceptional properties that make them able to play a critical role in the rapid progress of field science. With these excellent properties, 1-D metal oxide semiconductors (MOS) have become the backbone of research in all fields of natural sciences.
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Nanotechnology deals with structures and materials of very small dimensions. Nanotechnology is the foundation and exploitation of nanomaterial with structural features in between those of atoms and their bulk material. The properties of the materials at nanoscale are extensively different from those of bulk materials. The high surface reactivity with the surrounding surface improves significantly. When the size of materials is in the nanoscale, the surface-area-to-volume-ratio (L/D) becomes large that makes the nanomaterial ideally an appropriate candidate for many types of sensing applications. That is why nanomaterial has opened up possibilities for new pioneering functional devices and technologies. Nanostructures have at least one dimension less than 100 nm. Crystal structures are much stable at nanoscale [1].
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Reduction of an object size results in large surface to volume ratio hence the surface turn out to more vital and that large surface to volume ratio greatly affected the chemical, electrical and optical properties of nanomaterials. Quantum effects owing to size confinement in nanostructures occurs, when the typical size of the object is equivalent to the crucial length (range 1–10 nm) of the equivalent physical properties’ screening length, then the mean free path of electrons; 0-D quantum dots, 1-D quantum dots, and 2-D quantum well are the characteristic structure forms.
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Low power consumptions, best crystallinity, and high integration density 1-D with high aspect ratio are shown by the 1-D nanostructures. The nanostructure materials show high sensitivity to surface chemical reactions, with increased surface-to-volume ratio and a Debye length matching with small size. Tunable band gap is enabled by size confinement [2]. In the recent past, various synthesis methods, such as vapor phase method, electrochemical method, liquid phase methods, and solution-gel methods, were used. Out of these growth techniques, vapor transport method, using vapor-liquid-solid (VLS) growth mechanism or VS growth, is one of the finest growth techniques used for the growth of metal oxide semiconductor nanostructures. It is a cost-effective easy method used to create many single-crystalline 1-D nanostructures [3, 4, 5, 6, 7, 8, 9, 10, 11].
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Smart and functional materials are based on metal oxides [10]. Synthesis and fabrication of devices based on metal oxide semiconductor have become more important recently, because the tuning of physical properties of these metal oxides is so easy. Among these MOS, ZnO is a material that has strong piezoelectric and optical properties on the bases of its wide band gap, stability at high temperature, large surface-to-volume ratio, and high excitonic binding energy. They are used in solar cells, photocatalysis, and antibacterial active material. Therefore research work has been carried out on ZnO nanostructures. Metal oxide materials possess electrical, chemical, and physical properties that are highly sensitive to the changes in a chemical environment, through a variety of detection principles based on ionic, conducting, photoconducting, piezoelectronic, pyroelectronic, and luminescence properties [12, 13, 14, 15, 16, 17, 18, 19, 20, 21].
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Doping is another technique utilized to improve ultraviolet (UV) sensing properties of metal oxides, where the dopant atoms are believed to act as activators for surface reactions. In MOS, the electrical, optical, and chemical properties can be changed by adding the doping materials or by creating oxygen defects which results in large concentration of carriers, mobility, and electrical resistivity. So doping offers another avenue for expanding their sensing capability [12].
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Up to now, various metal oxides’ 1-D nanostructures (SnO2 nanowhiskers, In2O3 nanowires, ZnO nanorods, WO3 nanowires, TiO2 nanowires etc.) have been fabricated into film-type nanosensors by means of thermal evaporation or vapor transport method. The most widely studied substances are SnO2 and ZnO nanowires [13]. In this research work, 1-D n-ZnO nanostructures (nanowires, nanorods, nanobelts with needle-like ends, and typical nanobelts) were grown by using vapor transport method using VLS mechanism on n-type Au-coated silicon substrate Si (100). The electrical and optical properties of ZnO nanostructures were investigated using different characterization techniques [14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37].
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2. Important properties of metal oxide semiconductors
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As work done in this chapter mainly deals with ZnO semiconductor, structural properties of ZnO material are presented below.
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2.1 Structural properties of ZnO
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ZnO is a key technological and prominent material. One of the important properties of ZnO is that it has a wide band gap that makes it suitable for optoelectronic applications of short wavelength. ZnO has high excitonic binding energy (60 meV) at room temperature by ensuring efficient excitonic emission. It has been noted that disordered nanoparticles and thin films at room temperature have ultraviolet (UV) luminescence. In addition, due to the unavailability of centrosymmetry in wurtzite structures that combines with large electromechanical coupling which result in strong piezoelectric and pyroelectric properties and make ZnO a prominent material in the use of mechanical actuators and piezoelectric sensors. As a versatile functional material, ZnO has a different group of growth morphologies, such as nanocombs, nanowires, nanobelts, nanosprings, etc. These ZnO nanostructures are easily obtained, even on cheap substrates such as glass. As work done in this thesis mainly deals with ZnO semiconductor, structural properties of this material are presented below.
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2.2 Crystal and surface structure of ZnO
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At normal temperature and pressure, ZnO crystallizes in wurtzite (B4 type) structure, as shown in Figure 1. It is a hexagonal lattice, belonging to the space group P63mc with lattice parameters a = 0.3296 nm and c = 0.52065 nm. The tetrahedral coordination in ZnO is responsible for noncentral symmetric structure and consequently results in piezoelectricity and pyroelectricity. Another important characteristic of ZnO is polar surfaces. The most common polar surface is the basal plane. The oppositely charged ions produced positively charged Zn+ (0001) and negatively charged O− (0001−) surfaces, which result in a normal dipole moment and spontaneous polarization along the c-axis as well as variance in surface energy. The two most commonly observed facets for ZnO are (2−1−10) and (01−10) which are nonpolar surfaces and have lower energy than the (0001) facets [14, 15]. ZnO has varied properties, covering all of its physical, chemical, or material properties. ZnO is a well-suited II–VI wide bandgap semiconductor, which is naturally found in three forms: cubic zinc blend, hexagonal wurtzite, and cubic rock salt which is not as common as other [16]. The most common phase of ZnO is hexagonal wurtzite, whose space group is C6v or P63mc, which can be found mainly in ambient condition [17].
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Figure 1.
(a) Crystal structure of hexagonal wurtzite ZnO, ZnO unit cell, including the tetrahedral coordination between Zn and its neighboring O. (b) ZnO has a noncentro-symmetric crystal structure that is made up of alternate layers of positive and negative ions, leading to spontaneous polarization.
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Samples
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Source material
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Catalyst used
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Catalyst thickness (nm)
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Synthesis temperature (°C)
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Gas flow rate (sccm)
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Growth time (min)
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S1
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ZnO + C
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Au
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4
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850
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50
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45
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S2
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900
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S3
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950
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S4
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1030
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Table 1.
Sample details (synthesis temperature, gas flow rate, growth time).
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In Figure 1(a) is a crystal structure of ZnO which is a combination of alternating planes with tetrahedral coordination of Zn+2 and O−2 ions along the c-axis. Due to the presence of polar surfaces, ZnO crystal becomes spontaneously polarized in two type of planes, i.e., tetrahedrally coordinated O−2 and Zn+2 ions stacked alternately along the c-axis.
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2.3 Gas sensing properties
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In recent times due to environmental pollution and other chemical hazards, the needs for the development of a trusted chemical sensor have been significantly increased. For sensing of trace vapor of chemicals, different types of sensors, for example, potentiometric, fiber optics, amperometric, and biological sensors, are used, but ZnO nanostructure-based sensor has its own importance owing to its stability, high sensitivity, selectivity, as well as wide operating temperature range and flexibility in processing during device fabrication [18, 19, 20, 21, 22, 23, 24].
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High surface area, well organized molecular structure, and single crystalline make ZnO nanostructures unique and prominent candidates for gas sensing application. Gas attachment sensing mechanism, such as O−, O2, H+, and OH− contact as analytes that result in change in the electrical conductivity of the charges, is mainly dependent on the redox reaction. This process can only be activated by activation energy because the classic metal oxide semiconductor sensors only operate at a temperature higher than 200°C. Because of the significant changes in optoelectronic properties at nanoscale, the problem of power consumption might be tackled, and the sensor with low energy consumption can operate even at room temperature. On exposing the surface of sensor to air, attachment of O or O2 takes place. Due to these attachments of O or O2 on the nanostructure surface, formation of space charge region with high resistivity takes place. Due to high aspect ratio (L/T), the nanobelt nanostructure surface give rise to a high resistance in the normal state; this is due to the thin thickness of nanobelt nanostructures that offer a significant amount of surface acceptor states. The removal of chemisorbed oxygen from nanostructure surface by chemical reaction on the surface of nanostructures results in the improvement of conductance of nanostructures in chemical environment as shown in Figure 2.
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Figure 2.
Schematic illustration of toxic chemical sensing process. (a) Adsorption of oxygen at surface of nanowires in air and creation of potential barrier and depletion region. (b) Modulation of potential barrier and depletion region after reaction of carbon monoxide (CO) at surface of n-type semiconductor.
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2.4 Gas sensors based on metal oxide semiconductor nanostructures
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It is important to note that two main types of semiconducting metal oxides exist which are used in chemiresistive sensors. The first one is n-type semiconductors (conductance increases, when redox reaction takes place on the surface of nanostructures, e.g., TiO2, ZnO, and SnO2) whose majority carriers are electrons. The second type of metal oxides used is p-type semiconductors (conductance decreases, when redox reaction takes place on the surface of nanostructures, e.g., NiO and CuO) whose majority carriers are holes. The majority of semiconducting metal oxides used in chemiresistive sensors are n-type because electrons are spontaneously produced via oxygen vacancies at the operating temperature of the sensors during the synthesis process. A typical metal oxide gas sensor can be described as an interactive material which interacts with the environment and generates a response (as receptor) plus a device which reads the response and converts it into an interpretable and quantifiable term (as transducer).
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2.4.1 Sensing mechanism of metal oxide semiconductor gas sensors
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It is necessary to understand the sensing mechanism of the chemiresistive gas sensors for the subsequent chapters in this thesis. Since sensing mechanism of metal oxide semiconductor is mainly based on band theory, band theory can be applied to the gas sensor to explain the sensing mechanism. On interaction of the analytes (undetected) with the surface of nanostructures, these analytes react with attached oxygen ions on the surface of nanostructures; a change in the carrier concentrations of the material occurs. Due to the change in carrier concentrations of the material, the electrical resistivity of the materials changes. Decrease in resistivity (increase in conductivity) occurs for n-type metal oxide semiconductor on interaction of reducing gas [25]. So the sensing mechanism of oxide semiconductor is mainly based on the principle of modification in electrical properties (resistivity/conductivity) as a consequence of chemical reaction between gas molecules and the reactive oxygen ions on the surface of MOS nanostructure material. The sensing mechanism can be divided into three sections: (a) adsorption of oxygen at surface, (b) detection of gases by a reaction with adsorbed oxygen, and (c) change in resistance due to charge transfer at the surface.
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2.4.2 Adsorption of oxygen at surface
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Interactions of oxygen with the surface of a metal oxide semiconductor are of utmost importance in gas sensing mechanism. Oxygen is a strong electron acceptor on the surface of a metal oxide. Since the majority of sensors operate in an air at ambient temperature, therefore the concentration of oxygen on the surface is directly related to the sensor electrical properties. The conversion to O2− or O− at prominent temperatures is useful in gas sensing mechanism, as only a monolayer of oxygen ions are present with these strongly chemisorbed species [26, 27]. Different forms of oxygen ions may be ionosorbed on the surface of metal oxide semiconductor nanostructures [28]. At low temperature ranges (150–200°C), molecules in the form of neutral O2 or charged O− are adsorbed. At higher temperatures ranges above 200°C, atomic form of oxygen as O− ions is adsorbed [29]. It is observed that the reaction kinetics increase with increase in temperature. Sensors based on resistivity/conductivity properties (resistive sensors) work better at temperature of 300°C or above to react with ionosorbed oxygen at the surface. At temperature T < 200°C, the following reactions take place at the surface of sensor (for physisorption):
Adsorption energy of oxygen on metals lies in the range of 4–6 eV. Extracted carriers originate from donor sites of the metal oxide surface in the material [30]. Intrinsic oxygen vacancies and other impurity defects give rise to donor sites and surface-trapped electrons. As a result of this, ionosorbed oxygen produces a depletion layer on the surface. A buildup charge is created on the surface of metal oxide semiconductors due to different events of adsorption, and this leads to upward band bending for n-type semiconductors [31].
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2.5 Classification of nanomaterials
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Over decades, the capability of varying surface morphologies and the structure of MOS with near atomic scale have led to further idealization of semiconductor structures: quantum wells, wires, and dots. These variations at nanoscale of metal oxide semiconductors have led to different concentrations and densities of electronic states. On the bases of their fundamental dimensions (x, y, and z) in space, nanostructures can be classified into 0-D (zero-dimensional), 1-D (one-dimensional), 2-D (two-dimensional), and 3-D (three-dimensional). 0-D nanostructures are quantum dots or nanoparticles; 1-D nanostructures are nanorods, nanowires, nanobelts, and nanotubes; 2-D nanostructures refer to nanosheets, nanowalls, and nanoplates; and 3-D nanostructures refer to nanoflowers and other complex structures such as nanotetrapods [32, 33, 34]. Quantum effects dominate most of the properties of the nanomaterials. There is a great difference between density of states of the nanomaterials and those of the bulk materials. The density of states which describe the electronic states versus energy in the band diagram of the 0-D, 1-D, 2-D, and bulk materials are shown in Figure 3.
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Figure 3.
The electron density of states in bulk metal oxide semiconductor and in that of quantum well (2-D), in quantum wire (1-D), and in quantum dot (0-D) nanomaterials.
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2.6 Synthesis of ZnO nanostructures
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Different methods are used for synthesis of ZnO nanostructures.
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2.6.1 Vapor transport synthesis
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Vapor transport process is one of the most common and cost-effective method used to synthesize ZnO nanostructures. In this process, ZnO vapors are transported usually by Argon (Ar) gas. Zinc (Zn) and oxygen (O) vapors can be generated by different ways. Decomposition of ZnO is a direct and simple method; however due to high melting point of ZnO, it requires high temperature (∼1975°C) [35]. To reduce the melting point of ZnO, graphite (C) powder is mixed with the same ratio with ZnO as a source material. At about 800–1000°C temperature, graphite reduces the melting point of ZnO to form Zn and CO/CO2 vapors. Zn and CO/CO2 later react and result in ZnO nanostructures. The advantage of this method is that the existence of graphite significantly reduces the decomposition temperature of ZnO, i.e., graphite acts as a catalyst. On the bases of difference on nanostructure formation mechanisms, the vapor transport process can be divided into the following:
A rich variety of nanostructures, such as nanorods, nanowires, nanobelts, and other complex structures, can be synthesized by utilizing vapor-solid mechanism. In this mechanism, the nanostructures are produced by condensing directly from vapor phase. This mechanism is not so capable to provide best control on the geometry, alignment, and precise location of ZnO nanostructures.
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Vapor-liquid-solid mechanism is a catalyst-assisted mechanism which is used for controlled growth of oxide semiconductor nanostructures. So nanowires, nanorods, and nanobelts have been achieved by VLS mechanism [36]. In this mechanism metals such as Au, Cu, Co, Sn, etc. are used as catalyst materials [37]. Alloy droplets are formed at high temperature as a result of the reaction between catalyst film and the substrate surface interface. In the growth of 1-D oxide nanostructures, the liquid droplet plays the role of nucleation sites for the precursor’s vapors [38]. The vapors of the precursor are transported through carrier gases (usually noble gases are used as carrier gas) toward the substrate placed in the furnace tube during the growth of oxide semiconductor. During this process some materials are evaporated. The selection of catalyst is mainly based on its high surface tension and its high accommodation coefficient. These properties directly link with the supersaturation of the droplet with the source material vapors. The high Gibbs free energy carried by the precursor’s vapors enables it to diffuse into the alloy droplet in order to minimize its energy.
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The supersaturation of liquid droplet (that acts as nucleation’s site) with the source material vapors results in crystal structures of source material at the liquid-solid interface on the substrate, consequently forming one-dimensional nanostructure as shown in Figure 4.
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Figure 4.
Schematic illustration of VLS mechanism for ZnO nanorod catalyst droplets at the tip of nanorods.
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2.6.2 Other synthesis methods
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Despite the growth of 1-D oxide semiconductor nanostructures such as ZnO, GaN, and nanowires, the vapor transport process is the most dominant and cost-effective synthesis method; other growth methods such as electrochemical deposition (ECD), sol-gel, polymer assisted growth, etc. have been developed so far in parallel [39]. The possibility of forming ZnO nanostructures even at low temperature may be provided by these methods.
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2.7 Catalyst effect on the growth of metal oxide semiconductors
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Thickness of the catalyst layer coated on the substrate plays a vital role in the growth of MOS nanostructure materials by reducing the activation energy of the reaction without taking part in the chemical reaction.
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In supersaturation state catalyst droplet acts as a sink for source material in vapor-liquid-solid mechanism. The supersaturation level of droplet becomes smaller than the surrounding atmosphere’s supersaturation level, when supersaturation of catalyst occurs. This difference creates a driving force, which drives the precursor vapors into the droplet, and growth of 1-D structures takes place in energetically favored crystallographic directions.
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In vapor-solid mechanism, various types of substances are used as catalyst for the growth of 1-D nanostructures. The size and morphology of nanostructures can be controlled by using various types and thicknesses of catalysts. The finest catalyst has ideal rough surface whose sticking coefficient for the impinging of precursor material’s atom from vapor phase is almost 1 [39].
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2.8 Effect of gold catalyst on growth
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Owing to its high surface tension, high accommodation coefficient, and high sticking power, gold (Au) is generally used as a catalyst in the synthesis of 1-D oxide nanostructure. Growth of 1-D oxide nanostructures with high crystallinity, density, and long controlled diameter can be obtained by using Au as a catalyst. Growth of 1-D nanostructures has been reported by Borchers et al. with high density using Au catalyst [40]. ZnO nanowires can be grown through VLS mechanism by adding the catalyst substance which provides the nucleation sites for the growth of nanowires. The formation of these nuclei takes place through internal chemical reaction. This is considered to be a self-catalytic VLS growth. During the growth process, the reaction at low temperature can be fastening for vapor generation by adding some external materials in the source material. ZnO powder has a melting point of 1975°C, so pure ZnO does not sublimate at 900–1100°C. So for this purpose carbon powder is mixed with ZnO power with equal mass ratio that gives rise to the formation of Zn or Zn suboxide vapors at 1000°C [41], i.e.,
Various forms of ZnO nanostructures grow even at lower temperature because Zn or Zn suboxides act as nucleation sites for ZnO nanostructures. Other parameters like vacuum conditions, carrier gases, and catalysts are not essential in this condition. So the temperature is the only parameter that plays a vital role in the formation of various kinds of ZnO nanostructures. The formation of CO takes place by the direct reaction between graphite (C) and ZnO or O2 depending upon the reaction condition (tube condition).
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The formations of suboxides take place in open quartz tube due to the partially oxidized Zn vapor or droplet by the addition of graphite (C) at low melting temperature. Due to the high reactive power of suboxides as compared to ZnO, the deposition of zinc at the tips of grown nanostructures may increase during the synthesis process [42]. It is the main advantage of self-catalytic growth that impurity-free growth can be obtained as compared to catalyst-assisted growth of VLS.
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2.9 Temperature effect on the growth of 1-D nanostructures
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Temperature plays a crucial role in the growth of 1-D oxide nanostructures by thermal evaporation method through vapor-liquid-solid mechanism.
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The thermodynamic phenomena like stability, dissociation adsorption, surface diffusion, and solubility of certain phases can be directly affected by temperature.
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There are three types of ZnO fast growth direction from the structure point of view, namely, <2−1−10>, <01−10>, and ± [0001], as shown in Figure 5. ZnO consists of various structures due to the polar surface activities of different growth facets. Every crystal has a unique crystal plane with different kinetic parameters, which are to be considered under controlled growth conditions.
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Figure 5.
(a) Wurtzite structure. (b) Growth direction model of ZnO.
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The tetrahedral coordination of ZnO is shown, which has noncentral symmetry and piezoelectric effect [43, 44]. [0001] is the fastest growing direction which is along the c-axis because its activation temperature is lower than other two directions. Due to activation, energy growth of nanorods with smaller lengths and diameters takes place at lower temperature, but when temperature increases, length and diameter of nanowires increase because the energy of this fast-growing direction [0001] increases. At the higher temperatures, nanobelts with further increase in temperature facets <2−1−10> and <0−1−10> get high activation energies to grow nanosheets.
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2.10 Doping of nanostructures
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Doping of the nanowires and nanorods through in situ or post processing techniques will provide a far more favorable approach to modulate their electrical, optical, and piezoelectric properties. Most metal dopant ions result in the increase of density of the conduction carriers by occupying the lattice sites in the ZnO crystal. The complete picture of the crystal can be changed by changing the doping level. The controlled modification of morphological features as well as enhancement of electrical and optical properties can be achieved by introducing dopant element in metal oxide semiconductor [45]. The electrical as well as optical properties of MOS can be tuned by adding the foreign elements or by the alternation of oxygen stoichiometry. By making these changes, one can get an increase in carrier’s concentration, electrical resistivity, and mobility [45]. Doped nanostructure-based sensors are fully capable of sensing different harmful gases, with good stability, selectivity, and sensitivity. Out of many other methods, doping is considered to be one of the best methods for enhancement of gas sensing properties of ZnO nanostructures at room temperature. Doped ZnO nanostructures were used in the past by many researchers for the detection of harmful gases in the environment. For example, the gas sensing properties of Sn-doped ZnO nanostructures were investigated by S.C. Navel and I.S. Mulla using the thermal evaporation method. The results show good response to different gases for pure Sn-doped nanostructures, in temperature range of 275°C to 300°C. They proved that the sensitivity toward UV sensing can be increased by the doping of Sn material [46].
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3. Experimental procedure
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Experimental process comprises the following steps:
Preparation of substrate for growth
Coating of Au catalyst in ultrahigh vacuum (UHV) chamber on Si substrate
Preparation of nanostructure samples by vapor transport method through VLS mechanism
Fabrication of sensor for toxic gas sensing applications
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3.1 Preparation of substrate for growth
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By using the diamond cutter, Si substrates were cut in suitable sizes and shapes. In order to avoid the contamination, the substrates were cleaned before the deposition of catalyst, as oily layer and dust particles may stick to the surface of the substrates. For the cleaning purpose, the acetone was poured into a beaker, and the beaker was filled up to half level. The substrates were put into the acetone-filled beaker to completely immerse in them. The acetone-filled beaker was placed in ultrasonic bath at room temperature for 30 min. Si (100) substrates were then put into ethanol and deionized water for decontamination purpose for 30 min.
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3.2 Deposition of Au catalyst on Si substrate in UHV chamber
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For the growth of 1-D ZnO nanostructures, n-type silicon substrates Si (100) were used through the following steps:
Si substrates were cleaned in isopropyl alcohol (IPA), acetone, and deionized water (DI) by sonication to remove the contaminations in ultrasonic bath for 30 min at room temperature.
Sample substrates were loaded in the ultrahigh vacuum chamber for deposition of thin film of gold under vacuum of 10−7 Torr.
In nm, a thin layer of gold catalyst was deposited on Si (100) substrates for the growth of ZnO nanostructures.
Around 200 nm of thin layer of gold catalyst was deposited on Si (100) and glass substrates for preparation of sensor.
The samples were taken out from UHV chamber and used for growth process of ZnO nanostructures.
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3.3 Preparation of samples by vapor transport method through VLS mechanism
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The growth was performed by thermal evaporation in a temperature-controlled horizontal tube furnace by vapor transport process through VLS mechanism. An equimolar mixture (mixed in a ball mill for 2 h with 250 rpm) of ZnO (purity 99.99%) and graphite (purity 99.9%) was placed in a ceramic boat (88 mm of length) with a mass ratio1:1 (measured by physical balance). This boat containing the source material (mixture of ZnO + C) was placed at the center of quartz tube (length 100 cm and diameter 3.5 cm). Tube furnace was set at a temperature of 850, 900, 950, and 1030°C for the four different experiments. Catalyst-coated substrates of 4 nm labeled as S1, S2, S3, and S4 were placed at the downstream of the source material at a distance of 18 cm (S1, 850°C), 12 cm (S2, 900°C), 9 cm (S3, 950°C), and 6 cm (S4, 1030°C), respectively. Furnace temperature was raised at the rate of 10°C per minute. At the start Ar gas (99.99%) was introduced at a rate of 50 standard cubic centimeter per minute (sccm) to flush out the residual present in the tube. Brass rod fitted in the rubber cork was inserted in the quartz tube to connect it to argon (Ar) gas source through a plastic pipe of 5 mm diameter. Argon gas was used as a carrier for transport of vapors from source material to gold-coated substrates. The other end of quartz tube was kept opened. The temperature of the furnace was increased from room temperature to 850°C (S1), 900°C (S2), 950°C (S3), and 1030°C (S4) in four different experiments. When the temperature of the furnace reached the set temperature, the dwell or growth time was noted for 45 min. After 45 min the furnace program was “OFF,” and the temperature started decrease gradually. When the temperature decreased to 650°C, the Ar gas flow was switched “OFF.” Furnace was then cooled to room temperature after the reaction.
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Doping of Mg was carried out, and for that purpose 0.05 g and 0.08 g of magnesium acetate [Mg(CH3COO)2·4H2O] (purity 99.99%) was added in 1 g of source material (ZnO + C). Mg-doped ZnO nanostructures were synthesized by thermal evaporation in a temperature-controlled horizontal furnace on an Au-coated Si (100) substrate. Vapor transport method has been used for the synthesis of Mg-doped ZnO nanostructures which was done in a temperature-controlled tube furnace. The temperature, growth time, and gas flow rate were 900°C, 45 min, and 50 sccm, respectively.
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3.4 Sensor fabrication
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The synthesized ZnO nanostructures were used for UV as well as for chemical sensing applications. ZnO nanostructures were annealed by heating it in digital furnace at 400°C for 2 h. The annealing process was usually done for attachment of oxygen on the surface of ZnO nanostructures. The nanostructures were scratched with the help of blades, and the gaps or cuts on gold-coated quartz substrate were filled with the scratched nanostructures as shown in Figure 6. A small drop of methanol was dropped on the nanostructures with the help of 5 cc disposable syringe so that a thick paste was formed. The sensor was then placed under IR (infrared) light for 10 min for the purposes of sticking material on the quartz substrate. The experimental setup for chemical sensing is shown in Figure 6.
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Figure 6.
Schematic illustration of chemical sensing experimental setup.
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4. Morphological properties of ZnO nanostructures
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Morphology, size, and shape of the synthesized ZnO nanostructures were characterized by using scanning electron microscopy (SEM) characterization technique. The four samples were synthesized at different temperatures with the same flow rate of 50 sccm of Ar (argon) gas and with same growth time of 45 min. A total eight samples was prepared in four different experiments; out of eight samples, four samples were optimized. Four experiments were done at different temperatures, i.e., 850, 900, 950, and 1030°C. The catalyst used was 4 nm thin layer of gold coated on n-type Si (100) substrate.
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4.1 Sample S1
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In the first experiment, ZnO nanowires with various dimensions were obtained. Figure 7(a) shows the SEM micrograph of the ZnO nanostructures of sample S1, consisting of randomly oriented ZnO nanowires. These nanowires were grown at a temperature of 850°C on a thin layer of pure gold-coated Si (100) substrate. The nanowires intertwine with each other and distribute on the whole substrate surface randomly. The average diameter and the average length are 0.95 ± 0.11 μm and 35.59 ± 9.90 μm, respectively.
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Figure 7.
SEM images of different morphologies of ZnO nanostructures at different synthesized temperatures. (a) SEM images of nanowires grown at 850°C. (b) SEM images of nanorods grown at 900°C. (c) SEM images of nanobelts with needle-like ends grown at 950°C. (d) SEM images of nanobelts grown at 1030°C.
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4.2 Sample S2
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In the second experiment, ZnO nanorods of different dimensions were obtained. Figure 7(b) shows the SEM micrograph of complex ZnO nanorods of sample S2. These complex nanorods were grown at temperature of 900°C on a thin layer of gold-coated Si (100) substrate. The average diameter and the average length of S2 SEM images are 12.66 ± 3.72 μm and 319.48 ± 93.50 μm, respectively.
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4.3 Sample S3
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In the third experiment, ZnO nanobelts with needle-like ends were obtained. Figure 7(c) shows the SEM micrograph of ZnO nanobelts of sample S3 with needle-like ends. These nanobelts were obtained with different dimensions at temperature of 950°C grown on 4 nm Au-coated thin layer of Si substrate. The average width, average length, and average thickness of tips are 1.39 ± 0.44 μm, 10.34 ± 2.71 μm, and 0.38 ± 0.086 μm, respectively.
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4.4 Sample S4
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Figure 7 shows the SEM micrograph of ZnO nanobelts of the fourth experiment which was grown at 1030°C on gold-coated Si substrate. The average length of 2.67 ± 0.42 μm, average width of 0.33 ± 0.03 μm, and the average thickness of 0.09 ± 0.01 μm of nanobelts were obtained.
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The scanning electron micrographs clearly showed that the morphologies tuned from nanowires and nanorods to nanobelts due to change in temperature. High temperature and supersaturation conditions lead to the formation of nanobelts with needle-like ends and typical nanobelts.
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The possible reason for this tune in morphologies is attributed to supersaturation, growth rate, and quick availability of ZnO polar surfaces for growth [46]. Overall, the supersaturation conditions are different at different temperatures which eventually change the morphology.
\n
\n
\n
4.5 Energy diffraction X-ray (EDX) analysis
\n
EDX spectroscopy analytic technique was used for the chemical composition analysis of the synthesized ZnO nanostructures. Figure 8 shows the typical EDX spectrum of the sample S1 (ZnO nanowires). Only the Zn, O, and Au peaks were observed. The observation of Au peak may suggest that the growth is catalyst-assisted [47, 48, 49, 50, 51, 52]. The approximate atomic ratio was found to be 58:32. These ratios show nonstoichiometry, i.e., crystal defects of grown nanostructures during the growth process. Deviation from the stoichiometry is large due to carbothermal reaction and oxygen-deficient environment (Ar gas) during the growth process. Most of the oxygen is used in the formation of CO2, i.e.,
\n
Figure 8.
(a) SEM images of ZnO nanowires and (b) EDX image of the corresponding ZnO nanowires grown at 900°C.
\n
\n\nZnO\n+\nC\n→\nZn\n+\nCO\n\nE7
\n
\n\nZnO\n+\nCO\n→\nZn\n+\n\nCO\n2\n\n\nE8
\n
\n
\n
4.6 Synthesis of Mg-doped ZnO nanostructures
\n
The whole process of Mg-doped ZnO nanowires could be explained in two steps:
\n
In the first step, a thin layer (4 nm) of Au film was coated on Si (100) substrate in UHV chamber by ion sputtering technique. Cleaning of Si (100) substrates was carried out by sonicating in acetone, ethanol, and deionized water for 30 min. Si (100) substrates were then coated with SiO2 for 2 h at temperature of 1050°C for insulation purpose. The quartz tube was cleaned first with chromosulfuric acid (cleaning agent) to remove the permanent residue, then the deionized water was used to wash the tube, and last ethanol was used to clean the tube.
\n
In the second step, the Mg-doped ZnO nanostructures were grown by vapor transport method through VLS mechanism in a temperature-controlled digital horizontal furnace as shown in the schematic illustration. In the first experiment, doping of sample S1 (nanowires) was carried out. A mixture of ZnO (purity 99.9%), magnesium acetate [Mg(CH3COO)2·4H2O] (purity 99.99%), and graphite powders (carbon) with mass ratio in gram (weighted by physical balance) of 1:1:0.05 was used as the source materials. The source material was placed at the center of quartz tube of length 100 cm and diameter 3.5 cm in a ceramic boat of 88 mm length. Sample S1 substrate was placed on a second ceramic boat at the downstream at a distance of 18 cm away from the source materials in the quartz tube. The temperature of the furnace was maintained at 850°C.
\n
At the start Ar gas was introduced at the rate of 50 sccm to flush out the residual present in the tube. As the temperature reached 850°C, the dwell time was noted for 45 min. After 45 min the furnace program was “OFF,” and the temperature started to decrease gradually. When the temperature decreased to 650°C, the Ar gas flow was switch “OFF.” Furnace was then cooled down to room temperature after the reaction. In the second experiment, Mg doping of sample S2 (ZnO nanorods) was carried out. The same condition and parameters were used for doping of S2, except the magnesium acetate [Mg(CH3COO)2·4H2O] weight was 0.08 g, and the sample distance from the source material was 12 cm.
\n
The collected Mg-doped ZnO nanostructure sample characterization was carried out for crystallinity, morphology and elemental composition, and optical properties. Optical and gas sensing response of the respective Mg-doped ZnO nanostructures was carried out by measuring respective resistances by two probe methods using a multimeter (Keithly 2100).
\n
\n
\n
4.7 Morphology analysis
\n
Mg-doped ZnO nanostructure morphology was probed by means of SEM. Figure 9(a) shows the SEM image of undoped ZnO nanorods (S2) with average diameter and length of 12.66 ± 3.72 μm and 319.48 ± 93.50 μm, respectively. Figure 9(b) shows SEM images of Mg-doped (0.05 g) ZnO nanobelts. The average thickness of 1.88 ± 0.70 μm, average width of 4.7 ± 1.04 μm, and average length of 72.03 ± 18.84 μm of the Mg-doped ZnO nanobelts were measured. Figure 9(c) shows the SEM image of undoped typical ZnO nanowires (S1) with different dimensions, having average diameter and average length of 0.95 ± 0.11 μm and 35.59 ± 9.90 μm, respectively. Figure 9(d) shows the respective EDX analysis spectrum of the undoped ZnO nanowires (S1). The EDX spectra show the attachment of O (oxygen) and Zn (zinc) in the ratio O/Zn which was found to be 32:58, respectively. These composition analyses clearly showed that no impurity peak was observed, showing the purity of ZnO nanostructures. The aspect ratio of undoped and doped ZnO nanorods and nanobelts was found to be 25 and 51, respectively. Figure 9(e) shows the Mg-doped (0.08 g) ZnO nanobelts having average thickness of 0.05 ± 0.009 μm, average width of 0.28 ± 0.02 μm, and average length of 2.93 ± 0.87 μm. The corresponding elemental compositions of the synthesized ZnO nanobelts were confirmed by EDX spectroscopy. Figure 9(f) shows the corresponding EDX analysis of the doped ZnO nanobelts, showing the presence of oxygen, magnesium, and zinc in the ratio O/Mg/Zn which was found to be 28:0.35:72 respectively. EDX analysis confirmed that the compositions of the products are Mg-doped ZnO without impurity. The aspect ratio of undoped ZnO nanowires and Mg-doped ZnO nanobelts was found to be 37 and 38, respectively. The possible reason for the formation of thin and transparent nanobelts is due to the morphology tuning from nanorods and nanowires to nanobelts by Mg doping, because doping of definite elements plays a key role in the alteration of the dimensions of nanostructures [52, 53, 54, 55, 56, 57, 58]. Growth rates and polar surfaces can provoke the asymmetric growth. Formation of nanobelts was explained as continuous process of 1-D branching and subsequent 2-D interspace filling.
\n
Figure 9.
(a) SEM image of undoped ZnO nanorods (S2). (b) SEM images of Mg-doped ZnO nanobelts. (c) SEM image of undoped ZnO nanowires (S1). (d) SEM images of Mg-doped ZnO nanobelts. (e) and (f) show EDX analysis of undoped and Mg-doped ZnO nanowires and nanobelts, respectively.
\n
Polar surfaces of wurtzite crystals of oxide semiconductors can induce asymmetric growth which leads to the diverse nanostructures, e.g., nanocombs, nanobrushes, needle-like belts/rods, etc. [59].
\n
\n
\n
4.8 CH4 gas sensing response
\n
The first step was the preparation of CH4 gas sensor. In the fabrication of CH4 gas sensor, a thick layer (200 nm) of Au was coated by ion sputtering technique on Si (100) wafers. A small amount of ZnO nanostructures was put on a pair of interdigitated electrodes on Si substrates having a gap of 55 μm. A small drop of methanol was dropped on the nanomaterials so that a thick paste was formed. The annealing of sensors was carried out in an open furnace tube for 2 h at 400°C before performing the gas sensing experiments, for the purpose of attachment of oxygen on the surface of sensors. The sensing experiment was performed at 200°C with 5-min cycles of dry air and 400 ppm CH4 gas concentration. The sensing response (S = Ra/Rg) of the device was measured by resistance change upon exposure to air (Ra) and CH4 gas (Rg). Figure 10(a) and (b) shows the sensitivity response of CH4 (methane gas) at 200°C for undoped ZnO nanowires and for Mg-doped ZnO nanobelts, respectively. Research papers showed that the sensitivity of the resistive sensors is highly affected by the Mg doping. The sensors were tested in a temperature range of 50–200°C for 400 ppm of CH4 gas. Sensors show some response magnitude from 100°C temperature. Undoped ZnO nanowire sensors get its optimal point at 200°C with response magnitude of 1.84. Doped ZnO nanobelts also get its optimal operating point at 200°C. Its response magnitude was obtained at 2.06. The best sensing signal response of CH4 was found at 200°C. The sensing response at 50, 100, and 150°C (not shown) was comparatively negligible. The sensing response of undoped ZnO nanowires and Mg-doped ZnO nanobelts was found to be 1.84 and 2.06 at 200°C for the same concentration, respectively. The enhanced sensitivity response was observed for the ZnO nanostructures as shown in Figure 10(b). Large amount of oxygen molecules and atoms are adsorbed on Mg-doped ZnO nanobelts due to large surface area (i.e., large defects are created) due to which interaction chance of CH4 gas increases as compared to undoped ZnO nanostructures [60, 61]. On exposing the surface of the ZnO nanostructures to air, oxygen is adsorbed at the ZnO nanostructures surface by capturing an electron from conduction band of surface sites of undoped and Mg-doped ZnO nanostructures [62, 63]. Reactive O2 (oxygen molecules) are chemisorbed or trapped by these ZnO nanostructures from the air, forming active oxygen species O2− and O−; as a result transformation of electrons takes place, due to which a wide space charge is formed that results in a decrease in carrier concentration due to which the resistance of the material is increased.
\n
Figure 10.
(a) CH4 gas sensing response of undoped ZnO nanowires (S1). (b) CH4 gas sensing response of Mg-doped ZnO nanobelts.
\n
\n
\n
\n
5. Conclusions
\n
Growth of 1-D ZnO nanostructures was presented in the present chapter. Vapor-liquid-solid mechanism has been employed for the synthesis of ZnO nanostructures. It was found that the morphologies tuned with change in temperature which leads to the formation of nanowires at 850°C, nanorods at 900°C, nanobelts at 950°C, and nanobelts with needle-like ends at 1030°C. The dimensions of the morphologies have been measured by SEM. The length of the structures from 2.93 to 319.48 μm, thickness of the structures from 0.05 to 1.88 μm, and diameter of the structures from 0.95 to 12.66 μm have been obtained successfully. XRD peaks show that the crystallinity and intensity increase with increase in temperature. Doping of magnesium acetate (0.05 g) in ZnO through vapor transport method was successfully achieved. The sensing response of doped ZnO nanostructures for UV light at room temperature and CH4 gas at 200°C has increased. ZnO nanowires show great selectivity response toward different volatile organic compounds (ethanol, methanol, and acetone). At the same concentration and temperature, the ZnO nanowires show a huge sensing response to acetone (14), and those of the other solvents are no greater than 8.6.
\n
\n
Acknowledgments
\n
The Higher Education Commission (HEC) of Pakistan is acknowledged for financial support through project No. 9294/NRPU/R&D/HEC/2017. Thanks to Prof. Dr. Syed Zafar Ilyas and Dr. Waqar. A. Syed. The authors would also be thankful to COMSATS University Islamabad for necessary funds for the project.
\n
\n
Conflict of interest
\n
There is no conflict of interest in this chapter.
\n
\n',keywords:"metal oxide, semiconductor material, Mg doping, nanobelts, structural and morphological properties, band gap, gas sensing",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69915.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69915.xml",downloadPdfUrl:"/chapter/pdf-download/69915",previewPdfUrl:"/chapter/pdf-preview/69915",totalDownloads:27,totalViews:0,totalCrossrefCites:0,dateSubmitted:"March 7th 2019",dateReviewed:"May 13th 2019",datePrePublished:"November 6th 2019",datePublished:null,readingETA:"0",abstract:"Zinc oxide (ZnO) is a unique and important metal oxide semiconductor for its valuable and huge applications with wide band gap (\n\n3.37\n\n eV) and most promising candidate for gas sensor due to its high surface-to-volume ratio, good biocompatibility, stability, and high electron mobility. Due these properties, metal oxide shows good crystallinity, higher carrier mobility, and good chemical and thermal stability at moderately high temperatures. In this chapter nanostructures have been investigated, main focus being their synthesis and sensing mechanism of different toxic chemicals, synthesized by thermal evaporation through vapor transport method using vapor-liquid-solid (VLS) mechanism. The doped ZnO nanobelts showed significant enhanced sensing properties at room temperature, indicating that doping is very much effective in improving the methane CH4 sensing of ZnO nanostructures. ZnO nanowires showed a remarkable sensing response toward acetone and CH4 gas.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69915",risUrl:"/chapter/ris/69915",signatures:"Nazar Abbas Shah, Majeed Gul, Murrawat Abbas and Muhammad Amin",book:{id:"8724",title:"Gas Sensors",subtitle:null,fullTitle:"Gas Sensors",slug:null,publishedDate:null,bookSignature:"Dr. Sher Bahadar Khan, Dr. Abdullah M. Asiri and Dr. Kalsoom Akhtar",coverURL:"https://cdn.intechopen.com/books/images_new/8724.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"245468",title:"Dr.",name:"Sher Bahadar",middleName:null,surname:"Khan",slug:"sher-bahadar-khan",fullName:"Sher Bahadar Khan"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Important properties of metal oxide semiconductors",level:"1"},{id:"sec_2_2",title:"2.1 Structural properties of ZnO",level:"2"},{id:"sec_3_2",title:"2.2 Crystal and surface structure of ZnO",level:"2"},{id:"sec_4_2",title:"2.3 Gas sensing properties",level:"2"},{id:"sec_5_2",title:"2.4 Gas sensors based on metal oxide semiconductor nanostructures",level:"2"},{id:"sec_5_3",title:"2.4.1 Sensing mechanism of metal oxide semiconductor gas sensors",level:"3"},{id:"sec_6_3",title:"2.4.2 Adsorption of oxygen at surface",level:"3"},{id:"sec_8_2",title:"2.5 Classification of nanomaterials",level:"2"},{id:"sec_9_2",title:"2.6 Synthesis of ZnO nanostructures",level:"2"},{id:"sec_9_3",title:"2.6.1 Vapor transport synthesis",level:"3"},{id:"sec_10_3",title:"2.6.2 Other synthesis methods",level:"3"},{id:"sec_12_2",title:"2.7 Catalyst effect on the growth of metal oxide semiconductors",level:"2"},{id:"sec_13_2",title:"2.8 Effect of gold catalyst on growth",level:"2"},{id:"sec_14_2",title:"2.9 Temperature effect on the growth of 1-D nanostructures",level:"2"},{id:"sec_15_2",title:"2.10 Doping of nanostructures",level:"2"},{id:"sec_17",title:"3. Experimental procedure",level:"1"},{id:"sec_17_2",title:"3.1 Preparation of substrate for growth",level:"2"},{id:"sec_18_2",title:"3.2 Deposition of Au catalyst on Si substrate in UHV chamber",level:"2"},{id:"sec_19_2",title:"3.3 Preparation of samples by vapor transport method through VLS mechanism",level:"2"},{id:"sec_20_2",title:"3.4 Sensor fabrication",level:"2"},{id:"sec_22",title:"4. Morphological properties of ZnO nanostructures",level:"1"},{id:"sec_22_2",title:"4.1 Sample S1",level:"2"},{id:"sec_23_2",title:"4.2 Sample S2",level:"2"},{id:"sec_24_2",title:"4.3 Sample S3",level:"2"},{id:"sec_25_2",title:"4.4 Sample S4",level:"2"},{id:"sec_26_2",title:"4.5 Energy diffraction X-ray (EDX) analysis",level:"2"},{id:"sec_27_2",title:"4.6 Synthesis of Mg-doped ZnO nanostructures",level:"2"},{id:"sec_28_2",title:"4.7 Morphology analysis",level:"2"},{id:"sec_29_2",title:"4.8 CH4 gas sensing response",level:"2"},{id:"sec_31",title:"5. 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Thin Films Technology Laboratory, Department of Physics, COMSATS University, Pakistan
Centre of Excellence in Science and Applied Technologies, Pakistan
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Openness - We communicate honestly and transparently. We are open to constructive criticism and committed to learning from it.
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